U.S. patent application number 14/448499 was filed with the patent office on 2014-11-20 for combination of sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression.
This patent application is currently assigned to Sunovion Inc.. The applicant listed for this patent is Sunovion Inc.. Invention is credited to Timothy BARBERICH, Judy CARON, Karim LALJI, Thomas WESSEL.
Application Number | 20140343069 14/448499 |
Document ID | / |
Family ID | 34714379 |
Filed Date | 2014-11-20 |
United States Patent
Application |
20140343069 |
Kind Code |
A1 |
LALJI; Karim ; et
al. |
November 20, 2014 |
COMBINATION OF SEDATIVE AND A NEUROTRANSMITTER MODULATOR, AND
METHODS FOR IMPROVING SLEEP QUALITY AND TREATING DEPRESSION
Abstract
One aspect of the present invention relates to pharmaceutical
compositions containing two or more active agents that when taken
together can be used to treat, e.g., insomnia. The first component
of the pharmaceutical composition is a GABA receptor modulating
compound. The second component of the pharmaceutical composition is
a serotonin reuptake inhibitor, a norepinephrine reuptake
inhibitor, a 5-HT.sub.2A modulator, or dopamine reuptake inhibitor.
In certain embodiments, the pharmaceutical composition comprises
eszopiclone. In a preferred embodiment, the pharmaceutical
composition comprises eszopiclone and fluoxetine. The present
invention also relates to a method of treating a sleep abnormality,
treating insomnia, treating depression, augmenting antidepressant
therapy, eliciting a dose-sparing effect, reducing depression
relapse, improving the efficacy of antidepressant therapy or
improving the tolerability of antidepressant therapy, comprising
co-administering to a patient in need thereof a
GABA-receptor-modulating compound; and a SRI, NRI, 5-HT.sub.2A
modulator or DRI.
Inventors: |
LALJI; Karim; (Sudbury,
MA) ; BARBERICH; Timothy; (Concord, MA) ;
CARON; Judy; (Westwood, MA) ; WESSEL; Thomas;
(Lenox, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sunovion Inc. |
Marlborough |
MA |
US |
|
|
Assignee: |
Sunovion Inc.
Marlborough
MA
|
Family ID: |
34714379 |
Appl. No.: |
14/448499 |
Filed: |
July 31, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13305007 |
Nov 28, 2011 |
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14448499 |
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11761235 |
Jun 11, 2007 |
8097625 |
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13305007 |
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11007795 |
Dec 8, 2004 |
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11761235 |
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60529156 |
Dec 11, 2003 |
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60541614 |
Feb 4, 2004 |
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60633213 |
Dec 3, 2004 |
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Current U.S.
Class: |
514/249 |
Current CPC
Class: |
A61P 25/24 20180101;
A61K 31/138 20130101; A61K 31/4985 20130101; A61K 31/495 20130101;
A61P 25/20 20180101; A61P 43/00 20180101; A61K 31/724 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/495
20130101; A61K 31/137 20130101; A61K 45/06 20130101; A61K 31/138
20130101; A61K 31/4985 20130101; A61K 31/137 20130101; A61K 31/724
20130101 |
Class at
Publication: |
514/249 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61K 31/137 20060101 A61K031/137 |
Claims
1. A pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a norepinephrine reuptake inhibitor.
2. A pharmaceutical composition according to claim 1 comprising
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof, and a norepinephrine
reuptake inhibitor, wherein said norepinephrine reuptake inhibitor
is desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
3. A method of treating a patient suffering from a sleep
abnormality, comprising the step of co-administering to a patient
in need thereof a therapeutically effective amount of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof, and a therapeutically effective
amount of norepinephrine reuptake inhibitor.
4. A method according to claim 3 of treating a patient suffering
from a sleep abnormality wherein said sleep abnormality is
transient, short-term or chronic insomnia, comprising the step of
co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a norepinephrine reuptake
inhibitor.
5. A pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a dopamine reuptake inhibitor.
6. A pharmaceutical composition according to claim 5 comprising
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof, and a dopamine
reuptake inhibitor, said dopamine reuptake inhibitor is amineptine,
bupropion, GBR-12935, venlafaxine, desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
7. A method of treating a patient suffering from a sleep
abnormality, comprising the step of co-administering to a patient
in need thereof a therapeutically effective amount of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof, and a therapeutically effective
amount of a dopamine reuptake inhibitor.
8. A method according to claim 7 of treating a patient suffering
from a sleep abnormality wherein said sleep abnormality is
transient, short-term or chronic insomnia, comprising the step of
co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a dopamine reuptake inhibitor.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/305,007, filed Nov. 28, 2011. U.S. Ser. No. 13/305,007 was a
continuation of U.S. application Ser. No. 11/761,235, filed Jun.
11, 2007. U.S. application Ser. No. 11/761,235 was a divisional of
U.S. application Ser. No. 11/007,795, Dec. 8, 2004. U.S. Ser. No.
11/007,795 claimed the benefit of priority to U.S. Provisional
Patent Application Ser. No. 60/529,156, filed Dec. 11, 2003; U.S.
Provisional Patent Application Ser. No. 60/541,614, filed Feb. 4,
2004; and U.S. Provisional Patent Application Ser. No. 60/633,213,
filed Dec. 3, 2004. These six earlier applications are hereby
incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Sleep is controlled by two biological processes, the
homeostatic drive and the circadian rhythm. The homeostatic drive
manifests itself as an increased drive for sleep. This drive for
sleep accumulates across the period of wakefulness (typically
daytime) and dissipates across the sleep period. The circadian
rhythm of sleep-wake shows a biphasic curve with the greatest drive
for sleep occurring between midnight and 5 AM, and between 2 PM and
4 PM. It is believed that major circadian influences are an
alerting pulse in the evening and in the morning. It is the
interaction of these processes which give rise to the 24-hour sleep
schedule. For individuals with a usual sleep period of 11 PM to 7
AM, sleep onset in the evening occurs primarily as a function of
homeostatic drive. After about four hours of sleep (at about 3 AM)
homeostatic drive dissipates significantly and wakefulness begins
to intrude into the sleep period. This propensity to increased
wakefulness is further increased by the rise in the circadian
alerting pulse at about 5 AM. In terms of the pharmacological
management of insomnia, two vulnerabilities have been recognized.
The first is difficulty initially falling asleep, with the second
being reawakening in the middle of the night.
[0003] Many physiological functions are characterized by diurnal
rhythms, in which levels of circulating hormones, catecholamines
and other compounds fluctuate during the day and/or night. Certain
medical disorders, such as insomnia, are associated with
abnormalities in these rhythms. The time, within a 24 hour period,
of administration of drugs for the prevention and treatment of such
disorders can be a critical factor in determining efficacy of the
therapy.
[0004] The term "insomnia" refers to the perception of inadequate
or non-restful sleep by a patient. Insomnia is a frequent
complaint, reported by 32% of the adult population surveyed in the
Los Angeles area (Bixler et al, Amer. Journal of Psychiatry
136:1257-1262, 1979), and 13% of the population surveyed in San
Marino, Italy (Lugaresi et al., Psychiatric Annals 17:446-453,
1987). Fully 45% of the surveyed adult population of Alachua
County, Florida, reported trouble getting to sleep or staying
asleep (Karacan et al., Social Science and Medicine 10:239-244,
1976). The prevalence of insomnia has also been shown to be related
to the age and sex of the individuals, being more prevalent in
older individuals, especially adults aged 65 and over, and in
females.
[0005] Early treatments for insomnia commonly employed central
nervous system (CNS) depressants such as barbiturates. These
compounds are typically long acting (on the order of 8-50 hours)
due to long terminal half-lives, and have a well-known spectrum of
side effects, including lethargy, confusion, depression and next
day hangover effects. In addition, chronic use has been associated
with a high potential for addiction involving both physical and
psychological dependence.
[0006] During the 1980s, the pharmaceutical treatment of insomnia
shifted away from barbiturates and other CNS depressants toward the
benzodiazepine class of sedative-hypnotic agents. This class of
compounds produces a calming effect that results in a sleep-like
state in humans and animals, with a greater safety margin than
prior hypnotics. However, many benzodiazepines possess side effects
that limit their usefulness in certain patient populations. These
problems include synergy with other CNS depressants (especially
alcohol), the development of tolerance upon repeat dosing,
dependency, withdrawal, rebound insomnia following discontinuation
of dosing, hangover effects the next day and impairment of
psychomotor performance and memory. Next day sleepiness and memory
impairment, which can include amnesia for events occurring prior to
and after drug administration, is of particular concern in the
elderly whose cognitive functions may already be impaired by the
aging process.
[0007] More recent treatments for insomnia have used
non-benzodiazepine compounds, which show an improved side effect
profile over the benzodiazepine class of sedative-hypnotics. The
first of these agents to be approved by the United States Food and
Drug Administration (FDA) for marketing in the United States was
zolpidem, marketed by Sanofi-Synthelabo as AMBIEN.RTM. (zolpidem
tartrate), which is based on the imidazopyridine backbone (see U.S.
Pat. Nos. 4,382,938 and 4,460,592). In addition to zolpidem,
zaleplon, which is marketed by Jones Pharma as SONATA.RTM., was
been approved by the FDA; zaleplon is a pyrazolopyrimidine-based
compound (see U.S. Pat. No. 4,626,538). Other non-benzodiazepine
compounds and/or methods for making or using the same have also
been reported (see, e.g., U.S. Pat. Nos. 4,794,185, 4,808,594,
4,847,256, 5,714,607, 4,654,347; 5,538,977, 5,891,891). Attempts
have also been disclosed to provide controlled-release dosage
forms, particularly in the context of zolpidem and salts thereof
(see WO 00/33835 and EP 1 005 863 A1).
[0008] Norepinephrine and serotonin are mammalian neurotransmitters
that play important roles in a wide variety of physiological
processes. Norepinephrine, also called noradrenaline, is a
neurotransmitter that doubles part-time as a hormone. As a
neurotransmitter, norepinephrine helps to regulate arousal,
dreaming, and moods. As a hormone, it acts to increase blood
pressure, constrict blood vessels and increase heart
rate--responses that occur when we feel stress.
[0009] Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed
in animals and plants, occurring in vertebrates, fruits, nuts, and
venoms. A number of congeners of serotonin are also found in nature
and have been shown to possess a variety of peripheral and central
nervous system activities. Serotonin may be obtained from a variety
of dietary sources; however, endogenous 5-HT is synthesized from
tryptophan through the actions of the enzymes tryptophan
hydroxylase and aromatic L-amino acid decarboxylase. Both dietary
and endogenous 5-HT are rapidly metabolized and inactivated by
monoamine oxidase and aldehyde dehydrogenase to the major
metabolite, 5-hydroxyindoleacetic acid (5-HIAA).
[0010] Serotonin is implicated in the etiology or treatment of
various disorders, particularly those of the central nervous
system, including anxiety, depression, obsessive-compulsive
disorder, schizophrenia, stroke, obesity, pain, hypertension,
vascular disorders, migraine, and nausea. Recently, understanding
of the role of 5-HT in these and other disorders has advanced
rapidly due to increasing understanding of the physiological role
of various serotonin receptor subtypes.
[0011] Neurotransmitters (NTs) produce their effects as a
consequence of interactions with cellular receptors.
Neurotransmitters, including serotonin, are synthesized in brain
neurons and stored in vesicles. Upon a nerve impulse, they are
released into the synaptic cleft, where they interact with various
postsynaptic receptors. The actions of 5-HT are terminated by three
major mechanisms: diffusion; metabolism; and uptake back into the
synaptic cleft through the actions of specific amine membrane
transporter systems. The major mechanism by which the action of
serotonin is terminated is by uptake through presynaptic membranes.
After 5-HT acts on its various postsynaptic receptors, it is
removed from the synaptic cleft back into the nerve terminal
through an uptake mechanism involving a specific membrane
transporter in a manner similar to that of other biogenic amines.
Thus, the actions of 5-HT, or any neurotransmitter, can be
modulated by agents that: stimulate or inhibit its biosynthesis;
agents that block its storage; agents that stimulate or inhibit its
release; agents that mimic or inhibit its actions at its various
postsynaptic receptors; agents that inhibit its reuptake into the
nerve terminal; and agents that affect its metabolism.
[0012] Accordingly, there is a need in the art for serotonin
reuptake inhibitor-sedative, norepinephrine reuptake
inhibitor-sedative, 5-HT.sub.2A modulator-sedative, and dopamine
reuptake inhibitor-sedative compositions that induce and maintain
sleep as single dose nocturnal formulations, but without the side
effects associated with the longer-acting hypnotics. The present
invention fulfills this need and further provides other related
advantages.
SUMMARY OF THE INVENTION
[0013] The present invention generally relates to pharmaceutical
compositions comprising a sedative agent; and serotonin reuptake
inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake
inhibitors, CRS antagonists and 5-HT.sub.2A receptor modulators.
The sedative agent is a GABA receptor modulating compound. In a
preferred embodiment, the sedative agent is eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof. The pharmaceutical compositions of the
invention are useful in the treatment of various sleep disorders.
In addition, the present invention also relates to a method of
treating a patient suffering from a sleep abnormality or insomnia,
comprising administering a therapeutically effective amount of a
pharmaceutical composition of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention relates generally to pharmaceutical
compositions containing two or more active agents that when taken
together improve the quality of sleep for a patient. In certain
embodiments, the present invention relates to a pharmaceutical
composition comprising a NRI and a sedative agent. In certain
embodiments, the present invention relates to a pharmaceutical
composition comprising a dopamine reuptake inhibitor and a sedative
agent. The sedative agent is a GABA receptor modulating compound.
In a preferred embodiment, the sedative agent is eszopiclone, or a
pharmaceutically acceptable salt, solvate, clatherate, polymorph,
or co-crystal thereof. Another aspect of the present invention
relates to a method of treating a patient suffering from a sleep
disorder comprising the step of administering to said patient a
therapeutically effective dose of a pharmaceutical composition
containing two or more active agents that when taken together
improve the quality of sleep or sleep disorders for said patient.
Another aspect of the present invention relates to a method of
treating a patient suffering from depression comprising the step of
administering to said patient a therapeutically effective dose of a
pharmaceutical composition of the invention.
In certain embodiments, said pharmaceutical composition comprises a
norepinephrine reuptake inhibitor and a sedative agent. In certain
embodiments, said pharmaceutical composition comprises a dopamine
reuptake inhibitor and a sedative agent. In a preferred embodiment,
the sedative is eszopiclone, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof. Sleep
Difficulties and Insomnia
[0015] Several epidemiologic studies suggest that 10% to 15% of
adults suffer from chronic insomnia, and an additional 25% to 35%
have transient or occasional insomnia (Roth T. Int. J. Clin. Pract.
Suppl. 2001, 3-8).
[0016] The National Sleep Foundation's 2002 Sleep in America survey
assessed the occurrence of four symptoms of insomnia in adults in
the United States: difficulty falling asleep; waking a lot during
the night; waking up too early and not being able to get back to
sleep; and waking up feeling unrefreshed. In the survey, 58% of the
respondents reported experiencing at least one of these symptoms a
few nights a week or more, and 35% reported difficulties every
night or almost every night within the past year (National Sleep
Foundation. 2002 Sleep in America Poll. Washington, D.C.: WB &
A Market Research, 2002, 1-43). In addition, of those reporting
insomnia symptoms at least a few nights a week, 40% reported
feeling unrefreshed upon awakening, 36% reported being awake a lot
during the night, 25% reported difficulty falling asleep, and 24%
reported waking up too early and being unable to fall back
asleep.
[0017] The major types of insomnia are often described as primary
and secondary insomnia (as in the American Psychiatric
Association's Diagnostic and Statistical Manual of Mental
Disorders, Text Revision. 4th ed. Washington, D.C.: American
Psychiatric Publishing, Inc, 2000 [DSM]), chronic versus
acute/transient insomnia, intrinsic versus extrinsic insomnia (as
in the International Classification of Sleep Disorders [ICSD]), and
sleep-onset versus sleep maintenance (Diagnostic Classification
Steering Committee. International Classification of Sleep Disorders
(ICSD): Diagnostic and Coding Manual. Rochester, Minn.: American
Sleep Disorders Association, 1990). Many patients with sleep
disturbance will fall into more than one of these categories or
will have unspecified dissatisfaction with the quality of their
sleep (Roth T. Int. J. Clin. Pract. Suppl. 2001, 3-8). The fourth
edition of the DSM (DSM-IV) defines insomnia as difficulties in
sleep onset (or initiation), difficulties in sleep maintenance, or
sleep that is nonrestorative.
[0018] Chronic insomnia may result from several different sources
(Rajput et al., Am. Fam. Physician, 1999, 60:1431-1438). Patients
with chronic insomnia can often have several sleep complaints
simultaneously and experience a range of sleep disturbances,
including prolonged latency to sleep onset, increased time awake
during the sleep period, and reduced total sleep time (Benca R M,
J. Clin. Psychiatry, 2001, 62 Suppl 10:33-38).
[0019] Sleep maintenance problems may take several forms, including
frequent awakenings, an increase in time spent awake after
initially falling asleep (wake time after sleep onset, or WASO,
which is a robust measure of sleep maintenance), sleep
fragmentation (transient microarousals appearing on an EEG but not
necessarily involving full wakefulness), and unrefreshing sleep. Of
these, WASO is a particularly sensitive measure of sleep
improvement. WASO may include a number of microarousals, as well as
all periods of full wakefulness, and thus increases in WASO of only
a few minutes may be indicative of substantially improved sleep
continuity.
[0020] The severity of insomnia can be directly correlated to
severity of next-day functional impairment. There is also strong
evidence that, compared with patients without insomnia, patients
with chronic insomnia experience a subjective deterioration in
waking behaviors and psychosocial functioning, including impaired
memory, concentration, ability to accomplish tasks, and enjoyment
of interpersonal relationships (Roth et al., Sleep, 1999, 22 Suppl
2:S354-S358).
[0021] Sleep maintenance problems may cause decreases in next-day
functioning. Bonnet studied healthy volunteers with normal sleep
habits and found that, with increasing periods of induced arousal
or insomnia during the night, residual effects of next-day
performance on evaluations of vigilance, reaction time, sleepiness,
and other measures experienced corresponding decreases (Bonnet M H,
Physiol. Behav., 1989, 45:1049-1055).
Sertraline
[0022] Sertraline is a serotonin reuptake inhibitor which is
marketed as an antidepressant. It is disclosed by U.S. Pat. No.
4,536,518. The therapeutic effect of sertraline is attributed to
inhibition of CNS neuronal uptake of serotonin. Clinical studies in
man indicate that sertraline blocks the uptake of serotonin in
human platelets. In addition, in vitro studies indicate that it is
a very poor inhibitor of norepinephrine and dopamine neuronal
uptake. Sertraline is a naphthaleneamine that is generally marketed
as the hydrochloride salt under the brand name ZOLOFT.RTM..
[0023] Sertraline hydrochloride has the molecular formula
C.sub.17H.sub.17NCl.sub.2.HCl and has the chemical name
(1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalena-
mine hydrochloride. The preparation of sertraline may be carried
using preparatory methods such as those described in Welch, et al.
European Patent Application 30,081 and U.S. Pat. No. 4,536,518. The
chemical structure of Sertraline hydrochloride is presented
below.
##STR00001##
[0024] The size of a prophylactic or therapeutic dose of sertraline
in the acute or chronic management of disease will vary with the
severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight, and response of the
individual patient. In general, the total daily dose ranges, for
the conditions described herein, is from about 1 mg to about 500
mg. Preferably, a daily dose range should be between about 10 mg to
about 200 mg. Most preferably, a daily dose range should be between
about 20 mg to about 100 mg. In certain embodiments, a daily dosage
of 30, 50, 70, or 80 mg may be preferred depending upon patient
response. In managing the patient, the therapy may be initiated at
a lower dose, perhaps about 10 mg to about 15 mg and increased up
to about 20 mg or higher depending-on the patient's global
response. It may be necessary to use dosages outside these ranges
in some cases. Additional information for sertraline hydrochloride
including product information, dosage amounts, and administration
is given in Physicians' Desk Reference, 48th Edition, 1994, pp.
2000-2003.
Norepinephrine Reuptake Inhibitors (NRI)
[0025] Many compounds, including those discussed at length below,
are norepinephrine reuptake inhibitors, and no doubt many more will
be identified in the future. In the practice of the present
invention, it is intended to include reuptake inhibitors which can
be identified using the protocol described by Wong et al., Drug
Development Research, 6, 397 (1985). In certain embodiments, the
norepinephrine reuptake inhibitors used in the present invention
are characterized in being selective for the inhibition of
neurotransmitter reuptake relative to their ability to act as
direct agonists or antagonists at other receptor.
[0026] The ability of compounds to inhibit the reuptake of
norepinephrine may be measured by the general procedure of Wong, et
al., Drug Development Research, 6, 397 (1985). Male Sprague-Dawley
rats weighing 150-250 gm are decapitated and brains are immediately
removed. Cerebral cortices are homogenized in 9 volumes of a medium
containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal
preparations are isolated after differential centrifugation at
1000.times.g for 10 minutes and 17,000.times.g for 28 minutes. The
final pellets are suspended in the same medium and kept in ice
until use within the same day.
[0027] Synaptosomal uptake of .sup.3H-norepinephrine is determined
as follows. Cortical synaptosomes (equivalent to 1 mg of protein)
are incubated at 37.degree. C. for 5 minutes in 1 mL
Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM
iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 nM
.sup.3H-norepinephrine. The reaction mixture is immediately diluted
with 2 mL of ice-chilled Krebs-bicarbonate buffer and filtered
under vacuum with a cell harvester (Brandel, Gaithersburg, Md.).
Filters are rinsed twice with approximately 5 mL of ice-chilled
0.9% saline and the uptake of .sup.3H-norepinephrine assessed by
liquid scintillation counting. Accumulation of
.sup.3H-norepinephrine at 4.degree. C. is considered to be
background and is subtracted from all measurements. The
concentration of the test compound required to inhibit 50% of the
.sup.3H-norepinephrine accumulation (IC.sub.50 values) are
determined by linear regression analysis.
[0028] In general, a suitable dose of a norepinephrine reuptake
inhibitor or a pharmaceutically acceptable salt thereof for
administration to a human will be in the range of 0.01 to 50 mg per
kilogram body weight of the recipient per day, preferably in the
range of 0.1 to 3 mg per kilogram body weight per day. Unless
otherwise stated all weights of active ingredients are calculated
in terms of drug per se. The desired dose is preferably presented
as two, three, four, five or more sub-doses administered at
appropriate intervals throughout the day. These sub-doses may be
administered in unit dosage forms, for example, containing 5 to 50
mg.
Reboxetine
[0029] Reboxetine is active on the central nervous system and has
been used to treat depression, oppositional defiant disorder,
attention-deficit/hyperactivity disorder, and conduct disorder. See
WO 99/15163, WO 95/15176, and WO 99/15177. Reboxetine does not act
like most antidepressants. Reboxetine is ineffective in the
8-OH-DPAT hypothermia test, indicating that reboxetine is not a
SSRI. Brian E. Leonard, "Noradrenaline in basic models of
depression." European-Neuropsychopharmacol., 7 Suppl. 1 pp. S 11-6
and S71-3 (April 1997). Reboxetine is a norepinephrine reuptake
inhibitor, with only marginal serotonin and no dopamine reuptake
inhibitory activity. Reboxetine displays no anticholinergic binding
activity in different animal models, and is substantially devoid of
monoamine oxidase (MAO) inhibitory activity. Racemic reboxetine
exhibits a pharmacological selectivity of serotonin
(K.sub.i)/norepinephrine (K.sub.i) of about 80.
[0030] Reboxetine is a safe drug, and its use in ADHD, in both
adults and children, is a superior treatment for that disorder
because of its improved safety. The compound is particularly
selective, having few if any physiological effects besides those on
norepinephrine processing, and therefore is free of side effects
and unwanted activities. Further, it is effective at relatively low
doses, as discussed below, and may safely and effectively be
administered once per day. Thus, difficulties created by the
multiple dosing of patients, who are children and disorganized
adults, are completely avoided.
[0031] The racemate form of reboxetine is well tolerated and has a
wide safety range. The effective dose of reboxetine for ADHD is in
the range from about 1 mg/day to about 100 mg/day. The preferred
adult dose is in the range from about 5 to about 80 mg/day, and a
more highly preferred adult dose is from about 10 to about 60
mg/day. The children's dose of course is smaller, in the range from
about 1 to about 70 mg/day, more preferably from about 5 to about
60 mg/day and still more preferably from about 4 to about 10
mg/day. The optimum dose for each patient, as always, must be set
by the physician in charge of the case, taking into account the
patient's size, other medications which the patient requires,
severity of the disorder and all of the other circumstances of the
patient.
[0032] Reboxetine was first taught by U.S. Pat. No. 4,229,449 and
has the chemical name
2-[.alpha.-(2-ethoxy)phenoxy-benzyl]morpholine. Reboxetine is also
described in U.S. Pat. Nos. 5,068,433; 5,391,735; 6,642,235; and in
GB 2,167,407. Individual stereoisomers of reboxetine can be
obtained by resolution of the racemic mixture of enantiomers using
conventional methods generally known by those skilled in the art.
Such methods include, but are not limited to, resolution by simple
crystallization and chromatographic techniques, for example, as set
forth in GB 2,167,407. The structure of reboxetine is presented
below.
##STR00002##
[0033] Generally, reboxetine is administered as the racemate.
However, in certain instances, it may be advantageous to administer
reboxetine in the form of a single enantiomer. Specifically, it has
been found that compositions containing an optically pure (S,S)
reboxetine are about 5 to about 8.5 times more effective at
inhibiting the reuptake of norepinephrine than compositions
containing the racemic mixture of the (R,R) and (S,S)
stereoisomers. Accordingly, the typical daily dosage of the racemic
mixture (i.e., commercially available reboxetine) can be reduced by
about 50% to about 80% when using an optically pure (S,S)
reboxetine. The reduction in dosage does not lead to a reduction in
efficacy, but the reduction or elimination of various adverse side
effects was observed.
[0034] In particular, because an optically pure (S,S) reboxetine
selectively inhibits norepinephrine reuptake compared to serotonin
reuptake, adverse side effects associated with serotonin reuptake
are reduced or eliminated. Such adverse side effects include, but
are not limited to, gastrointestinal disturbances, anxiety, sexual
dysfunction, and undesirable side effects associated with drug-drug
interactions.
Tomoxetine
[0035] Tomoxetine is a notably safe drug for use in adults and
children for treatment of attention deficit hyperactivity disorder.
It is a superior treatment for that disorder because of its
improved safety. Tomoxetine is effective at relatively low doses
and may safely and effectively be administered once per day. In
addition, the results from animal studies indicate that tomoxetine
selectively inhibits norepinephrine uptake indicating that
tomoxetine would be useful in treating depression. Tomoxetine has
been administered in single oral doses up to 90 mg to humans. In
addition, no serious drug-related adverse effects were observed
when tomoxetine was administered to humans at a dosage of 20 or 40
mg b.i.d. for 7 days.
[0036] Tomoxetine has the chemical name
(R)-(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. The
mechanism of tomoxetine's activity is attributed to its ability to
inhibit norepinephrine reuptake. See Gehlert, et al. Neuroscience
Letters 1993, 157, 203-06. Tomoxetine is quite active in that
function, and moreover is substantially free of other central
nervous system activities at the concentrations or doses at which
it effectively inhibits norepinephrine reuptake. Thus, it is quite
free of side effects and is properly considered to be a selective
drug. Tomoxetine is usually administered as the hydrochloride
salt.
[0037] The effective dose of tomoxetine for ADHD is in the range
from about 5 mg/day to about 100 mg/day. The preferred adult dose
is in the range from about 10 to about 80 mg/day, and a more highly
preferred adult dose is from about 20 to about 60 mg/day. The
children's dose of course is smaller, in the range from about 5 to
about 70 mg/day, more preferably from about 10 to about 60 mg/day
and still more preferably from about 10 to about 50 mg/day. The
optimum dose for each patient, as always, must be set by the
physician in charge of the case, taking into account the patient's
size, other medications which the patient requires, severity of the
disorder and all of the other circumstances of the patient.
[0038] Since tomoxetine is readily orally absorbed and requires
only once/day administration, there is little or no reason to
administer it in any other way than orally. It may be produced in
the form of a clean, stable crystal, and thus is easily formulated
in the usual oral pharmaceutical forms, such as tablets, capsules,
suspensions, and the like. The usual methods of pharmaceutical
scientists are applicable. It may usefully be administered, if
there is any reason to do so in a particular circumstance, in other
pharmaceutical forms, such as injectable solutions, depot
injections, suppositories and the like, which are well known to and
understood by pharmaceutical scientists. It will substantially
always be preferred, however, to administer tomoxetine as a tablet
or capsule and such pharmaceutical forms are recommended.
(S,S)-hydroxybupropion
[0039] The present invention contemplates the use of norepinephrine
reuptake inhibitors in general, including nortriptyline,
maprotiline, protriptyline, trimipramine, venlafaxine,
amitriptyline, amoxapine, doxepin, nefazodone, and lamotrigine.
Dopamine Reuptake Inhibitors
[0040] A large number of dopamine reuptake inhibitors are known in
the art and are amenable to the present invention. Dopamine
reuptake inhibitors can be identified using the rat corpus striatum
assay described in US Patent Application 20040180857, which is
hereby incorporated by reference. In general, a dose of a dopamine
reuptake inhibitor or a pharmaceutically acceptable salt thereof
suitable for administration to a human will be in the range of 0.01
to 50 mg per kilogram body weight of the recipient per day,
preferably in the range of 0.1 to 3 mg per kilogram body weight per
day. Unless otherwise stated all weights of active ingredients are
calculated in terms of drug per se. In certain embodiments, the
desired dose is presented as two, three, four, five or more
sub-doses administered at appropriate intervals throughout the day.
These sub-doses may be administered in unit dosage forms, for
example, containing about 5 to 50 mg.
Amineptine
Sedative Agent: GABA Receptor Modulating Agents
[0041] .gamma.-Aminobutyric acid (GABA) is the major inhibitory
neurotransmitter in the mammalian central nervous system. Receptors
for GABA have traditionally been divided into GABA.sub.A and
GABA.sub.B receptor subtypes. The GABA.sub.A receptor is the more
prominent GABA receptor subtype, and is a ligand-gated chloride ion
channel that is opened after release of GABA from presynaptic
neurons. The GABA.sub.B receptor is a member of the G
protein-coupled receptor family coupled both to biochemical
pathways and to regulation of ion channels. See Goodman and
Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill,
New York, N.Y., 9.sup.th Edition, (1996) and Kerr, D. I. B. and
Ong, J. Pharmac. Ther. 1995, 67, 187-246.
[0042] In general, a dose of the GABA-receptor modulating agent or
a pharmaceutically acceptable salt thereof suitable for
administration to a human will be in the range of 0.01 to 50 mg per
kilogram body weight of the recipient per day, preferably in the
range of 0.1 to 3 mg per kilogram body weight per day. Unless
otherwise stated all weights of active ingredients are calculated
in terms of drug per se. In certain embodiments, the desired dose
is presented as two, three, four, five or more sub-doses
administered at appropriate intervals throughout the day. These
sub-doses may be administered in unit dosage forms, for example,
containing about 5 to 50 mg.
GABA Binding Assay
[0043] The affinity of a compound to bind to a GABA receptor can be
measured using procedures known in the art. In addition, assay kits
for determining GABA-receptor binding affinity can be purchased
from MDS Pharma Services. For representative examples of procedures
to determine GABA-receptor binding affinity see Enna, S. J.;
Snyder, S. H. Mol. Pharmacol. 1976, 13, 442; C. Martini et al. J.
Neurochem. 1983, 41, 1183; Lewin, A. H. et al. Mol. Pharmacol.
1989, 35, 189; Schwartz, R. D.; Mindlin, M. C. J Pharmacol. Exp.
Ther. 1988, 244, 963; Facklam, M.; Bowery, N. G. Br. J. Pharmacol.
1993, 110, 1291; P. Mathivet et al. Eur. J. Pharmacol. 1992, 321,
67; A. Green et al. Br. J. Pharmacol. 2000, 131(8), 1766; K.
Kaupmann et al. Nature 1997, 386, 239; H. W. Damm et al. Res. Comm.
Chem. Pathol. Pharmacol. 1978, 22, 597; and R. C. Speth et al. Life
Sci. 1979, 24, 351. Furthermore, a representative procedure for
determining the binding affinity of a compound to a GABA receptor
is described below. For additional details pertaining to the
following procedure see U.S. Pat. No. 6,743,789.
[0044] The affinity of a compound at GABA.sub.A-receptor subtypes
can be measured by competition for [.sup.3H]flumazenil (85 Ci/mmol;
Amersham) binding to SF9 cells expressing rat receptors of
composition .alpha.1.beta.3.gamma.2, .alpha.2.beta.3.gamma.2,
.alpha.3.beta.3.gamma.2 and .alpha.5.beta.3.gamma.2.
[0045] Importantly, compounds known in the art that modulate the
activity of the GABA receptor are amenable to the present
invention. Accordingly, GABA analogs with pharmaceutical activity
have been synthesized and described in U.S. Pat. Nos. 4,024,175;
5,563,175; 6,020,370; 6,028,214; 6,103,932; and 6,117,906; and
International Patent Applications WO 92/09560, WO 93/23383, WO
97/29101, WO 97/33858, WO 97/33859, WO 98/17627, WO 99/08671, WO
99/21824, WO 99/31057, WO 99/31074, WO 99/31075, WO 99/61424, WO
00/15611, WO 00/31020, and WO 00/50027, each of which is hereby
incorporated by reference. In addition, GABA.sub.B receptor
agonists are disclosed in EP 0356128; EP 0181833, EP 0399949, EP
0463969, and FR 2,722,192, each of which is hereby incorporated by
reference.
Racemic Zopiclone
[0046] Zopiclone is the first of a chemically distinct class of
hypnotic and anxiolytic compounds that offers a psychotherapeutic
profile of efficacy and side effects similar to the
benzodiazepines. This class of compounds, the cyclopyrrolones,
appears to cause less residual sedation and slowing of reaction
times than the benzodiazepines, and it offers the promise of an
improved therapeutic index over benzodiazepines.
[0047] The pharmacology of zopiclone has been shown both
preclinically and clinically to be characterized by five distinct
elements. It is predominantly a hypnotic-sedative, offering
significant activity on first treatment in the absence of
respiratory or cardiac depression. Additionally, zopiclone is an
anticonvulsant, and it further exhibits muscle relaxant,
anti-aggressive, and anxiolytic activities.
[0048] The compound binds to the benzodiazepine receptor complex,
or to a site linked closely to this receptor complex. (See Goa, K.
L. and Heel, R. C. Drugs, 32:48-65, (1986); Brun, J. P.,
Pharmacology, Biochemistry and Behavior, 29:831-832, (1988); Julou,
L. et al., Pharmacology, Biochemistry and Behavior, 23:653-659,
(1985); Verma, A. and Snyder S. H., Annu. Rev. Pharmacol. Toxicol,
29:307-322, (1989). The central benzodiazepine receptor is a
macromolecular complex that includes a site for the binding of
gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter,
suggesting that benzodiazepines and chemically unrelated agonists
including zopiclone may exert their effects by facilitating the
synaptic effects of GABA. While it interacts with the
benzodiazepine receptor, zopiclone apparently has minimal effects
on memory, no interaction with alcohol, and little or no abuse or
dependence potential.
[0049] The pharmacologic activity of zopiclone is predominantly
that of a sedative or hypnotic, particularly at low doses.
Accordingly, the drug may improve sleep in adults and geriatric
patients with several types of sleep disorders, and situational,
transient, primary, and secondary insomnia. Following a bedtime
dose of zopiclone, there is minimal impairment of psychomotor
skills and mental acuity the following morning. The drug is well
absorbed from the stomach, and it is not highly bound to plasma
proteins.
[0050] The racemic mixture of zopiclone is presently used outside
the United States primarily as an hypnotic, improving sleep
patterns in chronic insomniacs and providing sleep induction before
surgical procedures in hospitalized patients.
[0051] Insomnia is characterized by difficulty in sleeping or
disturbed sleep patterns. Insomnia may be of a primary nature with
little apparent relationship to immediate somatic or psychic
events, or secondary to some acquired pain, anxiety or depression.
Where possible, treatment is directed to the underlying cause of
the condition; hypnotic medication such as zopiclone is generally
reserved for insomnia of emotional disturbances and for refractory
cases due to more common causes. In these cases, zopiclone provides
sedative-hypnotic effects from the first day of treatment, an
activity that is maintained following subsequent doses over long
treatment periods. There appears to be no diminution or
potentiation of activity in adult or geriatric patients, and little
or no effect on alertness and performance some ten hours following
the bedtime dose. (Brun, J. P. Pharmacology, Biochemistry and
Behavior 1988, 29, 831-832).
[0052] In addition, the racemic mixture of zopiclone may be useful
in treating other disorders such as convulsive states like
epilepsy. Seizure disorder or epilepsy represents a broad group of
central nervous system disorders of function that are characterized
by recurrent, sudden, often brief attacks, which may alter
consciousness, motor activity, sensory phenomena, and autonomic
responses, and which may prompt inappropriate behavior. Recurrent
seizure patterns of either an idiopathic or symptomatic etiology
are termed epilepsy. The most common form of these recurrent but
transient episodes are convulsive seizures, which may include loss
of consciousness, motor function and control, and which may produce
tonic or clonic jerking of the extremities. Pharmacological
treatment of epilepsy has been directed to control based on seizure
type, rather than etiology. Accordingly, the convulsions have been
grouped in broad but rather distinct types including Tonic-clonic
(Grand Mal), Partial (Focal) seizures, psychomotor (Complex
partial) seizures, pyknoepileptic or Absence (Petit Mal) and the
less frequent Myoclonic seizures.
[0053] The binding of zopiclone at or near the benzodiazepine
receptor complex suggests that the compound may facilitate the
inhibitory action of the neurotransmitter GABA and therefore its
synaptic effects. As stated above, benzodiazepine receptors, which
can be located both within the central nervous system and
peripherally (e.g., in the endocrine system), are comprised of
macromolecular complexes characterized by sites for binding of the
benzodiazepines, GABA, and zopiclone. The benzodiazepine receptor
complex is further associated with, and interacts with, a
transmembrane channel for chloride ion transport. The effect of
zopiclone's interaction with the benzodiazepine receptor/GABA
receptor/chloride channel complex is to cause GABA to inhibit
cerebral neuronal discharge, presumably by increasing membrane
conductance of chloride ion, thus stabilizing membrane potentials
and dampening excitatory input. (See Meldrum, B. S., Brit. J. Clin.
Pharm., 27 (suppl. 1): 3S-11S, (1989)). It is believed that through
mediation of this process zopiclone may be useful in treating
epilepsy and a number of other conditions in which GABA is believed
to exert a physiologic role.
[0054] While the racemic mixture of zopiclone may be useful in the
treatment of the above-described disorders, it has a low
therapeutic index and also causes adverse effects. These adverse
effects include, but are not limited to, the development of a
bitter taste due to the salivary secretion of the drug, dry mouth,
drowsiness, morning tiredness, headache, dizziness, impairment of
psychomotor skills and related effects.
[0055] It has recently been discovered that by using optically pure
or substantially optically pure (+) zopiclone yields an increase in
the potency of therapeutic effect as compared to that found in the
racemic mixture. In addition, utilizing the optically pure isomer
of (+) zopiclone results in clearer dose-related definitions of
efficacy, diminished adverse effects, and accordingly, an improved
therapeutic index. Hence, it is generally more desirable to use the
(+) isomer of zopiclone.
Eszopiclone
[0056] Eszopiclone (or (+)-Zopiclone or (S)-zopiclone) is a potent
drug useful for the treatment of sleep disorders, convulsive
disorders, and disorders that are affected by the binding of
agonists to central nervous system or peripheral benzodiazepine
receptors. Administration of isomerically pure or substantially
isomerically pure (e.g., 90%, 95%, or 99% isomeric purity)
(+)-zopiclone is generally preferred because this isomer possesses
potent activity in treating sleep disorders while avoiding adverse
effects including but not limited to drowsiness, next day effects,
such as tiredness in the morning, inability to concentrate and
headache.
[0057] Eszopiclone is a cyclopyrrolone that has the chemical name
(+) 6-(5-chloro-pyri-2-dyl)-5-(4-methylpiperazin-1-yl)
carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3-4b]pyrazin or (+)
6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4b]pyrazin-5-yl
4-methylpiperazine-1-carboxylate. The chemical structure of
zopiclone is shown below:
##STR00003##
[0058] Eszopiclone is an optical isomer, the (+)-isomer, of the
compound zopiclone, which is described in U.S. Pat. Nos. 6,319,926
and 6,444,673, and in Goa and Heel, [Drugs, 32:48-65 (1986)] and in
U.S. Pat. Nos. 3,862,149 and 4,220,646. This isomer, which will
hereinafter be referred to as eszopiclone, includes optically pure
and the substantially optically pure (e.g., 90%, 95% or 99% optical
purity) (+)-zopiclone isomer.
[0059] Racemic zopiclone is commercially available and can be made
using various methods, such as those disclosed in U.S. Pat. Nos.
3,862,149 and 4,220,646. Eszopiclone may be prepared from racemic
zopiclone using standard methods, such as chiral-phase
chromatography, resolution of an optically active salt,
stereoselective enzymatic catalysis by means of an appropriate
microorganism, or asymmetric synthesis. U.S. Pat. No. 6,319,926
discloses methods for making eszopiclone, including resolution from
racemic zopiclone by means of an optically active acid, such as
D(+)--O,O'-dibenzoyltartaric acid.
[0060] Another method for making eszopiclone (or (S)-zopiclone) is
by synthesis from racemic zopiclone (or (RS)-zopiclone) by chemical
resolution via the D-malate salt as shown in the following
synthesis schematic.
##STR00004##
[0061] In the synthetic route shown above, (RS)-Zopiclone and
D-malic acid are dissolved in a mixture of acetone and methanol to
form (S)-zopiclone D-malate and (R)-zopiclone D-malate. The two
diastereomeric salts are resolved in-situ by selective
crystallization, filtration and rinsing to produce highly
(S)-enriched zopiclone D-malate salt. In this process, the majority
of (R)-zopiclone D-malate remains in the mother liquors. In this
method, the use of an acetone/methanol co-solvent system results in
a highly diastereoselective salt crystallization, and preferably,
the co-solvent ratio used should be in the range of approximately
1.9/1 to 2.3/1 w/w acetone in methanol. Preferably, this stage of
the process may also include cooling the reaction mixture during
the isolation step to a temperature in the inclusive range of about
10.degree. C. to 15.degree. C., and washing or rinsing the wet cake
obtained after filtration with cold solvent, such as cold
methanol.
[0062] The resulting (S)-zopiclone D-malate salt is converted to
optically pure eszopiclone free base by treatment with aqueous
potassium carbonate and ethyl acetate, followed by phase separation
and crystallization. In this process, once a solution of
eszopiclone free-base is obtained, additional enantiomeric
enrichment (typically 1 to 4%) can be achieved by crystallization
from ethyl acetate of low water content. The water content can be
controlled, e.g., by azeotropic distillation, and incorporating an
in-process control of water content into the crystallization
process can further improve the robustness of enantiomeric purity.
Preferably, the water level during this step is 2% or less, more
preferably 1% or less, and most preferably 0.6% or less.
[0063] The resulting optically pure eszopiclone free base can then
be milled to a desired size for use as an active ingredient in a
pharmaceutical composition according to or for use in methods of
the present invention Eszopiclone possess potent activity in
treating sleep disorders such as insomnia Eszopiclone also possess
potent activity in treating sleep disorders while avoiding the
usual adverse effects including but not limited to drowsiness, next
day effects tiredness in the morning, inability to concentrate and
headache, which are associated with the administration of the
racemic mixture of zopiclone. Eszopiclone also possess potent
activity in treating convulsive disorders such as epilepsy while
avoiding the adverse effects which are associated with the
administration of the racemic mixture of zopiclone.
[0064] Additionally, compositions containing optically pure
eszopiclone are useful in treating disorders that are affected by
the binding of agonists to central nervous system and peripheral
benzodiazepine receptors. Such disorders include but are not
limited to aggressive behavior, muscle tension, behavioral
disorders, depression, schizophrenia, and disorders associated with
abnormal plasma hormone levels such as endocrine disorders. These
compositions are useful in treating disorders that are affected by
the binding of agonists to central nervous system and peripheral
benzodiazepine receptors.
[0065] The size of a prophylactic or therapeutic dose of
eszopiclone in the acute or chronic management of disease will vary
with the severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight, and response of the
individual patient. In general, the total daily dose ranges, for
the conditions described herein, is from about 0.25 mg to about 15
mg. Preferably, a daily dose range should be between about 0.5 mg
to about 10 mg. Most preferably, a daily dose range should be
between about 1.0 mg to about 5.0 mg. In managing the patient, the
therapy may be initiated at a lower dose, perhaps about 0.5 mg to
about 3 mg and increased up to about 5 mg or higher depending-on
the patient's global response. It is further recommended that
children and patients over 65 years, and those with impaired renal
or hepatic function, initially receive low doses, and that they be
titrated based on global response and blood level. It may be
necessary to use dosages outside these ranges in some cases.
[0066] In the case where an oral composition is employed, a
suitable dosage range for use is from about 0.25 mg to about 15.0
mg with, in the usual case, the lower doses serving more common
insomnia, and the higher doses, presented in divided dosing,
reserved for control of psychiatric disorders. Preferably, a dose
range of between about 0.5 mg to about 10 mg is given as a once
daily administration or in divided doses if required; most
preferably, a dose range of from about 1.0 mg to about 5 mg is
given, either as a once daily administration or in divided doses if
required. Patients may be upward titrated from below to within this
dose range to a satisfactory control of symptoms as
appropriate.
Zolpidem
[0067] Zolpidem is a hypnotic agent that is known to induce or
maintain sleep.
[0068] Zolpidem is an imidazopyridine having IUPAC chemical
nomenclature
N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-s]pyridine-3-acetamide.
The structure of zolpidem is presented below.
##STR00005##
[0069] The zolpidem free base was disclosed generically in EP 50563
of Synthelabo. Zolpidem tartrate was subsequently disclosed in EP
251859 (U.S. Pat. No. 4,794,185). More recently, zolpidem has been
suggested as useful in treating Parkinson's disease, parkinsonian
symptoms, obsessive-compulsive disorder and certain forms of
dementia in U.S. Pat. No. 5,891,891.
[0070] Zolpidem has been marketed as an immediate release tablet
for oral application under the trade marks AMBIEN.RTM. and
STILNOX.RTM.. In these commercial pharmaceutical dosage forms,
zolpidem is present as a salt with L(+)tartaric acid wherein the
molar ratio of zolpidem to tartaric acid is 2:1. This salt is
conventionally called zolpidem hemitartrate but a more correct
denomination thereof, which will be used hereinafter, is zolpidem
tartrate. The European Pharmacopoeia, Monograph No. 1999:1280,
states that zolpidem tartrate is characterized as a white or almost
white crystalline powder, hygroscopic, slightly soluble in water,
sparingly soluble in methanol, and practically insoluble in
methylene chloride. Commercially available zolpidem tablets are
conventional film coated tablets for immediate release of the
active substance after ingestion and they contain 5 or 10 mg of
zolpidem tartrate. The inactive ingredients are: lactose,
microcrystalline cellulose, sodium starch glycolate,
hydroxypropylmethylcellulose and magnesium stearate. The film
coating layer consists of hydroxypropylmethylcellulose,
polyethylene glycol and colorants.
[0071] Zolpidem is generally administrated orally by means of a
tablet or other solid dosage form. Indeed pharmacokinetic and
pharmacodynamic data show that zolpidem has both a rapid absorption
and onset of hypnotic action. Its bioavailability is 70% following
oral administration and demonstrates linear kinetics in the
therapeutical dose range, which lies between 5 and 10 mg in
conventional forms, peak plasma concentration is reached at between
0.5 and 3 hours, the elimination half-life is short, with a mean of
2.4 hours and a duration of action of up to 6 hours. Generally, the
dosage of zolpidem is between 1 and 50 mg.
[0072] Traditionally, only immediate release dosage forms were
developed which disintegrated rapidly in the gastrointestinal
tract, dissolved in the fluid of the gastrointestinal tract and
underwent systemic absorption, where zolpidem, can exert its
pharmacological effect and induce sleep of the patient. More
recently, new dosage forms have been developed which sustain
release of zolpidem over a period compatible with the desired time
of sleep and the time needed for elimination of the drug from the
human body to a sufficiently low level. See U.S. Pat. Nos.
6,638,535 and 6,514,531.
Zaleplon
[0073] Zaleplon (Wyeth-Ayerst), also known as "Sonata", is a
nonbenzodiazipine recently approved by the FDA as sedative-hypnotic
(see U.S. Pat. No. 4,626,538). Zaleplon is a pyrazolopyrimidine
that has the chemical name
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide.
Zaleplon is a white powder that has very low solubility in water
and limited solubility in alcohol or propylene glycol. The
structure of Zaleplon is given below.
##STR00006##
[0074] Zaleplon binds to the gamma-aminobutyric acid benzodiazepine
(GABA-BZ) receptor complex. Binding studies have revealed that
Zaleplon binds selectively to the brain omega-1 receptor located on
alpha subunit of the GABA.sub.A/chloride ion channel receptor
complex. This interaction modulates the binding of
t-butylbicyclophosphorothionate binding. Importantly, the
pharmacological properties of benzodiazepines, e.g. sedative,
anxiolytic, muscle relaxant, and anticonvulsive effects in animals,
are linked to modulation of the GABA-BZ receptor chloride channel
complex.
[0075] The size of a prophylactic or therapeutic dose of Zaleplon
in the acute or chronic management of disease will vary with the
severity of the condition to be treated and the route of
administration. The dose, and perhaps the dose frequency, will also
vary according to the age, body weight, and response of the
individual patient. In general, the total daily dose ranges, for
the conditions described herein, is from about 1 mg to about 50 mg.
Preferably, a daily dose range should be between about 1 mg to
about 25 mg. Most preferably, a daily dose range should be between
about 5 mg to about 20 mg. In certain embodiments, the daily dose
range should be about 5, 10, 15, or 20 mg. In managing the patient,
the therapy may be initiated at a lower dose, perhaps about 2 mg to
about 5 mg and increased up to about 10 mg or higher depending-on
the patient's global response.
[0076] Generally, Zaleplon should be taken just prior to bedtime or
immediately if a patient the patient has already gone to bed is
having difficulty falling asleep. In certain instances the dose of
Zaleplon should be adjusted in accord with diet or special needs of
the patient. For example, the dosage of Zaleplon should be
approximately 5 mg for elderly or debilitated patients whom are
likely to be particularly sensitive to hypnotic medications. In
addition, patients suffering from mild to moderate hepatic
impairment should be administered only a 5 mg dose because systemic
removal of drug is reduced in such patients.
Combination Therapy
[0077] One aspect of the present invention relates to combination
therapy. This type of therapy is advantageous because the
co-administration of active ingredients achieves a therapeutic
effect that is greater than the therapeutic effect achieved by
administration of only a single therapeutic agent. In one
embodiment, the co-administration of two or more therapeutic agents
achieves a synergistic effect, i.e., a therapeutic affect that is
greater than the sum of the therapeutic effects of the individual
components of the combination. In another embodiment, the
co-administration of two or more therapeutic agents achieves an
augmentation effect.
[0078] The active ingredients that comprise a combination therapy
may be administered together via a single dosage form or by
separate administration of each active agent. In certain
embodiments, the first and second therapeutic agents are
administered in a single dosage form. The agents may be formulated
into a single tablet, pill, capsule, or solution for parenteral
administration and the like.
[0079] Alternatively, the first therapeutic agent and the second
therapeutic agents may be administered as separate compositions,
e.g., as separate tablets or solutions. The first active agent may
be administered at the same time as the second active agent or the
first active agent may be administered intermittently with the
second active agent. The length of time between administration of
the first and second therapeutic agent may be adjusted to achieve
the desired therapeutic effect. In certain instances, the second
therapeutic agent may be administered only a few minutes (e.g., 1,
2, 5, 10, 30, or 60 min) after administration of the first
therapeutic agent. Alternatively, the second therapeutic agent may
be administered several hours (e.g., 2, 4, 6, 10, 12, 24, or 36 hr)
after administration of the first therapeutic agent. In certain
embodiments, it may be advantageous to administer more than one
dosage of the second therapeutic agent between administrations of
the first therapeutic agent. For example, the second therapeutic
agent may be administered at 2 hours and then again at 10 hours
following administration of the first therapeutic agent.
Alternatively, it may be advantageous to administer more than one
dosage of the first therapeutic agent between administrations of
the second therapeutic agent. Importantly, it is preferred that the
therapeutic effects of each active ingredient overlap for at least
a portion of the duration of each therapeutic agent so that the
overall therapeutic effect of the combination therapy is
attributable in part to the combined or synergistic effects of the
combination therapy.
[0080] The dosage of the active agents will generally be dependent
upon a number of factors including pharmacodynamic characteristics
of each agent of the combination, mode and route of administration
of active agent(s), the health of the patient being treated, the
extent of treatment desired, the nature and kind of concurrent
therapy, if any, and the frequency of treatment and the nature of
the effect desired. In general, dosage ranges of the active agents
often range from about 0.001 to about 250 mg/kg body weight per
day. For example, for a normal adult having a body weight of about
70 kg, a dosage in the range of from about 0.1 to about 25 mg/kg
body weight is typically preferred. However, some variability in
this general dosage range may be required depending upon the age
and weight of the subject being treated, the intended route of
administration, the particular agent being administered and the
like. Since two or more different active agents are being used
together in a combination therapy, the potency of each agent and
the interactive effects achieved using them together must be
considered. Importantly, the determination of dosage ranges and
optimal dosages for a particular mammal is also well within the
ability of one of ordinary skill in the art having the benefit of
the instant disclosure.
[0081] In certain embodiments, it may be advantageous for the
pharmaceutical combination to have a relatively large amount of the
first component compared to the second component. In certain
instances, the ratio of the first active agent to second active
agent is 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. In
certain embodiments, it may be preferable to have a more equal
distribution of pharmaceutical agents. In certain instances, the
ratio of the first active agent to the second active agent is 4:1,
3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. In certain embodiments, it may be
advantageous for the pharmaceutical combination to have a
relatively large amount of the second component compared to the
first component. In certain instances, the ratio of the second
active agent to the first active agent is 30:1, 20:1, 15:1, 10:1,
9:1, 8:1, 7:1, 6:1, or 5:1. Importantly, a composition comprising
any of the above-identified combinations of first therapeutic agent
and second therapeutic agent may be administered in divided doses
1, 2, 3, 4, 5, 6, or more times per day or in a form that will
provide a rate of release effective to attain the desired results.
In a preferred embodiment, the dosage form contains both the first
and second active agents. In a more preferred embodiment, the
dosage form only has to be administered one time per day and the
dosage form contains both the first and second active agents.
[0082] For example, a formulation intended for oral administration
to humans may contain from 0.1 mg to 5 g of the first therapeutic
agent and 0.1 mg to 5 g of the second therapeutic agent, both of
which are compounded with an appropriate and convenient amount of
carrier material varying from about 5 to about 95 percent of the
total composition. Unit dosages will generally contain between from
about 0.5 mg to about 1500 mg of the first therapeutic agent and
0.5 mg to about 1500 mg of the second therapeutic agent. In a
preferred embodiment, the dosage comprises 0.5 mg, 1 mg, 2 mg, 3
mg, 4 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400
mg, 500 mg, 600 mg, 800 mg, or 1000 mg, etc., up to 1500 mg of the
first therapeutic agent. In a preferred embodiment, the dosage
comprises 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 25 mg, 50
mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000
mg, etc., up to 1500 mg of the second therapeutic agent.
[0083] The optimal ratios of the first and second therapeutic agent
can be determined by standard assays known in the art. For example,
the phenyl-p-benzoquinone test may be used to establish analgesic
effectiveness. The phenyl-p-benzoquinone induced writhing test in
mice (H. Blumberg et al., 1965, Proc. Soc. Exp. Med. 118:763-766)
and known modifications thereof is a standard procedure which may
be used for detecting and comparing the analgesic activity of
different classes of analgesic drugs with a good correlation with
human analgesic activity. Data for the mouse, as presented in an
isobologram, can be translated to other species where the orally
effective analgesic dose of the individual compounds are known or
can be estimated. The method consists of reading the percent
ED.sub.50 dose for each dose ratio on the best fit regression
analysis curve from the mouse isobologram, multiplying each
component by its effective species dose, and then forming the ratio
of the amount of COX-2 inhibitor and opioid analgesic. This basic
correlation for analgesic properties enables estimation of the
range of human effectiveness (E. W. Pelikan, 1959, The
Pharmacologist 1:73). Thus, application of an equieffective dose
substitution model and a curvilinear regression analysis utilizing
all the data for the individual compounds and various dose ratios
for the combinations can be used to establish the existence of
unexpectedly enhanced analgesic activity of combinations of active
agents, i.e., the resulting activity is greater than the activity
expected from the sum of the activities of the individual
components.
[0084] The toxicity and therapeutic efficacy of such compounds can
be determined by standard pharmaceutical procedures in cell
cultures or experimental animals, e.g., for determining the
LD.sub.50 (the dose lethal to 50% of the population) and the
ED.sub.50 (the dose therapeutically effective in 50% of the
population). The dose ratio between toxic and therapeutic effects
is the therapeutic index and it can be expressed as the ratio
LD.sub.50/ED.sub.50. Compounds which exhibit large therapeutic
indices are preferred. The data obtained from these cell culture
assays and animal studies can be used in formulating a range of
dosage for use in humans. The dosage of such compounds lies
preferably within a range of circulating concentrations that
include the ED.sub.50 with little or no toxicity. The dosage may
vary within this range depending upon the dosage form employed and
the route of administration utilized. For any compound used in the
method of the invention, the therapeutically effective dose can be
estimated initially from cell culture assays. A dose may be
formulated in animal models to achieve a circulating plasma
concentration range that includes the IC.sub.50 (i.e., the
concentration of the test compound which achieves a half-maximal
inhibition of RT production from infected cells compared to
untreated control as determined in cell culture. Such information
can be used to more accurately determine useful doses in humans.
Levels in plasma may be measured, for example, by high performance
liquid chromatography (HPLC).
Synergism and Augmentation
[0085] The term "synergistic" refers to a combination which is more
effective than the additive effects of any two or more single
agents. A synergistic effect permits the effective treatment of a
disease using lower amounts (doses) of either individual therapy.
The lower doses result in lower toxicity without reduced efficacy.
In addition, a synergistic effect can result in improved efficacy,
e.g., improved antiviral activity. Finally, synergy may result in
an improved avoidance or reduction of disease as compared to any
single therapy.
[0086] Combination therapy can allow for the use of lower doses of
the first therapeutic or the second therapeutic agent (referred to
as "apparent one-way synergy" herein), or lower doses F both
therapeutic agents (referred to as "two-way synergy" herein) than
would normally be required when either drug is used alone.
[0087] In certain embodiments, the synergism exhibited between the
second therapeutic agent and the first therapeutic agent is such
that the dosage of the first therapeutic agent would be
sub-therapeutic if administered without the dosage of the second
therapeutic agent. Alternatively, the synergism exhibited between
the second therapeutic agent and the first therapeutic agent is
such that the dosage of the second therapeutic agent would be
sub-therapeutic if administered without the dosage of the first
therapeutic agent.
[0088] The terms "augmentation" or "augment" refer to combination
where one of the compounds increases or enhances therapeutic
effects of another compound or compounds administered to a patient.
In some instances, augmentation can result in improving the
efficacy, tolerability, or safety, or any combination thereof, of a
particular therapy.
[0089] In certain embodiments, the present invention relates to a
pharmaceutical composition comprising a therapeutically effective
dose of a first therapeutic agent together with a dose of a second
therapeutic agent effective to augment the therapeutic effect of
the first therapeutic agent. In other embodiments, the present
invention relates to methods of augmenting the therapeutic effect
in a patient of a first therapeutic agent by administering the
second therapeutic agent to the patient. In other embodiments, the
present invention relates to a pharmaceutical composition
comprising an therapeutically effective dose of a second
therapeutic agent together with a dose of a first therapeutic agent
effective to augment the therapeutic effect of the second
therapeutic agent. In other embodiments, the present invention
relates to methods of augmenting the therapeutic effect in a
patient of a second therapeutic agent by administering the first
therapeutic agent to the patient.
[0090] In certain preferred embodiments, the invention is directed
in part to synergistic combinations of the first therapeutic agent
in an amount sufficient to render a therapeutic effect together
with a second therapeutic agent. For example, in certain
embodiments a therapeutic effect is attained which is at least
about 2 (or at least about 4, 6, 8, or 10) times greater than that
obtained with the dose of the first therapeutic agent alone. In
certain embodiments, the synergistic combination provides a
therapeutic effect which is up to about 20, 30 or 40 times greater
than that obtained with the dose of first therapeutic agent alone.
In such embodiments, the synergistic combinations display what is
referred to herein as an "apparent one-way synergy", meaning that
the dose of second therapeutic agent synergistically potentiates
the effect of the first therapeutic agent, but the dose of first
therapeutic agent does not appear to significantly potentiate the
effect of the second therapeutic agent.
[0091] In certain embodiments, the combination of active agents
exhibit two-way synergism, meaning that the second therapeutic
agent potentiates the effect of the first therapeutic agent, and
the first therapeutic agent potentiates the effect of the second
therapeutic agent. Thus, other embodiments of the invention relate
to combinations of a second therapeutic agent and a first
therapeutic agent where the dose of each drug is reduced due to the
synergism between the drugs, and the therapeutic effect derived
from the combination of drugs in reduced doses is enhanced. The
two-way synergism is not always readily apparent in actual dosages
due to the potency ratio of the first therapeutic agent to the
second therapeutic agent. For instance, two-way synergism can be
difficult to detect when one therapeutic agent displays much
greater therapeutic potency relative to the other therapeutic
agent.
[0092] The synergistic effects of combination therapy may be
evaluated by biological activity assays. For example, the
therapeutic agents are be mixed at molar ratios designed to give
approximately equipotent therapeutic effects based on the EC.sub.90
values. Then, three different molar ratios are used for each
combination to allow for variability in the estimates of relative
potency. These molar ratios are maintained throughout the dilution
series. The corresponding monotherapies are also evaluated in
parallel to the combination treatments using the standard primary
assay format. A comparison of the therapeutic effect of the
combination treatment to the therapeutic effect of the monotherapy
gives a measure of the synergistic effect. Further details on the
design of combination analyses can be found in B E Korba (1996)
Antiviral Res. 29:49. Analysis of synergism, additivity, or
antagonism can be determined by analysis of the aforementioned data
using the CalcuSyn.TM. program (Biosoft, Inc.). This program
evaluates drug interactions by use of the widely accepted method of
Chou and Talalay combined with a statistically evaluation using the
Monte Carlo statistical package. The data are displayed in several
different formats including median-effect and dose-effects plots,
isobolograms, and combination index [CI] plots with standard
deviations. For the latter analysis, a CI greater than 1.0
indicates antagonism and a CI less than 1.0 indicates
synergism.
[0093] Compositions of the invention present the opportunity for
obtaining relief from moderate to severe cases of disease. Due to
the synergistic and/or additive effects provided by the inventive
combination of the first and second therapeutic agent, it may be
possible to use reduced dosages of each of therapeutic agent. By
using lesser amounts of other or both drugs, the side effects
associated with each may be reduced in number and degree. Moreover,
the inventive combination avoids side effects to which some
patients are particularly sensitive.
Compositions & Methods of the Invention
[0094] .
[0095] .
[0096] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a norepinephrine reuptake inhibitor.
[0097] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a norepinephrine reuptake inhibitor,
wherein said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, or (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0098] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is desipramine, reboxetine,
oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0099] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0100] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a norepinephrine reuptake
inhibitor; and at least one pharmaceutically acceptable
carrier.
[0101] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a norepinephrine reuptake
inhibitor, wherein said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and at least one pharmaceutically
acceptable carrier.
[0102] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is desipramine, reboxetine,
oxaprotiline, or (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0103] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0104] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of
norepinephrine reuptake inhibitor.
[0105] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of
norepinephrine reuptake inhibitor, wherein said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0106] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is desipramine, reboxetine, oxaprotiline, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0107] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof.
[0108] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of
norepinephrine reuptake inhibitor; and at least one
pharmaceutically acceptable carrier.
[0109] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of
norepinephrine reuptake inhibitor, wherein said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of them;
and at least one pharmaceutically acceptable carrier.
[0110] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is desipramine, reboxetine, oxaprotiline, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0111] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof.
[0112] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sleep abnormality is difficulty
falling asleep, difficulty staying asleep, or waking up too
early.
[0113] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of norepinephrine reuptake
inhibitor.
[0114] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of norepinephrine reuptake
inhibitor, wherein said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0115] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is desipramine, reboxetine, oxaprotiline, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0116] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0117] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of norepinephrine reuptake
inhibitor; and at least one pharmaceutically acceptable
carrier.
[0118] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of norepinephrine reuptake
inhibitor, wherein said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, or (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and at least one pharmaceutically
acceptable carrier.
[0119] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is desipramine, reboxetine, oxaprotiline, or
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0120] In certain embodiments, the present invention relates to the
aforementioned method, wherein said norepinephrine reuptake
inhibitor is (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0121] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is transient
insomnia
[0122] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is short-term
insomnia.
[0123] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is chronic
insomnia
[0124] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of
norepinephrine reuptake inhibitor.
[0125] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a dopamine reuptake inhibitor.
[0126] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a dopamine reuptake inhibitor, said
dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0127] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, or GBR-12935, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them.
[0128] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0129] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them.
[0130] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
desmethylvenlafaxine is racemic desmethylvenlafaxine,
(+)-desmethylvenlafaxine, or (-)-desmethylvenlafaxine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0131] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a dopamine reuptake inhibitor;
and at least one pharmaceutically acceptable carrier.
[0132] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a dopamine reuptake inhibitor,
said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine, desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0133] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, or GBR-12935, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them.
[0134] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0135] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is venlafaxine, desmethylvenlafaxine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them.
[0136] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
desmethylvenlafaxine is racemic desmethylvenlafaxine,
(+)-desmethylvenlafaxine, or (-)-desmethylvenlafaxine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0137] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
dopamine reuptake inhibitor.
[0138] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
dopamine reuptake inhibitor, wherein said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0139] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0140] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0141] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0142] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0143] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
dopamine reuptake inhibitor; and at least one pharmaceutically
acceptable carrier.
[0144] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
dopamine reuptake inhibitor, wherein said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0145] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0146] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0147] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0148] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0149] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sleep abnormality is difficulty
falling asleep, difficulty staying asleep, or waking up too
early.
[0150] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a dopamine reuptake
inhibitor.
[0151] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a dopamine reuptake inhibitor,
wherein said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine, desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0152] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0153] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0154] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0155] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0156] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of a dopamine reuptake inhibitor;
and at least one pharmaceutically acceptable carrier.
[0157] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of a dopamine reuptake inhibitor,
wherein said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine, desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0158] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0159] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0160] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0161] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0162] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is transient
insomnia
[0163] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is short-term
insomnia.
[0164] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is chronic
insomnia
[0165] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
dopamine reuptake inhibitor.
[0166] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
dopamine reuptake inhibitor, wherein said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0167] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0168] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0169] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0170] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0171] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
dopamine reuptake inhibitor; and at least one pharmaceutically
acceptable carrier.
[0172] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
dopamine reuptake inhibitor, wherein said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
desmethylvenlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0173] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or GBR-12935, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0174] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0175] In certain embodiments, the present invention relates to the
aforementioned method, wherein said dopamine reuptake inhibitor is
venlafaxine, desmethylvenlafaxine, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them.
[0176] In certain embodiments, the present invention relates to the
aforementioned method, wherein said desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0177] In certain embodiments, the present invention relates to the
aforementioned method, wherein said depression is a major
depressive disorder.
[0178] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a 5-HT.sub.2A modulator.
[0179] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein the 5-HT.sub.2A
modulator is a 5-HT.sub.2A antagonist.
[0180] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein the 5-HT.sub.2A
modulator is a 5-HT.sub.2A inverse agonist.
[0181] Another aspect of the present invention relates to a
pharmaceutical composition comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a 5-HT.sub.2A modulator, wherein said 5
HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, or azacyclic compounds D,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal of any one of them.
[0182] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine
compounds A, or phenylindole compounds A, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co crystal of
any one of them.
[0183] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0184] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator, wherein said 5-HT.sub.2A modulator is piperidinyl
compounds B, spiroazacyclic compounds C, or azacyclic compounds D,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal of any one of them.
[0185] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a 5-HT.sub.2A modulator; and at
least one pharmaceutically acceptable carrier.
[0186] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein the 5-HT.sub.2A
modulator is a 5-HT.sub.2A antagonist.
[0187] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein the 5-HT.sub.2A
modulator is a 5-HT.sub.2A inverse agonist.
[0188] Another aspect of the present invention relates to a
pharmaceutical composition consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; a 5-HT.sub.2A modulator, wherein
said 5 HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992,
fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, or azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and at
least one pharmaceutically acceptable carrier.
[0189] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine
compounds A, or phenylindole compounds A, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0190] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, or fananserin, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0191] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator, wherein said 5 HT2A modulator is piperidinyl compounds
B, spiroazacyclic compounds C, or azacyclic compounds D, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0192] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
5-HT.sub.2A modulator.
[0193] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0194] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0195] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
5-HT.sub.2A modulator, wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0196] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0197] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0198] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0199] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
5-HT.sub.2A modulator; and at least one pharmaceutically acceptable
carrier.
[0200] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0201] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0202] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
5-HT.sub.2A modulator, wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0203] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0204] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0205] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0206] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sleep abnormality is difficulty
falling asleep, difficulty staying asleep, or waking up too
early.
[0207] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a 5-HT.sub.2A modulator.
[0208] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0209] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0210] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof, and a
therapeutically effective amount of a 5-HT.sub.2A modulator,
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0211] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0212] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0213] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0214] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of a 5-HT.sub.2A modulator; and at
least one pharmaceutically acceptable carrier.
[0215] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0216] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0217] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of a 5-HT.sub.2A modulator,
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and at
least one pharmaceutically acceptable carrier.
[0218] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0219] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0220] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0221] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is transient
insomnia
[0222] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is short-term
insomnia.
[0223] In certain embodiments, the present invention relates to the
aforementioned method, wherein said insomnia is chronic
insomnia
[0224] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
5-HT.sub.2A modulator.
[0225] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0226] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0227] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a therapeutically effective amount of a
5-HT.sub.2A modulator, wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0228] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0229] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0230] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0231] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
5-HT.sub.2A modulator; and at least one pharmaceutically acceptable
carrier.
[0232] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A antagonist.
[0233] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is a
5-HT.sub.2A inverse agonist.
[0234] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
5-HT.sub.2A modulator, wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and at least one pharmaceutically acceptable
carrier.
[0235] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A, or
phenylindole compounds A, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0236] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, or fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0237] In certain embodiments, the present invention relates to the
aforementioned method, wherein the 5-HT.sub.2A modulator is
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0238] In certain embodiments, the present invention relates to the
aforementioned method, wherein said depression is a major
depressive disorder.
[0239] Another aspect of the present invention relates to a method
for augmentation of antidepressant therapy in a patient comprising
administering to the patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0240] Another aspect of the present invention relates to a method
for eliciting a dose sparing effect in a patient undergoing
treatment with an antidepressant, comprising administering to the
patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0241] Another aspect of the present invention relates to a method
for reducing depression relapse in a patient who received
antidepressant treatment, comprising administering to the patient
in need thereof a therapeutically effective amount of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof.
[0242] In certain embodiments, the present invention relates to the
aforementioned method, wherein the eszopiclone is administered
chronically or long-term.
[0243] Another aspect of the present invention relates to a method
for improving the tolerability of antidepressant therapy in a
patient suffering from depression, comprising administering to the
patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0244] In certain embodiments, the present invention relates to the
aforementioned method, wherein the antidepressant is citalopram,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, clominpramine, femoxetine, indapline,
alaprolclate, cericlamine, ifoxetine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0245] In certain embodiments, the present invention relates to the
aforementioned method, wherein the antidepressant is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S) hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0246] In certain embodiments, the present invention relates to the
aforementioned method, wherein the antidepressant is bupropion,
venlafaxine, or desmethylvenlafaxine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0247] In certain embodiments, the present invention relates to the
aforementioned method, wherein the desmethylvenlafaxine is racemic
desmethylvenlafaxine, (+)-desmethylvenlafaxine, or
(-)-desmethylvenlafaxine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0248] In certain embodiments, the present invention relates to the
aforementioned method, wherein the antidepressant is a dopamine
reuptake inhibitor or an atypical antidepressant.
[0249] One aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and an
antidepressant. In certain embodiments, the antidepressant is a
serotonin reuptake inhibitor, including without limitation
selective serotonin reuptake inhibitors, a norepinephrine reuptake
inhibitor, including without limitation a selective norepinephrine
reuptake inhibitor, a dopamine reuptake inhibitor, or an atypical
antidepressant. In other embodiments, the antidepressant is
citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,
milnacipran, paroxetine, sertraline, clominpramine, femoxetine,
indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0250] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
serotonin reuptake inhibitor; wherein said sedative agent is a
compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0251] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0252] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0253] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0254] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
serotonin reuptake inhibitor; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0255] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said sedative
agent is racemic zopiclone, eszopiclone, indiplon, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0256] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said sedative
agent is eszopiclone, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof.
[0257] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said serotonin
reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran,
paroxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0258] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
serotonin reuptake inhibitor; wherein said sedative agent is
racemic zopiclone, eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them; and said serotonin reuptake inhibitor is fluoxetine,
paroxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of either of them.
[0259] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
serotonin reuptake inhibitor; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said serotonin
reuptake inhibitor is fluoxetine or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0260] Another aspect of the present invention relates to a
pharmaceutical composition, comprising eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof and fluoxetine hydrochloride or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0261] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
norepinephrine reuptake inhibitor; wherein said sedative agent is a
compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0262] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0263] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0264] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0265] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
norepinephrine reuptake inhibitor; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0266] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
norepinephrine reuptake inhibitor; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0267] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is desipramine, reboxetine,
oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0268] Another aspect of the present invention relates to a
pharmaceutical composition, comprising eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and a norepinephrine reuptake inhibitor;
wherein said norepinephrine reuptake inhibitor is desipramine,
reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0269] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
5-HT.sub.2 receptor modulator. In certain embodiments, the
5-HT.sub.2 receptor modulator is a 5-HT.sub.2A receptor antagonist
or a 5-HT.sub.2A inverse agonist.
[0270] In one embodiment, the pharmaceutical composition comprises
a sedative agent and a 5-HT.sub.2 receptor modulator, wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said 5-HT.sub.2 receptor modulator
is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds
A, phenylindole compounds A, piperidinyl compounds B,
spiroazacyclic compounds C, azacyclic compounds D, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0271] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0272] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0273] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0274] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
5-HT.sub.2A modulator; wherein said sedative agent is racemic
zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them; and said 5-HT.sub.2A modulator is
MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0275] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
5-HT.sub.2A modulator; wherein said sedative agent is eszopiclone
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof; and said 5-HT.sub.2A modulator is
MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0276] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0277] Another aspect of the present invention relates to a
pharmaceutical composition, comprising eszopiclone and a
5-HT.sub.2A modulator; wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0278] Another aspect of the present invention relates to a
pharmaceutical composition, comprising eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a 5-HT.sub.2A inverse agonist. In certain
embodiments, the 5-HT.sub.2A inverse agonist is piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them
[0279] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
dopamine reuptake inhibitor; wherein said sedative agent is a
compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0280] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0281] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0282] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0283] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
dopamine reuptake inhibitor; wherein said sedative agent is racemic
zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them; and said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0284] Another aspect of the present invention relates to a
pharmaceutical composition, comprising a sedative agent and a
dopamine reuptake inhibitor; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said dopamine
reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, 2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0285] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, GBR-12935, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
either of them.
[0286] Another aspect of the present invention relates to a
pharmaceutical composition, comprising eszopiclone and bupropion,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal of either of them.
[0287] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0288] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0289] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0290] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0291] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0292] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said sedative
agent is racemic zopiclone, eszopiclone, indiplon, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0293] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said serotonin
reuptake inhibitor is fluoxetine, fluvoxamine, milnacipran,
paroxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0294] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them; and said serotonin reuptake inhibitor is fluoxetine,
paroxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of either of them.
[0295] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said serotonin
reuptake inhibitor is fluoxetine or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0296] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of eszopiclone
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof, fluoxetine hydrochloride or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof, and at least one pharmaceutically acceptable
carrier.
[0297] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0298] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0299] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0300] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0301] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0302] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0303] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said
norepinephrine reuptake inhibitor is desipramine, reboxetine,
oxaprotiline, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0304] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of eszopiclone
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal thereof, a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said norepinephrine reuptake inhibitor is desipramine,
reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0305] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a 5-HT.sub.2A modulator, and at least one pharmaceutically
acceptable carrier; wherein said sedative agent is a compound that
modulates the activity of a GABA receptor and has a K.sub.i less
than about 300 nM in a GABA-receptor binding assay; and said
5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them.
[0306] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0307] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0308] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0309] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a 5-HT.sub.2A modulator, and at least one pharmaceutically
acceptable carrier; wherein said sedative agent is racemic
zopiclone, eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them; and said 5-HT.sub.2A modulator is
MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0310] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a 5-HT.sub.2A modulator, and at least one pharmaceutically
acceptable carrier; wherein said sedative agent is eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and said 5-HT.sub.2A modulator is MDL 100907,
SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0311] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0312] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of eszopiclone,
or a pharmaceutically acceptable salt, solvate, clathrate,
polymorph, or co-crystal of any one of them, a 5-HT.sub.2A
modulator, and at least one pharmaceutically acceptable carrier;
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0313] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0314] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 150 nM.
[0315] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 75 nM.
[0316] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said K.sub.i is
less than about 30 nM.
[0317] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, 2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0318] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of a sedative
agent, a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said dopamine
reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, 2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0319] In certain embodiments, the present invention relates to the
aforementioned pharmaceutical composition, wherein said dopamine
reuptake inhibitor is bupropion, GBR-12935, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
either of them.
[0320] Another aspect of the present invention relates to a
pharmaceutical composition, consisting essentially of eszopiclone
and bupropion, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of either of them, and at least
one pharmaceutically acceptable carrier.
[0321] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative and a
therapeutically effective amount of an antidepressant; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said antidepressant is a serotonin
reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT.sub.2A
modulator, or dopamine reuptake inhibitor.
[0322] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sedative is racemic zopiclone,
(S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, or hydrate of any one of
them; and said antidepressant is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D,
amineptine, bupropion, GBR-12935, venlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, or hydrate of any one of them.
[0323] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a serotonin reuptake
inhibitor; wherein said sedative agent is a compound that modulates
the activity of a GABA receptor and has a K.sub.i less than about
300 nM in a GABA-receptor binding assay; and said serotonin
reuptake inhibitor is citalopram, duloxetine, escitalopram,
fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline,
clominpramine, femoxetine, indapline, alaprolclate, cericlamine,
ifoxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0324] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a serotonin reuptake
inhibitor; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and said serotonin reuptake
inhibitor is citalopram, duloxetine, escitalopram, fluoxetine,
fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine,
femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0325] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a serotonin reuptake
inhibitor; wherein said sedative agent is racemic zopiclone,
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of either of them; and said
serotonin reuptake inhibitor is fluoxetine, paroxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them.
[0326] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a serotonin reuptake
inhibitor; wherein said sedative agent is eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and said serotonin reuptake inhibitor is
fluoxetine or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0327] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
fluoxetine hydrochloride or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof.
[0328] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is a compound that modulates
the activity of a GABA receptor and has a K.sub.i less than about
300 nM in a GABA-receptor binding assay; and said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0329] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and said norepinephrine reuptake
inhibitor is desipramine, maprotiline, lofepramine, reboxetine,
oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0330] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0331] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal; and a therapeutically effective amount of a
norepinephrine reuptake inhibitor; wherein said norepinephrine
reuptake inhibitor is desipramine, reboxetine, oxaprotiline,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0332] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said 5-HT.sub.2A modulator
is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds
A, phenylindole compounds A, piperidinyl compounds B,
spiroazacyclic compounds C, azacyclic compounds D, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0333] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said 5-HT.sub.2A modulator is MDL 100907, SR
46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole
compounds A, piperidinyl compounds B, spiroazacyclic compounds C,
azacyclic compounds D, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0334] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B,
YM 992, fananserin, oxazolidine compounds A, phenylindole compounds
A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0335] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone and a
therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0336] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a dopamine reuptake
inhibitor; wherein said sedative agent is a compound that modulates
the activity of a GABA receptor and has a K.sub.i less than about
300 nM in a GABA-receptor binding assay; and said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0337] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a dopamine reuptake
inhibitor; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and said dopamine reuptake inhibitor
is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0338] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent and
a therapeutically effective amount of a dopamine reuptake
inhibitor; wherein said sedative agent is eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and said dopamine reuptake inhibitor is
amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0339] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
bupropion or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0340] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said serotonin reuptake inhibitor
is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,
milnacipran, paroxetine, sertraline, clominpramine, femoxetine,
indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0341] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said serotonin reuptake inhibitor is citalopram,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, clominpramine, femoxetine, indapline,
alaprolclate, cericlamine, ifoxetine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0342] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them; and said serotonin reuptake inhibitor
is fluoxetine, paroxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0343] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said serotonin reuptake inhibitor is fluoxetine or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0344] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of
fluoxetine hydrochloride or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof; and at least
one pharmaceutically acceptable carrier.
[0345] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0346] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0347] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0348] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
norepinephrine reuptake inhibitor; and at least one
pharmaceutically acceptable carrier; wherein said norepinephrine
reuptake inhibitor is desipramine, reboxetine, oxaprotiline,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0349] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0350] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0351] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992,
fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0352] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; a therapeutically effective amount
of a 5-HT.sub.2A modulator; and at least one pharmaceutically
acceptable carrier; wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0353] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said dopamine reuptake inhibitor
is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0354] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said dopamine reuptake inhibitor is amineptine,
bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0355] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0356] Another aspect of the present invention relates to a method
of treating a patient suffering from a sleep abnormality,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
bupropion or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof, and at least one
pharmaceutically acceptable carrier.
[0357] In certain embodiments, the present invention relates to the
aforementioned methods, wherein said sleep disturbance is
difficulty falling asleep, difficulty staying asleep, or waking up
too early.
[0358] Another aspect of the present invention relates generally to
a method of treating a patient suffering from insomnia, comprising
the step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative and a
therapeutically effective amount of an antidepressant; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said antidepressant is a serotonin
reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT.sub.2A
modulator, or dopamine reuptake inhibitor.
[0359] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sedative is racemic zopiclone,
(S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, or hydrate of any one of
them; and said antidepressant is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D,
amineptine, bupropion, GBR-12935, venlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, or hydrate of any one of them.
[0360] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a serotonin reuptake inhibitor; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said serotonin reuptake inhibitor
is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,
milnacipran, paroxetine, sertraline, clominpramine, femoxetine,
indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0361] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a serotonin reuptake inhibitor; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said serotonin reuptake inhibitor is citalopram,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, clominpramine, femoxetine, indapline,
alaprolclate, cericlamine, ifoxetine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0362] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a serotonin reuptake inhibitor; wherein said
sedative agent is racemic zopiclone, eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them; and said serotonin reuptake inhibitor
is fluoxetine, paroxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0363] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a serotonin reuptake inhibitor; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said serotonin reuptake inhibitor is fluoxetine or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0364] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and a
therapeutically effective amount of fluoxetine hydrochloride or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0365] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a norepinephrine reuptake inhibitor; wherein
said sedative agent is a compound that modulates the activity of a
GABA receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said norepinephrine reuptake
inhibitor is desipramine, maprotiline, lofepramine, reboxetine,
oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0366] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a norepinephrine reuptake inhibitor; wherein
said sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0367] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a norepinephrine reuptake inhibitor; wherein
said sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0368] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal; and a
therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said norepinephrine reuptake inhibitor is
desipramine, reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0369] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a 5-HT.sub.2A modulator; wherein said sedative
agent is a compound that modulates the activity of a GABA receptor
and has a K.sub.i less than about 300 nM in a GABA-receptor binding
assay; and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0370] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a 5-HT.sub.2A modulator; wherein said sedative
agent is racemic zopiclone, eszopiclone, indiplon, zolpidem,
zaleplon, gaboxadol, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of them;
and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992,
fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0371] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a 5-HT.sub.2A modulator; wherein said sedative
agent is eszopiclone or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof; and said
5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them.
[0372] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone and a therapeutically effective
amount of a 5-HT.sub.2A modulator; wherein said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0373] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a dopamine reuptake inhibitor; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said dopamine reuptake inhibitor
is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0374] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a dopamine reuptake inhibitor; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said dopamine reuptake inhibitor is amineptine,
bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0375] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent and a therapeutically
effective amount of a dopamine reuptake inhibitor; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0376] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and a
therapeutically effective amount of bupropion or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof.
[0377] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0378] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
serotonin reuptake inhibitor is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0379] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of either of
them; and said serotonin reuptake inhibitor is fluoxetine,
paroxetine, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of either of them.
[0380] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a serotonin reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said serotonin
reuptake inhibitor is fluoxetine or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof.
[0381] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of fluoxetine hydrochloride or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and at least one pharmaceutically acceptable
carrier.
[0382] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0383] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0384] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a norepinephrine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said
norepinephrine reuptake inhibitor is desipramine, maprotiline,
lofepramine, reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0385] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; a
therapeutically effective amount of a norepinephrine reuptake
inhibitor; and at least one pharmaceutically acceptable carrier;
wherein said norepinephrine reuptake inhibitor is desipramine,
reboxetine, oxaprotiline, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0386] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a 5-HT.sub.2A modulator, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992,
fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0387] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a 5-HT.sub.2A modulator, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D, or
a pharmaceutically acceptable salt, solvate, clathrate, polymorph,
or co-crystal of any one of them.
[0388] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a 5-HT.sub.2A modulator, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said 5-HT.sub.2A
modulator is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine
compounds A, phenylindole compounds A, piperidinyl compounds B,
spiroazacyclic compounds C, azacyclic compounds D, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0389] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; a therapeutically effective amount of a 5-HT.sub.2A
modulator; and at least one pharmaceutically acceptable carrier;
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0390] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
a compound that modulates the activity of a GABA receptor and has a
K.sub.i less than about 300 nM in a GABA-receptor binding assay;
and said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0391] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
racemic zopiclone, eszopiclone, indiplon, zolpidem, zaleplon,
gaboxadol, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them; and said
dopamine reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, 2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0392] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of a sedative agent, a therapeutically effective
amount of a dopamine reuptake inhibitor, and at least one
pharmaceutically acceptable carrier; wherein said sedative agent is
eszopiclone or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof; and said dopamine
reuptake inhibitor is amineptine, bupropion, GBR-12935,
venlafaxine, 2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0393] Another aspect of the present invention relates to a method
of treating a patient suffering from insomnia, comprising the step
of co-administering to a patient in need thereof a therapeutically
effective amount of eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and a
therapeutically effective amount of bupropion or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof, and at least one pharmaceutically acceptable carrier.
[0394] In certain embodiments, the present invention relates to the
aforementioned methods, wherein said insomnia is transient
insomnia.
[0395] In certain embodiments, the present invention relates to the
aforementioned methods, wherein said insomnia is short-term
insomnia.
[0396] In certain embodiments, the present invention relates to the
aforementioned methods, wherein said insomnia is chronic
insomnia
[0397] Another aspect of the present invention relates generally to
a method of treating a patient suffering from depression,
comprising the step of co-administering to a patient in need
thereof a therapeutically effective amount of a sedative and a
therapeutically effective amount of an antidepressant; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said antidepressant is a serotonin
reuptake inhibitor, norepinephrine reuptake inhibitor, 5HT.sub.2A
modulator, or dopamine reuptake inhibitor.
[0398] In certain embodiments, the present invention relates to the
aforementioned method, wherein said sedative is racemic zopiclone,
(S)-zopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, or hydrate of any one of
them; and said antidepressant is citalopram, duloxetine,
escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine,
sertraline, clominpramine, femoxetine, indapline, alaprolclate,
cericlamine, ifoxetine, desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, MDL 100907, SR 46349B, YM 992, fananserin,
oxazolidine compounds A, phenylindole compounds A, piperidinyl
compounds B, spiroazacyclic compounds C, azacyclic compounds D,
amineptine, bupropion, GBR-12935, venlafaxine, or
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, or hydrate of any one of them.
[0399] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a serotonin reuptake inhibitor;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said serotonin reuptake
inhibitor is citalopram, duloxetine, escitalopram, fluoxetine,
fluvoxamine, milnacipran, paroxetine, sertraline, clominpramine,
femoxetine, indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0400] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a serotonin reuptake inhibitor;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said serotonin reuptake inhibitor is
citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,
milnacipran, paroxetine, sertraline, clominpramine, femoxetine,
indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0401] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a serotonin reuptake inhibitor;
wherein said sedative agent is racemic zopiclone, eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them; and said serotonin reuptake inhibitor
is fluoxetine, paroxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0402] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a serotonin reuptake inhibitor;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said serotonin reuptake inhibitor is fluoxetine or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0403] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
fluoxetine hydrochloride or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof.
[0404] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is a compound that modulates
the activity of a GABA receptor and has a K.sub.i less than about
300 nM in a GABA-receptor binding assay; and said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0405] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; and said norepinephrine reuptake
inhibitor is desipramine, maprotiline, lofepramine, reboxetine,
oxaprotiline, fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0406] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a norepinephrine reuptake
inhibitor; wherein said sedative agent is eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0407] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal; and a therapeutically effective amount of a
norepinephrine reuptake inhibitor; wherein said norepinephrine
reuptake inhibitor is desipramine, reboxetine, oxaprotiline,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0408] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said 5-HT.sub.2A modulator
is MDL 100907, SR 46349B, YM 992, fananserin, oxazolidine compounds
A, phenylindole compounds A, piperidinyl compounds B,
spiroazacyclic compounds C, azacyclic compounds D, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0409] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said 5-HT.sub.2A modulator is MDL 100907, SR
46349B, YM 992, fananserin, oxazolidine compounds A, phenylindole
compounds A, piperidinyl compounds B, spiroazacyclic compounds C,
azacyclic compounds D, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0410] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B,
YM 992, fananserin, oxazolidine compounds A, phenylindole compounds
A, piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0411] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone and a
therapeutically effective amount of a 5-HT.sub.2A modulator;
wherein said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0412] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a dopamine reuptake inhibitor;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said dopamine reuptake
inhibitor is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0413] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a dopamine reuptake inhibitor;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said dopamine reuptake inhibitor is
amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0414] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent and a
therapeutically effective amount of a dopamine reuptake inhibitor;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said dopamine reuptake inhibitor is amineptine,
bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0415] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
bupropion or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0416] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said serotonin reuptake inhibitor
is citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine,
milnacipran, paroxetine, sertraline, clominpramine, femoxetine,
indapline, alaprolclate, cericlamine, ifoxetine, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0417] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said serotonin reuptake inhibitor is citalopram,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, clominpramine, femoxetine, indapline,
alaprolclate, cericlamine, ifoxetine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0418] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of either of them; and said serotonin reuptake inhibitor
is fluoxetine, paroxetine, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of either of them.
[0419] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a serotonin reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said serotonin reuptake inhibitor is fluoxetine or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0420] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of
fluoxetine hydrochloride or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal thereof; and at least
one pharmaceutically acceptable carrier.
[0421] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is a compound that modulates the
activity of a GABA receptor and has a K.sub.i less than about 300
nM in a GABA-receptor binding assay; and said norepinephrine
reuptake inhibitor is desipramine, maprotiline, lofepramine,
reboxetine, oxaprotiline, fezolamine, tomoxetine,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0422] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is racemic zopiclone, eszopiclone,
indiplon, zolpidem, zaleplon, gaboxadol, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them; and said norepinephrine reuptake inhibitor is
desipramine, maprotiline, lofepramine, reboxetine, oxaprotiline,
fezolamine, tomoxetine, (S,S)-hydroxybupropion, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0423] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a norepinephrine reuptake
inhibitor, and at least one pharmaceutically acceptable carrier;
wherein said sedative agent is eszopiclone or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal
thereof; and said norepinephrine reuptake inhibitor is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0424] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; a therapeutically effective amount of a
norepinephrine reuptake inhibitor; and at least one
pharmaceutically acceptable carrier; wherein said norepinephrine
reuptake inhibitor is desipramine, reboxetine, oxaprotiline,
(S,S)-hydroxybupropion, or a pharmaceutically acceptable salt,
solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0425] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, oxazolidine compounds A,
phenylindole compounds A, piperidinyl compounds B, spiroazacyclic
compounds C, azacyclic compounds D, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0426] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM
992, fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0427] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a 5-HT.sub.2A modulator, and at
least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said 5-HT.sub.2A modulator is MDL 100907, SR 46349B, YM 992,
fananserin, oxazolidine compounds A, phenylindole compounds A,
piperidinyl compounds B, spiroazacyclic compounds C, azacyclic
compounds D, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal of any one of them.
[0428] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them; a therapeutically effective amount
of a 5-HT.sub.2A modulator; and at least one pharmaceutically
acceptable carrier; wherein said 5-HT.sub.2A modulator is MDL
100907, SR 46349B, YM 992, fananserin, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0429] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay; and said dopamine reuptake inhibitor
is amineptine, bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0430] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them; and said dopamine reuptake inhibitor is amineptine,
bupropion, GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0431] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of a sedative agent, a
therapeutically effective amount of a dopamine reuptake inhibitor,
and at least one pharmaceutically acceptable carrier; wherein said
sedative agent is eszopiclone or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal thereof; and
said dopamine reuptake inhibitor is amineptine, bupropion,
GBR-12935, venlafaxine,
2.beta.-propanoyl-3.beta.-(4-tolyl)-tropane, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0432] Another aspect of the present invention relates to a method
of treating a patient suffering from depression, comprising the
step of co-administering to a patient in need thereof a
therapeutically effective amount of eszopiclone or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof; and a therapeutically effective amount of
bupropion or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof, and at least one
pharmaceutically acceptable carrier.
[0433] Another aspect of the present invention relates to a method
of augmentation of antidepressant therapy in a patient, comprising
the step of administering to a patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of a
sedative agent; wherein said sedative agent is a compound that
modulates the activity of a GABA receptor and has a K.sub.i less
than about 300 nM in a GABA-receptor binding assay.
[0434] Another aspect of the present invention relates to a method
of augmentation of antidepressant therapy in a patient, comprising
the step of administering to a patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of a
sedative agent; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0435] Another aspect of the present invention relates to a method
for augmentation of antidepressant therapy in a patient comprising
administering to the patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of
eszopiclone, or a pharmaceutically acceptable salt, solvate,
clathrate, polymorph, or co-crystal thereof.
[0436] Another aspect of the present invention relates to a method
for eliciting a dose sparing effect in a patient undergoing
treatment with an antidepressant, comprising the step of
administering to a patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of a
sedative agent; wherein said sedative agent is a compound that
modulates the activity of a GABA receptor and has a K.sub.i less
than about 300 nM in a GABA-receptor binding assay.
[0437] Another aspect of the present invention relates to a method
for eliciting a dose sparing effect in a patient undergoing
treatment with an antidepressant, comprising the step of
administering to a patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of a
sedative agent;
[0438] wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0439] Another aspect of the present invention relates to a method
for eliciting a dose sparing effect in a patient undergoing
treatment with an antidepressant, comprising administering to the
patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0440] Another aspect of the present invention relates to a method
for reducing depression relapse in a patient who received
antidepressant treatment, comprising the step of administering to a
patient in need thereof, receiving antidepressant treatment, a
therapeutically effective amount of a sedative agent; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay.
[0441] Another aspect of the present invention relates to a method
for reducing depression relapse in a patient who received
antidepressant treatment, comprising the step of administering to a
patient in need thereof, receiving antidepressant treatment, a
therapeutically effective amount of a sedative agent; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0442] Another aspect of the present invention relates to a method
for reducing depression relapse in a patient who received
antidepressant treatment, comprising administering to the patient
in need thereof receiving antidepressant treatment, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0443] In certain embodiments, the present invention relates to the
aforementioned method, wherein the eszopiclone is administered
chronically or long-term.
[0444] Another aspect of the present invention relates to a method
for improving the efficacy of antidepressant therapy in a patient
suffering from depression, comprising the step of administering to
a patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of a sedative agent; wherein said
sedative agent is a compound that modulates the activity of a GABA
receptor and has a K.sub.i less than about 300 nM in a
GABA-receptor binding assay.
[0445] Another aspect of the present invention relates to a method
for improving the efficacy of antidepressant therapy in a patient
suffering from depression, comprising the step of administering to
a patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of a sedative agent; wherein said
sedative agent is racemic zopiclone, eszopiclone, indiplon,
zolpidem, zaleplon, gaboxadol, or a pharmaceutically acceptable
salt, solvate, clathrate, polymorph, or co-crystal of any one of
them.
[0446] Another aspect of the present invention relates to a method
for improving the tolerability of antidepressant therapy in a
patient suffering from depression, comprising administering to the
patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0447] Another aspect of the present invention relates to a method
for improving the tolerability of antidepressant therapy in a
patient suffering from depression, comprising the step of
administering to a patient in need thereof, undergoing
antidepressant therapy, a therapeutically effective amount of a
sedative agent; wherein said sedative agent is racemic zopiclone,
eszopiclone, indiplon, zolpidem, zaleplon, gaboxadol, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal of any one of them.
[0448] Another aspect of the present invention relates to a method
for improving the tolerability of antidepressant therapy in a
patient suffering from depression, comprising administering to the
patient in need thereof, undergoing antidepressant therapy, a
therapeutically effective amount of eszopiclone, or a
pharmaceutically acceptable salt, solvate, clathrate, polymorph, or
co-crystal thereof.
[0449] In certain embodiments, the present invention relates to the
aforementioned methods, wherein the antidepressant is citalopram,
duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran,
paroxetine, sertraline, clominpramine, femoxetine, indapline,
alaprolclate, cericlamine, ifoxetine, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0450] In certain embodiments, the present invention relates to the
aforementioned methods, wherein the antidepressant is desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, (S,S)-hydroxybupropion, or a pharmaceutically
acceptable salt, solvate, clathrate, polymorph, or co-crystal of
any one of them.
[0451] In certain embodiments, the present invention relates to the
aforementioned methods, wherein the antidepressant is a dopamine
reuptake inhibitor or an atypical antidepressant.
Immediate/Sustained Release Combination Therapy Dosage Forms
[0452] The combination therapy may be formulated in an immediate
release dosage form or a sustained release dosage form. In certain
embodiments, the present invention relates to immediate release
dosage forms of the first and second therapeutic agents. An
immediate release dosage form may be formulated as a tablet or
multiparticulate which may be encapsulated. Other immediate release
dosage forms known in the art can be employed. In certain
embodiments, the combination of therapeutic agents may be
formulated to provide for an increased duration (sustained release)
of therapeutic action. These formulations, at comparable daily
dosages of conventional immediate release drug, are often
associated with a lower incidence or severity of adverse drug
reactions; and they can also be administered at a lower daily dose
than conventional oral medication while maintaining therapeutic
activity.
[0453] In certain embodiments, the combination therapy can be
formulated to delivery the therapeutic agents at the same time or
at separate times. In certain embodiments, the first and second
therapeutic agents are administered via an oral solid dosage form
that includes a sustained release carrier causing the sustained
release of the first therapeutic agent, or both the first
therapeutic agent and the second therapeutic agent when the dosage
form contacts gastrointestinal fluid. The sustained release dosage
form may comprise a plurality of substrates which include the
drugs. The substrates may comprise matrix spheroids or may comprise
inert pharmaceutically acceptable beads which are coated with the
drugs. The coated beads are then preferably overcoated with a
sustained release coating comprising the sustained release carrier.
The matrix spheroid may include the sustained release carrier in
the matrix itself; or the matrix may comprise a normal release
matrix containing the drugs, the matrix having a coating applied
thereon which comprises the sustained release carrier. In other
embodiments, the oral solid dosage form comprises a tablet core
containing the drugs within a normal release matrix, with the
tablet core being coated with a sustained release coating
comprising the sustained release carrier. In further embodiments,
the tablet contains the drugs within a sustained release matrix
comprising the sustained release carrier. In additional
embodiments, the tablet contains the first therapeutic agent within
a sustained release matrix and the second therapeutic agent coated
into the tablet as an immediate release layer.
[0454] The term "sustained release" is defined for purposes of the
present invention as the release of the therapeutic agent from the
formulation at such a rate that blood (e.g., plasma) concentrations
(levels) are maintained within the therapeutic range (above the
minimum effective analgesic concentration or "MEAL") but below
toxic levels over a period of time of about 12 hours or longer.
[0455] The first and second therapeutic agents can be formulated as
a controlled or sustained release oral formulation in any suitable
tablet, coated tablet or multiparticulate formulation known to
those skilled in the art. The sustained release dosage form may
optionally include a sustained released carrier which is
incorporated into a matrix along with the active agents, or which
is applied as a sustained release coating.
[0456] The sustained release dosage form may include the first
therapeutic agent in sustained release form and second therapeutic
agent in the sustained release form or in immediate release form.
The first therapeutic agent may be incorporated into the sustained
release matrix along with the second therapeutic agent;
incorporated into the sustained release coating; incorporated as a
separated sustained release layer or immediate release layer; or
may be incorporated as a powder, granulation, etc., in a gelatin
capsule with the substrates of the present invention.
Alternatively, the sustained release dosage form may have the first
therapeutic agent in the sustained release form and the second
therapeutic agent in the sustained release form or immediate
release form.
[0457] An oral dosage form according to the invention may be
provided as, for example, granules, spheroids, beads, pellets
(hereinafter collectively referred to as "multiparticulates")
and/or particles. An amount of the multiparticulates which is
effective to provide the desired dose of the therapeutic agents
over time may be placed in a capsule or may be incorporated in any
other suitable oral solid form. In one certain embodiments of the
present invention, the sustained release dosage form comprises such
particles containing or comprising the active ingredient, wherein
the particles have diameter from about 0.1 mm to about 2.5 mm,
preferably from about 0.5 mm to about 2 mm.
[0458] In certain embodiments, the particles comprise normal
release matrixes containing the first therapeutic agent with the
second therapeutic agent. These particles are then coated with the
sustained release carrier in embodiments where the first
therapeutic agent is immediately released, the first therapeutic
agent may be included in separate normal release matrix particles,
or may be co-administered in a different immediate release
composition which is either enveloped within a gelatin capsule or
is administered separately. In other embodiments, the particles
comprise inert beads which are coated with the second therapeutic
agent with the first therapeutic agents. Thereafter, a coating
comprising the sustained release carrier is applied onto the beads
as an overcoat.
[0459] The particles are preferably film coated with a material
that permits release of the active agents at a sustained rate in an
aqueous medium. The film coat is chosen so as to achieve, in
combination with the other stated properties, a desired in vitro
release rate. The sustained release coating formulations of the
present invention should be capable of producing a strong,
continuous film that is smooth and elegant, capable of supporting
pigments and other coating additives, non-toxic, inert, and
tack-free.
Coatings
[0460] The dosage forms of the present invention may optionally be
coated with one or more materials suitable for the regulation of
release or for the protection of the formulation. In one
embodiment, coatings are provided to permit either pH-dependent or
pH-independent release, e.g., when exposed to gastrointestinal
fluid. A pH-dependent coating serves to release the first active
agent, second active agent, or both in the desired areas of the
gastro-intestinal (GI) tract, e.g., the stomach or small intestine,
such that an absorption profile is provided which is capable of
providing at least about twelve hours and preferably up to
twenty-four hours of therapeutic benefit to a patient. When a
pH-independent coating is desired, the coating is designed to
achieve optimal release regardless of pH-changes in the
environmental fluid, e.g., the GI tract. It is also possible to
formulate compositions which release a portion of the dose in one
desired area of the GI tract, e.g., the stomach, and release the
remainder of the dose in another area of the GI tract, e.g., the
small intestine. In certain embodiments, the first therapeutic
agent is released in one area of the GI tract and the second
therapeutic agent is released in a second area of the GI tract. In
certain embodiments, the first and second therapeutic agents are
released in nearly equal amounts at the same location in the GI
tract.
[0461] Formulations according to the invention that utilize
pH-dependent coatings to obtain formulations may also impart a
repeat-action effect whereby unprotected drug is coated over the
enteric coat and is released in the stomach, while the remainder,
being protected by the enteric coating, is released further down
the gastrointestinal tract. Coatings which are pH-dependent may be
used in accordance with the present invention include shellac,
cellulose acetate phthalate (CAP), polyvinyl acetate phthalate
(PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic
acid ester copolymers, zein, and the like. Thus, one aspect of the
present invention relates to a formulation wherein the first
therapeutic agent is coated over the enteric coat and released into
the stomach while the second therapeutic agent is protected by the
enteric coating and is released further down the GI tract.
Alternatively, one aspect of the present invention relates to a
formulation wherein the second therapeutic agent is coated over the
enteric coat and released into the stomach while the first
therapeutic agent is protected by the enteric coating and is
released further down the GI tract.
[0462] In certain preferred embodiments, the substrate (e.g.,
tablet core bead, matrix particle) containing the first therapeutic
agent (with or without the second therapeutic agent) is coated with
a hydrophobic material selected from (i) an alkylcellulose; (ii) an
acrylic polymer; or (iii) mixtures thereof. The coating may be
applied in the form of an organic or aqueous solution or
dispersion. The coating may be applied to obtain a weight gain from
about 2 to about 25% of the substrate in order to obtain a desired
sustained release profile. Alternatively, the invention relates to
instances wherein the substrate (e.g., tablet core bead, matrix
particle) containing the second therapeutic agent (with or without
the first therapeutic agent) is coated with a hydrophobic material.
Such formulations are described, e.g., in detail in U.S. Pat. Nos.
5,273,760 and 5,286,493. Other examples of sustained release
formulations and coatings which may be used in accordance with the
present invention include U.S. Pat. Nos. 5,324,351; 5,356,467, and
5,472,712.
Alkylcellulose Polymers
[0463] Cellulosic materials and polymers, including
alkylcelluloses, provide hydrophobic materials well suited for
coating the formulations according to the invention. Simply by way
of example, one preferred alkylcellulosic polymer is
ethylcellulose, although the artisan will appreciate that other
cellulose and/or alkylcellulose polymers may be readily employed,
singly or in any combination, as all or part of a hydrophobic
coating.
[0464] One commercially-available aqueous dispersion of
ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is prepared by dissolving the ethylcellulose
in a water-immiscible organic solvent and then emulsifying the same
in water in the presence of a surfactant and a stabilizer. After
homogenization to generate submicron droplets, the organic solvent
is evaporated under vacuum to form a pseudolatex. The plasticizer
is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior to using the same as a coating, it is necessary
to intimately mix the Aquacoat.RTM. with a suitable plasticizer
prior to use.
[0465] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic
acid) is prepared as a homogeneous mixture, which is then diluted
with an alkaline solution to obtain an aqueous dispersion which can
be applied directly onto substrates.
Acrylic Polymers
[0466] In other preferred embodiments of the present invention, the
hydrophobic material comprising the controlled release coating is a
pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic
acid anhydride), and glycidyl methacrylate copolymers.
[0467] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers Ammonio
methacrylate copolymers are well known in the art, and are
copolymers of acrylic and methacrylic acid esters with a low
content of quaternary ammonium groups. In order to obtain a
desirable dissolution profile, it may be necessary to incorporate
in a coating two or more ammonio methacrylate copolymers having
differing physical properties, such as different molar ratios of
the quaternary ammonium groups to the neutral (meth)acrylic
esters.
[0468] Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent coatings which may be used in accordance
with the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylate and
other neutral methacrylic esters, also known as methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit.RTM. from Rohm Tech, Inc. There are several different
types of Eudragit.RTM.. For example, Eudragit.RTM. E is an example
of a methacrylic acid copolymer which swells and dissolves in
acidic media. Eudragit.RTM. L is a methacrylic acid copolymer which
does not swell at about pH<5.7 and is soluble at about pH>6.
Eudragit.RTM. S does not swell at about pH<6.5 and is soluble at
about pH>7. Eudragit.RTM. RL and Eudragit.RTM. RS are water
swellable, and the amount of water absorbed by these polymers is
pH-dependent, however, dosage forms coated with Eudragit.RTM. RL
and RS are pH-independent.
[0469] In certain preferred embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers commercially
available from Rohm Pharma under the Tradenames Eudragit.RTM. RL30D
and Eudragit.RTM. RS30D, respectively. Eudragit.RTM. RL30D and
Eudragit.RTM. RS30D are copolymers of acrylic and methacrylic
esters with a low content of quaternary ammonium groups, the molar
ratio of ammonium groups to the remaining neutral (meth)acrylic
esters being 1:20 in Eudragit.RTM.RL30D and 1:40 in Eudragit.RTM.
RS30D. The mean molecular weight is about 150,000. The code
designations RL (high permeability) and RS (low permeability) refer
to the permeability properties of these agents. Eudragit.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids.
[0470] The Eudragit.RTM. RL/RS dispersions of the present invention
may be mixed together in any desired ratio in order to ultimately
obtain a sustained release formulation having a desirable
dissolution profile. Desirable sustained release formulations may
be obtained, for instance, from a retardant coating derived from
100% Eudragit.RTM. RL, 50% Eudragit.RTM. RL and 50% Eudragit.RTM.
RS, and 10% Eudragit.RTM. RL:Eudragit.RTM. 90% RS. Of course, one
skilled in the art will recognize that other acrylic polymers may
also be used, such as, for example, Eudragit.RTM. L.
Plasticizers
[0471] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic material, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic material will further improve the
physical properties of the sustained release coating. For example,
because ethylcellulose has a relatively high glass transition
temperature and does not form flexible films under normal coating
conditions, it is preferable to incorporate a plasticizer into an
ethylcellulose coating containing sustained release coating before
using the same as a coating material. Generally, the amount of
plasticizer included in a coating solution is based on the
concentration of the film-former, e.g., most often from about 1 to
about 50 percent by weight of the film-former. Concentration of the
plasticizer, however, can only be properly determined after careful
experimentation with the particular coating solution and method of
application.
[0472] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is an especially preferred
plasticizer for the aqueous dispersions of ethyl cellulose of the
present invention.
[0473] Examples of suitable plasticizers for the acrylic polymers
of the present invention include, but are not limited to citric
acid esters such as triethyl citrate NF XVI, tributyl citrate,
dibutyl phthalate, and possibly 1,2-propylene glycol. Other
plasticizers which have proved to be suitable for enhancing the
elasticity of the films formed from acrylic films such as
Eudragit.RTM. RL/RS lacquer solutions include polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, and triacetin.
Triethyl citrate is an especially preferred plasticizer for the
aqueous dispersions of ethyl cellulose of the present
invention.
[0474] It has further been found that the addition of a small
amount of talc reduces the tendency of the aqueous dispersion to
stick during processing, and acts as a polishing agent.
Pharmaceutical Compositions
[0475] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically-effective amount of one or more of the compounds
described above, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specially formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets, e.g.,
those targeted for buccal, sublingual, and systemic absorption,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular, intravenous or epidural injection as, for example, a
sterile solution or suspension, or sustained-release formulation;
(3) topical application, for example, as a cream, ointment, or a
controlled-release patch or spray applied to the skin; (4)
intravaginally or intrarectally, for example, as a pessary, cream
or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)
nasally.
[0476] The phrase "therapeutically-effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect in at least a
sub-population of cells in an animal at a reasonable benefit/risk
ratio applicable to any medical treatment.
[0477] 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, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0478] The phrase "pharmaceutically-acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc
stearate, or steric acid), or solvent encapsulating material,
involved in carrying or transporting the subject compound from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can
serve as pharmaceutically-acceptable carriers include: (1) sugars,
such as lactose, glucose and sucrose; (2) starches, such as corn
starch and potato starch; (3) cellulose, and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters,
polycarbonates and/or polyanhydrides; and (22) other non-toxic
compatible substances employed in pharmaceutical formulations.
[0479] As set out above, certain embodiments of the present
compounds may contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. The term "pharmaceutically-acceptable salts" in this
respect, refers to the relatively non-toxic, inorganic and organic
acid addition salts of compounds of the present invention. These
salts can be prepared in situ in the administration vehicle or the
dosage form manufacturing process, or by separately reacting a
purified compound of the invention in its free base form with a
suitable organic or inorganic acid, and isolating the salt thus
formed during subsequent purification. Representative salts include
the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts and the like. (See, for
example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19)
[0480] The pharmaceutically acceptable salts of the subject
compounds include the conventional nontoxic salts or quaternary
ammonium salts of the compounds, e.g., from non-toxic organic or
inorganic acids. For example, such conventional nontoxic salts
include those derived from inorganic acids such as hydrochloride,
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, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like.
[0481] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately reacting the purified
compound in its free acid form with a suitable base, such as the
hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary
amine Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like. (See, for example, Berge et al., supra)
[0482] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0483] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0484] Formulations of the present invention include those suitable
for oral, nasal, topical (including buccal and sublingual), rectal,
vaginal and/or parenteral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated, the particular mode of administration. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 0.1 percent to
about ninety-nine percent of active ingredient, preferably from
about 5 percent to about 70 percent, most preferably from about 10
percent to about 30 percent.
[0485] In certain embodiments, a formulation of the present
invention comprises an excipient selected from the group consisting
of cyclodextrins, celluloses, liposomes, micelle forming agents,
e.g., bile acids, and polymeric carriers, e.g., polyesters and
polyanhydrides; and a compound of the present invention. In certain
embodiments, an aforementioned formulation renders orally
bioavailable a compound of the present invention.
[0486] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0487] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0488] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules, trouches and the like), the active ingredient is mixed
with one or more pharmaceutically-acceptable carriers, such as
sodium citrate or dicalcium phosphate, and/or any of the following:
(1) fillers or extenders, such as starches, lactose, sucrose,
glucose, mannitol, and/or silicic acid; (2) binders, such as, for
example, carboxymethylcellulose, alginates, gelatin, polyvinyl
pyrrolidone, sucrose and/or acacia; (3) humectants, such as
glycerol; (4) disintegrating agents, such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; (5) solution retarding agents,
such as paraffin; (6) absorption accelerators, such as quaternary
ammonium compounds and surfactants, such as poloxamer and sodium
lauryl sulfate; (7) wetting agents, such as, for example, cetyl
alcohol, glycerol monostearate, and non-ionic surfactants; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, zinc stearate, sodium stearate,
stearic acid, and mixtures thereof; (10) coloring agents; and (11)
controlled release agents such as crospovidone or ethyl cellulose.
In the case of capsules, tablets and pills, the pharmaceutical
compositions may also comprise buffering agents. Solid compositions
of a similar type may also be employed as fillers in soft and
hard-shelled gelatin capsules using such excipients as lactose or
milk sugars, as well as high molecular weight polyethylene glycols
and the like.
[0489] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0490] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be formulated for rapid release, e.g.,
freeze-dried. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0491] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0492] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0493] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0494] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically-acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0495] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0496] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0497] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the compound in a polymer matrix
or gel.
[0498] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0499] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
sugars, alcohols, antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0500] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0501] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0502] The therapeutic agent alone or on combination with other
therapeutic agents can be employed in admixtures with conventional
excipients, i.e., pharmaceutically acceptable organic or inorganic
carrier substances suitable for oral, parenteral, nasal,
intravenous, subcutaneous, enteral, or any other suitable mode of
administration, known to the art. Suitable pharmaceutically
acceptable carriers include but are not limited to water, salt
solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols,
polyethylene glycols, gelate, carbohydrates such as lactose,
amylose or starch, magnesium stearate talc, silicic acid, viscous
paraffin, perfume oil, fatty acid monoglycerides and diglycerides,
pentaerythritol fatty acid esters, hydroxymethylcellulose,
polyvinylpyrrolidone, etc. The pharmaceutical preparations can be
sterilized and if desired mixed with auxiliary agents, e.g.,
lubricants, preservatives, stabilizers, wetting agents,
emulsifiers, salts for influencing osmotic pressure buffers,
coloring, flavoring and/or aromatic substances and the like. They
can also be combined where desired with other active agents, e.g.,
other analgesic agents. For parenteral application, particularly
suitable are oily or aqueous solutions, as well as suspensions,
emulsions, or implants, including suppositories. Ampoules are
convenient unit dosages. For oral application, particularly
suitable are tablets, dragees, liquids, drops, suppositories, or
capsules, caplets and gelcaps. The compositions intended for oral
use may be prepared according to any method known in the art and
such compositions may contain one or more agents selected from the
group consisting of inert, non-toxic pharmaceutically excipients
which are suitable for the manufacture of tablets. Such excipients
include, for example an inert diluent such as lactose; granulating
and disintegrating agents such as cornstarch; binding agents such
as starch; and lubricating agents such as magnesium stearate. The
tablets may be uncoated or they may be coated by known techniques
for elegance or to delay release of the active ingredients.
Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredient is mixed with an inert
diluent.
[0503] Aqueous suspensions contain the above-identified combination
of drugs and that mixture has one or more excipients suitable as
suspending agents, for example pharmaceutically acceptable
synthetic gums such as hydroxypropylmethylcellulose or natural
gums. Oily suspensions may be formulated by suspending the
above-identified combination of drugs in a vegetable oil or mineral
oil. The oily suspensions may contain a thickening agent such as
beeswax or cetyl alcohol. A syrup, elixir, or the like can be used
wherein a sweetened vehicle is employed. Injectable suspensions may
also be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed. It is also possible
to freeze-dry the active compounds and use the obtained lyophilized
compounds, for example, for the preparation of products for
injection.
[0504] One aspect of combination therapy pertains to a method for
providing effective therapeutic treatment in humans, comprising
administering an effective or sub-therapeutic amount of a first
therapeutic agent; and administering an effective amount of a
second therapeutic agent in an amount effective to augment the
therapeutic effect provided by said first therapeutic agent. The
second therapeutic agent can be administered before, simultaneously
with, or after administration of the first therapeutic agent, as
long as the dosing interval of the second therapeutic agent
overlaps with the dosing interval of the first therapeutic agent
(or its therapeutic effect). In other words, according to the
method of the present invention, in certain preferred embodiments
the second therapeutic agent need not be administered in the same
dosage form or even by the same route of administration as the
first therapeutic agent. Rather, the method is directed to the
surprising synergistic and/or additive benefits obtained in humans,
when therapeutically effective levels of a first therapeutic agent
have been administered to a human, and, prior to or during the
dosage interval for the second therapeutic agent or while the human
is experiencing the therapeutic effect, an effective amount of a
second therapeutic agent to augment the therapeutic effect of the
first therapeutic agent is administered. If the second therapeutic
agent is administered prior to the administration of the first
therapeutic agent, it is preferred that the dosage intervals for
the two drugs overlap, i.e., such that the therapeutic effect over
at least a portion of the dosage interval of the first therapeutic
agent is at least partly attributable to the second therapeutic
agent.
[0505] In an additional method of the invention, the surprising
synergistic and/or additive benefits obtained in the patient are
achieved when therapeutically effective levels of the second
therapeutic agent have been administered to the patient, and,
during the dosage interval for the second therapeutic agent or
while the patient is experiencing the therapeutic effect by virtue
of the administration of a second therapeutic agent, an effective
amount of a first therapeutic agent to augment the therapeutic
effect of the second therapeutic agent is administered.
[0506] Another aspect of combination therapy relates to an oral
solid dosage form comprising an therapeutically effective amount of
a first therapeutic agent together with an amount of a second
therapeutic agent or pharmaceutically acceptable salt thereof which
augments the effect of the first therapeutic agent.
[0507] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99% (more preferably, 10 to 30%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0508] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given in forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc. administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administrations are
preferred.
[0509] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticulare, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0510] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0511] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0512] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically-acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0513] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0514] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the rate and extent of absorption, the duration of the
treatment, other drugs, compounds and/or materials used in
combination with the particular compound employed, the age, sex,
weight, condition, general health and prior medical history of the
patient being treated, and like factors well known in the medical
arts.
[0515] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0516] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, oral, intravenous, intracerebroventricular and
subcutaneous doses of the compounds of this invention for a
patient, when used for the indicated analgesic effects, will range
from about 0.0001 to about 100 mg per kilogram of body weight per
day.
[0517] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. Preferred
dosing is one administration per day.
[0518] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical formulation (composition).
[0519] The compounds according to the invention may be formulated
for administration in any convenient way for use in human or
veterinary medicine, by analogy with other pharmaceuticals.
[0520] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically-effective amount of one or more of the subject
compounds, as described above, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specially formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular or intravenous injection as, for example, a sterile
solution or suspension; (3) topical application, for example, as a
cream, ointment or spray applied to the skin, lungs, or mucous
membranes; or (4) intravaginally or intrarectally, for example, as
a pessary, cream or foam; (5) sublingually or buccally; (6)
ocularly; (7) transdermally; or (8) nasally.
[0521] The term "treatment" is intended to encompass also
prophylaxis, therapy, management and cure.
The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals
Processes for Preparing Matrix-Based Beads
[0522] In order to facilitate the preparation of a solid,
controlled release, oral dosage form according to this invention,
any method of preparing a matrix formulation known to those skilled
in the art may be used. For example incorporation in the matrix may
be effected, for example, by (a) forming granules comprising at
least one water soluble hydroxyalkyl cellulose and the active
agent; (b) mixing the hydroxyalkyl cellulose containing granules
with at least one C.sub.12-C.sub.36 aliphatic alcohol; and (c)
optionally, compressing and shaping the granules. Preferably, the
granules are formed by wet granulating the hydroxyalkyl
cellulose/active agent with water. In a particularly preferred
embodiment of this process, the amount of water added during tie
wet granulation step is preferably between 1.5 and 5 times,
especially between 1.75 and 3.5 times, the dry weight of the active
agent.
[0523] In yet other alternative embodiments, a spheronizing agent,
together with the active ingredient can be spheronized to form
spheroids. Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments,
in addition to the active ingredient and spheronizing agent, the
spheroids may also contain a binder. Suitable binders, such as low
viscosity, water soluble polymers, will be well known to those
skilled in the pharmaceutical art. However, water soluble hydroxy
lower alkyl cellulose, such as hydroxypropylcellulose, are
preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethyl cellulose. In such embodiments, the sustained
release coating will generally include a hydrophobic material such
as (a) a wax, either alone or in admixture with a fatty alcohol; or
(b) shellac or zein.
Melt Extrusion Matrix
[0524] Sustained release matrices can also be prepared via
melt-granulation or melt-extrusion techniques. Generally,
melt-granulation techniques involve melting a normally solid
hydrophobic material, e.g. a wax, and incorporating a powdered drug
therein. To obtain a sustained release dosage form, it may be
necessary to incorporate an additional hydrophobic substance, e.g.
ethylcellulose or a water-insoluble acrylic polymer, into the
molten wax hydrophobic material. Examples of sustained release
formulations prepared via melt-granulation techniques are found in
U.S. Pat. No. 4,861,598.
[0525] The additional hydrophobic material may comprise one or more
water-insoluble wax-like thermoplastic substances possibly mixed
with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble wax-like
substances. In order to achieve constant release, the individual
wax-like substances in the formulation should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases. Useful water-insoluble wax-like substances
may be those with a water-solubility that is lower than about
1:5,000 (w/w).
[0526] In addition to the above ingredients, a sustained release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art. The quantities of these additional materials will be
sufficient to provide the desired effect to the desired
formulation. In addition to the above ingredients, a sustained
release matrix incorporating melt-extruded multiparticulates may
also contain suitable quantities of other materials, e.g. diluents,
lubricants, binders, granulating aids, colorants, flavorants and
glidants that are conventional in the pharmaceutical art in amounts
up to about 50% by weight of the particulate if desired.
[0527] Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate oral dosage forms are
described in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (1986).
[0528] Many of the sedative agents, antidepressants, including
without limitation, serotonin reuptake inhibitors, norepinephrine
reuptake inhibitors, and 5-HT.sub.2A modulators are chiral
compounds that can exist as a racemic mixture, a non-equal mixture
of enantiomers, or as a single enantiomer. Importantly, the
recitation of a compound that can exist as a racemic mixture, a
non-equal mixture of enantiomers, or a single enantiomer is meant
to encompass all three aforementioned forms, unless stated
otherwise. The term "enantiomeric excess" is well known in the art
and is defined for a resolution of ab 6a+b as:
ee a = ( conc . of a - conc . of b conc . of a + conc . of b )
.times. 100 ##EQU00001##
[0529] The term "enantiomeric excess" is related to the older term
"optical purity" in that both are measures of the same phenomenon.
The value of e.e. will be a number from 0 to 100, zero being
racemic and 100 being pure, single enantiomer. A compound which in
the past might have been called 98% optically pure is now more
precisely described as 96% e.e.; in other words, a 90% e.e.
reflects the presence of 95% of one enantiomer and 5% of the other
in the material in question. In instances when a specific
enantiomer is recited (e.g., eszopiclone) for use in the
compositions or methods of the present invention, this indicates
that the composition contains a significantly greater proportion of
the specified enantiomer in relation to the non-specified
enantiomer. In a preferred embodiment, compositions comprising a
specified enantiomer contain the specified enantiomer in at least
90% e.e. More preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 95% e.e.
Even more preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 98% e.e.
Most preferably, such compositions comprising a specified
enantiomer contain the specified enantiomer in at least 99%
e.e.
[0530] For example, compositions comprising eszopiclone contain the
S-enantiomer of zopiclone in at least 90% e.e. More preferably,
compositions comprising eszopiclone contain the S-enantiomer of
zopiclone in at least 95% e.e. Even more preferably, such
compositions comprising eszopiclone contain the S-enantiomer of
zopiclone in at least 98% e.e. Most preferably, such compositions
comprising eszopiclone contain the S-enantiomer of zopiclone in at
least 99% e.e.
[0531] The term "serotonin reuptake inhibitor" refers to a compound
that at least partially inhibits the reuptake of serotonin. In a
preferred embodiment, the serotonin reuptake inhibitor is a
selective serotonin reuptake inhibitor.
[0532] The term "selective serotonin reuptake inhibitor" refers to
a compound that preferentially inhibits serotonin reuptake relative
to its ability to modulate the activity of other receptors.
[0533] The term "norepinephrine reuptake inhibitor" refers to a
compound that at least partially inhibits the reuptake of
norepinephrine. In a preferred embodiment, the norepinephrine
reuptake inhibitor is a selective norepinephrine reuptake
inhibitor.
[0534] The term "selective norepinephrine reuptake inhibitor"
refers to a compound that preferentially inhibits norepinephrine
reuptake relative to its ability to modulate the activity of other
receptors.
[0535] The term "5-HT.sub.2A modulator" refers to a compound that
modulates the activity of 5-HT.sub.2A receptor. The term
"5-HT.sub.2A modulator" includes 5-HT.sub.2A antagonists and
5-HT.sub.2A inverse agonists and 5-HT.sub.2A partial agonists.
[0536] The term "antagonist" refers to a compound that binds to a
receptor site, but does not cause any physiological changes.
[0537] The terms "inverse agonist" and "negative antagonist" and
"neutral antagonist" refer to compounds that inhibit an unoccupied,
but active receptor.
[0538] The term "patient" refers to a mammal in need of a
particular treatment. In a preferred embodiment, a patient is a
primate, canine, feline, or equine. In another preferred
embodiment, a patient is a human.
[0539] The terms "co-administration" and "co-administering" refer
to both concurrent administration (administration of two or more
therapeutic agents at the same time) and time varied administration
(administration of one or more therapeutic agents at a time
different from that of the administration of an additional
therapeutic agent or agents), as long as the therapeutic agents are
present in the patient to some extent at the same time.
[0540] The term "solvate" refers to a pharmaceutically acceptable
form of a specified compound, with one or more solvent molecules,
that retains the biological effectiveness of such compound.
Examples of solvates include compounds of the invention in
combination with solvents such, for example, water (to form the
hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl
acetate, acetic acid, ethanolamine, or acetone. Also included are
formulations of solvate mixtures such as a compound of the
invention in combination with two or more solvents.
[0541] The term "screened subject" refers to any subject who signs
the Informed Consent and completes at least one study related
procedure.
[0542] The term "screen failure subject" refers to any subject who
has signed the informed consent and completed at least one study
related procedure and discontinues for any reason prior to
receiving any study medication.
[0543] The term "randomized subject" refers to any subject who
receives a randomization number.
[0544] The term "completed subject" refers to any subject who
completes all study visits.
[0545] The term "early termination subject" refers to any subject
who is assigned a randomization number but does not complete all
study visits.
[0546] The phrases "sleep disorders" or "sleep abnormality" refers
to primary insomnia; secondary insomnia; situational insomnia;
transient insomnia; short-term insomnia; chronic insomnia; acute
insomnia; prolonged latency to sleep onset; difficulty falling
asleep; difficulty staying asleep; sleep maintenance problems,
including without limitation, frequent awakenings, an increase in
time spent awake after initially falling asleep (wake time after
sleep onset, or WASO), sleep fragmentation, transient
microarousals, and unrefreshing sleep; increased time awake during
the sleep period; waking up too early; and reduced total sleep
time.
[0547] The term "depression" refers to major depression, major
depressive disorder, mild depression, moderate depression, severe
depression without psychosis, severe depression with psychosis,
dysthymia, bipolar disorder, or manic depression.
[0548] The term "antidepressant" refers to compounds used to treat
depression, including without limitation: tricyclic
antidepressents, such as clomipramine, amoxapine, nortriptyline,
moprotilene, trimipramine, imipramine, or protriptyline; monoamine
oxidase inhibitors; serotonin reuptake inhibitors, including
selective serotonin reuptake inihibitors, such as citalopram,
escitalopram, duloxetine, fluoxetine, sertraline, norsertraline,
paroxetine, mirtrazepine, fluvoxamine, milnacipran, clominpramine,
femoxetine, indapline, alaprolclate, cericlamine, or ifoxetine;
norepinephrine reuptake inhibitors, including selective
norepinephrine reuptake inhibitors, such as desipramine,
maprotiline, lofepramine, reboxetine, oxaprotiline, fezolamine,
tomoxetine, or (S,S)-hydroxybupropion; and atypical
antidepressants, such as venlafaxine, desmethylvenlafaxine,
nefazadone, or trazodone; therapeutically active isomers or
metabolites of any of the foregoing; and pharmaceutically
acceptable salts, solvates, clathrates, polymorphs, or co-crystals
of any one of the foregoing.
[0549] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
EXEMPLIFICATION
[0550] The invention now being generally described, it will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1
[0551] Depression Response to Eszopiclone in Adults With Major
Depressive Disorder (DREAMDD): A Randomized, Double-Blind,
Placebo-Controlled, Parallel-Group, 8-Week, Safety and Efficacy
Study of Eszopiclone 3 mg Compared to Placebo in Subjects with
Insomnia Related to Major Depressive Disorder Rationale &
Objectives
[0552] Insomnia often occurs simultaneously with the onset of major
depression, and may negatively impact the depressed subject's
quality of life (QoL) and functional abilities. In fact, in some
patients, insomnia is the most disabling of the depressive symptom
complex. In addition, many subjects are treated with selective
serotonin re-uptake inhibitors (SSRIs) that may accentuate insomnia
initially following treatment with these agents. This study aims to
establish that the early addition of continuous eszopiclone 3 mg at
bedtime to a standard antidepressant treatment with fluoxetine
hydrochloride (20 or 40 mg) daily in the morning for 8 weeks is
safe and provides improved sleep to depressed subjects. Beyond
direct impact on sleep efficacy measures, differences in time to
onset and amplitude of antidepressant effects, and improvements in
quality of life and functional restoration are investigated
[0553] A primary objective of the present study was to evaluate
subjective sleep efficacy during eight weeks of treatment with
eszopiclone 3 mg nightly (at bed time) in subjects with insomnia
related to major depressive disorder and treated concurrently with
fluoxetine hydrochloride. A secondary objective of the study was to
evaluate the potential for eszopiclone 3 mg to augment the
antidepressant effect of fluoxetine hydrochloride by investigating
the differences in time to onset and amplitude of antidepressant
responses over an 8-week treatment period.
Study Design
[0554] This study was a double-blind randomized,
placebo-controlled, parallel group study. The study consisted of
subjects with major depression disorder treated for ten weeks with
a common antidepressant regimen, 20-40 mg of fluoxetine
hydrochloride per day, and randomized to receive (in addition)
either eszopiclone 3 mg or placebo for eight weeks. All subjects
must satisfy DSM-IV criteria for insomnia related to major
depression.
[0555] Visit 1 (Screening):
[0556] After signing the Informed Consent, subjects were screened
with the following assessments: administration of the Hamilton
Depression Rating Scale (17 item; HAM-D-17) via interactive voice
response system, medical and sleep history, physical examination
including vital signs, clinical laboratory assessments, and
standard 12-lead electrocardiogram (ECG). Subjects returned for
Visit 2 within 5 to 14 days.
[0557] Visit 2 (Week 0; Baseline):
[0558] Subjects meeting inclusion and exclusion criteria begin a
3-7 day baseline period. At this visit safety assessments and
evaluation of adverse events (AEs) were performed. In addition,
subjects were trained on use of the interactive voice response
system (IVRS) system for collection of sleep and depression
endpoints and the frequency of assessments. Subjects completed 7
selected items of the HAM-D-17 via IVRS the morning after this
visit. During this 3-7 day period, subjects made daily IVRS calls
to evaluate sleep parameters, and depression symptoms [Daily
Telephone Assessment (DTA) and Symptoms Questionnaire (SQ; 23-item
Depression subscale)].
[0559] Visit 3 (End of Week 0; Randomization):
[0560] Subjects with a minimum of three complete IVRS assessments
during the baseline week were randomized to eszopiclone 3 mg or
matching placebo nightly (at bedtime) for eight weeks in addition
to taking open-label fluoxetine hydrochloride administered in the
morning. On the morning of this visit (prior to the visit),
subjects completed the Hamilton Depression Rating Scale (7 selected
items of the HAM-D-17) via IVRS in addition to the daily sleep
diary. At this visit, the HAM-D-17 was administered by a clinician;
safety assessments and evaluation of adverse effects (AEs) were
performed; and the study drug was dispensed. Following this visit,
subjects continued to make daily IVRS calls to evaluate sleep and
depression symptoms until the morning of Visit 4.
[0561] Visits 4 (Week 1), 5 (Week 2), 6 (Week 3), 7 (Week 4), 8
(Week 6); and Visit 9 (Week 8; End of Double-Blind):
[0562] On the morning of each visit, subjects completed the 7
selected items of the HAM-D-17 and sleep diary via IVRS. In clinic,
the subject completed sleep and quality of life questionnaires. In
addition, the HAM-D-17 was administered by a clinician (at Visits 7
and 9 only); safety assessments and an evaluation of AEs were
performed; and study drug and supplies were dispensed. On the
morning following each office visit, subjects completed the sleep
diary and depression symptoms questionnaires via IVRS. Beginning
one week prior to Visit 9 until Visit 10, subjects resumed daily
IVRS for completion of the sleep diary. Subjects completed
randomized double-blind (DB) study drug the night prior to Visit 9
but remained on fluoxetine hydrochloride for the two-week wash-out
period. At Visit 9, the end of treatment assessments were performed
(ECG, clinical laboratory assessments, physical exam, vital
sign).
[0563] Visit 10 (Week 10; End of Study):
[0564] Subjects completed their last dose of fluoxetine
hydrochloride for this study on the day of this visit. On the
morning of the day prior to Visit 10, subjects completed the IVRS
sleep diary and HAM-D-7. On the morning of Visit 10, prior to the
visit, subjects completed their final IVRS call during which the
sleep diary and depression symptoms (DTA/SQ) questionnaires were
administered. At the clinic visit, the HAM-D-17 was administered by
a clinician. Final safety assessments [physical examination, ECG,
clinical laboratory assessments] and an evaluation of AEs were
performed and study drug and supplies are collected. At this time,
subjects were referred for follow-up to their primary
physicians.
[0565] Sample Population: Approximately 600 subjects were
randomized in order to complete 360. Subjects are males and females
between the ages of 21 and 64, inclusive. All subjects were
required to meet the DSM IV criteria for insomnia related to a
major depressive disorder. Subjects must have reported all of the
following: sleep onset time >30 minutes, wake time after sleep
onset >45 minutes and total sleep time of <6.5 hours.
Subjects must also have had a minimum HAM-D-17 score of 14, not
including scores for sleep items, at Visit 1.
[0566] Dose Description: All subjects received fluoxetine
hydrochloride 20 mg daily until Week 4 (Visit 7). At Week 4 (Visit
7), the dose of fluoxetine hydrochloride was permitted to 40 mg if
the investigator's clinical global impression of the subject's
depression symptoms was rated at >3 compared symptoms at
baseline (Visit 3). In addition, subjects were randomized at Visit
3 (end of baseline) to treatment with one of the following nightly
(at bedtime): eszopiclone (3 mg) or matching placebo.
Study Methods
[0567] Primary Efficacy Endpoint: The primary endpoint was the mean
subjective wake time after sleep onset (WASO) during Week 1.
[0568] Key Secondary Endpoints: Time to onset of 30% antidepressant
response, defined as the time from Visit 3 to the first of two
successive clinic assessment time points at which the subject
achieved a .gtoreq.30% reduction from baseline, on the HAM-D-6
(Bech) was a key secondary endpoint. 30% antidepressant response,
defined as a .gtoreq.30% reduction from baseline for at least two
successive clinic assessment time points, on the HAM-D-6 (Bech)
score was also a key secondary endpoint.
[0569] Secondary Endpoints: Secondary sleep endpoints were the
following:
[0570] Mean wake time after sleep onset (WASO) at weeks 2, 3, 4, 6
and 8 post randomization.
[0571] Mean subjective total sleep time (TST) at weeks 1, 2, 3, 4,
6 and 8 post randomization.
[0572] Mean subjective sleep latency (SL) at weeks 1, 2, 3, 4, 6
and 8 post randomization.
[0573] Mean number of awakenings at weeks 1, 2, 3, 4, 6 and 8 post
randomization.
[0574] Quality and depth of sleep at weeks 1, 2, 3, 4, 6 and 8 post
randomization.
[0575] Daytime alertness at weeks 1, 2, 3, 4, 6 and 8 post
randomization.
[0576] Ability to concentrate at weeks 1, 2, 3, 4, 6 and 8 post
randomization.
[0577] Physical well-being at weeks 1, 2, 3, 4, 6 and 8 post
randomization.
[0578] Ability to function at weeks 1, 2, 3, 4, 6, and 8 post
randomization.
[0579] In addition, the double-blind average (average of weeks 1,
2, 3, 4, 6, and 8) and the rebound and withdrawal effects were
analyzed for each of the subjective sleep endpoints. Other
secondary efficacy endpoints were the following: [0580] Time to
onset of 50% antidepressant response, defined as the time from
Visit 3 to the first of two successive clinic assessment time
points at which the subject achieved a .gtoreq.50% reduction from
baseline, on the HAM-D-6 (Bech). [0581] 50% antidepressant
response, defined as a .gtoreq.50% reduction from baseline for at
least two successive clinic assessment time points, on the HAM-D-6
(Bech) score. [0582] Time to onset of 30% antidepressant response
on HAM-D-6 (Maier) for at least two successive clinic assessment
time points. [0583] 30% antidepressant response on HAM-D-6 (Maier)
score for at least two successive clinic assessment time points.
[0584] Time to onset of 50% antidepressant response on HAM-D-6
(Maier) for at least two successive clinic assessment time points.
[0585] 50% antidepressant response on HAM-D-6 (Maier) score for at
least two successive clinic assessment time points. [0586] The
change in the HAM-D-6 (Bech) and HAM-D-6 (Maier) from baseline to
each visit. [0587] The change in the HAM-D-17 from baseline to
weeks 4 and 8. [0588] SQ score (Depression Subscale) during weeks
1, 2, 3, 4, 6, and 8. [0589] DTA score during weeks 1, 2, 3, 4, 6,
and 8. [0590] The change in HAM-D-6 (Bech), HAM-D-6 (Maier),
HAM-D-17, SQ, and DTA during the wash-out phase until end of study
(Week 8 minus Week 10). [0591] SF-36 score at weeks 4, 8, and 10.
[0592] WLQ score at weeks 2, 4, 8, and 10. [0593] ESS at weeks 1,
2, 3, 4, 6, 8, and 10. [0594] ISI score at weeks 2, 4, 8, and 10.
[0595] Clinical Global Impression (CGI) at weeks 1, 2, 3, 4, 6, 8,
and 10.
Safety Assessments
[0596] Safety was assessed by physical examinations, a standard
12-lead ECG, vital signs, clinical laboratory assessments and AE
reporting.
Subjective Assessments
[0597] IVRS questionnaire: Subjective sleep assessments, depression
symptoms and quality of life were evaluated via an IVRS. At Visit
1, subjects were trained on the use of the system and received a
unique user ID and password. [0598] Sleep Diary: This questionnaire
asked the subjects to report information about the previous night's
sleep. [0599] Daily Telephone Assessment: This questionnaire rated
the subjects depressive symptoms over the past day on a scale of 0
to 9. [0600] The Symptoms Questionnaire (Depression Subscale): This
questionnaire asked if subjects have experienced a number of
depressive symptoms over the previous day. [0601] The
Hamilton-Depression-7: Depression symptoms and general well being
over the previous 2 weeks were assessed by 7 selected items of the
Hamilton-Depression Rating Scale-17. The items included in the 7
item scale are mood (Item 1), feelings of guilt (Item 2); work
activities (Item 7); retardation (Item 8), agitation (Item 9);
anxiety psychic (Item 10); and somatic symptoms (Item 13). For data
analysis, two 6 item sub scales were evaluated: the Bech HAM-D-6
(9) which includes Items 1, 2, 7, 8, 10 and 13; and the Maier
HAM-D-7 (10) which includes Items 1, 2, 7, 8, 9, and 10.
[0602] Subject compliance with the use of the IVRS was tracked.
Sites were notified of non-compliance and were required to
follow-up with the subject.
[0603] Sleep, Depression, and Productivity Questionnaires and
Clinical Global Impression: The following questionnaires were
administered as listed below. [0604] Epworth Sleepiness Scale
(ESS): ESS was completed by the subject at Visits 2-10. The ESS is
a subjective assessment of the likelihood of falling asleep in
various situations. [0605] Insomnia Severity Index (ISI): ISI was
completed by the subject at Visits 3, 5, 7, 9 and 10. The ISI is a
subjective assessment of sleep quality, restedness/refreshness upon
arising, daytime fatigue, attention/concentration and relationship
and mood disturbances. [0606] Work Limitations Questionnaire (WLQ):
WLQ was completed by the subject at Visits 3, 5, 7, 9, and 10. The
WLQ is a validated self-report instrument for measuring the degree
to which chronic health problems interfere with ability to perform
job roles, addressing the content of the job through a demand-level
methodology. [0607] Hamilton Depression-17: HAM-D-17 was
administered via IVRS at screening and rated by a trained clinician
at Visits 3, 7, 9, and 10. [0608] SF-36: SF-36 was completed by the
subject at Visits 3, 7, 9 and 10. The SF-36 represents multiple
operational definitions of health, including function and
dysfunction, distress and well-being, objective reports and
subjective ratings, and both favorable and unfavorable
self-evaluations of general health status. [0609] Clinical Global
Impression (CGI): CGI was completed by the investigator at Visits
3-10 The CGI is the investigator's subjective assessment of
improvement in the subject's depressive symptoms. The response on
the CGI at Visit 7 (Week 4 of double-blind treatment) was used by
the investigator to assess the need for increasing the dose of
fluoxetine to 40 mg daily (in the morning). If in the opinion of
the investigator the subject's condition has not improved on the
Global Improvement question of the CGI to a score of 1 (very much
improved) or 2 (much improved), the investigator was permitted to
increase the dose of fluoxetine hydrochloride to 40 mg.
Study Conduct
[0610] Inclusion Criteria: [0611] 1. Subject must give appropriate
written informed consent and privacy authorization prior to
participation in the study. A female subject must also sign the
Women of Childbearing Potential Informed Consent Addendum. [0612]
2. Subject must understand the purpose of the study and be willing
to adhere to the study schedule and procedures described in this
protocol. [0613] 3. Subject must be 21 to 64 years of age
(inclusive) on the day of signing consent. [0614] 4. Subject must
meet DSM IV criteria for a primary and principal diagnosis of Major
Depressive Disorder (MDD; 296.XX), moderate (296.X2) or severe
depression without psychotic features (296.X3) with the presences
of either a single episode (296.2.times.) or recurrent episode
(296.3.times.) based on a clinical interview with the primary
investigator or sub-investigator (see below for definitions).
[0615] 5. Subject's current depressive episode is at least 2 weeks
but not longer than 6 months in duration. [0616] 6. Subject must
score a minimum of 14 on the Hamilton-D-17 (not including sleep
items). [0617] 7. Subject must meet DSM IV criteria for insomnia
related to MDD and the symptoms of insomnia must not pre-date the
symptoms of MDD by more than 10 weeks (see below for definitions).
[0618] 8. Subject must report a sleep onset time of .gtoreq.30
minutes, and wake time after sleep onset of .gtoreq.45 minutes, and
.ltoreq.6.5 hours of total sleep time at least three times a week
over the previous month. [0619] 9. Subject physical examination
must show no clinically significant abnormal findings (other than
MDD) at screening. [0620] 10. Subject must have no known clinically
significant abnormal laboratory findings at screening. [0621] 11.
Subject must have no clinically significant ECG abnormalities at
screening. [0622] 12. Subject must meet one of the following
conditions: [0623] Subject is not taking antidepressant medications
at the time of Visit 1. [0624] Subject is taking a sub-therapeutic
dose of antidepressant or other disallowed psychotropic medication
and with the approval of the investigator agrees to taper off of
this medication, prior to completion of screening assessments at
Visit 1.
[0625] Exclusion Criteria [0626] 1. Female subject is pregnant,
lactating or within 6 months post partum. [0627] 2. Subject has
known sensitivity to any selective SSRI, zopiclone, or eszopiclone.
[0628] 3. Subject is, in the opinion of the investigator, at
significant suicide risk as determined by a clinical interview by
the investigator or sub-investigator. [0629] 4. Subject has history
of major depressive disorder that was refractory to treatment with
SSRIs as determined by the Antidepressant Treatment History
Questionnaire. [0630] 5. Subject has a current primary DSM-IV Axis
I psychiatric diagnosis of any of the following disorders:
dementia, delirium, schizophrenia, psychosis, other psychotic
disorders, dysthymic disorder; bipolar disorders; cyclothymic
disorder, other mood disorders, nocturnal panic disorder, primary
anxiety disorders, primary panic disorders or any other psychiatric
disorder that would compromise the investigator's ability to
evaluate the safety and efficacy of the study medication. Note:
Subjects with Sexual and Gender Identity Disorders or other
non-psychotic Axis I disorders were considered on a case-by-case
basis (see below for DSM-IV criteria for disallowed psychiatric
diagnoses). Subjects with MDD and a secondary diagnosis of
generalized anxiety disorder, panic disorders other than nocturnal
panic disorder or seasonal affective disorder were allowed. [0631]
6. Subject has any of the following DSM IV Axis II Personality
Disorders diagnoses: schizotypal, schizoid, borderline personality
disorder; mental retardation or any other personality disorder that
would compromise the investigator's ability to evaluate the safety
and efficacy of the study medication. [0632] 7. Subject has
difficulties in sleep initiation or maintenance associated with
known medical diagnosis [e.g. sleep apnea, restless leg syndrome
(RLS), or periodic leg movement syndrome (PLMS)], or has any
condition that has or may affect sleep [(e.g., chronic pain, benign
prostatic hypertrophy (BPH)]. [0633] 8. Subject has any clinically
significant unstable medical or neurologic abnormality, unstable
chronic disease, or a history of a clinically significant
abnormality of the cardiovascular, respiratory, hepatic, or renal
systems. [0634] 9. Subject has a disorder or history of a condition
(e.g., malabsorption, gastrointestinal surgery) that may interfere
with drug absorption, distribution, metabolism, or excretion.
[0635] 10. Subject has a history of malignancy within 5 years, or
current malignancy, except for non-melanoma skin cancer. [0636] 11.
Subject is using any of the disallowed medications, or has not met
the required wash-out period for disallowed medications listed
below. [0637] 12. Subject has a history of drug or alcohol abuse or
dependence in the past 6 months or positive urine drug and alcohol
test at screening. [0638] 13. Subject is participating in, has
participated in, or plans to participate in any investigational
drug study within 30 days prior to screening until the end of this
study. [0639] 14. Subject has history of circadian rhythm disorder,
or travels across .gtoreq.3 time zones on a regular basis. [0640]
15. Subject is known to be seropositive for Human Immunodeficiency
Virus (HIV). [0641] 16. Subject has used any drugs known or
suspected to affect hepatic or renal clearance capacity within a
period of 30 days prior to screening. [0642] 17. Subject is
unwilling to refrain from drinking alcoholic beverages during study
participation. [0643] 18. Subject is a rotating or third/night
shift worker. [0644] 19. Subject is a staff member or relative of a
staff member.
Randomization Criteria
[0645] To be eligible for randomization, the subject must have
completed a minimum of 3 daily diary assessments via IVRS during
the baseline period.
Concurrent Medications and Restrictions
Disallowed Medications
[0646] The following medications were disallowed during study
participation and must have been discontinued for minimum periods
as listed below:
TABLE-US-00001 Drug Class Wash-out Periods* Any antipsychotic
medications 30 days prior to Visit 2 Fluoxetine 35 days prior to
completion of screening assessments Any other SSRI 14 days prior to
completion of screening assessments Any monoamine oxidase
inhibitors 14 days prior to completion of screening assessments Any
tricyclic antidepressant (TCA) 14 days prior to completion of
screening assessments Any serotonin-norepinephrine 14 days prior to
completion re-uptake inhibitors (NSRIs) of screening assessments
Other antidepressants (trazadone, 14 days prior to completion
nefazadone, bupropion, mirtazapine) of screening assessments
Benzodiazepine sedative hypnotics 14 days prior to Visit 2 or
anxiolytics Any drugs including over-the-counter 14 days prior to
Visit 2 drugs and herbal supplements known to affect sleep wake
function *The wash-out period begins after the subject has
successfully tapered from prior therapy and is no longer taking any
of the disallowed medication.
[0647] Concurrent Medications for the Duration of the Study:
[0648] Chronic medications other than those listed above taken at a
stable dose for at least 30 days prior to clinical assessment
screening (Visit 2) were allowed. Standard over the counter
medications other than those listed above (analgesics, topical
ointments, etc) were also allowed. All females on oral
contraceptives and hormonal therapy were encouraged to dose at the
same time of day each day while on study.
[0649] Additional Instructions:
[0650] Subjects were to be instructed not to consume alcohol during
this study. Subjects were to eat dinner at least 2 hours prior to
their scheduled double-blind study medication dosing time. Subjects
were to refrain from driving or using heavy machinery within 7
hours after taking double-blind study medication.
Drugs and Dosage
Study Medication Description
[0651] Eszopiclone was supplied as 3 mg tablets. Subjects received
a 3 mg dose as one tablet. In addition to eszopiclone, the active
ingredient, each tablet contained: microcrystalline cellulose, USP;
calcium phosphate anhydrous, USP; croscarmellose sodium, USP;
colloidal silicon dioxide, USP and magnesium stearate, USP. The
tablets were coated with opadry II. The matching placebo contains
all ingredients, except the active eszopiclone.
[0652] Fluoxetine hydrochloride is a white to off-white crystalline
solid with a solubility of 14 mg/mL in water. Each capsule
contained fluoxetine hydrochloride equivalent to 20 mg or 40 mg of
fluoxetine. The capsules also contained starch, gelatin, silicone,
titanium dioxide, iron oxide, and other inactive ingredients.
Administration of Study Medication
[0653] Randomized Double-Blind Kits:
[0654] Eligible subjects were randomized and assigned a numbered
double-blind kit containing 6 blister packs. Kits were dispensed in
ascending order (lowest to highest) from the sites double-blind
drug supply. Each kit contained the following: [0655] Four blister
packs clearly labeled with the visit number (Visits 3, 4, 5, and
6). Each Visit 3, 4, 5, and 6 blister pack will contain a 7 (+/-2)
day supply of double-blind study medication and fluoxetine
hydrochloride capsules. [0656] Four blister packs clearly labeled
with the visit number (Visits 7-20 mg fluoxetine hydrochloride;
Visit 7-40 mg fluoxetine hydrochloride; Visit 8-20 mg fluoxetine
hydrochloride and Visit 8-40 mg fluoxetine hydrochloride). Each
Visit 7 and Visit 8 blister pack will contain a 14 (+/-2) day
supply of double-blind study drug and fluoxetine hydrochloride
capsules. At the investigator's discretion based on lack of
improvement or minimal improvement on the Clinical Global
Impression (rating of .gtoreq.3), the dose of fluoxetine may be
increased to 40 mg at Visit 7. If the subject requires the 40 mg
dose of fluoxetine hydrochloride, the Visit 7--a 40 mg fluoxetine
hydrochloride blister pack will be dispensed. Choose only one Visit
7 and one Visit 8 card. The Visit 7 and Visit 8 card that is not
used will remain in the kit and will be returned.
[0657] Single-Blind Wash-Out:
[0658] Subjects who completed the 8-week double-blind treatment
period were entered into a two-week single-blind wash-out period.
At Visit 9, subjects were provided with a blister pack containing a
14 (+/-2) day supply of single blind placebo tablets and open-label
fluoxetine hydrochloride capsules.
Dosing Instructions
[0659] Subjects were instructed to take one double- or single-blind
tablet each night (at bedtime) beginning the evening of each office
visit. Subject were instructed to take one fluoxetine hydrochloride
capsule each morning beginning at Visit 3. Subjects were to return
each blister pack at the next office visit. The morning dose of
fluoxetine hydrochloride on the day of Visits 4-10 was to be taken
prior to coming into clinic (from the previous visit's blister
pack).
Treatment Plan
Standardization of Data Capture
[0660] Vital Signs:
[0661] For each visit, vital signs consist of 5 minutes resting,
seated blood pressure, respiration rate, heart rate, and oral or
auricular body temperature.
[0662] ECG:
[0663] An ECG was performed at Visits 1, 9 and Visit 10. Collection
was started after 5 minutes of supine rest. When possible, this ECG
was obtained prior to drawing blood samples for clinical laboratory
evaluations.
[0664] Clinical Laboratory:
[0665] Blood and urine samples for clinical laboratory assessments
were obtained at Visits 1, 3, 7, 9, and 10 and analyzed
accordingly. The analysis included Hematology: 1) Total WBC Count;
2) Differential: neutrophils, lymphocytes, monocytes, eosinophils,
basophils; 3) Hemoglobin; 4) Hematocrit; 5) Platelet Count; and 6)
RBC Count. Qualitative Urinalysis: 1) glucose, 2) ketones, 3)
protein, and 4) blood. Other Urine Laboratory Tests: urine drug and
alcohol screen. Blood chemistry tests included tests for
electrolytes, certain enzymes, and certain other tests as described
herein. Electrolytes: carbon dioxide, calcium, chloride, phosphorus
(inorganic), potassium, sodium, and magnesium. Enzymes: alkaline
phosphatase, SGOT (AST), and SGPT (ALT). Other: albumin, bilirubin
(total), creatinine, glucose, protein (total), blood urea nitrogen,
uric acid, and T4. Other tests: serum .beta.-hCG pregnancy test
(all females) and serum cortisol.
[0666] IVRS:
[0667] All subjects were instructed on the use of the IVRS for the
collection of sleep and depressive symptom endpoints at Visit 2. A
brief review was conducted at subsequent visits, as needed. The
following assessments were completed via IVRS: [0668] Sleep Diary:
Daily in the morning beginning the morning after Visit 2 until the
morning after Visit 4; Morning of and morning after Visits 5, 6, 7,
8; Beginning on the first morning of the last week on DB (start of
week 8) until the morning of Visit 10. [0669] 7 selected items of
the HAM-D-17: Once on the morning after Visit 2; once on the
morning of clinic visits 3 through 9; and once in between Visit 9
and 10 at approximately 7 days post visit 9 (on the first day of
the daily diary at Week 9 on DB) and on the morning to prior to
Visit 10. [0670] Daily Telephone Assessment (DTA) and Symptoms
Questionnaire (SQ): Daily in the morning beginning the morning
after Visit 2 until the morning after Visit 4; Morning after Visits
5, 6, 7, 8, 9; Eight days post Visit 9; Morning of Visit 10.
[0671] QoL Measurements:
[0672] All subjects completed the sleep and quality of life
questionnaires in the clinic as described above. The questionnaires
were reviewed by study staff with the subjects for completeness
only. Patients were not questioned about any of their responses or
given suggestions on how to answer any of the questions.
[0673] Medical Events Calendar (MEC):
[0674] All subjects were given a Medical Event Calender (MEC) to be
completed throughout their time on study. The MED simply provided a
place for patients to record the medications taken each day and any
illnesses, symptoms or medical conditions they experience each day.
At each return visit, the MEC was reviewed, collected, and a new
MEC was dispensed.
[0675] Adverse Events (AEs):
[0676] Subjects were queried in a non-leading manner, without
specific prompting (e.g., "How are you feeling?") to assess whether
they are suffering from any adverse events.
[0677] Concomitant Medications and Medical History:
[0678] Subject-self report was acceptable for listing all
concomitant medication use, medical history and evaluation for
inclusion/exclusion except where specific protocols procedures are
mandated to ensure appropriate enrollment (e.g. certain baseline
lab values).
Screening (Visit 1)
[0679] No protocol-related procedures were performed prior to
obtaining written informed consent. Subjects were evaluated at
screening to determine their eligibility for study participation.
All clinical assessments (clinical laboratory, physical
examination, ECG, etc.) was completed and reviewed by the
Investigator prior to Visit 2.
[0680] Subject informed consent was obtained prior to initiation of
study specific tapering of any disallowed medications.
Investigators discussed the process of tapering antidepressant
medications with subjects prior to signing consent and should note
the discussion in progress notes in the source documentation.
Tapering of antidepressant or other disallowed psychotropic
medications was approached cautiously taking into consideration the
subjects current depression symptoms and medical history and the
manufacturer's package insert instructions for withdrawing therapy.
Under no circumstances did the Investigators withdraw
antidepressant or other disallowed psychotropic therapy:
[0681] 1) prior to obtaining informed consent;
[0682] 2) improperly/abruptly to adhere to the protocol specified
wash-out periods.
[0683] If a tapering period was required, the screening visit was
completed on multiple dates. At the first office visit, subjects
were seen for the signing of the informed consent, collection of
medical history and concomitant medications. The investigator
performed a brief examination to assess the subject's status and to
evaluate the potential for the subject to safely taper off of
antidepressant or other disallowed psychotropic medication. The
investigator documented rationale for enrolling a subject currently
on antidepressant or other psychotropic therapy and the plan for
tapering this medication in the source documents. Subjects did not
complete the sleep history questionnaire or the Ham-D-17 via IVRS
until the end of the wash-out period. If all screening procedures
were not completed within 30 days from the date of signed Informed
Consent, the subject returned to the clinic to sign a new Informed
Consent.
[0684] The following study-related procedures were performed at
screening: [0685] 1. Signed informed consent (including women of
child-bearing potential addendum, if applicable) and privacy
authorization from the subject before conducting any other visit
procedures were obtained [0686] 2. A medical history (including
psychiatric history), sleep history, demographic information, and
alcohol use and any prior treatments for insomnia was obtained.
NOTE: If tapering from antidepressant or other disallowed
psychotropic medication was required, the sleep history
questionnaire was not completed until the subject had completed the
wash-out period. [0687] 3. The subject was registered on the IVRS
and trained in its use. The subject completed the Hamilton-D-17 via
IVRS to assess depression symptoms. NOTE: If tapering from
antidepressant or other disallowed psychotropic medication was
required, the Ham-D-17 should was not completed until the subject
had completed the wash-out period. [0688] 4. All concurrent
medications were recorded, including OTC and health and dietary
supplements, taken within the previous 30 days; the Antidepressant
Treatment History Questionnaire to evaluate prior response to
antidepressants was completed. [0689] 5. A physical examination was
performed, including a brief neurological examination (excluding
genitourinary, breast and rectal). [0690] 6. Vital signs (seated),
height and weight were obtained. [0691] 7. A 12-lead ECG was
obtained [0692] 8. A blood sample for clinical laboratory tests
(including hematology, chemistry and a serum pregnancy test for all
women), and urine samples for urinalysis and urine alcohol and drug
screen was obtained. [0693] 9. All inclusion and exclusion criteria
were reviewed. [0694] 10. Issued MEC to all subjects and instructed
subject on their use. [0695] 11. Scheduled Visit 2 in 5-14
days.
Visit 2 (Start of Baseline Period)
[0696] Visit 2 occurred 5-14 days after Visit 1. Subjects begin
using the IVRS daily until Visit 4 following this visit. The
following study-related procedures were performed: [0697] 1.
Reviewed all inclusion and exclusion criteria including clinical
laboratory assessments, and the IVRS HAM-D-17 score. [0698] 2.
Subjects meeting all inclusion and exclusion criteria completed the
ESS questionnaire prior to performing any other study related
procedures. The questionnaire was reviewed for completeness by
study staff. Any items left blank were returned to the subject for
completion. [0699] 3. Collected and reviewed the MEC. Recorded all
changes in concurrent medications, including OTC and health and
dietary supplements, and AEs that may have occurred between Visit 1
and Visit 2. [0700] 4. Obtained vital signs (seated) and weight.
[0701] 5. Instructed subjects on the use of the IVRS. Subjects will
begin IVRS calls in the morning following Visit 2 and will continue
daily calls for two-weeks until Visit 4. [0702] 6. Issued MEC and
instruct the subject on its use. [0703] 7. Scheduled Visit 3 in 3-7
days.
Visit 3 (Randomization; Beginning of Double-Blind Treatment
Period)
[0704] Visit 3 occurred 3-7 days after Visit 2. The first dose of
fluoxetine hydrochloride 20 mg was administered in clinic at Visit
3. Open-label fluoxetine hydrochloride dosing (in the morning)
continued daily through Visit 10. The first dose of double-blind
study medication was administered at bedtime on the day of Visit 3.
Double-blind dosing (at bedtime) continued nightly through Visit 9.
[0705] 1. Collected and reviewed the MEC. Recorded all changes in
concurrent medications, including OTC and health and dietary
supplements, and AEs that may have occurred between Visit 2 and
Visit 3. [0706] 2. Reviewed randomization criteria. [0707] 3.
Subjects meeting all randomization criteria completed the ESS, ISI,
WLQ, and SF-36 questionnaires prior to performing any other study
related procedures. Questionnaires were reviewed for completeness
by study staff. Any items left blank were returned to the subject
for completion. [0708] 4. A trained clinician administered the
Hamilton-D-17 to assess depression symptoms. [0709] 5. The
investigator completed the Clinical Global Impression of the
subject's depression symptoms. [0710] 6. Obtained vital signs
(seated) and weight. [0711] 7. Obtained blood and urine samples for
clinical laboratory assessments including urinalysis, urine drug
and alcohol screen, and serum pregnancy tests for all women. [0712]
8. Assigned a randomization number and dispensed the Visit 3
double-blind blister pack from the randomization kit. Instructed
the subject to begin taking one double-blind tablet nightly at
bedtime and one fluoxetine hydrochloride 20 mg capsule daily (in
the morning). The first dose of fluoxetine hydrochloride was taken
in clinic. The first dose of double-blind study medication was
administered at bedtime on the day of Visit 3. [0713] 9. Reviewed
use of IVRS and the schedule for calling. Subjects continued daily
IVRS calls in the morning until Visit 4. [0714] 10. Issued MEC and
instruct the subject on its use. [0715] 11. Scheduled Visit 4 in 7
(+/-2) days.
Visit 4 (Double-blind Treatment Week 1)
[0716] Visit 4 occurred 7 (+/-2) days after Visit 3. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. [0717] 1. Collected and reviewed the MEC.
Recorded all changes in concurrent medications, including OTC and
health and dietary supplements, and AEs that may have occurred
between Visit 3 and Visit 4. [0718] 2. Collected the Visit 3
study-drug blister pack (fluoxetine hydrochloride and double-blind)
and reviewed subject compliance. [0719] 3. Subjects completed the
ESS questionnaire prior to performing any other study related
procedures. The questionnaire was reviewed for completeness by
study staff. Any items left blank were returned to the subject for
completion. [0720] 4. The investigator completed the Clinical
Global Impression of the subject's depression symptoms. [0721] 5.
Obtained vital signs (seated) and weight. [0722] 6. Dispensed the
Visit 4 double-blind blister pack. Instructed the subject to take
one double-blind tablet nightly (at bedtime) and one open-label
fluoxetine hydrochloride 20 mg capsule daily (in the morning).
[0723] 7. Reviewed use of IVRS and the schedule for calling.
Subjects called the IVRS on morning of Visit 5 (prior to coming to
the visit). [0724] 8. Issued MEC and instructed the subject on its
use. [0725] 9. Scheduled Visit 5 in 7 (+/-2) days.
Visit 5 (Double-Blind Treatment Week 2)
[0726] Visit 5 occurred 7 (+/-2) days after Visit 4. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. [0727] 1. Collected and reviewed the MEC.
Recorded all changes in concurrent medications, including OTC and
health and dietary supplements, and AEs that may have occurred
between Visit 4 and Visit 5. [0728] 2. Collected the Visit 4
study-drug blister pack (fluoxetine hydrochloride and double-blind)
and reviewed subject compliance. [0729] 3. Subjects completed the
ESS, ISI, and WLQ questionnaires prior to performing any other
study related procedures. The questionnaires were reviewed for
completeness by study staff. Any items left blank were returned to
the subject for completion. [0730] 4. The investigator completed
the Clinical Global Impression of the subject's depression
symptoms. [0731] 5. Obtained vital signs (seated) and weight.
[0732] 6. Dispensed the Visit 5 double-blind blister pack.
Instructed the subject to take one tablet nightly (at bedtime) and
one open-label fluoxetine hydrochloride 20 mg capsule daily (in the
morning). [0733] 7. Reviewed use of IVRS and the schedule for
calling. Subjects called the IVRS the morning following this visit
and on the morning of Visit 6 (prior to the visit). [0734] 8.
Issued MEC and instructed the subject on its use. [0735] 9.
Scheduled Visit 6 in 7 (+/-2) days.
Visit 6 (Double-Blind Treatment Week 3)
[0736] Visit 6 occurred 7 (+/-2) days after Visit 5. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. [0737] 1. Collected and reviewed the MEC.
Recorded all changes in concurrent medications, including OTC and
health and dietary supplements, and AEs that may have occurred
between Visit 5 and Visit 6. [0738] 2. Collected the Visit 5
study-drug blister pack (fluoxetine hydrochloride and double-blind)
and reviewed subject compliance. [0739] 3. Subjects completed the
ESS questionnaire prior to performing any other study related
procedures. The questionnaire was reviewed for completeness by
study staff. Any items left blank were returned to the subject for
completion. [0740] 4. The investigator completed the Clinical
Global Impression of the subject's depression symptoms. [0741] 5.
Obtained vital signs (seated) and weight. [0742] 6. Dispensed the
Visit 6 double-blind blister pack. Instructed the subject to take
one double-blind tablet nightly (at bedtime) and one open-label
fluoxetine hydrochloride 20 mg capsule daily (in the morning).
[0743] 7. Reviewed use of IVRS and the schedule for calling.
Subjects called the IVRS the morning following this visit and on
the morning of Visit 7 (prior to the visit). [0744] 8. Issued MEC
and instruct the subject on its use. [0745] 9. Scheduled Visit 7 in
7 (+/-2) days.
Visit 7 (Double-Blind Treatment Week 4)
[0746] Visit 7 occurred 7 (+/-2) days after Visit 6. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. [0747] 1. Collected and reviewed the MEC.
Recorded all changes in concurrent medications, including OTC and
health and dietary supplements, and AEs that may have occurred
between Visit 6 and Visit 7. [0748] 2. Collected Visit 6 study-drug
blister pack (fluoxetine hydrochloride and double-blind) and review
subject compliance. [0749] 3. Subjects completed the ESS, ISI, WLQ,
and SF-36 questionnaires prior to performing any other study
related procedures. The questionnaires were reviewed for
completeness by study staff. Any items left blank were returned to
the subject for completion. [0750] 4. A trained clinician
administered the Hamilton-D-17 to assess depression symptoms.
[0751] 5. The investigator completed the Clinical Global
Impression. If in the investigators opinion the subject's
depressive symptoms had not improved beyond minimal improvement
(rating of .gtoreq.3), the investigator could increase the dose of
fluoxetine hydrochloride to 40 mg daily (in the morning). If an
increased dose of fluoxetine was required, the investigator
dispensed the double-blind blister pack containing the 40 mg dose
of fluoxetine. [0752] 6. Dispensed the appropriate Visit 7
double-blind blister pack. Instructed the subject to take one
double-blind tablet nightly (at bedtime) and one open-label
fluoxetine hydrochloride 20 mg or 40 mg capsule daily (in the
morning). Note: only one Visit 7 blister card was dispensed. [0753]
7. Obtained vital signs (seated) and weight. [0754] 8. Obtained
blood and urine samples for clinical laboratory assessments
including urinalysis, urine drug and alcohol screen, and a serum
pregnancy tests on all women. [0755] 9. Reviewed use of IVRS and
the schedule for calling. Subjects call the IVRS the morning
following this visit and on the morning of Visit 8 (prior to the
visit). [0756] 10. Issued MEC and instruct the subject on its use.
[0757] 11. Scheduled Visit 8 in 14 (+/-2) days.
Visit 8 (Double-Blind Treatment Week 6)
[0758] Visit 8 occurred 14 (+/-2) days after Visit 7. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. [0759] 1. Collected and reviewed the MEC.
Recorded all changes in concurrent medications, including OTC and
health and dietary supplements, and AEs that may have occurred
between Visit 7 and Visit 8. [0760] 2. Collected Visit 7 study-drug
blister pack (fluoxetine hydrochloride and double-blind) and
reviewed subject compliance. [0761] 3. Subjects completed the ESS
questionnaire prior to performing any other study related
procedures. The questionnaire was reviewed for completeness by
study staff. Any items left blank were returned to the subject for
completion. [0762] 4. The investigator completed the Clinical
Global Impression of the subject's depression symptoms. [0763] 5.
Obtained vital signs (seated) and weight. [0764] 6. Dispensed one
Visit 8 double-blind blister pack (20 mg or 40 mg fluoxetine
hydrochloride). Instructed the subject to take one double-blind
tablet nightly (at bedtime) and one open-label fluoxetine
hydrochloride 20 or 40 mg capsule daily (in the morning). [0765] 7.
Reviewed use of IVRS and the schedule for calling. Subjects called
the IVRS the morning following this visit and resumed daily calls
one week following Visit 8 until the morning of Visit 10 (prior to
the visit). [0766] 8. Issued MEC and instruct the subject on its
use. [0767] 9. Scheduled Visit 9 in 14 (+/-2) days.
Visit 9 (End of Double-Blind Treatment Week 8)
[0768] Visit 9 occurred 14 (+/-2) days after Visit 8. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through the night prior to Visit 9. [0769] 1. Collected and
reviewed the MEC. Recorded all changes in concurrent medications,
including OTC and health and dietary supplements, and AEs that may
have occurred between Visit 7 and Visit 8. [0770] 2. Collected
Visit 8 the study-drug blister pack (fluoxetine hydrochloride and
double-blind) and review subject compliance. [0771] 3. Subjects
completed the ESS, ISI, WLQ, and SF-36 questionnaires prior to
performing any other study related procedures. The questionnaire
were reviewed for completeness by study staff. Any items left blank
were returned to the subject for completion [0772] 4. A trained
clinician administered the Hamilton-D-17 to assess depression
symptoms. [0773] 5. The investigator completed the Clinical Global
Impression of the subject's depression symptoms [0774] 6. Obtained
vital signs (seated) and weight [0775] 7. Obtained standard 12-lead
ECG [0776] 8. Obtained blood and urine samples for clinical
laboratory assessments including urinalysis, urine drug and alcohol
screen, serum pregnancy test on all women. [0777] 9. Performed the
end of treatment physical exam to assess changes that have occurred
since Visit 1. [0778] 10. Dispensed one Visit 9 single-blind
placebo blister pack (Blister pack contains 20 mg or 40 mg
fluoxetine hydrochloride) and instructed the subject to continue
taking one single-blind tablet nightly (at bedtime) and one
open-label fluoxetine hydrochloride 20 mg or 40 mg capsule daily
(in the morning). [0779] 11. Reviewed use of IVRS and the schedule
for calling. Subjects called the IVRS daily until the morning of
Visit 10. [0780] 12. Issued MEC and instruct the subject on its
use. [0781] 13. Scheduled Visit 10 in 14 (+/-2) days.
Visit 10 (End of Study)
[0782] Visit 10 occurred 14 (+/-2) days after Visit 9. Open-label
fluoxetine hydrochloride dosing (in the morning) continued daily
through Visit 10. Double-blind dosing (at bedtime) continued
nightly through Visit 9. Subject completed the final IVRS
assessment on the morning of Visit 10. [0783] 1. Collected and
reviewed the MEC. Recorded all changes in concurrent medications,
including OTC and health and dietary supplements, and AEs that may
have occurred between Visit 9 and Visit 10. [0784] 2. Collected the
Visit 9 blister pack and review subject compliance. [0785] 3.
Subjects completed the ESS, ISI, WLQ, and SF-36 questionnaires
prior to performing any other study related procedures. The
questionnaires were reviewed for completeness by study staff. Any
items left blank were returned to the subject for completion.
[0786] 4. A trained clinician administered the Hamilton-D-17 to
assess depression symptoms. [0787] 5. The investigator completed
the Clinical Global Impression of the subject's depression symptoms
[0788] 6. Obtained vital signs (seated) and weight. [0789] 7.
Obtained a standard 12-lead ECG. [0790] 8. Obtained blood and urine
samples for clinical laboratory assessments including urinalysis,
urine drug and alcohol screen, serum pregnancy tests on all
women.
Discontinuation and Replacement of Subjects
[0791] Subjects in this study were discontinued for any of the
following reasons: 1) adverse reactions; 2) protocol violations; 3)
withdrawal of consent; 4) lost to follow-up; 5) treatment failure;
6) does not meet inclusion/exclusion/randomization criteria; 7)
other. All subjects prematurely discontinuing from the trial during
the double-blind period, regardless of cause, were seen for an End
of Study evaluation, at which time Visit 9 procedures 1-9 were
performed. Subjects who discontinued early for any reason were
replaced.
Statistics
General Design
[0792] This is a randomized, double-blind, multi-center,
placebo-controlled, parallel group study of the efficacy and safety
of Eszopiclone in the treatment of subjects diagnosed with major
depressive disorder associated with insomnia. Approximately 600
subjects were randomized in a 1:1 ratio to receive one of the two
treatments, eszopiclone 3 mg or placebo, for eight weeks in a
double-blind fashion.
Analysis Variables
[0793] Primary and Secondary Efficacy Endpoints are described
above.
Analysis Populations
[0794] The Intent-To-Treat (ITT) population included all randomized
subjects who received at least one dose of study medication. All
analyses were conducted using this population.
Data Analysis
[0795] Continuous variables were summarized using descriptive
statistics, including number of subjects, mean, standard deviation,
minimum, 25.sup.th percentile, median, 75.sup.th percentile, and
maximum. For categorical variables, summaries included counts of
subjects and percentages. Baseline was defined as the last
non-missing value prior to the first dose of study medication. All
statistical tests were two-sided and were conducted at the 5%
significance level, unless otherwise specified.
[0796] To facilitate assessment of site effects and treatment by
site interactions for analysis of efficacy data, all sites with
fewer than 3 subjects per treatment group were ranked according to
the number of subjects randomized. These sites were sequentially
pooled together, starting with the site that has the fewest number
of subjects (lowest rank), until a pseudo-site was formed that
meets the 3 subjects per treatment group criterion. Then a second
pseudo-site was formed by combining the next lowest ranking sites
until the 3 subjects per treatment group criteria is met, and so
on. If the final pseudo-site created did not meet the 3 subjects
per treatment group criterion, then it was combined with the
previous pseudo-site created.
[0797] All statistical procedures were performed using SAS Version
8.2 or higher. All p-values were reported to four decimal points
with p-values less than 0.0001 reported at <0.0001.
[0798] Subject Disposition and Drug Exposure:
[0799] Subject disposition was summarized and presented for the
number and percentage of subjects, who were screened, randomized,
received treatment, completed the study, and discontinued early
(including reasons for discontinuations). For each subject, the
number of doses taken was computed from the study drug dispensation
and accountability CRF records obtained at each visit, assuming
that subjects took their study drug medication evenly throughout
the between-visits periods. The extent of exposure to the
double-blind medication as well as the number of doses taken during
the double-blind treatment period was summarized with descriptive
statistics and presented by treatment group.
[0800] Important Protocol Deviations:
[0801] Important protocol deviations (IPDs) which were reviewed
include, but are not limited to, subjects who: [0802] Did not meet
inclusion/exclusion criteria or eligibility was not adequately
verified [0803] Did not meet baseline eligibility criteria [0804]
Received any disallowed concomitant medication post-baseline [0805]
Developed withdrawal criteria but were not withdrawn [0806]
Received less than 80% or more than 120% of the prescribed dose or
had another dosing error that would be likely to impact efficacy
outcome measures
[0807] The potentially important protocol deviations were
identified shortly before database lock and treatment unblinding
either programmatically (e.g., inclusion/exclusion criteria
violations, compliance assessment) or through review of
treatment-blinded data listings (e.g., investigator comments,
concomitant medications). Appropriate personnel (including, at a
minimum, an M.D. and a biostatistician) reviewed the list of
potential IPDs to identify which protocol deviations will be
considered IPDs. The final list of IPDs was documented and used to
generate a data listing.
[0808] Demographic and Baseline Characteristics:
[0809] Demographic and baseline characteristics, including age,
gender, race, height, weight, as well as sleep history parameters,
was summarized using descriptive statistics. Continuous variables
were compared across treatment groups using an ANOVA model with
fixed effects for treatment and site, while categorical variables
were compared using Cochran-Mantel-Haenszel (CMH) test for general
association controlling for site. Sleep history was summarized by
treatment group.
[0810] Efficacy Analysis:
[0811] Efficacy analyses were conducted using ITT population. All
subjective sleep parameters assessed via the IVRS were summarized
descriptively (m, mean, SD, minimum, 25.sup.th percentile, median,
75.sup.th percentile and maximum) at each week and were presented
by treatment group.
[0812] Primary Analysis:
[0813] The primary analysis was conducted using the ITT population
for the primary efficacy variable, mean WASO during the first week
of double-blind medication. This endpoint was computed by averaging
the daily WASO values obtained via IVRS from Visit 3 to Visit 4.
The analysis was conducted using an analysis of variance model
(ANOVA) with treatment and site as fixed effects. The analysis was
performed on rank-transformed data, using the SAS MIXED procedure.
The cumulative distribution function by treatment was plotted.
[0814] Key Secondary Analyses:
[0815] An analysis of the time to onset of 30% antidepressant
response, defined as the time from Visit 3 to the first of two
successive clinic assessment time points at which the subject
achieved a .gtoreq.30% reduction from baseline on the HAM-D-6
(Bech) score was analyzed using PROC LIFETEST within SAS. The
number of subjects with antidepressant response, and the number of
subjects censored were presented for each treatment along with one
minus the Kaplan-Meier estimates. Subjects without an
antidepressant response of .gtoreq.30% reduction in HAM-D-6 (Bech)
score for at least two successive assessment time points were
censored at the minimum of the end of study or the end of
double-blind treatment+14 days. Additionally, the p-value from the
log-rank test for equality of survival curves across treatments was
reported and a time-to-onset plot (one minus Kaplan-Meier estimate)
was produced. The percentage of subjects achieving antidepressant
response, defined as a .gtoreq.30% reduction from baseline in
HAM-D-6 (Bech) score for at least two successive clinic assessments
was also analyzed using a logistic regression model with treatment
and site as fixed effects.
[0816] Other Secondary Analyses:
[0817] Analysis of the secondary subjective sleep parameters, the
1, 2, 3, 4, 6, and 8 week post-randomization and double-blind
averages of WASO (except week 1 average, which is the primary
efficacy endpoint), TST, SL, mean number of awakenings, depth and
quality of sleep, daytime alertness, ability to concentrate,
physical well-being and ability to function was conducted on
rank-transformed data using the same method as for the primary
analysis.
[0818] Analysis of the time to onset of 50% antidepressant
response, defined as the time from Visit 3 to the first of two
successive clinic assessment time points at which the subject
achieved a .gtoreq.50% reduction from baseline on the HAM-D-6
(Bech) score was analyzed using the same method as for the key
secondary analysis based on 30% antidepressant response. A 50%
antidepressant response, defined as .gtoreq.50% reduction from
baseline in on the HAM-D-6 (Bech) score for at least two successive
clinic assessments was also analyzed using a logistic regression
model with treatment and site as fixed effects. These analyses were
repeated using both .gtoreq.30% reduction from baseline on the
HAM-D-6 (Maier) and .gtoreq.50% reduction from baseline on the
HAM-D-6 (Maier) as the criteria used to define antidepressant
response.
[0819] The change from baseline to each double-blind,
post-treatment visit in the HAM-D-17 score as well as the change
from baseline to each double-blind, weekly, post-treatment
assessments in the HAM-D-6 (Bech) scores and HAM-D-6 (Maier) scores
was presented descriptively (m, mean, median, standard deviation,
minimum, 25.sup.th percentile, median, 75.sup.th percentile, and
maximum) by treatment. Treatment comparisons were performed at each
assessed time point. The analysis compared the eszopiclone 3 mg
group to placebo using an analysis of variance model (ANOVA) with
treatment and site as fixed effects. The analysis was performed
using the SAS MIXED procedure.
[0820] Treatment comparisons were performed on the Mean Symptoms
Questionnaire (SQ) Score during Week 1, defined as the average of
the daily SQ scores obtained via IVRS from Visit 3 to Visit 4 using
an analysis of variance model (ANOVA) with treatment and site as
fixed effects. Mean Daily Telephone Assessment (DTA) Scores during
Week 1, defined as the average of the daily DTA scores obtained via
IVRS from Visit 3 to Visit 4 were analyzed using the same method as
for the Week 1 SQ score. SQ and DTA scores were also summarized
descriptively at each assessed time point, with treatment
comparisons performed at Weeks 2, 3, 4, 6 and 8, using the same
method as for the Week 1 SQ score.
[0821] All quality of life and productivity parameters were
summarized descriptively at each assessed time point for the
double-blind treatment period and were presented by treatment.
Treatment comparisons were performed at each assessed time point
using an analysis of variance model (ANOVA) with treatment and site
as fixed effects.
[0822] Analyses of Rebound and Withdrawal Effects:
[0823] The occurrence of rebound insomnia and withdrawal effects
was assessed for WASO, TST, and SL. For each sleep parameter, the
baseline value was computed by averaging the values obtained from
IVRS for the SB period (i.e., Visit 2 to Visit 3). The change from
baseline to each post-treatment IVRS assessment obtained during the
single-blind washout period (Visit 9 to Visit 10), as well as to
the average of the washout period assessments, was computed.
Descriptive statistics (mean, standard deviation, minimum,
25.sup.th percentile, median, 75.sup.th percentile and maximum)
were presented by treatment at each time point. A Wilcoxon
signed-rank test was performed for each treatment group to assess
whether the distribution of changes from baseline are centered at
zero. In addition, between-group comparisons were performed for
these change-from-baseline variables using the same method as for
the primary analysis.
[0824] The same analyses were performed for the change from the end
of treatment (i.e., mean value during the last week of double-blind
treatment) to each night of the washout period, as well as for the
change from the end of treatment to the average over the washout
period.
[0825] Assessment of rebound and withdrawal was also performed for
the depression measures, HAM-D-17, HAM-D-6 (Bech), HAM-D-6 (Maier),
SQ and DTA. Baseline will be defined as the Visit 3 value for the
HAM-D-17, the single-blind average scores from Visit 2 and Visit 3
for HAM-D-6 (Bech) and HAM-D-6 (Maier) and the average of daily
values obtained via IVRS during the single-blind period (from Visit
2 to Visit 3) for SQ and DTA. The change from baseline to Visit 10
in HAM-D-17 score, and the change from baseline to each
post-treatment assessment obtained during the single-blind washout
period (Visit 9 to Visit 10) was computed for all the other
depression measures. Descriptive statistics (mean, standard
deviation, minimum, 25.sup.th percentile, median, 75.sup.th
percentile and maximum) was presented by treatment at each time
point. A Wilcoxon signed-rank test was performed for each treatment
group to assess whether the distribution of changes from baseline
are centered at zero. In addition, between-group comparisons will
be performed for these change-from-baseline variables using an
analysis of variance model (ANOVA) with treatment and site as fixed
effects.
[0826] The same analyses were performed for the change from the end
of treatment (i.e., value obtained during the last week of
double-blind treatment) to the washout period (Visit 10).
[0827] Exploratory Analyses:
[0828] The full ANOVA model including treatment by site interaction
was used for exploratory analysis of the homogeneity of response by
investigative sites using the primary and the secondary subjective
sleep variables for the intent-to-treat population. If the
interaction is statistically significant at the 0.10 significance
level, additional analyses will be completed to more thoroughly
explore this interaction.
[0829] Treatment comparisons (eszopiclone 3 mg versus placebo) were
also performed, using an ANOVA model with treatment, site, and
baseline as fixed effects for Week 1 average of WASO, TST, and SL.
Baseline is defined as the average of daily IVRS values obtained
between Visit 2 and Visit 3. WASO and SL, the values were log
transformed prior to averaging.
[0830] An analysis exploring the time to onset of antidepressant
response was performed on a subset of those subjects who had a
.gtoreq.30% n antidepressant response, defined as the time from
Visit 3 to the first of two successive clinic assessment time
points at which the subject achieved a .gtoreq.30% reduction from
baseline on the HAM-D-6 (Bech) score. The number of subjects with
antidepressant response was presented along with one minus the
Kaplan-Meier estimate (which in this case, would be the sample
proportions of subjects with response times greater than t).
Additionally, the p-value from the log rank test for equality of
survival curves across treatments was reported and a time to onset
plot (one minus Kaplan-Meier estimate) was produced. This analysis
was repeated for a 50% antidepressant response on the using a
.gtoreq.50% reduction in the HAM-D-6 (Bech), and a 30% and 50%
antidepressant response on the HAM-D-6 (Maier) as the criteria used
to define antidepressant response.
[0831] Adverse Events:
[0832] All adverse experiences were coded using the COSTART
dictionary (Coding Symbols for a thesaurus of Adverse Event Terms;
version 5.0, 1995). Treatment emergent adverse experiences was
defined as 1) AEs that occurred or worsened (increased in severity
and/or frequency) on or after the first dose of study medication,
2) AEs with a missing start data and a stop date on or after the
first dose of study medication, or 3) AEs with both a missing start
and stop date. Treatment emergent AEs was summarized by treatment
and by COSTART body system and preferred term. AEs that occurred
within 14 days after treatment discontinuation was considered
treatment-emergent AEs.
[0833] The following treatment emergent adverse experience
summaries were summarized and presented by treatment group and by
COSTART body system and preferred term: [0834] All AEs (including
number of events and subject incidence) [0835] AEs by Severity
(mild, moderate, severe) [0836] AEs by Relationship to Treatment
(not related, unknown, possible, probable, or definite)
[0837] The following conventions were followed in summarizing AEs:
[0838] For subject incidence summaries, each subject will be
counted only once within each body system and within each preferred
term. [0839] If a subject reports more than one adverse event
within a preferred term and/or a body system, the adverse event
with the highest known severity within each body system and within
each preferred term will be included in the summaries by severity.
[0840] For summaries by relationship to study medication, adverse
event will be reported by the strongest relationship within each
body system and within each preferred term (AEs with unknown
relationship will be considered "more related" than events not
related to study drug).
[0841] Appearance of all new adverse events following
discontinuation of treatment or occurring the day after the last
dose of study drug through the end of the study were summarized and
presented by treatment group. For each subject, an adverse event is
considered a new event if the subject does not experience that
event during treatment or the event worsens in severity after the
end of the treatment.
Subjective Assessments and Questionnaires
[0842] Epworth Sleepiness Scale:
[0843] The Epworth Sleepiness Scale test asks patients to how
likely they are to doze off or fall asleep, in contrast to feeling
just tired, in the following situations: a) sitting and reading, b)
watching TV, c) sitting inactive in a public place, e.g, theatre or
meeting, d) as a passenger in a car for 1 hour without a break, e)
lying down to rest in the afternoon, f) sitting and talking to
someone, g) sitting quietly after lunch (when you've had no
alcohol), and h) in a car while stopped in traffic for a few
minutes. Patients rate their likelihood of dozing off or fall
asleep according to by selecting one of the following: 1) would
never doze, 2) slight chance of dozing, 3) moderate chance of
dozing, or 4) high chance of dozing.
[0844] Insomnia Severity Index:
[0845] The insomnia severity index test is a series of thirteen
questions used to evaluate insomnia.
[0846] Work Limitations Questionnaire:
[0847] The work limitations questionnaire is a series of questions
used to evaluate how the patient's health has affected his or her
work. In part I of the questionnaire, patients are asked to
indicate how satisfied they are with a) their local schools, and b)
their local police department. Patients indicate that they are 1)
not at all satisfied, 2) moderately satisfied, or 3) very
satisfied. In Part II of the questionnaire, patients are asked 25
questions related to work performance. First, patients are asked
how much of the time in the last two weeks did their physical
health or emotional problems make it difficult for them to do the
following: a) work the required number of hours, b) get going
easily at the beginning of the workday, c) start on your job as
soon as you arrived at work, d) do your work without stopping to
take breaks or rests, or e) stick to a routine or schedule. Second,
patients are asked how much of the time in the past two weeks were
they able to do the following without difficulty caused by physical
health or emotional problems: a) walk or move around different work
locations (for example, go to meetings) b) lift, carry, or move
objects at work weighing more than 10 lbs., c) sit, stand, or stay
in one position for longer than 15 minutes while working, d) repeat
the same motions over and over again while working, e) bend, twist,
or reach while working, or f) use hand-held tools or equipment (for
example, a phone, pen, keyboard, computer mouse, drill, hairdryer,
or sander). Third, patients were asked how much of the time in the
past two weeks did their physical health or emotional problems make
it difficult to do the following: a) keep your mind on your work,
b) think clearly when working, c) do work carefully, d) concentrate
on your work, e) work without losing your train of thought, or f)
easily read or use your eyes when working. Fourth, patients were
asked how much of the time in the past two weeks did their physical
health or emotional problems make it difficult to do the following:
a) speak with people in-person, in meetings or on the phone, b)
control your temper around people when working, or c) help other
people to get work done. Fifth, patients were asked how much of the
time in the past two weeks did their physical health or emotional
problems make it difficult to do the following: a) handle the
workload, b) work fast enough, c) finish work on time, d) do your
work without making mistakes, or e) feel you've done what you are
capable of doing. Patients respond to the aforementioned questions
by indicating one of the following responses: 1) All of the time
(100%), 2) most of the time, 3) some of the time (about 50%), 4) a
slight bit of the time, 5) none of the time (0%), or 6) does not
apply to my job.
[0848] Acute Health Survey:
[0849] The Acute Health Survey is a series of eleven questions
answered by the patient to evaluate how they perceive their
health.
[0850] Hamilton Depression Rating Scale (HAM-D17):
[0851] During this analysis, a medical professional evaluates the
patient according to seventeen criteria by selecting the response
that best characterizes the patient's behavior during the past
week. The criteria and responses are based on that described in Br.
J. Soc. Clin. Psychol. 6: 278-296 (1967) and are reproduced below.
Question 1: Depressed mood (Sadness, hopeless, helpless,
worthless); Response: 0--Absent, 1--These feeling states indicated
only on questioning, 2--These feeling states spontaneously reported
verbally, 3--Communicates feeling states non-verbally i.e., through
facial expression, posture, voice, and tendency to weep, or
4--Patient report virtually only these feeling states in his
spontaneous verbal and non-verbal communication. Question 2:
Feeling of guilt; Response: 0--Absent, 1--Self reproach, feels he
has let people down, 2--Ideas of guilt or rumination over past
errors or sinful deeds, 3--Present illness is a punishment and/or
has delusions of guilt, or 4--Hears accusatory or denunciatory
voices and/or experiences threatening visual hallucinations.
Question 3: Suicide; Response: 0--Absent, 1--Feels life is not
worth living, 2--Wishes he were dead or any thoughts of possible
death to self, 3--Suicide ideas or gesture, 4--Attempts at suicide
(any serious attempt rates 4). Question 4: Insomnia early;
Response: 0--No difficulty falling asleep; 1--Complains of
occasional difficulty falling asleep--i.e., more than 1/2 hour; or
2--complains of nightly difficulty falling asleep. Question 5:
Insomnia middle; Response: 0--No difficulty, 1--patient complains
of being restless and disturbed during the night, or 2--Waking
during the night--any getting out of bed rates 2 (except for
purposes of voiding). Question 6: Insomnia Late; Response: 0--No
difficulty, 1--Waking in early hours of the morning but goes back
to sleep, or 2--Unable to fall asleep again if he gets out of bed.
Question 7: Work and activities; Response: 0--No difficulty,
1--Thoughts and feelings of incapacity, fatigue or weakness related
to activities, work or hobbies; 2--Loss of interest in activity,
hobbies or work--either directly reported by patient, or indirect
in listlessness, indecision and vacillation (feels he has to push
self to work or activities); 3--Decrease in actual time spent in
activities or decrease in productivity (In hospital, rate 3 if
patient does not spend at least three hours a day in activities
(hospital job or hobbies) exclusive of ward chores); or 4--Stopped
working because of present illness (In hospital, rate 4 if patient
engages in no activities except ward chores, or if patient fails to
perform ward chores unassisted). Question 8: Retardation (Slowness
of thought and speech; impaired ability to concentrate; decreased
motor activity); Response: 0--Normal speech and thought, 1--Slight
retardation at interview, 2--Obvious retardation at interview,
3--Interview difficult, or 4--Complete stupor. Question 9:
Agitation; Response: 0--None; 1--Fidgetiness; 2--Playing with
hands, hair, etc.; 3--Moving about, can't sit still; or 4--Hand
wringing, nail biting, hair-pulling, biting of lips. Question 10:
Anxiety psychic: 0--No difficulty, 1--Subjective tension and
irritability, 2--Worrying about minor matters, 3--Apprehensive
attitude apparent in face or speech, or 4--Fears expressed without
questioning. Question 11: Anxiety somatic (Physiological
concomitants of anxiety, such as: --Gastro-intestinal: dry mouth,
wind, indigestion, diarrhea, cramps, belching. --Cardio-vascular:
palpitations, headaches. --Respiratory: hyperventilation, sighing.
--Urinary frequency --Sweating); Response: 0--Absent, 1--Mild,
2--Moderate, 3--Severe, or 4--Incapacitating. Question 12: Somatic
symptoms gastro-intestinal; Response: 0--None, 1--Loss of appetite
but eating without staff encouragement and/or heavy feelings in
abdomen; or 2--Difficulty eating without staff urging and/or
requests or requires laxatives or medication for bowels or
medication for gastro-intestinal symptoms. Question 13: Somatic
symptoms general; Response: 0--None; 1--Heaviness in limbs, back or
head; backaches, headache, or muscle aches; or loss of energy and
fatigability; or 2--Any clear-cut symptom rates 2. Question 14:
Genital symptoms (Symptoms such as loss of libido, menstrual
disturbances); Response: 0--Absent, 1--Mild, or 2--Severe. Question
15: Hypochondriasis; Response: 0--Not present, 1--Self-absorption
(bodily); 2--Preoccupation with health; 3--Frequent complaints,
requests for help, etc.; or 4--Hypochondriacal delusions. Question
16: Loss of Weight; Response: A) When rating by history: 0--No
weight loss, 1--Probable weight loss associated with present
illness, or 2--Definite (according to patient) weight loss. B) On
weekly rating by ward psychiatrist, when actual weight changes are
measured: 0--Less than 1 lb (500 g), weight loss in week;
1--Greater than 1 lb (500 g), weight loss in week; or 2--Greater
than 2 lb (1000 g), weight loss in week. Question 17: Insight:
0--Acknowledges being depressed and ill; 1--Acknowledges illness
but attributes cause to bad food, climate, overwork, virus, need
for rest, etc.; or 2--Denies being ill at all.
[0852] Clinical Global Impression:
[0853] In this test, a medical professional rates the patient's
depression and whether the improvement in depression is due to the
drug treatment. Question 1) Severity: Considering your total
clinical experience with this particular population, how depressed
is the patient at this time? Respond by indicating 1=normal, not at
all depressed, 2=borderline depressed, 3=mildly depressed,
4=moderately depressed, 5=markedly depressed, 6=severely depressed,
or 7=among the most extremely depressed patients. Question 2)
Global Improvement: Rate total improvement whether or not, in your
judgment, it is due entirely to drug treatment. Compared to his/her
condition at Visit 3, how much has he/she changed? Respond by
indicating 1=very much improved, 2=much improved, 3=minimally
improved, 4=no change, 5=minimally worse, 6=much worse, or 7=very
much worse.
[0854] Sleep Diary Test:
[0855] Patients are to call between 6 a.m. and 10 a.m. and answer
the following questions. 1) Did you take study medication last
night? 2) What time did you go to bed to go to sleep last night? 3)
Did you fall asleep last night? (If No, go to question 10) 4) How
long did it take you to fall asleep last night? Hours+Minutes? 5)
Last night, did you wake up during the night, after falling asleep?
5a) How many times, did you wake up after falling asleep? 5b) After
falling asleep for the first time, how much total time did you
spend awake during the night? Hours+Minutes? 6) How long did you
sleep last night? Hours+Minutes? 7) What time did you get out of
bed to rise for the day? 8) What number best describes the quality
of your sleep last night? (0=poor and 10=excellent) 9) How would
you describe the depth of your sleep last night? (0=very light and
10=very deep) 10) What number best describes how you generally felt
yesterday during the day? (0=very sleepy and 10=wide awake and
alert) 11) What number best describes your ability to concentrate
or think clearly during the day yesterday (0=poor, 10=excellent)
12) What number best describes your sense of physical well being
yesterday? (0=poor, 10=excellent) 13) How would you describe your
ability to function during the day yesterday? (0=poor and
10=excellent)
[0856] Daily Telephone Assessment (DTA):
[0857] In this test, patients call in to and indicate their
condition relating to the following: Question 1) Sadness: On a
scale from 0 to 9, how sad or depressed have you felt in the last
24-hours? 0 means you have not felt sad or depressed at all in the
last 24 hours and 9 means you've been extremely depressed or sad.
Press a number from 0 to 9 that best describes your feelings of
sadness. Question 2) Nervousness: On a scale from 0 to 9, how
nervous or anxious have you felt in the last 24-hours? 0 means
you've not felt nervous or anxious at all in the last 24-hours and
9 means you've been extremely nervous or anxious. Press a number
from 0 to 9 that best describes your feelings of nervousness or
anxiety. Question 3) Irritability: On a scale from 0 to 9, how
easily annoyed, irritated or upset have you been in the last
24-hours? 0 means you've not become annoyed, irritated or upset at
all in the last 24-hours and 9 means you've been extremely easily
annoyed, irritated or upset. Press a number from 0 to 9 that best
describes your irritability. Question 4) Lack of energy: On a scale
from 0 to 9, how much has your energy level been a problem for you
in the last 24-hours? 0 means you've had plenty of energy and have
not felt tired at all in the last 24-hours and 9 means you've been
extremely tired, sluggish, or lacking in energy. Press a number
from 0 to 9 that best describes your lack of energy. Question 5)
Difficulty thinking: On a scale from 0 to 9, how difficult has it
been for you to think about or concentrate on things in the last
24-hours? 0 means you've had no trouble thinking or concentrating
at all in the last 24-hours and 9 means it's been extremely
difficult for you to think or concentrate. Press a number from 0 to
9 that best describes your difficulty in thinking or concentrating.
Question 6) Aches, pains or other discomforts: On a scale from 0 to
9, rate how much aches, pains, or other physical discomforts in
your head, back, chest, belly, arms, or legs have bothered you in
the last 24-hours. 0 means you've had no problems with aches,
pains, or other discomforts at all in the last 24-hours and 9 means
your aches, pains, or other discomforts have been extremely
bothersome. Press a number from 0 to 9 that best describes how much
your aches, pains, or other discomforts have been bothering you.
Question 7) Problems with sleep: On a scale from 0 to 9, rate how
much of a problem you had getting the sleep you wanted last night.
0 means you had no sleep problems at all. That is, you were able to
go to sleep easily, you slept well, and you woke up feeling
refreshed. 9 means you had great difficulty in getting to sleep,
slept extremely poorly, or woke up feeling exhausted as if you had
not slept. Press a number from 0 to 9 that best describes your
problems with sleep. Question 8) Difficulty enjoying things: On a
scale of 0 to 9, rate how hard it has been for you to enjoy things
in the last 24-hours. Press 0 if you have had no trouble enjoying
things. Press 9 if you have not been able to enjoy anything. Or
press the number from 0 and 9 that best describes how much
difficulty you have enjoying things in the last 24-hours. Question
9) Overall change since your last call, if you've not changed,
press 1; if you're feeling better, press 2; if you're feeling
worse, press 3. 9a) <<If better>> If you're a little
better, press 1; if you're much better, press 2; if you're very
much better, press 3. 9b) <<If worse>> If you're a
little worse, press 1; if you're much worse, press 2; if you're
very much worse, press 3.
[0858] The Symptom Questionnaire (23-Item Depression Subscale):
[0859] This test asks patients to describe how they have felt in
the last 24-hours regarding twenty-three criteria. Patients are
asked to answer yes or no to the criteria. Criteria: weary,
cheerful, sad or blue, happy, feeling unworthy, cannot enjoy
yourself, feeling guilty, feeling well, contented, feeling
desperate or terrible, thinking death or dying, enjoying yourself,
depressed, feeling a failure, not interested in things, blaming
yourself, thoughts of ending your life, looking forward toward the
future, feeling that life is bad, feeling inferior to others,
feeling useless, feel like crying, and feeling hopelessness.
DSM-IV: Criteria for Major Depressive Disorder
[0860] Diagnostic Criteria for 296.2x Major Depressive Disorder,
Single Episode:
[0861] A) Presence of a single Major Depressive Episode. B) The
Major Depressive Episode is not better accounted for by
Schizoaffective Disorder and is not superimposed on Schizophrenia,
Schizophreniform Disorder, Delusional Disorder, or Psychotic
Disorder Not Otherwise Specified. C) There has never been a Manic
Episode, a Mixed Episode, or a Hypomanic Episode. Note: This
exclusion does not apply if all of the manic-like, mixed-like, or
hypomanic-like episodes are substance or treatment-induced or are
due to the direct physiological effects of a general medical
condition.
[0862] Diagnostic Criteria for 296.3x Major Depressive Disorder,
Recurrent:
[0863] A) Presence of two or more Major Depressive Episodes. Note:
To be considered separate episodes, there must be an interval of at
least 2 consecutive months in which criteria are not met for a
Major Depressive Episode. B) The Major Depressive Episodes are not
better accounted for by Schizoaffective Disorder and are not
superimposed on Schizophrenia, Schizophreniform Disorder,
Delusional Disorder, or Psychotic Disorder Not Otherwise Specified.
C) There has never been a Manic Episode, a Mixed Episode, or a
Hypomanic Episode. Note: This exclusion does not apply if all of
the manic-like, mixed-like, or hypomanic-like episodes are
substance or treatment-induced or are due to the direct
physiological effects of a general medical condition.
[0864] DSM-IV Diagnostic Criteria for Insomnia Related to Major
Depressive Disorder:
[0865] A) The predominant complaint is difficulty initiating or
maintaining sleep, or nonrestorative sleep, for a least 1 month
that is associated with daytime fatigue or impaired daytime
functioning. B) The sleep disturbance (or daytime sequelae) causes
clinically significant distress or impairment in social,
occupational, or other important areas of functioning. C) The
insomnia is judged to be related to Major Depressive Disorder, but
is sufficiently severe to warrant independent clinical attention.
D) The disturbance is not better accounted for by another Sleep
Disorder (e.g., Narcolepsy, Breathing-Related Sleep Disorder, a
Parasomnia) E) The disturbance is not due to the direct
physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition.
[0866] Results of Study:
TABLE-US-00002 TABLE 1 Summary of Fluoxetine Titration During
Double-Blind Treatment Period (Intent-to-Treat Population) Placebo
Eszopiclone 3 mg (N = 274) (N = 269) Total Total Subjects
Fluoxetine Fluoxetine Subjects Fluoxetine Fluoxetine on
Hydrochloride Hydrochloride on Hydrochloride Hydrochloride Study 20
mg 40 mg Study 20 mg 40 mg Assessment n n (%) n (%) n n (%) n (%)
Visit 3 274 274 (100.0%) 0 (0.0%) 269 269 (100.0%) 0 (0.0%) Visit 4
274 274 (100.0%) 0 (0.0%) 268 268 (100.0%) 0 (0.0%) Visit 5 274 274
(100.0%) 0 (0.0%) 268 268 (100.0%) 0 (0.0%) Visit 6 274 274
(100.0%) 0 (0.0%) 268 268 (100.0%) 0 (0.0%) Visit 7 [1] 225 104
(46.2%) 121 (53.8%) 224 125 (55.8%) 99 (44.2%) Visit 8 204 91
(44.6%) 113 (55.4%) 213 115 (54.0%) 98 (46.0%) Visit 9 195 88
(45.1%) 107 (54.9%) 195 103 (52.8%) 92 (47.2%) [1] If the subject's
depressive symptoms had not improved in the investigator's opinion,
then fluoxetine dose was increased to 40 mg at Visit 7. Note(s):
Percentages are computed based on the total number of subjects on
study within each double-blind treatment group at each visit. All
subjects were administered single-blind placebo and fluoxetine
during the single-blind wash-out period.
TABLE-US-00003 TABLE 2 Subjective Wake Time After Sleep Onset
(WASO) (Minutes) (Intent-to-Treat Population) Placebo Eszopiclone 3
mg Week [1] Statistic (N = 274) (N = 269) 4 N 129 138 Mean (SD)
73.5 (69.5) 71.4 (80.3) 25th Percentile 30.0 20.0 Median 55.8 42.5
75th Percentile 90.0 90.0 Minimum, Maximum 0, 420 0, 420 p-value
vs. placebo [2] 0.0345 6 N 117 116 Mean (SD) 73.5 (83.4) 76.5
(88.1) 25th Percentile 30.0 15.0 Median 60.0 46.3 75th Percentile
90.0 111.5 Minimum, Maximum 0, 600 0, 605 p-value vs. placebo [2]
0.3789 8 N 164 160 Mean (SD) 82.0 (73.2) 63.8 (74.1) 25th
Percentile 36.3 21.9 Median 60.8 43.1 75th Percentile 105.0 80.1
Minimum, Maximum 0, 480 0, 600 p-value vs. placebo [2] 0.0003 [1]
For each subject, Week 1 = average of all post randomization
assessments obtained between Visit 3 and Visit 4, Week 2 = average
of all post randomization assessments obtained between Visit 4 and
Visit 5. Double-Blind Average includes all assessments obtained
from Visits 3, 4, 5, 6, 7, and 8. [2] The analysis is conducted
using an analysis of variance model (ANOVA) on the rank-transformed
data with treatment and site as fixed effects. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00004 TABLE 3 Subjective Wake Time After Sleep Onset
(WASO) (Minutes) (Intent-to-Treat Population) Placebo Eszopiclone 3
mg Week [1] Statistic (N = 274) (N = 269) Double-Blind N 242 242
Average Mean (SD) 84.1 (63.2) 72.6 (58.7) 25th Percentile 42.9 28.4
Median 73.4 57.4 75th Percentile 110.8 100.0 Minimum, Maximum 0,
490 2, 350 p-value vs. placebo [2] 0.0051 [1] For each subject,
Week 1 = average of all post randomization assessments obtained
between Visit 3 and Visit 4, Week 2 = average of all post
randomization assessments obtained between Visit 4 and Visit 5.
Double-Blind Average includes all assessments obtained from Visits
3, 4, 5, 6, 7, and 8. [2] The analysis is conducted using an
analysis of variance model (ANOVA) on the rank-transformed data
with treatment and site as fixed effects. The analysis is performed
using the SAS MIXED procedure.
TABLE-US-00005 TABLE 4 Subjective Sleep Latency (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) 1 N 236 238 Mean (SD) 79.2 (82.8)
62.6 (61.0) 25th Percentile 33.3 23.6 Median 57.9 43.3 75th
Percentile 94.0 75.0 Minimum, Maximum 6, 668 0, 435 p-value vs.
placebo [2] 0.0002 2 N 217 224 Mean (SD) 64.4 (78.3) 45.0 (52.2)
25th Percentile 30.0 15.0 Median 45.0 30.0 75th Percentile 75.0
58.8 Minimum, Maximum 1, 720 0, 458 p-value vs. placebo [2]
<.0001 3 N 205 217 Mean (SD) 62.9 (74.3) 54.1 (100.9) 25th
Percentile 25.0 15.0 Median 37.5 25.0 75th Percentile 75.0 60.0
Minimum, Maximum 0, 611 0, 1058 p-value vs. placebo [2] <.0001
[1] For each subject, Week 1 = average of all post randomization
assessments obtained between Visit 3 and Visit 4, Week 2 = average
of all post randomization assessments obtained between Visit 4 and
Visit 5. Double-Blind Average includes all assessments obtained
from Visits 3, 4, 5, 6, 7, and 8. [2] The analysis is conducted
using an analysis of variance model (ANOVA) on the rank-transformed
data with treatment and site as fixed effects. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00006 TABLE 5 Subjective Sleep Latency (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) 4 N 191 207 Mean (SD) 60.0 (68.8)
40.5 (50.5) 25th Percentile 22.5 15.0 Median 42.5 24.2 75th
Percentile 75.0 45.0 Minimum, Maximum 0, 665 0, 330 p-value vs.
placebo [2] <.0001 6 N 176 189 Mean (SD) 71.4 (122.1) 43.8
(77.3) 25th Percentile 20.0 12.5 Median 36.3 20.0 75th Percentile
69.6 45.0 Minimum, Maximum 0, 1200 0, 630 p-value vs. placebo [2]
<.0001 8 N 205 209 Mean (SD) 61.4 (56.1) 42.4 (42.3) 25th
Percentile 25.0 15.5 Median 45.0 30.0 75th Percentile 78.0 54.0
Minimum, Maximum 0, 326 1, 254 p-value vs. placebo [2] <.0001
[1] For each subject, Week 1 = average of all post randomization
assessments obtained between Visit 3 and Visit 4, Week 2 = average
of all post randomization assessments obtained between Visit 4 and
Visit 5. Double-Blind Average includes all assessments obtained
from Visits 3, 4, 5, 6, 7, and 8. [2] The analysis is conducted
using an analysis of variance model (ANOVA) on the rank-transformed
data with treatment and site as fixed effects. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00007 TABLE 6 Subjective Sleep Latency (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) Double-Blind N 257 257 Average Mean
(SD) 73.8 (65.4) 53.0 (52.6) 25th Percentile 33.1 22.5 Median 56.1
39.3 75th Percentile 92.6 65.0 Minimum, Maximum 6, 668 4, 465
p-value vs. placebo [2] <.0001 [1] For each subject, Week 1 =
average of all post randomization assessments obtained between
Visit 3 and Visit 4, Week 2 = average of all post randomization
assessments obtained between Visit 4 and Visit 5. Double-Blind
Average includes all assessments obtained from Visits 3, 4, 5, 6,
7, and 8. [2] The analysis is conducted using an analysis of
variance model (ANOVA) on the rank-transformed data with treatment
and site as fixed effects. The analysis is performed using the SAS
MIXED procedure.
TABLE-US-00008 TABLE 7 Subjective Total Sleep Time (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) 1 N 236 238 Mean (SD) 340.3 (86.3)
375.9 (76.5) 25th Percentile 281.7 330.0 Median 335.0 380.0 75th
Percentile 391.8 423.8 Minimum, Maximum 120, 780 80, 565 p-value
vs. placebo [2] <.0001 2 N 217 224 Mean (SD) 360.1 (91.6) 393.6
(103.0) 25th Percentile 300.0 333.1 Median 356.3 397.5 75th
Percentile 420.0 450.0 Minimum, Maximum 150, 720 140, 1200 p-value
vs. placebo [2] 0.0001 3 N 205 217 Mean (SD) 373.8 (88.4) 397.3
(88.1) 25th Percentile 315.0 345.0 Median 375.0 405.0 75th
Percentile 425.0 450.0 Minimum, Maximum 135, 793 0, 660 p-value vs.
placebo [2] 0.0035 [1] For each subject, Week 1 = average of all
post randomization assessments obtained between Visit 3 and Visit
4, Week 2 = average of all post randomization assessments obtained
between Visit 4 and Visit 5. Double-Blind Average includes all
assessments obtained from Visits 3, 4, 5, 6, 7, and 8. [2] The
analysis is conducted using an analysis of variance model (ANOVA)
on the rank-transformed data with treatment and site as fixed
effects. The analysis is performed using the SAS MIXED
procedure.
TABLE-US-00009 TABLE 8 Subjective Total Sleep Time (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) 4 N 191 207 Mean (SD) 370.4 (95.5)
395.6 (87.3) 25th Percentile 300.0 337.5 Median 371.7 390.0 75th
Percentile 450.0 450.0 Minimum, Maximum 60, 600 165, 653 p-value
vs. placebo [2] 0.0253 6 N 176 189 Mean (SD) 369.9 (95.9) 408.5
(84.3) 25th Percentile 315.0 360.0 Median 375.0 420.0 75th
Percentile 428.8 472.5 Minimum, Maximum 0, 720 150, 600 p-value vs.
placebo [2] <.0001 8 N 205 209 Mean (SD) 375.9 (87.2) 405.9
(80.6) 25th Percentile 321.4 365.0 Median 387.5 411.4 75th
Percentile 439.3 462.1 Minimum, Maximum 0, 554 60, 630 p-value vs.
placebo [2] 0.0009 [1] For each subject, Week 1 = average of all
post randomization assessments obtained between Visit 3 and Visit
4, Week 2 = average of all post randomization assessments obtained
between Visit 4 and Visit 5. Double-Blind Average includes all
assessments obtained from Visits 3, 4, 5, 6, 7, and 8. [2] The
analysis is conducted using an analysis of variance model (ANOVA)
on the rank-transformed data with treatment and site as fixed
effects. The analysis is performed using the SAS MIXED
procedure.
TABLE-US-00010 TABLE 9 Subjective Total Sleep Time (Minutes)
(Intent-to-Treat Population) Placebo Eszopiclone 3 mg Week [1]
Statistic (N = 274) (N = 269) Double-Blind N 257 257 Average Mean
(SD) 358.8 (75.4) 395.5 (66.9) 25th Percentile 310.4 353.7 Median
362.8 400.0 75th Percentile 405.0 441.2 Minimum, Maximum 23, 556
210, 630 p-value vs. placebo [2] <.0001 [1] For each subject,
Week 1 = average of all post randomization assessments obtained
between Visit 3 and Visit 4, Week 2 = average of all post
randomization assessments obtained between Visit 4 and Visit 5.
Double-Blind Average includes all assessments obtained from Visits
3, 4, 5, 6, 7, and 8. [2] The analysis is conducted using an
analysis of variance model (ANOVA) on the rank-transformed data
with treatment and site as fixed effects. The analysis is performed
using the SAS MIXED procedure.
TABLE-US-00011 TABLE 10 Summary of Change from Baseline in Clinical
Global Impression (CGI) - Severity (Intent-to-Treat Population)
Placebo Eszopiclone 3 mg Change Change Visit Observed from Observed
from [1] Statistic Value Baseline Value Baseline 3 N 274 269 (Base-
Mean (SD) 4.3 (0.6) 4.3 (0.6) line) 25th Percentile 4.0 4.0 Median
4.0 4.0 75th Percentile 5.0 5.0 Minimum, 2, 6 3, 6 Maximum 4 N 251
251 245 245 Mean (SD) 4.0 (0.7) -0.3 (0.6) 4.0 (0.7) -0.3 (0.7)
25th Percentile 4.0 0.0 4.0 -1.0 Median 4.0 0.0 4.0 0.0 75th
Percentile 4.0 0.0 4.0 0.0 Minimum, 1, 6 -3, 1 1, 6 -4, 1 Maximum
Least Squares -0.3 (0.0) -0.3 (0.0) Mean (SE) p-value vs. 0.2069
placebo [2] [1] For each subject, Baseline = Average of Daily IVRS
values obtained prior to or on the first dose of double-blind
treatment. [2] The pairwise comparison of the placebo treatment
mean to the eszopiclone treatment mean is performed using the
analysis of covariance model (ANCOVA) with treatment and site as
fixed effects and the baseline as a covariate. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00012 TABLE 11 Summary of Change from Baseline in Clinical
Global Impression (CGI) - Severity (Intent-to-Treat Population)
Placebo Eszopiclone 3 mg Change Change Visit Observed from Observed
from [1] Statistic Value Baseline Value Baseline 5 N 243 243 241
241 Mean (SD) 3.7 (0.8) -0.6 (0.8) 3.6 (0.9) -0.8 (0.9) 25th
Percentile 3.0 -1.0 3.0 -1.0 Median 4.0 0.0 4.0 -1.0 75th
Percentile 4.0 0.0 4.0 0.0 Minimum, 1, 6 -3, 2 1, 6 -4, 0 Maximum
Least Squares -0.6 (0.1) -0.8 (0.1) Mean (SE) p-value vs. 0.0364
placebo [2] 6 N 233 233 233 233 Mean (SD) 3.4 (1.0) -0.9 (0.9) 3.2
(1.0) -1.1 (1.0) 25th Percentile 3.0 -1.0 3.0 -2.0 Median 4.0 -1.0
3.0 -1.0 75th Percentile 4.0 0.0 4.0 0.0 Minimum, 1, 6 -4, 2 1, 6
-5, 1 Maximum Least Squares -0.9 (0.1) -1.1 (0.1) Mean (SE) p-value
vs. 0.0367 placebo [2] [1] For each subject, Baseline = Average of
Daily IVRS values obtained prior to or on the first dose of
double-blind treatment. [2] The pairwise comparison of the placebo
treatment mean to the eszopiclone treatment mean is performed using
the analysis of covariance model (ANCOVA) with treatment and site
as fixed effects and the baseline as a covariate. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00013 TABLE 12 Summary of Change from Baseline in Clinical
Global Impression (CGI) - Severity (Intent-to-Treat Population)
Placebo Eszopiclone 3 mg Change Change Visit Observed from Observed
from [1] Statistic Value Baseline Value Baseline 7 N 223 223.sup.
222 222 Mean (SD) 3.2 (1.1) -1.1 (1.2) 3.0 (1.1) -1.4 (1.1) 25th
Percentile 3.0 -2.0 2.0 -2.0 Median 3.0 -1.0 3.0 -1.0 75th
Percentile 4.0 0.0 4.0 0.0 Minimum, 1, 5 -4, 1 1, 5 -5, 1 Maximum
Least Squares -1.1 (0.1) -1.3 (0.1) Mean (SE) p-value vs. 0.0380
placebo [2] 8 N 200 200.sup. 212 212 Mean (SD) 2.7 (1.0) -1.5 (1.1)
2.5 (1.0) -1.8 (1.2) 25th Percentile 2.0 -2.0 2.0 -3.0 Median 3.0
-1.0 2.5 -2.0 75th Percentile 3.0 -1.0 3.0 -1.0 Minimum, 1, 5 -4, 1
1, 5 -5, 1 Maximum Least Squares -1.5 (0.1) -1.8 (0.1) Mean (SE)
p-value vs. 0.0124 placebo [2] [1] For each subject, Baseline =
Average of Daily IVRS values obtained prior to or on the first dose
of double-blind treatment. [2] The pairwise comparison of the
placebo treatment mean to the eszopiclone treatment mean is
performed using the analysis of covariance model (ANCOVA) with
treatment and site as fixed effects and the baseline as a
covariate. The analysis is performed using the SAS MIXED
procedure.
TABLE-US-00014 TABLE 13 Summary of Change from Baseline in Clinical
Global Impression (CGI) - Severity (Intent-to-Treat Population)
Placebo Eszopiclone 3 mg Change Change Visit Observed from Observed
from [1] Statistic Value Baseline Value Baseline 9 N 236 236.sup.
229 229 Mean (SD) 2.7 (1.2) -1.6 (1.2) 2.4 (1.2) -1.9 (1.3) 25th
Percentile 2.0 -3.0 1.0 -3.0 Median 3.0 -2.0 2.0 -2.0 75th
Percentile 4.0 -1.0 3.0 -1.0 Minimum, 1, 6 -5, 2 1, 6 -5, 1 Maximum
Least Squares -1.6 (0.1) -1.8 (0.1) Mean (SE) p-value vs. 0.0186
placebo [2] 10 N 191 191.sup. 188 188 (EOT) Mean (SD) 2.4 (1.1)
-1.9 (1.2) 2.0 (1.0) -2.3 (1.2) 25th Percentile 1.0 -3.0 1.0 -3.0
Median 2.0 -2.0 2.0 -2.0 75th Percentile 3.0 -1.0 3.0 -1.0 Minimum,
1, 5 -5, 0 1, 5 -5, 1 Maximum Least Squares -1.8 (0.1) -2.2 (0.1)
Mean (SE) p-value vs. 0.0004 placebo [2] [1] For each subject,
Baseline = Average of Daily IVRS values obtained prior to or on the
first dose of double-blind treatment. [2] The pairwise comparison
of the placebo treatment mean to the eszopiclone treatment mean is
performed using the analysis of covariance model (ANCOVA) with
treatment and site as fixed effects and the baseline as a
covariate. The analysis is performed using the SAS MIXED
procedure.
TABLE-US-00015 TABLE 14 Clinical Global Impression (CGI) - Global
Improvement (Intent-to-Treat Population) Placebo Eszopiclone 3 mg
Visit Statistic (N = 274) (N = 269) 4 N 250 242 Mean (SD) 3.5 (0.7)
3.3 (0.8) 25th Percentile 3.0 3.0 Median 4.0 3.0 75th Percentile
4.0 4.0 Minimum, Maximum 1, 5 0, 5 p-value vs. placebo [1]
<.0001 5 N 242 241 Mean (SD) 3.0 (0.8) 2.9 (0.8) 25th Percentile
3.0 2.0 Median 3.0 3.0 75th Percentile 4.0 3.0 Minimum, Maximum 0,
5 1, 4 p-value vs. placebo [1] 0.0180 6 N 233 233 Mean (SD) 2.8
(0.9) 2.6 (0.9) 25th Percentile 2.0 2.0 Median 3.0 3.0 75th
Percentile 3.0 3.0 Minimum, Maximum 1, 5 1, 6 p-value vs. placebo
[1] 0.0166 [1] The analysis is conducted using an analysis of
variance model (ANOVA) with treatment and site as fixed effects.
The analysis is performed using the SAS MIXED procedure.
TABLE-US-00016 TABLE 15 Clinical Global Impression (CGI) - Global
Improvement (Intent-to-Treat Population) Placebo Eszopiclone 3 mg
Visit Statistic (N = 274) (N = 269) 7 N 222 222 Mean (SD) 2.7 (1.1)
2.4 (1.0) 25th Percentile 2.0 2.0 Median 3.0 2.0 75th Percentile
3.0 3.0 Minimum, Maximum 1, 5 1, 5 p-value vs. placebo [1] 0.0011 8
N 200 211 Mean (SD) 2.2 (0.9) 1.9 (0.9) 25th Percentile 2.0 1.0
Median 2.0 2.0 75th Percentile 3.0 3.0 Minimum, Maximum 1, 4 1, 5
p-value vs. placebo [1] 0.0057 9 N 236 229 Mean (SD) 2.2 (1.1) 1.9
(1.0) 25th Percentile 1.0 1.0 Median 2.0 2.0 75th Percentile 3.0
2.0 Minimum, Maximum 1, 6 0, 6 p-value vs. placebo [1] 0.0009 [1]
The analysis is conducted using an analysis of variance model
(ANOVA) with treatment and site as fixed effects. The analysis is
performed using the SAS MIXED procedure.
TABLE-US-00017 TABLE 16 Clinical Global Impression (CGI) - Global
Improvement (Intent-to-Treat Population) Placebo Eszopiclone 3 mg
Visit Statistic (N = 274) (N = 269) 10 (EOT) N 190 188 Mean (SD)
2.0 (1.0) 1.6 (0.9) 25th Percentile 1.0 1.0 Median 2.0 1.0 75th
Percentile 3.0 2.0 Minimum, Maximum 1, 5 0, 5 p-value vs. placebo
[1] 0.0003 [1] The analysis is conducted using an analysis of
variance model (ANOVA) with treatment and site as fixed effects.
The analysis is performed using the SAS MIXED procedure.
TABLE-US-00018 TABLE 17 Subject Disposition Placebo Eszopiclone 3
mg Subject Disposition n (%) n (%) Randomized 275 (100.0) 270
(100.0) Completed 185 (67.3) 187 (69.3) Discontinued 89 (32.4) 83
(30.7) AE 21 (7.6) 17 (6.3) Protocol violation 14 (5.1) 10 (3.7)
Voluntary withdrawal 21 (7.6) 19 (7.0) Lost to follow-up 24 (8.7)
26 (9.6) Did not meet entry criteria 3 (1.1) 4 (1.5) Treatment for
Insomnia Failure 2 (0.7) 2 (0.7) Other 4 (1.5) 5 (1.9)
[0867] The results of this study clearly demonstrate a number of
unique and distinct responses, both for sleep and depression, when
eszopiclone 3 mg nightly was co-administered with flouxetine HCk 20
mg or 40 mg daily, as discuss below: [0868] 1. Co-administration of
eszopiclone and fluoxetine was well-tolerated and provided rapid
and sustained improvement in sleep in patients with
depression-related secondary insomnia. The rapid onset of sleep
improvement is an important consideration for adjunctive therapy or
co-administration with an antidepressant, such as an SSRI, as the
antidepressant effect demonstrated a relatively slower onset.
[0869] 2. These results indicate that patients co-administered a
sedative (e.g., SSRI plus eszopiclone) may be more likely to be
resistant to a recurring sleep disturbance which can be a prodromal
relapse signal. [0870] 3. A pronounced and immediate sleep response
was recorded for all three sleep parameters in this trial (sleep
onset, WASO, and TST). This response differed in its time course
from the observed augmentation effect on antidepressant therapy,
which took hold gradually over the course of several weeks, hand in
hand with the usually occurring antidepressant effect that is
typically seen in this kind of cohort of patients with major
depression. These different time courses indicate that separate,
but potentially interlinked, biological processes are being
affected by eszopiclone, leading to the distinct and temporally
divergent improvement responses in sleep and depression. [0871] 4.
Eszopiclone co-administration significantly improved sleep and
augmented the anti-depression response in patients with MDD and
insomnia, as shown by the HAMD changes, response rates, and CGI.
[0872] 5. The augmentation effect observed with eszopiclone was
larger than that observed with agents currently used for
augmentation therapy, such as lithium. [0873] 6. Eszopiclone
produced this augmentation effect with little risk to patients,
whereas currently commonly used augmentation agents can produce
considerable toxicity. In addition co-administration of eszopiclone
may specially reduce undesirable CNS adverse events, such as
agitation, confusion, and other symptoms related to the underlying
depression. [0874] 7. In terms of potential and clinically
meaningful benefits to depression patients during treatment
initiation, it is important to point out that these results
indicate that eszopiclone can help alleviate worsening of sleep
during introduction of antidepressants. Insomnia is a common
complaint during treatment initiation, and these symptoms may be
related to the antidepressant therapy chosen by the clinician, not
the underlying depression. [0875] 8. The augmentation effect
observed at the end of the 8 week treatment period in this study
was most pronounced in the most severely depressed patients. [0876]
9. These results suggest that the augmentation effect may apply to
de novo depressed patients, patients with relapsing depression, as
well as patient with refractory depression. [0877] 10. The observed
augmentation effect size grew gradually over time. [0878] 11. Quite
unexpectedly, less patients in this study required antidepressant
dose escalation to higher dose of fluoxetine, and indicating that
co-administration of eszopiclone provided a dose-sparing effect. A
dose-sparing effect can lead to significant improvements in
efficacy, tolerability, and greater adherence to antidepressant
therapy, as well as cost savings for health care payors. In
addition, another impact of a dose-sparing effect arising from
co-administration of a sedative, such as eszopiclone is that lower
likelihood that a second antidepression agent will be needed to
treat the depression. [0879] 12. These results indicate that
co-administration of eszopiclone may have the affect of reducing
depression relapse. In this study, the augmentation effect size
grows gradually over time, hand in hand with the antidepressant
effect, leading to greater improvement in depression in the
combination therapy group. These results suggest that these
patients receiving co-administration, especially if they receive
chronic or long-term treatment with eszopiclone, may be less prone
to depression relapse. [0880] 13. These results also suggest that
co-administration or administration of eszopiclone may delay
depression relapse: Depression relapse may be sudden onset for some
patients, while for others it might be considered a gradual decline
in mood and function which diminishes over time as the patient
approaches the state of relapse. The augmentation effect size seen
in this study, in and of itself, may delay the onset of depression
relapse due to the magnitude of the effect seen in depression
measures for those patients who experience a gradual decline. The
patients who experience sudden onset of depression relapse may also
potentially benefit from the augmentation therapy as the magnitude
of the effect of administering eszopiclone may maintain symptoms
above a "depression relapse" threshold. [0881] 14. These results
also suggest the eszopiclone can protect against relapsing
depression on its own, after withdrawal of the antidepressant
treatment, by suppressing recurrent insomnia or by affecting a
separate unknown process in the central nervous system that could
either trigger or sustain the emergence of symptoms of
depression.
Example 2
Adjunctive Eszopiclone with Fluoxetine for MDD and Insomnia
Sleep Effects
[0882] Insomnia and depression often co-exist. This study evaluated
the efficacy of eszopiclone for insomnia associated with MDD during
concurrent fluoxetine treatment.
[0883] Methods:
[0884] Patients (n=545) met DSM-IV criteria for MDD and insomnia,
including reported sleep latency (SL) .gtoreq.30 min (median 73
min), wake time after sleep onset (WASO) .gtoreq.45 min (median 90
min), and total sleep time (TST) 6.5 h (median 294 min). All
patients received fluoxetine QAM, and were randomly assigned to
double-blind treatment with eszopiclone 3 mg or placebo QHS for 8
weeks. Subjective sleep and daytime function were assessed
weekly.
[0885] Results:
[0886] Compared to placebo, eszopiclone was associated with
significantly lower SL and greater TST at each treatment week
(p<0.03); significantly lower WASO at Weeks 1, 3-5, and 7-8
(p<0.04); higher ratings across the treatment period in sleep
quality and depth (p<0.005); and higher ratings of daytime
alertness, ability to concentrate, and well-being (p0.02). Combined
treatment was well-tolerated. Unpleasant taste was more common with
eszopiclone.
[0887] Conclusions:
[0888] Co-administration of eszopiclone with fluoxetine was
well-tolerated and associated with rapid, sustained improvement in
sleep and daytime symptoms in patients with MDD and insomnia. The
rapid sleep improvement with adjunctive eszopiclone may be
important, given the relatively slower onset of antidepressant
effects with SSRIs.
Example 3
Adjunctive Eszopiclone and Fluoxetine in MDD & Insomnia
Depression Effects
[0889] Insomnia frequently co-exists with depression. This study
evaluated eszopiclone and fluoxetine co-administration in depressed
patients with co-morbid insomnia
[0890] Methods:
[0891] Patients who met DSM-IV criteria for new MDD and insomnia
received fluoxetine 20 mg QAM plus either eszopiclone 3 mg (n=275)
or placebo (n=270) nightly for 8 weeks. Efficacy was assessed using
HAMD17 and Clinical Global Impression Improvement (CGI-I) and
Severity (CGI-S). Response=50% decrease from baseline HAMD17;
remission=HAMD17.ltoreq.7.
[0892] Results:
[0893] Eszopiclone co-administration resulted in significantly
greater changes in HAMD17 scores at Week 4 (-9.9 vs -8.5 for
placebo, p=0.02) with progressive improvement at Week 8 (-13.8 vs
-11.8, p<0.001). At Week 8, significantly more eszopiclone
patients were responders (74% vs 61%, p<0.009) and remitters
(54% vs 41%, p<0.02). Even with removal of insomnia items,
significant differences were found at Week 8 (p<0.03). HAMD17
differences were greater in patients with more severe depression
(baseline HAMD17.gtoreq.22). CGI-I and CGI-S scores were
significantly greater with eszopiclone co-administration
(p<0.05). Fluoxetine dose increases were less frequent with in
eszopiclone (44% vs 54%; p<0.05). Treatment was well-tolerated;
drop-outs due to AEs were comparable.
[0894] Conclusions:
[0895] Eszopiclone/fluoxetine co-administration significantly
augmented the antidepressant response in patients with MDD and
insomnia. The sleep response occurred immediately, followed by
augmentation of the antidepressant response.
INCORPORATION BY REFERENCE
[0896] All of the patents and publications cited herein are hereby
incorporated by reference.
EQUIVALENTS
[0897] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *