Note: Descriptions are shown in the official language in which they were submitted.
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MALEATE, BESYLATE AND L-MALATE SALTS OF 6-(5-CHLOR0-2-
PYRIDYL)-5-1(4-METHYL-1-PIPERAZINYL)CARBONYLOXY]-7-0X0-6,7-
DIHYDRO-5H-PYRROL013,4-b]PYRAZINE
Field of the Invention
[0001] The present invention provides novel maleate, besylate and L-malate
salts of (6-
(5-chloro-2-pyridy1)-5- [(4-methyl-l-p iperazinyl)carbonyloxy]-7-oxo-6,7-
dihydro-5H-
pyrrolo[3,4-b]pyrazine), which exhibit superior taste characteristics and
improved
aqueous solubility/dissolution behavior compared to the free base. The
maleate,
besylate and L-malate salts are thus useful for pharmaceutical dosage forms,
particularly
for oral dosage forms.
BACKGROUND OF THE INVENTION
[0002] Eszopiclone, also known as (S)-zopiclone or (S)-(6-(5-chloro-2-
pyridy1)-5-[(4-
methyl-l-p iperazinyl)carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-
b]pyrazine), is
formulated as the free base and is sold as LUNESTAO. It is used to treat
different
types of sleep problems, such as difficulty in falling asleep, difficulty in
maintaining sleep
during the night, and waking up too early in the morning. Most people with
insomnia
have more than one of these problems. See, e.g., WO 93/10787; Brun, J. P.,
Pharm.
Biochem. Behav. 29: 831 832 (1988).
[0003] The compound eszopiclone and various methods of treatment are
disclosed at
least in the following U.S. Patents: 7,125,874; 6,864,257; 6,444,673;
6,319,926; and
5,786,357.
[0004] Racemic zopiclone, rac-(6-(5-chloro-2-pyridy1)-5-[(4-methyl-l-
piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine), also
formulated as the free base, has been sold in Europe for many years to treat
different
types of sleep problems.
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SUMMARY OF THE INVENTION
[0005] In one aspect, the present invention provides a composition
comprising the
maleate, besylate and L-malate salts of racemic or enantioenriched zopiclone:
(6-(5-
chloro-2-pyridy1)-5-[(4-methy1-1-piperazinyl)c arbonylo xy] -7-o xo-6,7-
dihydro-5H-
pyrrolo[3,4-b]pyrazine), having the formulae
0 0
N
N¨ N
/ ----/( N¨
/ .....--k
1 N¨c )¨CI L ..õ.....,<N¨c )¨CI
N-""-----( N
/ \ _______ 0 / \ __ 0 SO3H
¨N\ __ /N b N ( HOOC\ __________ / COOH ¨N\ /N < 0
0
and
,
0
N
N¨
/ .....--k
)¨CI
N-""-----(
0
-/ _________ \ __ ( HOOC pH
COOH , as well as pharmaceutical dosage forms
thereof
[0006] In another aspect, the present invention provides a composition
comprising the
maleate, besylate and L-malate salts of eszopiclone: (6-(5-chloro-2-pyridy1)-5-
[(4-
methyl-l-p iperazinyl)carbonyloxy] -7-oxo-6,7-dihydro-5H-pyrrolo [3 ,4-
b]pyrazine),
having the formulae
0
0
N
N
N¨ / _-----&
1 N¨c )¨CI ----------< NN¨c¨
N-"--------.( N
_________________________________________ (C) 0 SO3H
¨N N __ < HOOC COOH ¨N\ ___ /N __ \
\ __ / ICI \ __ ¨/ \O
and
,
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0
N......_j(
N¨
I N¨c )¨CI
/ __ 7 __ < \ 0
¨N\
HOOC\ OH ,
,
o
\
COOH , as well as pharmaceutical dosage forms
thereof
[0007] It has been found that maleate, besylate and L-malate salts can
exhibit superior
taste characteristics as well as improved aqueous solubility/dissolution
behavior
compared to the free base.
[0008] The invention is also directed towards the use of the maleate,
besylate and L-
malate salts of zopiclone or eszopiclone for the treatment of a sleep
disorder.
[0009] The invention is also directed towards the use of the maleate,
besylate and L-
malate salts of zopiclone or eszopiclone for the treatment of anxiety.
[0010] In one aspect, the invention provides a composition described above
wherein the
composition has at least a one unit difference on an E-tongue analysis
relative to
eszopiclone.
[0011] In another aspect, the invention is directed towards a composition
formed by
reacting 6-(5-chloro-2-pyridy1)-5- [(4-methyl-l-piperazinyl) carbonyloxy]-7-
oxo-6,7-
dihydro-5H-pyrrolo[3,4-b]pyrazine and maleic acid, benzenesulfonic acid or L-
malic
acid.
[0012] In another aspect, the invention provides a method of making a
maleate, besylate
or L-malate salt of 6-(5-chloro-2-pyridy1)-544-methyl-l-piperazinyl)
carbonyloxy]-7-
oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, comprising the steps of: admixing
zopiclone or eszopiclone in one or more solvents, admixing maleic acid,
benzenesulfonic
acid or L-malic acid with the zopiclone or eszopiclone, and isolating the
maleate,
besylate or L-malate salt.
[0013] In another aspect, the invention provides a method of making a
maleate, besylate
or L-malate salt of 6-(5-chloro-2-pyridy1)-544-methyl-l-piperazinyl)
carbonyloxy]-7-
oxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, comprising the steps of: a)
dissolving
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zopiclone or eszopiclone in an organic solvent; b) heating to form a
composition; c)
dissolving maleic acid, benzenesulfonic acid or L-malic acid in a solvent to
form a
composition; d) transferring the composition of step c) to the solution of
step b), or
transferring the composition of step b) to the solution of step c), or
admixing the
composition of step b) and step c); e) cooling to form a salt; and f)
isolating the maleate,
besylate or L-malate salt In certain instances, the composition of step e) is
filtered and
washed with one or more solvents. In certain instances, the salt is isolated
and in certain
instances the salt is dried.
Description of the DrawincYs
[0014] Figure 1 depicts an exemplary dissolution profile of the maleate
salt compared to
free base eszopiclone.
[0015] Figure 2 depicts an exemplary dissolution profile of the besylate
salt compared to
free base eszopiclone.
[0016] Figure 3 depicts an exemplary dissolution profile of the L-malate salt
compared
to free base eszopiclone.
DETATT XI) DESCRIPTION
[0017] In one aspect, the present invention provides a composition having
the formula
0 0
NCI¨
\ 0\ SO3H
¨14 ___ to HOOC COOH 0
\_/\___/N¨( 0
or
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0
N¨cCI
0
HOOC pH
/ 0
\COON
[0018] In another aspect, the invention provides a composition having the
formula
0
0
N¨
CI
/ ______ / 0 0 / \ SO3H
¨N N
¨N N < HOOC COOH
\_ 0
or
0
N¨c ci
/ 0
¨N ________ /N < HOOC pH
0
\COON
[0019] In another aspect, the invention provides a pharmaceutical dosage
form
comprising the maleate, besylate or L-malate salt of zopiclone or eszopiclone
and a
pharmaceutically acceptable carrier.
[0020] In another aspect, the invention provides a composition formed by
reacting 6-(5-
chloro-2-pyridy1)-5-[(4-methy1-1-piperazinyl) carbonyloxy]-7-oxo-6,7-dihydro-
5H-
pyrrolo[3,4-b]pyrazine and maleic acid, benzenesulfonic acid or L-malic acid.
[0021] As used herein, the terms zopiclone and 6-(5-chloro-2-pyridy1)-5-[(4-
methyl-
1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine refer
to
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0
N........ A
N¨
I N¨c )¨CI
\N%-------.<
\ 0
¨N/ \ 7 __________________________________________ <
compounds represented by the following structure: 0 ; the
terms eszopiclone, LUNESTAO, and [(9S)-8-(5-chloropyridin-2-y1)-7-oxo-2,5,8-
triazabicyclo[4.3.0]nona-1,3,5-trien-9-yl] 4-methyl piperazine-l-carboxylate
refer to an
individual enantiomer of the foregoing represented by the following structure:
0
N........ ...I(
N¨
I N¨c )¨CI
-----......<
N
\ 0
¨N/ \ II __ <
0
=
[0022] The salts of the invention contemplate both the racemic mixture
(also known as
zopiclone), and in certain embodiments, contemplate a single enantiomer, e.g.,
the S-
enantiomer (eszopiclone). Eszopiclone is the S-(+)-optical 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 by its USAN-approved
generic name,
eszopiclone, includes the optically pure and the substantially optically pure
(e.g., 90%,
95% or 99% optical purity) S-(+)-zopiclone isomer. As such, a salt of this
invention can
exist as an individual stereoisomer as well as a mixture of stereoisomers.
Accordingly,
the salts of the present invention will include not only a stereoisomeric
mixture, but also
individual respective stereoisomers substantially free from other
stereoisomers. In
certain embodiments, the salts of the invention are stereochemically pure
isomers or
racemic mixtures. For example, salts encompass non-racemic mixtures of
stereoisomers
of the same compound (e.g., about 90, 80, 70, or 60 weight percent of one
enantiomer
and about 10, 20, 30, or 40 weight percent of the opposite enantiomer); and
mixtures of
different racemic or stereomerically pure compounds (e.g., about 90, 80, 70,
or 60
weight percent of one compound and about 10, 20, 30, or 40 weight percent of
another).
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[0023] The compounds of the invention can be synthesized by techniques
known in the
art. The starting materials and certain intermediates used in the synthesis of
the
compounds of this invention are available from commercial sources or can
themselves be
synthesized using reagents and techniques known in the art, including those
synthesis
schemes delineated herein.
[0024] 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.
[0025] The synthesis of the maleate, besylate or L-malate salt of the
invention can be
carried out according to the reaction sequence of Scheme 1, and begins with
dissolving
(S)-zopiclone into an organic solvent. Organic solvents include, but are not
limited to
tetrahydrofuran, diethyl ether, methyl-t-butyl ether, toluene, cumene,
chloroform,
methylene chloride, hexanes, pentane, heptane, acetone, ethyl acetate,
methanol,
ethanol, propanol, i-PrOH, and butanol. The contents can be heated to
dissolve. The
reaction temperature can range from about 25 C to about 100 C; in certain
embodiments the temperature can range from about 25 C to about 50 C; in
certain
embodiments the temperature can range from about 50 C to about 100 C.
[0026] Maleic acid, benzenesulfonic or L-malic acid is dissolved into a
solvent and is
transferred slowly to the zopiclone solution at a temperature ranging from
about 25 C
to about 100 C. The reaction is optionally seeded with the desired salt and
allowed to
cool with stirring and aged. Filtration and washing with a solvent or mixture
of solvents
is carried out followed by filtration. Mixtures of solvents used for washing
and/or
filtration include but are not limited to ratios of 1:1, 2:1, 3:1, 4:1, 5:1,
10:1, and 20:1.
In certain embodiments, mixtures of three organic solvents can be used. The
resulting
salt is isolated and dried (optionally under vacuum) at a temperature ranging
from about
25 C to about 100 C, preferably about 60 C to about 65 C, and packaged in
an
appropriate container.
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[0027] Scheme 1. Synthesis of Salt
0 0
N....._...k N¨ N%._.. j( N¨
I N¨c )¨CI acid L ...........(N¨ )¨CI
N%"-------( N
VP
/ \ 0 solvent / \
¨N\ __________________________ ¨
N NN ____ (00 Salt / (
0 \ /
[0028] Higher order salts can also be prepared, e.g., salts having about
1:2
acid:eszopiclone. Such higher order salts can be prepared by using an
appropriate molar
excess of eszopiclone, which is easily determined by one of ordinary skill in
the art. For
example, two molar equivalents of eszopiclone to free acid form a 1:2
acid:eszopiclone
composition.
[0029] The compounds of the present invention contain asymmetric carbon
atoms. As
such, a compound of this invention can exist as an individual stereoisomer as
well as a
mixture of stereoisomers. Accordingly, a compound of the present invention
will in-
clude not only a stereoisomeric mixture, but also individual respective
stereoisomers
substantially free from other stereoisomers. The term "substantially free" as
used herein
means less than 25% of other stereoisomers, preferably less than 10% of other
stereoisomers, more preferably less than 5% of other stereoisomers and most
preferably
less than 2% of other stereoisomers, are present. Methods of obtaining or
synthesizing
stereoisomers are well known in the art and can be applied as practicable to
final
compounds or to starting material or intermediates. In another embodiment, the
compound is an isolated compound.
[0030] Methods for optimizing reaction conditions, if necessary to minimize
competing
by-products, are known in the art. Additional reaction schemes and protocols
can be
determined by the skilled artesian by use of commercially available structure-
searchable
database software, for instance, SciFinder0 (CAS division of the American
Chemical
Society) and CrossFire Beilstein0 (Elsevier MDL), or by appropriate keyword
searching using an intern& search engine such as Google0 or keyword databases
such
as the US Patent and Trademark Office text database.
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[0031] The synthetic methods described herein can also additionally include
steps, either
before or after the steps described specifically herein, to add or remove
suitable
protecting groups in order to ultimately allow synthesis of the compound of
the
formulae described herein.
[0032] In certain aspects, the invention provides a method for treating or
preventing
various disorders using a zopiclone maleate, besylate or L-malate salt. In one
embodiment, the invention provides a method for treating and/or preventing
sleep
disorders, including primary insomnia and sleep-awake rhythm disorders (e.g.,
work-
shift syndrome, time-zone syndrome (jet-lag)).
[0033] Insomnia is characterized by difficulty in sleeping or disturbed
sleep patterns.
Insomnia can be of a primary nature with little apparent relationship to
immediate
somatic or psychic events, or secondary to some acquired pain, anxiety or
depression.
In one aspect, the invention provides a method for treating or preventing a
sleep
disorder in a subject comprising administering to a subject in need thereof a
salt
composition having the formula
0 0
N¨
N¨c
\ 0 SO3H
¨N N HOOC COOH ¨N N __________ <
0 0
or
0
N¨c
¨N N HOOC gH
0
COOH such that administration of the
composition treats the sleep disorder.
[0034] In another aspect, the invention provides a method for treating or
preventing
anxiety in a subject comprising administering to a subject in need thereof a
salt
composition having the formula
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0 0
N-
0 0 SO3H
¨N N HOOC\_/ COOH ¨N N _______ <
0 0
or
0
N¨cN%-"=====.<
0
N¨
_/\(H000 gH
0
COOH such that administration of the
composition treats the anxiety.
[0035] As used herein the term "anxiety" refers to an anxiety disorder.
Examples of
anxiety disorders treatable by the compositions and methods disclosed herein
include,
but are not limited to: panic attack, agoraphobia, acute stress disorder,
specific phobia,
panic disorder, psychoactive substance anxiety disorder, organic anxiety
disorder,
obsessive-compulsive anxiety disorder, posttraumatic stress disorder and
generalized
anxiety disorder. Anxiety as referred to herein also includes situational
anxiety (e.g. as
experienced by a performer prior to a performance).
[0036] The named anxiety disorders have been characterized in the DSM-IV-R.
Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed.
(1994). The
DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the
American Psychiatric Association, and provides clear descriptions of
diagnostic
categories.
[0037] In a further aspect, the invention provides a use of the maleate,
besylate or L-
malate salt salt of zopiclone, particularly eszopiclone, for the treatment or
prevention of
a disorder disclosed herein. In a preferred embodiment, the disorder is sleep
disorders
or anxiety.
[0038] In a yet further aspect, the invention provides a use of the
maleate, besylate or L-
malate salt of zopiclone, particularly eszopiclone, for the preparation of
medicament for
the treatment or prevention of a disorder disclosed herein. In a preferred
embodiment,
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the disorder is sleep disorders or anxiety.
[0039] Preferred methods and uses of the invention include identifying
and/or
selecting a subject, particularly a human subject, that is susceptible to or
suffering from a
disorder disclosed herein, and thereafter administering to the identified and
selected
subject the maleate, besylate or L-malate salt of zopiclone, particularly
eszopiclone. In
certain embodiments, the disorder is sleep disorders or anxiety. Such
identification and
selection can be made e.g., by a physician or other health professional.
[0040] Other disorders treated by the invention include seasonal
melancholia, genital
disorder, neuroendocrine disorder, senile dementia, Alzheimer's disease,
various
disorders accompanied by aging, cerebrovascular disorders (e.g. cerebral
hemorrhage,
etc.), cranial injury, spinal injury, epilepsy, depression, manic-depressive
psychosis,
schizophrenia, alcoholism, Parkinson's disease, hypertension,
arteriosclerosis,
arrhythmia, premenstrual tension syndrome, glaucoma, metabolic disorders
(e.g.,
obesity, insulin resistance, etc.), cancer, AIDS and diabetes in mammals (e.g.
human,
cat, dog, monkey, etc.). In addition, it is also effective for protection
against aging,
immunoregulation, and ovulatory regulation (e.g., contraception).
[0041] In one embodiment, the invention provides a method of treating or
preventing a
disease or condition which is affected by the modulation of one or more
central
benzodiazepine sites in a subject which comprises administering to a subject
in need of
such treatment or prevention a therapeutically or prophylactically effective
amount of a
zopiclone maleate, besylate or L-malate salt. Such disorder include but are
not limited
to anxiety; affective disorders such as depression, attention deficit disorder
("ADD"),
and attention deficit disorder with hyperactivity ("ADDH") or attention
deficit/hyperactivity disorder ("ADHD"); convulsive disorders such as
epilepsy;
aggressive behavior; spasticity or acute muscle spasm; behavioral disorders
such as
mood anxiety and schizophrenia; and alcohol and drug addiction.
[0042] Another embodiment of the invention encompasses a method of treating
or
preventing anxiety in a subject which comprises administering to a subject in
need of
such treatment or prevention a therapeutically or prophylactically effective
amount of a
zopiclone maleate, besylate or L-malate salt. The anxiety can be acute or
chronic
anxiety, or can be a general anxiety disorder. In certain embodiments, the
invention
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provides for reducing the severity of at least one symptom associated with
acute anxiety,
chronic anxiety, general anxiety disorder caused by psychologic and/or
physiologic
factors, and other anxiety disorders such as panic disorders, mood anxiety,
panic
attacks, phobias, obsessive-compulsive disorders, or post traumatic distress
disorder.
Symptoms associated with acute anxiety include, but are not limited to, a fear
of losing
control of one's own actions, a sense of terror arising from no apparent
reason, and a
dread of catastrophe. Symptoms associated with chronic anxiety include, but
are not
limited to, uneasiness, nervousness, nagging uncertainty about future events,
headache,
fatigue, and subacute autonomic symptoms.
[0043] Another embodiment of the invention encompasses a method of treating
or
preventing a convulsive state in a subject which comprises administering to a
subject in
need of such treatment or prevention a therapeutically or prophylactically
effective
amount of a zopiclone maleate, besylate or L-malate salt. A particular method
of this
embodiment is the treatment or prevention of epilepsy or epileptic seizures.
In a further
embodiment, the invention provides for reducing the severity and/or frequency
of at
least one symptom associated with convulsive states which include, but are not
limited
to, recurrent, sudden, and often brief alterations of consciousness, motor
activity,
sensory phenomena, and autonomic responses which are often characterized by
convulsive seizures and/or tonic or clonic jerking of the extremities. The
term
"convulsive state" encompasses epilepsy and specific types of epileptic
seizures
including, but not limited to, Tonic-clonic (Grand Mal), Partial (Focal)
seizures,
psychomotor (Complex partial) seizures, pyknoepileptic or Absence (Petit Mal)
seizure,
and Myoclonic seizures.
[0044] Another embodiment of the invention encompasses a method of treating
or
preventing an affective disorder in a subject which comprises administering to
a subject
in need of such treatment or prevention a therapeutically or prophylactically
effective
amount of a zopiclone maleate, besylate or L-malate salt. A particular method
encompassed by this embodiment is the treatment or prevention of depression.
Another
method encompassed by this embodiment is the treatment or prevention of
attention
deficit disorder or attention deficit disorder with hyperactivity. The phrase
"treating or
preventing an affective disorder" means reducing the severity of at least one
symptom
associated with a psychological disorder characterized by abnormality of
emotional
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state, including but not limited to, depression, dysthymia, attention deficit
disorder,
attention deficit disorder with hyperactivity, bipolar disorders, bipolar and
manic
conditions, and the like. The terms "attention deficit disorder" ("ADD") and
"attention
deficit disorder with hyperactivity" ("ADDH"), or "attention
deficit/hyperactivity
disorder" ("ADHD"), are used herein in accordance with the accepted meanings
as
found in the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.,
American
Psychiatric Association (1997). In one embodiment, the phrase "treating or
preventing
depression" means reducing the severity of at least one symptom associated
with
depression which include, but are not limited to, changes in mood, feelings of
intense
sadness, despair, mental slowing, loss of concentration, pessimistic worry,
agitation, and
self-deprecation. Symptoms associated with depression can also be physical
symptoms,
which include, but are not limited to, insomnia, anorexia, weight loss,
decreased energy
and libido, weight gain, and abnormal hormonal circadian rhythms.
[0045] Another embodiment of the invention encompasses a method of treating
or
preventing aggressive behavior in a subject, which comprises administering to
a subject
in need of such treatment or prevention a therapeutically or prophylactically
effective
amount of a zopiclone maleate, besylate or L-malate salt. In certain
embodiments, the
method includes reducing the frequency and/or severity of at least one
manifestation of
aggressive behavior which include, but are not limited to, aggressive or
socially
inappropriate vocal outbursts and acts of physical violence.
[0046] Another embodiment of the invention encompasses a method of treating
or
preventing spasticity or acute muscle spasm spasticity in a subject which
comprises
administering to a subject in need of such treatment or prevention a
therapeutically or
prophylactically effective amount of a zopiclone maleate, besylate or L-malate
salt. In
certain instances the invention provides a method of "treating or preventing
spasticity,"
"treatment and prevention of spasticity," "treating or preventing spasticity
and acute
muscle spasm," and "treatment and prevention of spasticity and acute muscle
spasm,"
which includes reducing the severity of at least one symptom associated with a
range of
abnormalities of skeletal muscle regulation that result from problems of the
nervous
system. A predominant symptom is heightened muscle tone or hyper-excitability
of tonic
stretch muscle reflexes. Symptoms of acute muscle spasm include, but are not
limited to,
trauma, inflammation, anxiety, and pain.
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[0047] Another embodiment of the invention encompasses a method of treating
or
preventing a behavioral disorder in a subject which comprises administering to
a subject
in need of such treatment or prevention a therapeutically or prophylactically
effective
amount of a zopiclone maleate, besylate or L-malate salt. The phrase "treating
or
preventing a behavioral disorder" means reducing or relieving from at least
one symptom
of a behavioral disorder, which include, but are not limited to, a subjective
sense of
terror, a dread of catastrophe, uneasiness, nervousness, uncertainty,
headache, fatigue,
disturbed thinking, inappropriate effect, auditory hallucinations, and
aggressive
outbursts.
[0048] Another embodiment of the invention encompasses a method of treating
or
preventing a schizophrenic disorder in a subject which comprises administering
to a
subject in need of such treatment or prevention a therapeutically or
prophylactically
effective amount of a zopiclone maleate, besylate or L-malate salt. The phrase
"treating
or preventing a schizophrenic disorder" means reducing the severity of at
least one
symptom associated with schizophrenic disorders. Symptoms of schizophrenic
disorders
include, but are not limited to, psychotic symptoms of disturbed thinking,
feeling and
general behavior. Specific symptoms of schizophrenic disorders include the
inability to
form clear, goal-directed thought, and emotional changes such as blunting and
inappropriate affect. Other symptoms of schizophrenic disorders include
auditory
hallucinations, delusions of persecution, threats of violence, minor
aggressive outbursts,
aggressive behavior, disturbances of movement such as significant overactivity
and
excitement, and retardation and stupor.
[0049] Another embodiment of the invention encompasses a method of treating
alcohol
or drug addiction in a subject which comprises administering to a subject in
need of such
treatment a therapeutically or prophylactically effective amount of a
zopiclone maleate,
besylate or L-malate salt. As used herein, the phrase "treating alcohol or
drug
addiction" means reducing at least one symptom of disease or conditions
related to
alcohol or drug addiction including, but not limited to, drug or alcohol
addiction or
symptoms of withdrawal from alcohol or drugs. Symptoms of withdrawal include,
but
are not limited to, depression, pain, fever, restlessness, lacrimation,
rhinorrhea,
uncontrollable yawning, perspiration, piloerection, restless sleep, mydriasis,
twitching
and muscle spasms, severe aches in the back, abdomen and legs, abdominal and
muscle
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cramps, hot and cold flashes, insomnia, nausea, vomiting, diarrhea, coryza and
severe
sneezing, and increases in body temperature, blood pressure, respiratory rate,
and heart
rate. Another embodiment of the invention encompasses a method of treating or
preventing drug withdrawal, alcohol withdrawal, symptoms of drug withdrawal,
or
symptoms of alcohol withdrawal in a subject which comprises administering to a
subject
in need of such treatment a therapeutically or prophylactically effective
amount of a
zopiclone maleate, besylate or L-malate salt.
[0050] In another aspect, the invention provides a use of the maleate,
besylate or L-
malate salt of the invention in the manufacture of a medicament for treating
or
preventing any one of the disorders disclosed herein in a patient.
[0051] In one embodiment, the invention provides a use of the maleate,
besylate or L-
malate salt of the invention in the manufacture of a medicament for treating
or
preventing sleep disorder in a patient.
[0052] In one embodiment, the invention provides a use of the maleate,
besylate or L-
malate salt of the invention in the manufacture of a medicament for treating
or
preventing anxiety in a patient.
[0053] In certain aspects, the racemic zopiclone can be utilized herein in
the same
manner as described for the S-isomer eszopiclone. However, it is recognized
that use of
eszopiclone can provide advantages over use of the racemic zopiclone and
thereafter use
of eszopiclone will be preferred for many applications.
[0054] In a specific method, the zopiclone maleate, besylate or L-malate
salt used in the
treatment of the above disorders is stereomerically pure.
[0055] The term "treating" or "treated" refers to administering a compound
described
herein to a subject with the purpose to cure, heal, alleviate, relieve, alter,
remedy,
ameliorate, improve, or affect a disease, the symptoms of the disease or the
predisposition toward the disease.
[0056] "An effective amount" refers to an amount of a compound, which
confers a
therapeutic effect on the treated subject. The therapeutic effect can be
objective (i.e.,
measurable by some test or marker) or subjective (i.e., subject gives an
indication of or
feels an effect). Effective doses will also vary depending on route of
administration.
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[0057] As used herein, and unless otherwise specified, the terms "prevent,"
"preventing," "prevention," and "prophylactic" refer to the prevention of the
onset,
recurrence or intensification of a disorder disclosed herein. The terms
"prevent,"
"preventing," "prevention," and "prophylactic" include ameliorating and/or
reducing the
occurrence of symptoms of a disorder disclosed herein.
[0058] The maleate, besylate and L-malate salts described above have
exhibited
improved taste characteristics relative to the free base compound, as
demonstrated in the
examples which follow. Taste assessments were made with "Electronic-tongue" (E-
tongue) analysis systems, and also in human taste trials. Preferred salt
compounds have
at least a one unit difference on an E-tongue analysis relative to
eszopiclone, more
preferably at least a 2 or 3 unit difference on an E-tongue analysis relative
to
eszopiclone. E-tongue analysis is suitably performed as described in Example 3
which
follows using E-tongue apparatus commercially available from Alpha-mos
(Hillsborough, New Jersey). As referred to herein, a specified unit difference
on an E-
tongue analysis refers to a value using a protocol as specified in Example 8
which
follows.
[0059] The results in the E-tongue analysis are bolstered by the finding
that the maleate,
besylate and L-malate salts exhibit less bitterness than the free base when
tested with
human subjects as described in Example 10 below.
[0060] It also has been found that the present salt compounds exhibit good
solubility
and dissolution characteristics, as shown in Example 9 below.
[0061] The present invention relates to pharmaceutical compositions
containing the
maleate, besylate or L-malate salt of the dextrorotatory isomer of zopiclone,
the
levorotatory isomer of zopiclone, or its racemic mixture, in the pure state or
in the
presence of a diluent or a coating. These compositions can be employed orally,
rectally
or parenterally.
[0062] Pharmaceutical compositions and dosage forms of the invention
comprise one or
more of the active ingredients disclosed herein. Pharmaceutical compositions
and dosage
forms of the invention typically also comprise one or more pharmaceutically
acceptable
excipients or diluents.
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[0063] The term "pharmaceutically acceptable," as used herein, refers to a
component
that is, within the scope of sound medical judgment, suitable for use in
contact with the
tissues of humans and other mammals without undue toxicity, irritation,
allergic
response and the like, and is commensurate with a reasonable benefit/risk
ratio. A
"pharmaceutically acceptable salt" means any non-toxic salt that, upon
administration to
a recipient, is capable of providing, either directly or indirectly, a
compound or a
prodrug of a compound of this invention. A "pharmaceutically acceptable
counterion" is
an ionic portion of a salt that is not toxic when released from the salt upon
administration to a recipient.
[0064] The invention also provides compositions comprising an effective
amount of the
maleate, besylate or L-malate salt of zopiclone and an acceptable carrier.
Preferably, a
composition of this invention is formulated for pharmaceutical use ("a
pharmaceutical
composition"), wherein the carrier is a pharmaceutically acceptable carrier.
The
carrier(s) must be "acceptable" in the sense of being compatible with the
other
ingredients of the formulation and, in the case of a pharmaceutically
acceptable carrier,
not deleterious to the recipient thereof in amounts typically used in
medicaments.
[0065] Pharmaceutically acceptable carriers, adjuvants and vehicles that
can be used in
the pharmaceutical compositions of this invention include, but are not limited
to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as
human serum
albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium
sorbate,
partial glyceride mixtures of saturated vegetable fatty acids, water, salts or
electrolytes,
such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-
block
polymers, polyethylene glycol and wool fat.
[0066] Preparative methods include the step of bringing into association
with the
molecule to be administered ingredients such as the carrier that constitutes
one or more
accessory ingredients. In general, the compositions are prepared by uniformly
and
intimately bringing into association the active ingredients with liquid
carriers, liposomes
or finely divided solid carriers or both, and then if necessary shaping the
product.
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[0067] Single unit dosage forms of the invention are suitable for oral,
mucosa' (e.g.,
nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,
subcutaneous, intravenous,
bolus injection, intramuscular, or intraarterial), or transdermal
administration to a
patient. Examples of dosage forms include, but are not limited to: tablets;
caplets;
capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges;
dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders; dressings;
creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;
liquid dosage
forms suitable for oral or mucosa' administration to a patient, including
suspensions
(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a
water-in-
oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable
for parenteral
administration to a patient; and sterile solids (e.g., crystalline or
amorphous solids) that
can be reconstituted to provide liquid dosage forms suitable for parenteral
administration
to a patient.
[0068] The composition, shape, and type of dosage forms of the invention
will typically
vary depending on their use. For example, a dosage form used in the acute
treatment of
a disorder can contain larger amounts of one or more of the active ingredients
it
comprises than a dosage form used in the chronic treatment of the same
disease.
Similarly, a parenteral dosage form can contain smaller amounts of one or more
of the
active ingredients it comprises than an oral dosage form used to treat the
same disease
or disorder. These and other ways in which specific dosage forms encompassed
by this
invention will vary from one another will be readily apparent to those skilled
in the art.
See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton Pa.
(1990).
[0069] Typical pharmaceutical compositions and dosage forms comprise one or
more
excipients. Suitable excipients are well known to those skilled in the art of
pharmacy,
and non-limiting examples of suitable excipients are provided herein. Whether
a
particular excipient is suitable for incorporation into a pharmaceutical
composition or
dosage form depends on a variety of factors well known in the art including,
but not
limited to, the way in which the dosage form will be administered to a
patient. For
example, oral dosage forms such as tablets can contain excipients not suited
for use in
parenteral dosage forms. The suitability of a particular excipient can also
depend on the
specific active ingredients in the dosage form. For example, the decomposition
of some
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active ingredients can be accelerated by some excipients such as lactose, or
when
exposed to water. This invention encompasses pharmaceutical compositions and
dosage
forms that contain little, if any, lactose other mono- or di-saccharides. As
used herein,
the term "lactose-free" means that the amount of lactose present, if any, is
insufficient to
substantially increase the degradation rate of an active ingredient.
[0070] Lactose-free compositions of the invention can comprise excipients
that are well
known in the art. In general, lactose-free compositions comprise active
ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically
acceptable amounts. Preferred lactose-free dosage forms comprise active
ingredients,
microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
[0071] This invention further encompasses anhydrous pharmaceutical
compositions and
dosage forms comprising active ingredients, since water can facilitate the
degradation of
some compounds. For example, the addition of water (e.g., 5%) is widely
accepted in
the pharmaceutical arts as a means of simulating long-term storage in order to
determine
characteristics such as shelf-life or the stability of formulations over time.
See, e.g., Jens
T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y.,
1995, pp. 379 80. In effect, water and heat accelerate the decomposition of
some
compounds. Thus, the effect of water on a formulation can be of great
significance since
moisture and/or humidity are commonly encountered during manufacture,
handling,
packaging, storage, shipment, and use of formulations.
[0072] Anhydrous pharmaceutical compositions and dosage forms of the
invention can
be prepared using anhydrous or low moisture containing ingredients and low
moisture or
low humidity conditions. Pharmaceutical compositions and dosage forms that
comprise
lactose and at least one active ingredient that comprises a primary or
secondary amine
are preferably anhydrous if substantial contact with moisture and/or humidity
during
manufacturing, packaging, and/or storage is expected.
[0073] An anhydrous pharmaceutical composition should be prepared and
stored such
that its anhydrous nature is maintained. Accordingly, anhydrous compositions
are
preferably packaged using materials known to prevent exposure to water such
that they
can be included in suitable formulary kits. Examples of suitable packaging
include, but
are not limited to, hermetically sealed foils, plastics, unit dose containers
(e.g., vials),
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blister packs, and strip packs.
[0074] The invention further encompasses pharmaceutical compositions and
dosage
forms that comprise one or more compounds that reduce the rate by which an
active
ingredient will decompose. Such compounds, which are referred to herein as
"stabilizers," include, but are not limited to, antioxidants such as ascorbic
acid, pH
buffers, or salt buffers.
[0075] Pharmaceutical compositions of the invention that are suitable for
oral
administration can be presented as discrete dosage forms, such as, but are not
limited to,
tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,
flavored syrups).
Such dosage forms contain predetermined amounts of active ingredients, and can
be
prepared by methods of pharmacy well known to those skilled in the art. See
generally,
Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0076] Typical oral dosage forms of the invention are prepared by combining
the active
ingredient(s) in an intimate admixture with at least one excipient according
to
conventional pharmaceutical compounding techniques. Excipients can take a wide
variety of forms depending on the form of preparation desired for
administration. For
example, excipients suitable for use in oral liquid or aerosol dosage forms
include, but
are not limited to, water, glycols, oils, alcohols, flavoring agents,
preservatives, and
coloring agents. Examples of excipients suitable for use in solid oral dosage
forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not limited to,
starches, sugars,
micro-crystalline cellulose, diluents, granulating agents, lubricants,
binders, and
disintegrating agents.
[0077] Because of their ease of administration, tablets and capsules
represent the most
advantageous oral dosage unit forms, in which case solid excipients are
employed. If
desired, tablets can be coated by standard aqueous or nonaqueous techniques.
Such
dosage forms can be prepared by any of the methods of pharmacy. In general,
pharmaceutical compositions and dosage forms are prepared by uniformly and
intimately
admixing the active ingredients with liquid carriers, finely divided solid
carriers, or both,
and then shaping the product into the desired presentation if necessary.
[0078] For example, a tablet can be prepared by compression or molding.
Compressed
tablets can be prepared by compressing in a suitable machine the active
ingredients in a
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free-flowing form such as powder or granules, optionally mixed with an
excipient.
Molded tablets can be made by molding in a suitable machine a mixture of the
powdered
compound moistened with an inert liquid diluent.
[0079] Examples of excipients that can be used in oral dosage forms of the
invention
include, but are not limited to, binders, fillers, disintegrants, and
lubricants. Binders
suitable for use in pharmaceutical compositions and dosage forms include, but
are not
limited to, corn starch, potato starch, or other starches, gelatin, natural
and synthetic
gums such as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth,
guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose
acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl
pyaolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl
cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures
thereof
[0080] Examples of fillers suitable for use in the pharmaceutical
compositions and
dosage forms disclosed herein include, but are not limited to, talc, calcium
carbonate
(e.g., granules or powder), microcrystalline cellulose, powdered cellulose,
dextrates,
kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and
mixtures
thereof The binder or filler in pharmaceutical compositions of the invention
is typically
present in from about 50 to about 99 weight percent of the pharmaceutical
composition
or dosage form.
[0081] Disintegrants are used in the compositions of the invention to
provide tablets
that disintegrate when exposed to an aqueous environment. Tablets that contain
too
much disintegrant may disintegrate in storage, while those that contain too
little may not
disintegrate at a desired rate or under the desired conditions. Thus, a
sufficient amount
of disintegrant that is neither too much nor too little to detrimentally alter
the release of
the active ingredients should be used to form solid oral dosage forms of the
invention.
The amount of disintegrant used varies based upon the type of formulation, and
is
readily discernible to those of ordinary skill in the art. Typical
pharmaceutical
compositions comprise from about 0.5 to about 15 weight percent of
disintegrant,
preferably from about 1 to about 5 weight percent of disintegrant.
[0082] Disintegrants that can be used in pharmaceutical compositions and
dosage forms
of the invention include, but are not limited to, agar-agar, alginic acid,
calcium
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carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin
potassium, sodium starch glycolate, potato or tapioca starch, other starches,
pre-
gelatinized starch, other starches, clays, other algins, other celluloses,
gums, and
mixtures thereof.
[0083] Lubricants that can be used in pharmaceutical compositions and dosage
forms of
the invention include, but are not limited to, calcium stearate, magnesium
stearate,
mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil
(e.g., peanut
oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and
soybean oil), zinc
stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional
lubricants
TM
include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R.
Grace
Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by
Degussa
TM
Co. of Plano, Tex.), CAB-0-SIL (a pyrogenic silicon dioxide product sold by
Cabot Co.
of Boston, Mass.), and mixtures thereof. If used at all, lubricants are
typically used in an
amount of less than about 1 weight percent of the pharmaceutical compositions
or
dosage forms into which they are incorporated.
[0084] Active ingredients of the invention can be administered by
controlled release
means or by delivery devices that are well known to those of ordinary skill in
the art.
Examples include, but are not limited to, those described in U.S. Pat. Nos.
3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595,
5,591,767,
5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566.
Such dosage forms can be used to provide slow or
controlled-release of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels, permeable
membranes,
osmotic systems, multilayer coatings, microparticles, liposomes, microspheres,
or a
combination thereof to provide the desired release profile in varying
proportions.
Suitable controlled-release formulations known to those of ordinary skill in
the art,
including those described herein, can be readily selected for use with the
active
ingredients of the invention. The invention thus encompasses single unit
dosage forms
suitable for oral administration such as, but not limited to, tablets,
capsules, gelcaps, and
caplets that are adapted for controlled-release.
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[0085] All controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled
counterparts. Ideally,
the use of an optimally designed controlled-release preparation in medical
treatment is
characterized by a minimum of drug substance being employed to cure or control
the
condition in a minimum amount of time. Advantages of controlled-release
formulations
include extended activity of the drug, reduced dosage frequency, and increased
patient
compliance. In addition, controlled-release formulations can be used to affect
the time of
onset of action or other characteristics, such as blood levels of the drug,
and can thus
affect the occurrence of side (e.g., adverse) effects.
[0086] Most controlled-release formulations are designed to initially
release an amount
of drug (active ingredient) that promptly produces the desired therapeutic
effect, and
gradually and continually release of other amounts of drug to maintain this
level of
therapeutic or prophylactic effect over an extended period of time. In order
to maintain
this constant level of drug in the body, the drug must be released from the
dosage form
at a rate that will replace the amount of drug being metabolized and excreted
from the
body. Controlled-release of an active ingredient can be stimulated by various
conditions
including, but not limited to, pH, temperature, enzymes, water, or other
physiological
conditions or compounds.
[0087] Parenteral dosage forms can be administered to patients by various
routes
including, but not limited to, subcutaneous, intravenous (including bolus
injection),
intramuscular, and intraarterial. Because their administration typically
bypasses patients'
natural defenses against contaminants, parenteral dosage forms are preferably
sterile or
capable of being sterilized prior to administration to a patient. Examples of
parenteral
dosage forms include, but are not limited to, solutions ready for injection,
dry products
ready to be dissolved or suspended in a pharmaceutically acceptable vehicle
for
injection, suspensions ready for injection, and emulsions.
[0088] Suitable vehicles that can be used to provide parenteral dosage
forms of the
invention are well known to those skilled in the art. Examples include, but
are not
limited to: Water for Injection USP; aqueous vehicles such as, but not limited
to,
Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose
and Sodium
Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles
such as, but
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not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol;
and non-
aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut
oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0089] Transdermal, topical, and mucosa' dosage forms of the invention
include, but are
not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions,
ointments, gels,
solutions, emulsions, suspensions, or other forms known to one of skill in the
art. See,
e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton
Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,
Lea &
Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosa'
tissues within
the oral cavity can be formulated as mouthwashes or as oral gels. Further,
transdermal
dosage forms include "reservoir type" or "matrix type" patches, which can be
applied to
the skin and worn for a specific period of time to permit the penetration of a
desired
amount of active ingredients.
[0090] Suitable excipients (e.g., carriers and diluents) and other
materials that can be
used to provide transdermal, topical, and mucosa' dosage forms encompassed by
this
invention are well known to those skilled in the pharmaceutical arts, and
depend on the
particular tissue to which a given pharmaceutical composition or dosage form
will be
applied. With that fact in mind, typical excipients include, but are not
limited to, water,
acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form lotions,
tinctures, creams,
emulsions, gels or ointments, which are non-toxic and pharmaceutically
acceptable.
Moisturizers or humectants can also be added to pharmaceutical compositions
and
dosage forms if desired. Examples of such additional ingredients are well
known in the
art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).
[0091] Depending on the specific tissue to be treated, additional
components can be
used prior to, in conjunction with, or subsequent to treatment with active
ingredients of
the invention. For example, penetration enhancers can be used to assist in
delivering the
active ingredients to the tissue. Suitable penetration enhancers include, but
are not
limited to: acetone; various alcohols such as ethanol, oleyl, and
tetrahydrofuryl; alkyl
sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
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polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon
grades
(Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar
esters such
TM TM
as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
[0092] The pH of a pharmaceutical composition or dosage form, or of the
tissue to
which the pharmaceutical composition or dosage form is applied, can also be
adjusted to
improve delivery of one or more active ingredients. Similarly, the polarity of
a solvent
carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
Compounds
such as stearates can also be added to pharmaceutical compositions or dosage
forms to
advantageously alter the hydrophilicity or lipophilicity of one or more active
ingredients
so as to improve delivery. In this regard, stearates can serve as a lipid
vehicle for the
formulation, as an emulsifying agent or surfactant, and as a delivery-
enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates of the
active
ingredients can be used to further adjust the properties of the resulting
composition.
[0093] The maleate, besylate or L-malate salt of zopiclone can, for
example, be
administered with a dosage ranging from about 0.001 to about 0.2 mg/kg of body
weight, alternatively dosages between 0.1 mg and 15 mg/dose, or between about
0.1 mg
and about 10 mg/dose, or preferably between about 0.2 mg and about 5 mg/dose,
or
according to the requirements of the particular therapy. The methods herein
contemplate administration of an effective amount of compound or compound
composition to achieve the desired or stated effect. Typically, the
pharmaceutical
compositions of this invention will be administered from about 1 to about 6
times per
day or alternatively, as a continuous infusion. Such administration can be
used as a
chronic or acute therapy. The amount of active ingredient that can be combined
with the
carrier materials to produce a single dosage form will vary depending upon the
host
treated and the particular mode of administration. In some embodiments, such
preparations contain from about 20% to about 80% (w/w) active compound. In
some
embodiments, such preparations contain from about 0.5% to about 20% active
compound. A typical preparation will contain from about 0.5% to about 5%
active
compound (w/w).
[0094] Lower or higher doses than those recited above can be required.
Specific dosage
and treatment regimens for any particular patient will depend upon a variety
of factors,
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including the activity of the specific compound employed, the age, body
weight, general
health status, sex, diet, time of administration, rate of excretion, drug
combination, the
severity and course of the disease, condition or symptoms, the patient's
disposition to
the disease, condition or symptoms, and the judgment of the treating
physician.
[0095] Like the amounts and types of excipients, the amounts and specific
types of
active ingredients in a dosage form can differ depending on factors such as,
but not
limited to, the route by which it is to be administered to patients. In human
therapy, the
doses depend on the effect sought and the treatment period; taken orally, they
are
generally between 0.5 and 15 mg per day for an adult. For many applications,
unit
dosages containing 0.5 mg, 1 mg, 2 mg or 3 mg of a present eszopiclone salt
will be
suitable. In some embodiments, the unit dosages of the eszopiclone salts can
be adjusted
to contain the molar equivalent of 0.5 mg, 1 mg, 2 mg or 3 mg of eszopiclone
freebase.
[0096] The following non-limiting examples are illustrative of the
invention.
Example 1 ¨ Synthesis of (S)-Zopiclone L-malate
0
0 HOOC pH
N¨cCOOH
/ 0
ethyl acetate ¨N/ \N
0
HOOC pH
-N\ /N / 0
0
COOH
A 250 mL reactor was charged with 1.5 g (S)-zopiclone and 90 mL of ethyl
acetate
(Et0Ac). The contents were heated to 40 C to dissolve. A 125 mL flask was
charged
with 540 mg malic acid and 60 mL of ethyl acetate. The contents were heated to
40 C
and the acid solution was transferred slowly to the zopiclone solution. The
reaction was
stirred for 3 h. The slurry was filtered and washed with ethyl acetate in an
appropriate
filter. The wet cake was dried under vacuum, isolated and packaged in
appropriate
container. Isolated yield = 96%.
[0097] Example 2 ¨ Synthesis of (S)-Zopiclone L-malate
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0
0
ethanol ....õ..,(N¨c ¨CI
%-------.< N
N ___________________________________ OA- 0
/ \ __________ 0 HOOC pH / \
¨N N (
\ ____________ /N < 0 \ \ __ / 0 HOOC\ "pH
¨N
\
COOH COOH
A reactor was charged with 5.67g (S)-zopiclone and 194g ethanol (SDA 3A). The
mixture was heated to 65 C, and to the reactor was added a solution created by
combining 2.05 g of L-malic acid with 18.5 g ethanol. The reaction was rinsed
in with
26g ethanol. The mixture was seeded with 100mg powdered (S)-zopiclone-L-
malate,
and aged for 60 minutes. The mixture was cooled to 40 C at 0.3 C/minute and
aged for
30 mins. The mixture was cooled to 20 C at 0.5 C/minute and aged for 30 mins.
The
mixture was filtered and washed with 20g ethanol in one wash, dried in vacuo
until no
further weight loss at approximately 50 C (-6h), to provide the titled
compound in 86%
yield.
Example 3 ¨ Synthesis of (S)-Zopiclone Besylate
0
0
0 SOH
N......j( N_
1 N¨ )-01 L
............(N¨ )¨CI
N%----------( N
¨N/ \N ______ ( tetrahydrofuran ¨N N (
\ ______________________________________________ /
\ ____________ / 0 0
A 2000 mL reactor was charged with 10.0 g (S)-zopiclone and 400 mL
tetrahydrofuran
(THF). The contents were heated to 35 C to dissolve. Into a 1000 mL reactor
was
charged 4.4 g benzenesulfonic acid and 400 mL THF, and stirred until a
solution was
formed. The acid solution was transferred slowly to the zopiclone solution.
The
reaction was cooled to 15 C and stirred for 18 hr at 20-25 C. The reactor
slurry was
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filtered and washed with THF in an appropriate filter. The wet cake was dried
under
vacuum, isolated at 60-65 C and packaged in an appropriate container.
Isolated yield =
92.7%.
[0098] Example 4 ¨ Synthesis of (S)-Zopiclone Besylate
0
0
N N¨
N
/ .....A
L ............(N¨c )¨CI
1 N¨ )¨CI
N%-------.< ethanol N
______________________________________ ro- 0 SO3H
/ "N SO3H 0 0 SO3H / "N
¨N\ 7 __ (0 \ ____________ / <0 0
A reactor was charged with 0.123 g (S)-zopiclone. To the reactor was added
0.056 g
benzene sulfonic acid. The reaction charged with 17.2 g ethanol and agitated.
The
reaction was cooled to 0 C, and the reaction was allowed to stir for greater
than one
hour after a slurry appeared. The reaction mixture was filtered and washed
once with
0.5 g ethanol, dried in vacuo at approximately 50 C for approximately 6h to
yield the
titled compound in 52% yield.
[0099] Example 5 ¨ Synthesis of (S)-Zopiclone Besylate
0
0
N N¨
N
1 N¨ )¨CI 0 SO3H
N%---------( N
______________________________________ 0.- 0
0SO3H
¨N" "N ( ______________________ tetrahydrofuran ¨N/ \N (
\ ______________________________________________ /
[00100] Eszopiclone free base (10.0 g) was dissolved in tetrahydrofuran (THF)
solvent
(441.0 g) by mixing and heating between 45-55 C in a reactor vessel.
Benzenesulfonic
acid (4.27 g) was dissolved in THF (348.0 g) and a small portion (-10%) was
added to
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the eszopiclone free base solution. Eszopiclone besylate seed (-250 mg) was
added to
the solution. The mixture was aged for 30 minutes. The remainder of the
besylate
solution was added slowly to the reactor. The product slurry was then heated
to 63-67
C and was allowed to age for a minimum of 30 minutes. The product slurry was
slowly
cooled to 15 C and mixed for a minimum of 20 minutes. The reaction was
filtered and
washed once with 100 g tetrahydrofuran, dried in vacuo until no further weight
loss at
55 C (-6h) to provide the titled compound in 97% yield.
[00101] Example 6 ¨ Synthesis of (S)-Zopiclone Maleate
0
0
HOOC COOH
N¨ \_/ CI
N¨cethanol
0
¨N/
___________ 0
¨N( ____________________________________________ )N HOOC
/COOH
\_
\ 0 0
A reactor was charged with 0.101g (S)-zopiclone and 0.040g maleic acid. The
mixture
was agitated and then charged with 18g ethanol. The slurry was heated to 60 C
and
aged for 90 minutes. The slurry was cooled to 20 C and aged for 60 minutes.
The
reaction was filtered and washed once with 0.5g ethanol, dried in vacuo at
approximately 50 C for approximately 6 hr, and provided the titled compound in
76%
yield.
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[00102] Example 7 ¨ Synthesis of (S)-Zopiclone Maleate
0
0
HOOC COOH
N¨ \_/ N.____A N¨
I N¨ )¨CI
tetrahydrofuran L ............(N¨c )¨CI
---......< N
0
¨N N
/ \ 0
¨N\ /N _____________________________________________ ( 1000H
\
/ ______________________________________________ \
(
HOOC COOH
\
\ __ / 0 0
A reactor was charged with 10.1 g (S)-zopiclone, agitation was started, and
the reactor
was charged with 512.6 g of tetrahydrofuran. The mixture was heated to 50 C.
To the
reactor was added a 10% of a solution created by combining 3.20 g of maleic
acid with
155.7 g acetone. The mixture was seeded with 250 mg (S)-zopiclone maleate and
aged
for 25 minutes. The remaining acid solution was added over 25 minutes. (total
acid eq =
1.05). The mixture was aged for 30 minutes, cooled to 20 C at 0.5 C/minute,
aged for
2 hours, filtered and washed once with 70g tetrahydrofuran, and dried in vacuo
until no
further weight loss at 45 C (-4h) to provide the titled compound in 94% yield.
[00103] Example 8 ¨ Bitterness Results using E-Tongue
[00104] The a Astree II Bitterness Prediction Module (BPM) and Electronic
Tongue (E-
Tongue) was utilized to perform taste assessments. The sensory (E-tongue)
apparatus
utilized is commercially available (Alpha-mos, Hillsborough, New Jersey) and
includes
three arrays of seven sensors with the third array utilized to assess
bitterness of chemical
identities. The bitterness results were obtained with the a Astree II BPM used
in a
pharmaceutical configuration for bitterness assessment of eszopiclone, and its
salts
prepared at various concentrations using the third sensor array.
[00105] When analyzing a sample on the a Astree II Electronic Tongue, basic
parameters/ experimental conditions, such as analysis time and stirring rate
per sample
were established in accordance with standard operation of the analysis system.
The
various methods were saved on the BPM for the analysis of each test sample.
Each
method utilized all seven sensors (BD, EB, JA, JG, KA, OA, and OB) on sensor
array 3
to perform an instrumental characterization of the prepared formulations.
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[00106] Solutions of caffeine (0.05 and 0.5 mg/mL), acetaminophen (0.5 and 3.0
mg/mL), quinine (0.04 and 0.01 mg/mL), and prednisolone (0.25 and 0.5 mg/mL),
were
prepared to create a calibration curve, partial least square (PLS) to
correlate the sensory
panel scores and the measurements/values obtained from the prepared solutions
of
eszopiclone and its salt forms from the BPM.
[00107] Eszopiclone and its salts were prepared as solution in deionized water
at freebase
equivalent concentrations of 0.002 mg/mL and 0.02 mg/mL for analysis.
[00108] BPM data analysis model is based on a Partial Least Square PLS
statistical data
treatment. The PLS model allowed for correlation of the instrument result
(sensor
responses) to a BU (Bitterness Unit) defined by the sensory panel. The
proposed scale
of BU is from 1 to 20, which respectively corresponds to a non detectable
bitterness and
an unacceptable bitterness.
[00109] The in vivo measurements were then performed on a 1-20 scale where the
bitterness intensity increases for higher marks. This scale was divided into 5
different
categories: non detectable bitterness from marks 1 to 4.5; slight bitter taste
from marks
4.5 to 8.5; acceptable bitterness from marks 8.5 to 12.5; limit but acceptable
bitterness
from marks 12.5 to 16.5; and non acceptable bitterness from marks 16.5 to 20.
The
results of the e-tongue data are provided in Table 1. Desirable compositions
have at
least a one unit difference on an E-tongue analysis relative to control (in
this case the
corresponding free base).
[00110] Table 1. Average Predicted Bitterness
Sample Concentration Average Predicted
Bitterness
Free base 0.02 mg/mL 15.6
0.002 mg/mL 8.4
maleate 0.02 mg/mL 8
0.002 mg/mL 6.5
besylate 0.02 mg/mL 10.4
0.002 mg/mL 8.7
L-malate 0.02 mg/mL 12.1
0.002 mg/mL 7.5
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[00111] Example 9 ¨ Solubility and Dissolution
[00112] The aqueous solubility was determined by taking a filtered aliquot of
an
equilibrated (24 hour at ambient) suspension of the salt in water. The aliquot
was diluted
and analyzed by HPLC (Waters). The data was compared to a standard curve
generated
from a set of solutions of known concentrations. The standard curve and the
samples
were analyzed using a HPLC using the following conditions:
TM
Column: Symmetry C-18, 5 urn, 15 cm x 3.9 mm (Waters)
Mobile Phase: 0.05 M KH2PO4 ¨ 0.01 M Hexanesulfonic Acid/THF
(1000:125) (Apparent pH 5.0)
Column Temp: 20-30 C.
Flow Rate: 1.0 mL/min
Wavelength: 305 nm
Run Time: 15 min (zopiclone retention time is 9.5-10 min)
[00113] Table 2. Water Solubility Data for Eszopiclone Salts
Solubility
Compound pH
2
(mgA/mL)
Freebase 0.2' 7.6
Maleate 9 4.4
Besylate 34 4.4
L-Malate 150 3.9
24-hour value; experiment stopped because significant degradation was observed
2
pH measured at saturation.
[00114] The intrinsic dissolution (Table 3) was determined using USP 28 method
<1087> (United States Pharmacopeia, The National Formulary, USP 28, 28th
edition,
Rockville, MA, 2005). Preparation of each test sample was performed as per USP
28
method <1087> by weighing and transferring the material to the die cavity and
compressing for 1 minute at the minimum compression pressure necessary to form
a
nondisintegrating compacted pellet The dissolution media used was isotonic
50mM
acetate buffer (pH 4.5) at 37 C and speed was set at 50 rpm. Each run was
halted at 5
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min, irrespective of the percent dissolved. Each salt was run in duplicate.
Table 3. Intrinsic Dissolution Data for Eszopiclone Salts in
Isotonic 50mM
Acetate (pH 4.5) Buffer at 37 C
Run 1 Run 2 Average
Compound 2= 2 = 2 =
(mgA/cm /min) (mgA/cm /nun) (mgA/cm /min)
Freebase 0.6 0.5 0.5
Besylate 3.3 2.6 2.9
Maleate 1.4 1.2 1.3
[00115] Dissolution over time of eszopiclone salts was compared to that of
free base at
room temperature in pH 4.5 20mM acetate buffer using Hanson Research 5R8-Plus
Dissolution Apparatus and C-Technologies Fiber Optic Probes. A standard
dissolution
protocol was used. For example, 100.12 mg eszopiclone free base (MW 388.81;
purity
99.9%) or 129.98 mg L-malate (MW 504.88; purity 99.8%) or 140.93 mg besylate
(MW 546.99; purity 99.8%) or 129.98 mg maleate (MW 504.88; purity 99.9%) was
added to an empty vessel. 500mL of pH 4.5 20mM acetate buffer was added to
each of
the vessels and mixed at 50 rpm paddle speed. The dissolution program was
started
immediately and readings were taken at 350 nm for 60 min (every 1 min for 10
min and
then every 10 min). Each sample was run in triplicate. The results are shown
in FIG 1,
FIG 2 and FIG 3.
[00116] Example 10 ¨ Bitterness Results in an open-label taste assessment in
healthy
human subjects
[00117] The Flavor Profile is an art-recognized descriptive sensory analysis
method used
to measure the type and intensity of attributes in products and ingredients.
[see Keane,
P. The Flavor Profile Method. In C. Hootman (Ed.), Manual on Descriptive
Analysis
Testing for Sensory Evaluation ASTM Manual Series: MNL 13. Baltimore, MD.
(1992).] It is based on the concept that flavor consists of identifiable
taste, odor
(aroma), and chemical feeling attributes, plus an underlying complex of
attributes not
separately identifiable. The method consists of formal procedures for
describing and
assessing the flavor of a product in a reproducible manner.
[00118] Seven-point scales are used to measure the intensity or strength of
the flavor
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character notes as well as the amplitude, as shown below:
Value Intensity Amplitude
0 None None
IA Very Slight Very Low
1 Slight Low
11/2 Slight-to -Moderate Low-to-Moderate
2 Moderate Moderate
21/2 Moderate-to- Moderate-to-
Strong Strong
3 Strong Strong
[00119] Intensity is a constant scale; that is, when sweetness is designated
at a slight-to-
moderate strength (11/2) in both chocolate and orange juice, for example, the
sweetness
level detected can be related to reference materials of a slight-to-moderate
level of
sweetness exemplified by a certain concentration of sugar (sucrose). A
description of
aftertaste, the sensations that are still present in the mouth after
swallowing, is also
included in the Flavor Profile. Aftertaste was measured in terms of intensity
ratings at
various time intervals.
[00120] For the purpose of testing the compounds of the invention, the flavor
profile
panel consisted of four persons who have normal ability to smell and taste,
have been
trained in fundamental sensory principles and all aspects of the Flavor
Profile technique
and have considerable experience as panel members. The samples to be profiled
were
uniform and representative. Sample preparation and presentation were
standardized and
controlled. Each panel member received an aliquot for his/her own independent
analysis.
[00121] Eszopiclone salts were evaluated as solutions in water. Each panelist
constituted
his/her individual sample and mixed the solution with a magnetic stirrer for
20 minutes.
The samples were prepared at 0.01 mg/5 mL, 1.0 mg/5 mL and 3.0 mg/5 mL. The
0.01mg/5 mL concentration is believed to approximate a concentration that
could be
encountered during the brief period that a 3 mg tablet resides in the typical
patient's
mouth. For that reason, the results at 0.01 mg/5 mL are considered most
clinically
relevant. The 1.0 mg/5 mL concentration is probably the upper limit for
exposure and
would be considered quite uncommon. Achieving a 3.0 mg/5 mL concentration
under
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normal conditions of oral administration would require chewing the whole
tablet, which
is considered not relevant for the present purposes. The panelists sipped the
full 5 mL
solution, swished it around the oral cavity and expectorated after 10 seconds.
During
this time the panelists independently evaluated and recorded the initial
flavor
characteristics. The panelists then independently evaluated and recorded the
aftertaste
characteristics at 1, 3, 5, 10, 15, 20, 25 and 30 minutes. The taste element
that is most
noticed by patients taking eszopiclone free base is bitterness. The results of
the test for
bitterness are shown in the following table:
[00122] Table 4. Human Taste Bitterness Results for Eszopiclone Salts
dose t=0 t=1 t=3 t=5 t=10 t=15 t=20 t=25 t=30
0.01mg/5mL 1.6 1.7 1.7 1.5 1.3 1.1 0.9 0.6 0.4
free base
0.01mg/5mL 1.3 1.8 1.6 1.4 1.1 0.8 0.4 0.2 0.1
L-malate
0.01mg/5mL 1.0 1.3 1.4 1.2 0.9 0.7 0.6 0.3 0.2
besylate
0.01mg/5mL 0.9 1.2 1.1 0.9 0.6 0.4 0.4 0.3 0
maleate
1.0mg/5mL 2.7 2.8 2.6 2.4 2.2 2.0 1.8 1.5 1.4
free base
1.0mg/5mL 2.9 2.6 2.3 2.1 1.7 1.4 1.3 1.3 1.1
L-malate
1.0mg/5mL 2.7 3.0 2.8 2.4 2.3 2.1 1.8 1.8 1.7
besylate
1.0mg/5mL 2.7 2.4 2.1 2.0 1.8 1.7 1.6 1.4 1.2
maleate
[00123] Although the salts were tested at 3.0 mg/5 mL, the free base was not,
so
comparative data are not available.
[00124] Example 11 - Exemplary Compositions
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[00125] Suitable ingredients of a tablet dosage form using eszopiclone
naaleate, besylate
or L-malate as the active ingredient are provided in Table 5. Tablets
containing 3 mg of
active product and having the following composition can be prepared according
to a
usual technique:
[00126] Table 5. Exemplary Composition
Zopiclone Salt 0.003 g*
Microcrystalline Cellulose 0.060 g
Calcium Phosphate 0.035
Magnesium Stearate 0.005 2
* Adjust to contain molar equivalent of 0.003 g of freebase eszopiclone
[00127] Tablets of other strengths can be prepared by altering the ratio of
active
ingredient to pharmaceutically acceptable carrier, the compression weight, or
by using
different punches.
[00128] Those skilled in the art will recognize, or be able to ascertain using
no more than
routine experimentation, many equivalents of the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following
claims.
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