Note: Descriptions are shown in the official language in which they were submitted.
CA 02617420 2008-02-01
THERAPEUTIC COMBINATIONS OF ATYPICAL ANTIPSYCHOTICS WITH GABA
MODULATORS AND/OR ANTICONVULSANT DRUGS
Field of the Invention
The present invention relates to pharmaceutical compositions comprising
combinations of ziprasidone, a prodrug thereof or a pharmaceutically
acceptable salt of
ziprasidone or said prodrug and a GABA modulator, a prodrug thereof or a
pharmaceutically
acceptable salt of a GABA modulator or said prodrug, or an anticonvulsant
drug, a prodrug
thereof or a pharmaceutically acceptable salt of an anticonvulsant drug or
said prodrug
and/or a benzodiazepine, a prodrug thereof or a pharmaceutically acceptable
salt of a
benzodiazepine or said prodrug, kits containing such combinations and methods
of using
such combinations to treat patients, including humans, suffering from
treatment resistant
anxiety disorders, psychotic disorders or conditions, or mood disorders or
conditions. This
invention also relates to additive and synergistic combinations of
ziprasidone, a prodrug
thereof or a pharmaceutically acceptable salt of ziprasidone and a GABA
modulator, a
prodrug thereof or a pharmaceutically acceptable salt of said GABA modulator
or said
prodrug, whereby those additive and synergistic combinations are useful in
treating patients,
including humans, suffering from treatment-resistant anxiety disorders,
psychotic disorders or
conditions, and/or mood disorders or conditions.
Background of the Invention
Schizophrenia is a common and serious mental disorder characterized by loss of
contact with reality (psychosis), hallucinations (false perceptions),
delusions (false beliefs),
abnormal thinking, flattened affect, diminished motivation, and disturbed work
and social
functioning.
Atypical antipsychotics offer several clinical benefits over the conventional
antipsychotics, which were the mainstays of care until the past decade. The
principal
mechanism underlying the many clinical benefits of the atypical agents is
their ability to
separate the antipsychotic effect from the extrapyramidal side effect (EPS).
The distinct
advantages over traditional antipsychotic medications include greater
improvement in
negative and cognitive symptoms, better antidepressant and mood stabilization
effects, lower
risk of parkinsonian side effects and tardive dyskinesia, and greater efficacy
in otherwise
refractory or treatment-resistant patients.
The clinical profile of the atypical and conventional antipsychotics can be
understood
in terms of their different pharmacological profiles. The conventional
antipsychotics are
antagonists of dopamine (DZ ) receptors. The atypical antipsychotics also have
D2
antagonistic properties, but possess different binding kinetics to these
receptors and activity
at other receptors, particularly 5-HT2,o, , 5-HT2c and 5-HTIp (Schmidt B et
al, Soc. Neurosci.
Abstr. 24:2177, 1998).
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The class of atypical antipsychotics includes clozapine (clozaril ),
risperidone
(risperdal ), olanzapine (zyprexa ), quetiapine (seroquel ), aripiprazole
(abilify ) and
ziprasidone (geodon ). Ziprasidone is an atypical antipsychotic whose efficacy
in the
treatment of schizophrenia has been examined in an extensive clinical trial
program that
includes both short term and long term studies. Ziprasidone is indicated for
the treatment of
schizophrenia or psychotic disorders and is widely used in a variety of mood
disorders,
psychiatric medical syndromes and severe personality disorders.
Commonly assigned U.S. Pat. Nos. 4,831,031, 4,883,795, 6,245,766 and
6,126,373,
which are hereby incorporated by reference, each disclose that ziprasidone has
utility in the
treatment of treatment-resistant anxiety disorders, psychotic disorders, and
mood disorders.
The term "ziprasidone", as used herein, unless otherwise indicated,
encompasses the
free base of the compound ziprasidone and all pharmaceutically acceptable
salts thereof.
GABA is the major inhibitory neurotransmitter in the patient in the central
nervous
system (CNS). GABA receptors can be found in 60-80% of CNS neurons. Allosteric
facilitation of GABA receptors occurs at several distinct sites; the compounds
which bind
there are used as sedatives and anxiolytics.
GABA modulators have been disclosed to be useful in antiseizure therapy for
central
nervous system disorders such as epilepsy, Huntington's chorea, cerebral
ischemia,
Parkinson's disease, tardive dyskinesia and spasticity. GABA agonists have
also been
disclosed to be useful antidepressants, anxiolytics and antipsychotics.
Commonly assigned U.S. Pat. No. 4,024,175, which is hereby incorporated by
reference, discloses that GABA modulators have utility in the treatment of
treatment-resistant
anxiety, psychotic disorders and conditions, and mood disorders and
conditions.
GABA modulators well known in the art include muscimol, progabide, riluzole,
baclofen, gabapentin (Neurontin ), vigabatrin, valproic acid, (Depakene ,
Depakote )
tiagabine (Gabitril ), lamotrigine (Lamictal ), pregabalin, topiramate
(Topama)e) and analogs,
derivatives, prodrugs and pharmaceutically acceptable salts of those GABA
modulators.
Benzodiazepines have been used for several decades in connection with a broad
spectrum of diseases. The major known effects of benzodiazepines are
anticonvulsant,
muscle relaxing, sedative, hypnotic, anxiolytic, and antipsychotic. The
mechanism underlying
the effect of the benzodiazepine drugs is unknown but it is believed to relate
to the GABA
system of the CNS.
When any of the anxiolytic or antipsychotic effects are desired, it is often a
problem
that the sedative and hypnotic effects of benzodiazepines prohibit the use of
high dosages of
benzodiazepines, or, when such high dosages are nevertheless necessary to get
a
reasonable effect of the treatment, make it necessary to hospitalize the
patient. Even in the
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dosages used against disorders or conditions, e.g. anxiety, the sedative
effect of
benzodiazepines may be disadvantageous.
According to DSM-IV, Generalized Anxiety Disorder is characterized by
persistent
and excessive anxiety and worry about a number of events and activities
occurring on more
days than not, for at least 6 months. Anxiety disorders are the most common
form of mental
illness in the United States affecting more than 19 million adults yearly.
Treatments for anxiety
disorders include the Selective Serotonin Reuptake Inhibitors (SSRis),
buspirone, venlafaxine
and benzodiazepines. Typical and atypical antipsychotics investigated as
therapeutic agents
with utility for anxiety have demonstrated a more tolerable side effect
profile, and a lower
incidence of tardive dyskinesia. The serotoninergic properties of ziprasidone
may make it
useful in the treatment of anxiety disorders.
There remains a low rate of complete remission reported with benzodiazepines
and
antidepressants, thereby warranting alternative augmentation strategies to
reduce disability
and suffering in this chronic disorder.
Posttraumatic stress disorder (PTSD) is a severe and often chronic mental
illness.
PTSD has lifetime population prevalence of about 10% in the U.S., making it
among the most
prevalent of psychiatric disorders. The most common traumatic stressors are
rape, domestic
violence, child abuse, assault, accidents, and disasters. PTSD is
characterized by symptoms
in three clusters, intrusive, avoidant, and arousal. The intrusive symptom
cluster (flashbacks,
nightmares, intrusive thoughts, physiological and psychological arousal upon
reminders of
trauma) is considered unique to PTSD, and is not seen in any other psychiatric
condition.
Though classified as an anxiety disorder in DSM-IV, PTSD is accompanied by
psychotic
symptoms in almost half of patients. Treatment consists of the Selective
Serotonin Reuptake
Inhibitors (SSRis) such as sertraline, GABA modulators, and benzodiazepines.
The psychotic
symptoms are treated as add-on therapy with antipsychotic agents. Therefore, a
combination
product would have utility in this patient population.
Mood disorders, also known as affective disorders, are a group of
heterogeneous,
typically recurrent illnesses including unipolar (depressive) and bipolar
(manic-depressive)
disorders, dysthymic disorder, and cyclothymic disorder that are characterized
by pervasive
mood disturbances, psychomotor dysfunction, and vegetative symptoms. Mood
disorders
may affect 20% of women and 12% of men during their lifetime. They are the
most prevalent
of psychiatric disorders, accounting for as many as 65% of psychiatric
outpatients, and 10%
of all patients seen in nonpsychiatric medical settings (The Merck Manual,
17'h ed., Merck &
Co. 1999, p. 1526).
Lithium, the standard of care for mood disorder has a response rate of only
50% and
is associated with side effects. Anticonvulsants have been used in mood
disorders as mood
stabilizers and are indicated for use in bipolar disorders. For example,
valproic acid and
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derivatives, e.g. divalproex sodium or carbamazepine at doses of 500 to 2000
mg daily have
shown limited efficacy. Antipsychotic agents are also clinically used in this
patient population.
A combination product containing anticonvulsants and atypical antipsychotics
will have
significant utility in the treatment of these patients.
Mental illness is particularly difficult to treat in that not all patients
react similarly to the
same treatment regimen. Patients often require multiple drug therapies. There
also exists a
large number of untreated individuals and treatment-resistant patients in need
of effective
therapy.
Exacerbating this is the problem of patient noncompliance. For example, it is
conventionally thought that substantial numbers of patients with mental
illnesses are not or
only partially compliant with their medication. Poor compliance can cause
relapses thereby
negating whatever benefits were achieved through treatment in the first place.
Simplification of the regimen by combining several therapeutic agents, reduces
the
opportunity for patient noncompliance as occurs with a more rigorous schedule.
There is a
need for pharmaceutical combinations and pharmaceutical kits which employ
atypical
antipsychotics efficacious for the treatment of, e.g. treatment-resistant
anxiety, psychotic
disorders and conditions and mood disorders.
The present invention is directed to compositions which reduce or overcome
these
disadvantages in novel pharmaceutical combinations of ziprasidone and GABA
modulators,
anticonvulsants and benzodiazepines for the treatment of treatment-resistant
anxiety,
psychotic disorders and symptoms, and mood disorders and conditions.
Summary of the Invention
The present invention is directed to pharmaceutical compositions, therapeutic
methods of treatment, and kits which employ an atypical antipsychotic together
with a GABA
modulator, an anticonvulsant or a benzodiazepine.
According to the invention, it has surprisingly been found that the
pharmaceutical
combinations of the present invention can provide synergistic and additive
effects with less
side effects and a reduction in use of concomitant psychotropic medications
such as
antidepressants, sedatives and mood stabilizers such as lithium.
Thus according to one aspect, the present invention provides a combination of
an
atypical antipsychotic agent and a GABA modulator, or an anticonvulsant or a
benzodiazepine. Atypical antipsychotics which may be used in the present
invention include
olanazapine, clozapine, risperidone, sertindole, quetiapine, aripiprazole,
amisulpride and
ziprasidone. In general, pharmaceutical combinations and methods of treatment
using
ziprasidone as the first therapeutic agent are preferred.
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fn accordance with another aspect of the present invention, there is provided
a
pharmaceutical composition for use in treating a psychiatric condition
selected from the group
consisting of a treatment-resistant anxiety disorder, a psychotic disorder or
condition, or a
mood disorder in a mammal comprising (i) a first therapeutic agent which is an
atypical
antipsychotic and (ii) a second therapeutic agent which is a GABA modulator,
wherein the
amounts of (i) and (ii) are together effective in treating said psychiatric
condition.
In accordance with still another aspect of the present invention, there is
provided a
use of:
i) an amount of a first therapeutic agent which is an atypical antipsychotic;
and
ii) an amount of a second therapeutic agent which is a GABA modulator,
wherein the amounts of (i) and (ii) are together effective in treating a
disorder selected from
treatment-resistant anxiety disorder, a psychotic disorder or condition, or a
mood disorder;
for the preparation of a medicament for treatment of said disorder in a
mammal.
In accordance with a further aspect of the present invention, there is
provided
a use of:
i) an amount of a first therapeutic agent which is an atypical antipsychotic;
and
ii) an amount of a second therapeutic agent which is a GABA modulator,
wherein the amounts of (i) and (ii) are together effective in treating a
disorder selected from
treatment-resistant anxiety disorder, a psychotic disorder or condition, or a
mood disorder;
for treatment of said disorder in a mammal.
A further feature of the present invention is a method of reducing the amount
of the
atypical antipsychotic agent required to produce an anti-anxiety,
antipsychotic and mood
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stabilizing effect which comprises treating a patient with a therapeutically
effective amount of
a drug combination according to the present invention.
It is also a feature of this invention that the use of such drug combinations
will
enhance the effect of the atypical antipsychotic agent to be used and
therefore allow reduced
quantities of the antipsychotic agent to be used and, therefore allow better
management of
drug-related toxicity and side effects.
The invention offers advantages over previous methods for treating
neuropsychiatric
disorders. For example, in the method of treatment of the present invention,
the atypical
antipsychotic counteracts the typical sedative and hypnotic effects of the
benzodiazepine.
Other features and advantages of the invention will be apparent from the
following detailed
description and from the claims.
Detailed Description of the Invention
The present invention is directed to pharmaceutical compositions comprising:
an
amount of ziprasidone, a prodrug thereof or a pharmaceutically acceptable salt
of ziprasidone
or said prodrug; and an amount of a GABA modulator, an anticonvulsant drug
and/or a
benzodiazepine, prodrugs thereof or pharmaceutically acceptable salts of said
GABA
modulator, anticonvulsant drug or benzodiazepine; and a pharmaceutically
acceptable
vehicle, carrier or diluent.
The present invention is directed to a therapeutic method and pharmaceutical
compositions comprising ziprasidone and a GABA modulator useful for treating
treatment-
resistant anxiety disorders; ziprasidone and an anticonvulsant drug useful in
the treatment of
mood disorders or psychotic disorders or treatment; and ziprasidone and a
benzodiazepine
effective in the treatment of treatment-resistant anxiety and/or psychotic
disorders or
conditions.
The present invention is also directed to a therapeutic method and a
pharmaceutical
composition comprising ziprasidone and a GABA modulator useful for treatment
of treatment-
resistant anxiety disorders.
The present invention is further directed to a therapeutic method and a
pharmaceutical composition comprising ziprasidone and a benzodiazepine useful
for
treatment of psychotic disorders or conditions or treatment-resistant anxiety
disorders.
The present invention is still further directed to a therapeutic method and a
pharmaceutical composition comprising ziprasidone and an anticonvulsant drug
useful for
treating mood disorders or conditions, psychotic disorders or conditions, or
psychotic
symptoms.
This invention is also directed to kits for achieving a therapeutic effect in
a patient
comprising an amount of ziprasidone, a prodrug thereof or a pharmaceutically
acceptable salt
of said ziprasidone and a pharmaceutically acceptable vehicle, carrier or
diluent in a first unit
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dosage form; and an amount of a GABA modulator or an anticonvulsant drug or a
benzodiazepine, prodrugs thereof or pharmaceutically acceptable salts of said
GABA
modulator, anticonvulsant drug or benzodiazepine and a pharmaceutically
acceptable vehicle,
carrier or diluent in a second unit dosage form and a container.
This invention is also directed to methods of treating a patient in need of
therapy
comprising administering to said patient an amount of a first drug, the first
drug being
ziprasidone, a prodrug thereof or a pharmaceutically acceptable salt of
ziprasidone, and an
amount of a second compound, the second compound being a GABA modulator, an
anticonvulsant drug or a benzodiazepine, a prodrug thereof or a
pharmaceutically acceptable
salt of the GABA modulator, anticonvulsant drug or benzodiazepine.
This invention is further directed to methods for treating a patient in need
of therapy
comprising administering to said patient
an amount of a first compound, the first compound being ziprasidone, a prodrug
thereof or a pharmaceutically acceptable salt of ziprasidone or the prodrug;
and
an amount of a second compound, the second compound being a GABA modulator,
an anticonvulsant drug or a benzodiazepine, a prodrug thereof or a
pharmaceutically
acceptable salt of the GABA modulator, anticonvulsant drug or benzodiazepine
or said
prodrug;
wherein said first compound and said second compound are each optionally and
independently administered together with a pharmaceutically acceptable
vehicle, carrier or
diluent.
This invention is also directed to methods for treating a patient in need of
therapy
comprising administering to the patient a pharmaceutical composition
comprising
a) an amount of a first compound, the first compound being ziprasidone, a
pharmaceutically salt of ziprasidone, a prodrug of ziprasidone, or a
pharmaceutically
acceptable salt of a ziprasidone prodrug; and
b) an amount of a second compound, the second compound being a GABA
modulator, an anticonvulsant drug, a benzodiazepine, a prodrug thereof or a
pharmaceutically
acceptable salt of the GABA modulator, or anticonvulsant drug, or
benzodiazepine or the
prodrug; and, optionally,
a pharmaceutically acceptable vehicle, carrier or diluent.
The methods of this invention include therapeutic treatment of treatment-
resistant
anxiety. Treatment-resistant anxiety which may be treated by the methods of
this invention
includes, inter alia, treatment-resistant obsessive compulsive disorder or
treatment-resistant
post-traumatic stress disorder.
The methods of this invention include therapeutic treatment of psychotic
disorders or
conditions. Psychotic disorders which can be treated by the methods of this
invention include,
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inter alia, schizophrenia, schizophreniform disorder, schizoaffective
disorder, delusional
disorder, brief psychotic disorder, shared psychotic disorder.
The methods of this invention include therapeutic treatment of mood disorders
or
conditions. Mood disorders are a group of heterogeneous illnesses including
unipolar
(depressive) and bipolar (manic-depressive) disorders that are characterized
by pervasive
mood disturbances, psychomotor dysfunction, and vegetative symptoms. While
depression
and elation are the core affective components, anxiety and irritability are
equally common,
explaining the continued popularity of the broader rubric "affective
disorders", the previous
official designation.
Preferred GABA modulators for use in the combinations, pharmaceutical
compositions, methods and kits of this invention include: muscimol, progabide,
riluzole,
baclofen, gabapentin (Neurontin ), vigabatrin, valproic acid, tiagabine
(Gabitril ), lamotrigine
(Lamictal ), pregabalin, phenytoin (Dilantin ), carbamazepine (Tegretol ),
topiramate
(Topamae), prodrugs thereof and pharmaceutically acceptable salts of the GABA
modulators
and the prodrugs.
More preferred GABA modulators for use in the combinations, pharmaceutical
compositions, methods and kits of this invention include gabapentin,
tiagabine, lamotrigine,
topiramate, pregabalin, prodrugs thereof and pharmaceutically acceptable salts
of the GABA
modulators and the prodrugs.
A particularly preferred GABA modulator for use in the combinations,
pharmaceutical
compositions, methods and kits of this invention is pregabalin, a prodrug
thereof or a
pharmaceutically acceptable salt of pregabalin or a prodrug thereof.
Another particularly preferred GABA modulator for use in the combinations,
pharmaceutical compositions, methods and kits of this invention is gabapentin
(Neurontin ), a
prodrug thereof or a pharmaceutically acceptable salt of gabapentin (Neurontin
) or prodrug
thereof.
Preferred anticonvulsants for use in the combinations, pharmaceutical
compositions,
methods and kits of this invention include: hydantoins such as phenytoin
(Dilantin ),
mephenytoin (Mesantoin ); succinimides such as ethosuximide (Zarontin ),
oxazolidinediones such as trimethadione (Tridione ), carbamazepine (Tegretol
), primadone
(Mysoline ), vaiproic acid (Depakote ), prodrugs thereof and pharmaceutically
acceptable
salts of the anticonvulsants and prodrugs thereof.
More preferred anticonvulsants for use in the combinations, pharmaceutical
compositions, methods and kits of this invention include phenytoin and
valproic acid, prodrugs
thereof and pharmaceutically acceptable salts of the anticonvulsants and
prodrugs thereof,
and pharmaceutically acceptable salts of the prodrugs.
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A particularly preferred anticonvulsant for use in the combinations,
pharmaceutical
compositions, methods and kits of this invention is valproic acid, a prodrug
thereof or a
pharmaceutically acceptable salt of valproic acid or prodrug thereof.
Another particularly preferred anticonvulsant for use in the combinations,
pharmaceutical compositions, methods and kits of this invention is phenytoin,
a prodrug
thereof or a pharmaceutically acceptable salt of phenytoin or prodrug thereof.
Preferred benzodiazepines for use in the combinations, pharmaceutical
compositions,
methods and kits of this invention include: alprazolam, chlordiazepoxide,
clonazepam,
clorazepate, diazepam, halazepam, lorazepam, temazepam and oxaxepam, prodrugs
thereof
and pharmaceutically acceptable salts of benzodiazepines and prodrugs thereof.
More preferred benzodiazepines for the use in combinations, pharmaceutical
compositions, methods and kits of this invention include clonazepam, diazepam
and
lorazepam, prodrugs thereof and pharmaceutically acceptable salts of
anticonvulsants and
prodrugs thereof.
A particularly preferred benzodiazepine for the use in combinations,
pharmaceutical
compositions, methods and kits of this invention is clonazepam, a prodrug
thereof or a
pharmaceutically acceptable salt of clonazepam or a prodrug thereof.
Another particularly preferred benzodiazepine for the use in combinations,
pharmaceutical compositions, methods and kits of this invention is lorazepam,
a prodrug
thereof or a pharmaceutically acceptable salt of lorazepam or a prodrug
thereof.
The combinations of this invention comprise at least two active components:
ziprasidone, a prodrug thereof or a pharmaceutically acceptable salt, and a
GABA modulator,
a prodrug thereof or a pharmaceutically acceptable salt of the GABA modulator;
or
ziprasidone, a prodrug thereof or a pharmaceutically acceptable salt, and an
anticonvulsant,
a prodrug thereof or a pharmaceutically acceptable salt of an anticonvulsant
or a prodrug; or
ziprasidone, a prodrug or pharmaceutically acceptable salt and a
benzodiazepine, a prodrug
thereof or a pharmaceutically acceptable salt of a benzodiazepine. The
combinations of this
invention include a pharmaceutically acceptable vehicle, carrier or diluent.
The combinations result in synergistic action allowing a lower dose of the
atypical
antipsychotic to be administered while achieving the same psychotropic effect.
The dosage of
the atypical antipsychotic may be reduced by about 25-90%, for example, about
40-80% and
typically about 50-70%. The reduction in amount of antipsychotic required will
be dependent
on the amount of second therapeutic agent given.
The selection of the dosage of the first and second therapeutic agents is that
which
can provide relief to the patient as measured by a reduction or amelioration
of symptoms
associated with the disorder or condition of the patient. As is well known,
the dosage of each
component depends on several factors such as the potency of the selected
specific
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compound, the mode of administration, the age and weight of the patient, the
severity of the
condition to be treated, and the like. This is considered to be within the
skill of the artisan and
one can review the existing literature regarding each component to determine
optimal dosing.
To the extent necessary for completeness, the synthesis of the components of
the
compositions and dosages are as described in the listed patents or the
Physicians' Desk
Reference, 57th ed., Thompson, 2003 which are expressly incorporated herein by
reference.
Desirably, when ziprasidone is selected as the active agent, the daily dose
contains from
about 5 mg to about 460 mg. More preferably, each dose of the first component
contains
about 20 mg to about 320 mg of the ziprasidone, and even more preferably, each
dose
contains from about 20 mg to about 160 mg of zirpasidone. Pediatric dosages
may be less.
This dosage form permits the full daily dosage to be administered in one or
two oral doses, for
example.
General outlines of the dosages for the atypical antipsychotics, GABA
modulators,
anticonvulsants, and benzodiazepines, and some preferred dosages, are provided
herein.
This list is not intended to be complete but is merely a guideline for any of
the desired
combinations of the present invention.
Olanzapine: from about 0.25 to about 100 mg, once/day; preferred, from about 1
to
about 30 mg, once/day; and most preferably about 1 to about 25 mg once/day;
Clozapine: from about 12.5 to about 900 mg daily; preferred, from about 150 to
about
450 mg daily;
Risperidone: from about 0.25 to about 16 mg daily; preferred from about 2-8 mg
daily;
Sertindole: from about 0.0001 to about 1.0 mg/kg daily;
Quetiapine: from about 1.0 to about 40 mg/kg given once daily or in divided
doses;
Asenapine: from about 0.005 to about 60 mg total per day, given as a single
dose or
in divided doses;
Carbamezepine: from about 200 to about 1200 mg/day; preferably about 400
mg/day;
Valproic Acid: from about 250 to about 2500 mgday; preferably about 1000
mg/day;
Lamotrigine: from about 50 to about 600 mg/day in 1 to 2 doses; preferably
about 200
to about 400 mg; most preferably about 200 mg;
Gabapentin: from about 300 to about 3600 mg/day in 2 to 3 divided doses;
preferably
300 to about 1800 mg/day; most preferably about 900 mg/day;
Tiagabine: from about 2 to about 56 mg/day in 2 to 4 divided doses; preferably
about
32 to about 56 mg/day; most preferably about 56 mg/day.
Topiramate: from about 200 to about 600 mg/day divided in 2 doses; most
preferably
about 400 mg/day.
The Table below provides additional dosage ranges:
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Drug Name Dosage Range
Brand name Generic Name
Klonopin Clonazepam Minimum: 0.25 mg
Maximum: 20mg
Tranxene Clorazepate Minimum: 3.75 mg.
Dipotassium Maximum: 60 mg
Valium Diazepam Minimum: 1 mg.
Maximum: 40 mg.
Xanax Alprazolam Minimum: 0.25 mg
Maximum: 4 mg
Gabitril Tiagabine Minimum: 4 mg
Maximum: 56 mg
Neurontin Gabapentin Minimum: 100 mg
Maximum: 2400 mg
Dilantin Phenytoin Minimum: 50 mg
Maximum: 1200 mg
Carbatrol Carbamazepine Minimum: 200 mg
Capsules ER Maximum: 1200 mg
Depakote Valproic acid Minimum: 250 mg
Maximum: 2000 mg
Felbatol Felbamate Minimum: 1200 mg
Maximum: 3600 mg
Keppra Levetiracetam Minimum : 1000 mg
Maximum : 3000 mg
Tegretol Carbamazepine Minimum: 200 mg
Maximum: 1200 mg
Topamax Topiramate Minimum: 25 mg
Maximum: 400 mg
Celontin Methoximide Minimum: 150 mg
Maximum : 1200 mg
Trileptal Oxcarbazepine Minimum: 300 mg
Maximum: 2400 mg
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Drug Name Dosage Range
Brand name Generic Name
Zonegran Zonisamide Minimum: 100 mg
Maximum: 600 mg
Lamictal Lamotrigine Minimum: 200 mg
Maximum: 400 mg
Zarontin Capsules Ethosuximide Minimum : 250 mg
Maximum : 1500 mg
In more general terms, one would create a drug combination of the present
invention
by choosing a dosage of first and second component compounds according to the
spirit of the
above guideline.
The atypical antipsychotics of the present invention are useful in treating
schizophrenia, bipolar disorders, and dementia.
The presently preferred atypical antipsychotic used according to the invention
is
ziprasidone. Ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-
yl]ethyl]-6-chloroindolin-
2-one hydrochloride hydrate) is a benzisothiazolyl piperazine-type atypical
antipsychotic with
in vitro activity as a 5-HTlA receptor agonist and an inhibitor of serotonin
and norepinephrine
reuptake (See e.g. U.S. Pat. No. 4,831,031). The postsynaptic 5-HTlA receptor
has been
implicated in both depressive and anxiety disorders (NM Barnes, T Sharp, 38
Neuropharmacology 1083-152,1999). Oral bioavailability of ziprasidone taken
with food is
approximately 60%, half-life is approximately 6-7 hours, and protein binding
is extensive.
Ziprasidone is efficacious for the treatment of patients with schizophrenia
and
schizomood disorders, refractory schizophrenia, cognitive impairment in
schizophrenia,
affective and anxiety symptoms associated with schizoaffective disorder and
bipolar disorder.
The drug is considered a safe and efficacious atypical antipsychotic (Charles
Caley &
Chandra Cooper, 36 Ann. Pharmacother. 839-51, 2002).
The present invention is useful in treating mental disorders and conditions,
the
treatment of which is facilitated by the administration of ziprasidone. Thus,
the present
invention has application where ziprasidone use is indicated as, e.g., in U.S.
Pat. Nos.
6,245,766; 6,245,765; 6,387,904; 5,312,925; 4,831,031; and European EP 0901789
published March 17, 1999, all of which are incorporated herein by reference.
Other atypical antipsychotics which can be used include, but are not limited
to:
Olanzapine, 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-
b][1,5]benzodiazepine, is a
known compound and is described in U.S. Pat. No. 5,229,382 as being useful for
the
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treatment of schizophrenia, schizophreniform disorder, acute mania, mild
anxiety states, and
psychosis. U.S. Pat. No. 5,229,382 is herein incorporated by reference in its
entirety;
Clozapine, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e]
[1,4]diazepine, is described in U.S. Pat. No. 3,539,573, which is herein
incorporated by
reference in its entirety. Clinical efficacy in the treatment of schizophrenia
is described
(Hanes, et al., Psychopharmacol. Bull., 24, 62 (1988));
Risperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-
methyl-6,7,8,9
-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one, and its use in the treatment of
psychotic
diseases are described in U.S. Pat. No. 4,804,663, which is herein
incorporated by reference
in its entirety;
Sertindole, 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1 H-indol-3-yl ]-1-
piperidinyl]ethyl]imidazolidin-2-one, is described in U.S. Pat. No. 4,710,500.
Its use in the
treatment of schizophrenia is described in U.S. Pat. Nos. 5,112,838 and
5,238,945. U.S. Pat.
Nos. 4,710,500; 5,112,838; and 5,238,945 are herein incorporated by reference
in their
entirety;
Quetiapine, 5-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl -1-piperazinyl)
ethoxy]ethanol, and
its activity in assays which demonstrate utility in the treatment of
schizophrenia are described
in U.S. Pat. No. 4,879,288, which is herein incorporated by reference in its
entirety.
Quetiapine is typically administered as its (E)-2-butenedioate (2:1) salt;
Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3- ,4-
dihydro
carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro
-2(1H)-
quinolinone, is an atypical antipsychotic agent used for the treatment of
schizophrenia and
described in U.S. Pat. No. 4,734,416 and U.S. Pat. No. 5,006,528, which are
herein
incorporated by reference in their entirety;
Amisulpride is described in U.S. Pat. No. 4,401,822;
Asenapine, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-
dibenz[2,3:6,7]oxepino[4,5-c]pyrrole. Preparation and use of asenapine is
described in U.S.
Patent Nos. 4,145,434 and 5,763,476, which are incorporated herein in their
entireties by
reference.
A preferred combination is ziprasidone with a GABA modulator. The term "GABA",
where used in the description and the appendant claims, is synonymous with the
term
"gamma-aminobutyric acid." These terms are used interchangeably throughout the
description and appendant claims.
The term "GABA modulator" as used herein refers to a compound that either is
structurally related to the neurotransmitter GABA but does not interact with
the GABA
receptor (e.g. gabapentin), or interacts with the GABA receptors, or is
converted metabolically
into GABA or a GABA agonist; or is an inhibitor of GABA uptake or degradation;
or is a GABA
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receptor subtype-selective antagonist and/or agonist. This definition includes
pharmaceutically acceptable salts, prodrugs or pharmaceutically acceptable
salts of said
prodrugs.
The GABA modulators suitable for use herein include, but are not limited to,
muscimol, progabide, riluzole, baclofen, gabapentin (Neurontin ), vigabatrin,
tiagabine
(Gabitril ), lamotrigine (Lamictal ), pregabalin, topiramate (Topamax ), a
prodrug thereof or a
pharmaceutically acceptable salt of the GABA modulator or prodrug thereof. It
will be
recognized by those skilled in the art in light of this disclosure that other
GABA agonists are
also useful in the combinations, pharmaceutical compositions, methods and kits
of this
invention.
The GABA modulators disclosed herein are prepared by methods well known to
those skilled in the art. Specifically, the following patents and patent
applications, each of
which is hereby incorporated herein by reference, exemplify GABA modulators
which can be
used in the combinations, pharmaceutical compositions, methods and kits of
this invention,
and refer to methods of preparing those GABA modulators: U.S. Pat. No.
3,242,190
(specifically, muscimol); U.S. Pat. No. 4,094,992 (specifically, progabide);
U.S. Pat. No.
4,370,338 (specifically, riluzole); U.S. Pat. No. 3,471,548 (specifically,
baclofen); U.S. Pat.
No. 4,024,175 (specifically, gabapentin); U.S. Pat. No. 3,960,927
(specifically, vigabatrin);
U.S. Pat. No. 5,010,090 (specifically, tiagabine); U.S. Pat. No. 4,602,017
(specifically,
lamotrigine); U.S. Pat. No. 6,028,214 (specifically, pregabalin); and U.S.
Pat. No. 4,513,006
(specifically, topiramate).
Gabapentin, 1-(aminomethyl)cyclohexane acetic acid, is an anticonvulsant
indicated
as adjunctive therapy in the treatment of partial seizures with and without
secondary
generalization in adults with epilepsy. Gabapentin and its methods of use is
described in U.S.
Pat. Nos. 4,024,175 and 4,087,544 incorporated herein by reference in their
entirety.
It will be recognized that certain of the GABA modulators used in the
pharmaceutical
compositions, methods and kits of this invention contain either a free
carboxylic acid or a free
amine group as part of the chemical structure. Thus, this invention includes
pharmaceutically
acceptable salts of those carboxylic acids or amine groups.
For use in medicine, pharmaceutically acceptable salts may be useful in the
preparation of the compounds according to the invention. Suitable
pharmaceutically
acceptable salts of the compounds of this invention include acid addition
salts which may, for
example, be formed by mixing a solution of the compound according to the
invention with a
solution of a pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid,
methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid,
benzoic acid,
oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the
compounds of the invention carry an acidic moiety, suitable pharmaceutically
acceptable salts
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thereof may include alkali metal salts, e.g. sodium or potassium salts;
alkaline earth metal
salts, e.g. calcium or magnesium salts; and salts formed with suitable organic
ligands, e.g.
quaternary ammonium salts.
Where the GABA modulators of use in the invention have at least one asymmetric
center, they may accordingly exist as enantiomers. Where the compounds
according to the
invention possess two or more asymmetric centers, they may additionally exist
as
diastereoisomers. It is to be understood that all such isomers and mixtures
thereof in any
proportion are encompassed within the scope of the present invention.
Gabapentin may be in
the form of the crystalline monohydrate as described in EP340677 which is
incorporated
herein by reference or the anhydrous crystalline form as described in WO
03031391.
The expression "pharmaceutically acceptable salts" includes both
pharmaceutically
acceptable acid addition salts and pharmaceutically acceptable cationic salts.
The expression
"pharmaceutically-acceptable cationic salts" is intended to define but is not
limited to such
salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth
metal salts (e.g.,
calcium and magnesium), aluminum salts, ammonium salts, and salts with organic
amines
such as benzathine (N,N'-dibenzylethylenediamine), choline, diethanolamine,
ethylenediamine, meglumine (N-methylglucamine), benethamine (N-
benzylphenethylamine),
diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-
propanediol) and
procaine. The expression "pharmaceutically-acceptable acid addition salts" is
intended to
define but is not limited to such salts as the hydrochloride, hydrobromide,
sulfate, hydrogen
sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate,
succinate, citrate,
methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.
The pharmaceutically-acceptable cationic salts of GABA modulators containing
free
carboxylic acids may be readily prepared by reacting the free acid form of the
GABA
modulator with an appropriate base, usually one equivalent, in a co-solvent.
Typical bases are
sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium
methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline,
diethanolamine,
piperazine and tromethamine. The salt is isolated by concentration to dryness
or by addition
of a non-solvent. In many cases, salts are preferably prepared by mixing a
solution of the acid
with a solution of a different salt of the cation (e.g., sodium or potassium
ethylhexanoate,
magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the
desired cationic
salt precipitates, or can be otherwise isolated by concentration and/or
addition of a non-
solvent.
The pharmaceutically acceptable acid addition salts of GABA modulators
containing
free amine groups may be readily prepared by reacting the free base form of
the GABA
modulator with the appropriate acid. When the salt is of a monobasic acid
(e.g., the
hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the
hydrogen form of a
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dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen
form of a tribasic
acid (e.g., the dihydrogen phosphate, the citrate), at least one molar
equivalent and usually a
molar excess of the acid is employed. However, when such salts as the sulfate,
the
hemisuccinate, the hydrogen phosphate or the phosphate are desired, the
appropriate and
exact chemical equivalents of acid will generally be used. The free base and
the acid are
usually combined in a co-soivent from which the desired salt precipitates, or
can be otherwise
isolated by concentration and/or addition of a non-solvent.
The anticonvulsants disclosed herein are prepared by methods well known to
those
skilled in the art. Specifically, the following patents and patent
applications, each of which is
hereby incorporated herein by reference, exemplify anticonvulsants which can
be used in the
combinations, pharmaceutical compositions, methods and kits of this invention,
and refer to
methods of preparing those anticonvulsants:
Anticonvulsants contemplated as the second component include, but are not
limited
to, phenytoin, carbamezepine, valproic acid, lamotrigine and topiramate;
Carbamezepine, 5H-dibenz [b,f]azepine-5 -carboxamide is an anticonvulsant and
analgesic marketed for trigeminal neuralgia; U.S. Pat. No. 2,948,718 (herein
incorporated
herein by reference in its entirety), discloses carbamezepine and methods of
use;
Phenytoin, 5,5-diphenyl - 2,4-imidazolidinedione, is a well-known
anticonvulsant;
U.S. Patent No. 2,409,654 discloses phenytoin and methods of use; incorporated
herein by
reference in its entirety.
Valproic Acid, 2-propylpentanoic acid or dispropylacetic acid is a well known
antiepileptic agent which dissociates to the valproate ion in the
gastrointestinal tract; various
pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 4,699,927;
Valproic acid is
prepared as disclosed in Carraz et al., Therapie, 1965, 20, 419) incorporated
herein by
reference in its entirety;
Lamotrigine, 6-(2,3-dichlorophenyl)-1,2,4-trizine-3,5-diamine is an
antiepileptic drug
indicated as adjunctive therapy in the treatment of partial seizures in adults
with epilepsy.
Lamotrigine and its uses is disclosed in U.S. Pat. No. 4,486,354, incorporated
herein by
reference in its entirety; and
Topiramate, 2,3:4,5-di-O-(1-isopropylidine)-3-D-fructopyranose sulphamate is
an
antiepileptic indicated for the treatment of refractory partial seizures, with
or without
secondary generalization and disclosed in U.S. Pat. No. 4,513,006 incorporated
herein by
reference in its entirety.
The benzodiazepines are used as antianxiety agents and in psychiatric
disorders in
which anxiety is a prominent feature. For example, combination treatment with
a
benzodiazepine plus a typical antipsychotic (often haloperidol IM 5-10 mg plus
lorazepam 1-2
mg) is commonly employed. However, this combination may be associated with
intolerable
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side effects, particularly acute dystonia with conventional antipsychotics and
excessive
sedation with benzodiazepines. Also, some clinicians avoid benzodiazepines in
agitation
associated with intoxication.
Benzodiazepines are also associated with excessive sedation, confusion,
disinhibition, ataxia, nausea and vomiting, respiratory depression,
asymptomatic tachypnea,
and tachycardia (J. Modell, J Clin Psychopharmacol. 6:385-387, 1986).
According to the
invention it has surprisingly been found that an atypical antipsychotic
counteracts the typical
sedative and hypnotic effects of benzodiazepines.
Thus, by administering, in accordance with the principle of the present
invention, an
atypical antipsychotic such as ziprasidone to patients treated with
benzodiazepines, it will be
possible, because of the counteraction of the sedative and hypnotic effects,
to use effective
dosages of the benzodiazepines even where high dosages are necessary to obtain
an effect,
without disabling the patients from living a normal daily life.
In the present context, the term "a benzodiazepine" or "benzodiazepines"
designate
benzodiazepine as well as derivatives thereof which are normally classified as
benzodiazepines in pharmaceutical textbooks such as, e.g., Ernst Mutschler,
Arzneimittelwirkungen, Lehrbuch der Pharmaceutical makologie and Toxikologie,
Aug. 5,
1986, Wissenschaftliche Verlagsgasellschaft mbk, Stuttgart, including, e.g.,
diazepam,
dipotassium chlorazepate, chlorasepate, chlordiazapide, medazepam, flurazepam,
clobasam,
clonazepam, nitrasepam, flunitrasepam, astazolam, bromazepam, alprazolam,
lorazepam,
lormetasepam, oxazepam, temazepam, brotizolam, triazolam, chlordiazepam,
halazepam, or
prazepam. As defined herein the term benzodiazepines also refers to
benzodiazepine
receptor subtype compounds as well as pharmaceutically acceptable salts of
benzodiazepines, prodrugs of benzodiazepines and pharmaceutically acceptable
salts of
benzodiazepine prodrugs.
Some benzodiazepines are used for their sedative or hypnotic effect; these
benzodiazepines are typically those having a short half life. Other
benzodiazepines are used
for other effects where the sedative or the hypnotic effects are considered
undesirable or
even side effects of the benzodiazepine. These benzodiazepines are, e.g.,
diazepam,
dipotassium chlorazepate, chlorazepate, chlordiazepide, medazepam, clobazam,
clonazepam, estazolam, bromasepam, alprazolam, lorazepam, lormetazepam,
oxazepam,
brotizolam, chlordiazepam, halazepam, or prazepam.
The diseases treated with benzodiazepines constitute a broad spectrum of
diseases
because of the many effects of the benzodiazepines. Diseases where the
sedative or
hypnotic effects of the benzodiazepines are undesirable are diseases in
connection with
which the principle of the present invention is particularly important.
Especially the treatment
of the following diseases is accomplished by the drug combinations of the
present invention:
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treatment-resistant anxiety, psychotic disorders or conditions, psychotic
symptoms. These
diseases may benefit from the use of both a benzodiazepine and an antypical
antipsychotic in
accordance with the principle of the invention, as these diseases are known to
require high
dosages of benzodiazepine in order to obtain the benefit of the benzodiazepine
therapy.
However, the high dosages, on the other hand, incur the above-mentioned severe
disadvantages due to the sedative and hypnotic effects if no administration of
the atypical
antipsychotic is performed in connection with the benzodiazepine treatment.
Psychotic disorders or conditions, such as schizophrenia, schizoaffective
disorder,
schizophreniform disorder, and schizotypical disorder are conditions in which
benzodiazepine
therapy, such as treatment with clonazepam, is important. According to the
present invention,
these conditions can now also be treated with an atypical antipsychotic in
combination with a
benzodiazepine.
The atypical antipsychotic can be administered simultaneously with the
benzodiazepine, either as separate dosage forms in a kit product, or as one
combined
dosage form containing both the atypical antipsychotic and the benzodiazepine.
The effects of a pharmaceutical composition comprising ziprasidone and a GABA
modulator, or ziprasidone and a benzodiazepine of the present invention can be
examined by
using one or more of the published models of anxiety well known in the art.
The effects of a
pharmaceutical composition comprising ziprasidone and a benzodiazepine, or
ziprasidone
and an anticonvulsant of the present invention can be examined by using one or
more of the
published models of psychotic disorders or conditions well known in the art.
The effects of a
pharmaceutical composition comprising ziprasidone and an anticonvulsant of the
present
invention can be examined by using one or more of the published models of mood
disorders
such as bipolar disorder which are well known in the art.
The pharmaceutical compositions containing ziprasidone and a GABA modulator or
ziprazidone and a benzodiazepine of the present invention are particularly
useful for the
prevention of, reducing the development of, or reversal of, treatment-
resistant anxiety
disorders and are therefore particularly useful in the treatment of obsessive-
compulsive
disorder or post-traumatic stress disorder. This effect can be demonstrated,
for example, by
measuring markers such the Clinician Administered PTSD Scale or the Eysenck
Personality
Inventory and has been shown in clinical studies (MI Butterfield et al, 16
Int'l Clin
Psychopharmacol 197-203, 2001).
The pharmaceutical compositions containing ziprasidone and an anticonvulsant
or
ziprazidone and a benzodiazepine of the present invention are particularly
useful for the
prevention of, reducing the development of, or reversal of, psychotic
disorders, conditions or
symptoms and are therefore particularly useful in the treatment of
schizophrenia,
schizophreniform disorder, schizoaffective disorder or delusional disorder.
This can be
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demonstrated, for example, by measuring markers such Positive or Negative
Syndrome Scale
(PANSS) and Scales for the Assessment of Negative Symptoms (SANS) or BPRS
scores
(Kay et al, Schizophrenia Bulletin 13:261-276, 1987), or in various animal
models such as
PCP or methamphetamine induced locomotor test or the conditioned avoidance
response
test.
The pharmaceutical compositions containing ziprasidone and an anticonvulsant
are
particularly useful for the prevention of, reducing the development of, or
reversal of, mood
disorders and are therefore particularly useful in the treatment of bipolar
disorder, bipolar
depression or unipolar depression. This can be demonstrated, for example, by
measuring the
symptomatic picture and using various animal models such as the "mouse
behavioral despair
test."
In general, ziprasidone employed in the combinations, pharmaceutical
compositions,
methods and kits of this invention, will be administered at dosages between
about 20 and
about 460 mg per day, preferably from about 40 mg to about 200 mg, and most
preferably 40
mg to 160 mg together with therapeutically effective amounts of the second
therapeutic agent
in single or divided doses.
The term "therapeutically effective amount" as used herein refers to a
sufficient
amount of the compound to treat treatment-resistant anxiety disorders, mood
disorders and
psychotic disorders or conditions at a reasonable benefit/risk ratio
applicable to any medical
treatment.
The specific therapeutically effective dose level for any particular patient
will depend
upon a variety of factors including the disorder being treated and the
severity of the disorder;
activity of the specific compound employed; the specific composition employed;
the age.
However, some variation in dosage will necessarily occur depending upon the
condition of the
subject being treated. The person responsible for administration will, in any
event, determine
the appropriate dose for the individual subject.
The following dosage amounts and other dosage amounts set forth elsewhere in
this
description and in the appendant claims are for an average human subject
having a weight of
about 65 kg to about 70 kg. The skilled practitioner will readily be able to
determine the
dosage amount required for a subject whose weight falls outside the 65 kg to
70 kg range,
based upon the medical history of the subject. All doses set forth herein, and
in the
appendant claims, are daily doses.
In general, in accordance with this invention, the above GABA modulators used
in the
combinations, pharmaceutical compositions, methods and kits of this invention
will be
administered in a dosage amount of about 4 mg/kg body weight of the subject to
be treated
per day to about 60 mg/kg body weight of the subject to be treated per day, in
single or
divided doses. However, some variation in dosage will necessarily occur
depending upon the
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condition, age as well as factors which may alter pharmacokinetics of
absorption, distribution,
metabolism and excretion in the subject being treated. The person responsible
for
administration will, in any event, determine the appropriate dose for the
individual subject. In
particular, when used as the GABA modulator in this invention, pregabalin will
be dosed at
about 100 mg to about 1500 mg per day; and preferably about 300 mg to about
1200 mg per
day; gabapentin will be dosed at about 100 mg to about 4000 mg per day, and
preferably
about 600 mg to about 3600 mg per day.
In general, in accordance with this invention, the above anticonvulsants used
in the
combinations, pharmaceutical compositions, methods and kits of this invention
wili be
administered in a dosage amount of about 1 mg/kg body weight of the subject to
be treated
per day to about 10 mg/kg body weight of the subject to be treated per day, in
single or
divided doses. However, some variation in dosage will necessarily occur
depending upon the
condition of the subject being treated. The person responsible for
administration will, in any
event, determine the appropriate dose for the individual patient. In
particular, when used as
the anticonvulsant in this invention, phenytoin will be dosed at about 10 mg
to about 1500 mg
per day and preferably about 50 mg to about 1200 mg per day or doses to
achieve serum
levels in the range of about 10-20 mcg/mL; valproic acid will be dosed at
about 1 mg/kg/day
to about 100 mg/kg/day, and preferably about 5 mg/kg/day to about 70
mg/kg/day.
In general, in accordance with this invention, the above benzodiazepines used
in the
combinations, pharmaceutical compositions, methods and kits of this invention
will be
administered in a dosage amount of about 0.001 mg to about 200mg, in single or
divided
doses. However, some variation in dosage will necessarily occur depending upon
the
condition, age and pharmacokinetic altering physiology of the subject being
treated. The
person responsible for administration will, in any event, determine the
appropriate dose for
the individual patient. In particular, when used as the benzodiazepine in this
invention,
diazepam will be dosed at about 1 mg to about 40 mg per day; clonazepam will
be dosed at
about 0.001 mg/kg/day to about 1 mg/kg/day, and more preferably at about 0.01
mg/kg/day to
about 0.2 mg/kg/day.
The exact formulation, route of administration, and dosage can be chosen by
the
individual physician in view of the patient's condition. Dosage amount and
interval can be
adjusted individually to provide plasma levels of the active moiety which are
sufficient to
maintain therapeutic effects
It will be recognized by a skilled person that the free base form or other
salt forms of
the above GABA modulators, anticonvulsants and benzodiazepines may be used in
this
invention. Calculation of the dosage amount for these other forms of the free
base form or
other salt forms of a particular GABA modulator, anticonvulsant or
benzodiazepine is easily
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accomplished by performing a simple ratio relative to the molecular weights of
the species
involved.
The products of the present invention are of use in the treatment and/or
prevention of
a variety of disorders of the central nervous system. Such disorders include
treatment-
resistant anxiety disorders, such as obsessive-compulsive disorder, stress
disorders including
post-traumatic and acute stress disorder, and generalized or substance-induced
anxiety
disorder; neuroses; depressive or bipolar disorders, for example single-
episode or recurrent
major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic
disorders, and
cyclothymic disorder.
The products of the present invention have the advantage that they
surprisingly
provide relief from anxiety more rapidly than would be expected from
administration of either
compound alone. They are useful in reducing the complications associated with
treatment-
resistant anxiety disorders, including premature mortality and suicide.
The term "treatment-resistanY', as in "a method of treating a disorder",
refers to
reversing, alleviating, or inhibiting the progress of the disorder to which
such term applies, or
one or more symptoms of the disorder. For example, in some clinical studies it
is defined as
patients with a principal DSM-IV diagnosis of generalized anxiety disorder who
have not
responded sufficiently after an adequate trial (4-8 weeks) of first-line anti-
anxiety agents such
as SSRIs, buspirone or a benzodiazepine. As used herein, the term also
encompasses,
depending on the condition of the patient, preventing the disorder, including
preventing onset
of the disorder or of any symptoms associated therewith, as well as reducing
the severity of
the disorder or any of its symptoms prior to onset, or to preventing a
recurrence of a disorder.
Examples of treatment-resistant anxiety disorders that can be treated
according to
the present invention include, but are not limited to, treatment-resistant
obsessive-compulsive
disorder, treatment-resistant posttraumatic stress disorder, generalized or
substance-induced
anxiety disorder; neuroses and panic disorder.
The meanings attributed to the different types and subtypes of anxiety
disorders are
as stated in DSM-IV-TR the contents of which are incorporated by reference
herein.
(Diagnostic and Statistical Manual of Mental Disorders", 4th ed, American
Psychiatric Assoc.,
Washington, DC, 2002, p. 429-484). Though classified as an anxiety disorder in
DSM-IV,
PTSD is accompanied by psychotic symptoms in almost half of patients.
Examples of psychotic disorders that can be treated according to the present
invention include, but are not limited to, schizophrenia, for example of the
paranoid,
disorganized, catatonic, undifferentiated, or residual type; schizophreniform
disorder;
schizoaffective disorder, for example of the delusional type or the depressive
type; delusional
disorder; brief psychotic disorder; shared psychotic disorder; psychotic
disorder due to a
general medical condition; substance-induced psychotic disorder, for example
psychosis
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induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,
opioids, or
phencyclidine; personality disorder of the paranoid type; personality disorder
of the schizoid
type; psychotic disorder not otherwise specified.
The meanings attributed to the different types and subtypes of psychotic
disorders
are as stated in DSM-IV-TR the contents of which are incorporated by reference
herein.
(Diagnostic and Statistical Manual of Mental Disorders", 4th ed, American
Psychiatric Assoc.,
Washington, DC, 2002, p. 297-343).
Schizophrenia as used herein refers to a disorder that lasts for at least 6
months and
includes at least one month of active-phase symptoms (i.e., two [or more] of
the following:
delusions, hallucinations, disorganized speech, grossly disorganized or
catatonic behavior,
negative symptoms) (Diagnostic and Statistical Manual of Mental Disorders, DSM-
IV-TR, 4 th
ed, American Psychiatric Assoc., Washington, DC, 2002).
Schizoaffective disorder is defined as a disorder in which a mood episode and
the
active-phase symptoms of schizophrenia occur together and were preceded or are
followed
by at least 2 weeks of delusions or hallucinations without prominent mood
symptoms
(Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR, 4th ed,
American
Psychiatric Assoc., Washington, DC, 2002).
Schizophreniform disorder is defined as a disorder characterized by a
symptomatic
presentation that is equivalent to schizophrenia except for its duration
(i.e., the disturbance
lasts from 1 to 6 months) and the absence of a requirement that there be a
decline in
functioning (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR,
0 ed,
American Psychiatric Assoc., Washington, DC, 2002).
Schizotypical disorder is defined as a lifetime pattern of social and
interpersonal
deficits characterized by an inability to form close interpersonal
relationships, eccentric
behavior, and mild perceptual distortions.
The combinations of ziprasidone with anticonvulsant drugs or ziprasidone and
benzodiazepines in the present invention can be used to treat other psychotic
disorders such
as delusional disorder; brief psychotic disorder; shared psychotic disorder;
substance-induced
psychotic disorder, for example psychosis induced by alcohol, amphetamine,
cannabis,
cocaine, hallucinogens, inhalants, opioids, or phencyclidine; psychotic
disorder due to a
general medical condition; personality disorder of the paranoid type;
personality disorder of
the schizoid type; and psychotic disorder not otherwise specified.
For example, "treating schizophrenia, or schizophreniform or schizoaffective
disorder"
as used herein also encompasses treating one or more symptoms (positive,
negative, and
other associated features) of said disorders, for example treating, delusions
and/or
hallucination associated therewith. Other examples of symptoms of
schizophrenia and
schizophreniform and schizoaffecctive disorders include disorganized speech,
affective
CA 02617420 2008-02-01
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flattening, alogia, anhedonia, inappropriate affect, dysphoric mood (in the
form of, for
example, depression, anxiety or anger), and some indications of cognitive
dysfunction.
Delusional disorder as referred to herein is characterized by at least 1 month
of
nonbizarre delusions without other active-phase symptoms of schizophrenia.
(Diagnostic and
Statistical Manual of Mental Disorders, DSM-IV-TR, 4th ed, American
Psychiatric Assoc.,
Washington, DC, 2002).
Brief psychotic disorder is a disorder that lasts more than 1 day and remits
by 1
month. (Diagnostic and Statistical Manual of Mental Disorders , DSM-IV-TR, 4th
ed, American
Psychiatric Assoc., Washington, DC, 2002).
Shared psychotic disorder is characterized by the presence of a delusion in an
individual who is influenced by someone else who has a longer-standing
delusion with similar
content. (Diagnostic and Statistical Manual of Mental Disorders , DSM-IV-TR,
4th ed,
American Psychiatric Assoc., Washington, DC, 2002).
Psychotic disorder due to a general medical condition is characterized by
psychotic
symptoms judged to be a direct physiological consequence of a general medical
condition.
(Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR, 4th ed,
American
Psychiatric Assoc., Washington, DC, 2002).
Psychotic disorder not otherwise specified is a psychotic presentation that
does not
meet the criteria for any of the specific psychotic disorders defined in the
DSM-IV-TR
(American Psychiatric Assoc., Washington, DC, 2002).
In another embodiment, the compounds used in the present invention are useful
to
treat other disorders that may present with psychotic symptoms as associated
features such
as dementia of the Alzheimer's type; substance-induced delirium; and major
depressive
disorder with psychotic features.
In a preferred embodiment, the compounds used in the present invention are
useful
for treating schizophrenia, a schizoaffective disorder, schizophreniform
disorder, or a
schizotypical disorder.
The combinations of ziprasidone and an anticonvulsant may be used to treat
mood
disorders, formerly designated as "affective disorders." Although mood
disorders are not a
clearly delineated group of illnesses they include unipolar and bipolar
depression, generalized
anxiety disorder, and more specific anxiety disorders such as agoraphobia,
panic disorder
and social phobia, obsessive-compulsive disorder and post traumatic stress
disorder (PTSD).
There is a high level of similarity and co-morbidity between these illnesses
and clinicians may
consider them as a single group.
The meanings attributed to the different types and subtypes of mood disorders
are as
stated in DSM-IV-TR under depressive disorders ("unipoialar depression") and
bipolar
disorders, generalized anxiety disorder, and more specific anxiety disorders
such
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as agoraphobia, panic disorder and social phobia, obsessive-compulsive
disorder
and post traumatic stress disorder (PTSD), the contents of which are
incorporated by
reference herein. (Diagnostic and Statistical Manual of Mental Disorders", 4th
ed, American
Psychiatric Assoc., Washington, DC, 2002, p. 345-484).
The term "affective disorder" as used herein is interchangeable with the term
"mood
disorders" and refers to disorders that are characterized by changes in mood
as the primary
clinical manifestation, for example, depression.
The expression "prodrug" refers to compounds that are drug precursors which,
following administration, release the drug in vivo via a chemical or
physiological process (e.g.,
a prodrug on being brought to the physiological pH or through enzyme action is
converted to
the desired drug form).
The present invention includes within its scope the use of prodrugs of
ziprasidone,
GABA modulators, benzodiazepines or anticonvulsant drugs. In general, such
prodrugs will
be functional derivatives of these compounds which are readily convertible in
vivo.
Conventional procedures for the selection and preparation of suitable prodrug
derivatives are
described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier,
1985 and can be
achieved using methods well known to those skilled in the art. All such
prodrugs are within the
scope of the combinations, pharmaceutical compositions, methods and kits of
this invention.
The chemist of ordinary skill in the art will also recognize that certain
compounds
within the scope of this invention can exist in zwitterionic form, i.e., that
certain compounds
contain an amine portion and a carboxylic acid portion, which, depending upon
the pH of the
solution, may exist as a free amine and a free carboxylic acid or as a
zwitterion in which the
amine is protonated to form an ammonium ion and the carboxylic acid is
deprotonated to form
a carboxylate ion. All such zwitterions are included in this invention.
The chemist of ordinary skill in the art will also recognize that the
pharmaceutical
combinations contemplated by the present invention can exist in different
stereoisomers.
Specific stereoisomers may exhibit an ability to treat mental disorders with a
more favorable
efficacy or safety profile. The present invention includes all possible
stereoisomers and
geometric isomers of the active ingredients of each pharmaceutical
combination, and includes
not only racemic compounds but also optical isomers as well. In situations
where tautomers,
i.e. that an equilibrium exists between two isomers which are in rapid
equilibrium with each
other are possible, the present invention is intended to include all
tautomeric forms.
The combinations of the present invention can be administered in a standard
manner
for the treatment of treatment-resistant anxiety disorders, psychotic
disorders, or mood
disorders such as orally, parenterally, transmucosally (e.g., sublingually or
via buccal
administration), topically, transdermally, rectally, via inhalation (e.g.,
nasal or deep lung
inhalation). Parenteral administration includes, but is not limited to
intravenous, intraarterial,
CA 02617420 2008-02-01
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intraperitoneal, subcutaneous, intramuscular, intrathecal, and intraarticular,
or via a high
pressure technique, like Powderject.T"
For buccal administration, the composition can be in the form of tablets or
lozenges
formulated in conventional manner. For example, tablets and capsules for oral
administration
can contain conventional excipients such as binding agents (for example,
syrup, acacia,
gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone),
fillers (for example,
lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or
sorbitol),
lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene
glycol or silica),
disintegrants (for example, potato starch or sodium starch glycollate), or
wetting agents (for
example, sodium lauryl sulfate). The tablets can be coated according to
methods well known
in the art.
Such preparations can also be formulated as suppositories, e.g., containing
conventional suppository bases, such as cocoa butter or other glycerides.
Compositions for
inhalation typically can be provided in the form of a solution, suspension, or
emulsion that can
be administered as a dry powder or in the form of an aerosol using a
conventional propellant,
such as dichlorodifluoromethane or trichlorofluoromethane. Typical topical and
transdermal
formulations comprise conventional aqueous or nonaqueous vehicles, such as eye
drops,
creams, ointments, lotions, and pastes, or are in the form of a medicated
plaster, patch, or
membrane.
Additionally, compositions of the present invention can be formulated for
parenteral
administration by injection or continuous infusion. Formulations for injection
can be in the form
of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can
contain
formulation agents, such as suspending, stabilizing, and/or dispersing agents.
Alternatively,
the active ingredient can be in powder form for constitution with a suitable
vehicle (e.g.,
sterile, pyrogen-free water) before use.
A composition in accordance with the present invention also can be formulated
as a
depot preparation. Such long acting formulations can be administered by
implantation (for
example, subcutaneously or intramuscularly) or by intramuscular injection.
Accordingly, the
compounds of the invention can be formulated with suitable polymeric or
hydrophobic
materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or as
sparingly soluble
derivatives (e.g., a sparingly soluble salt).
Solubilized forms of aryl-heterocyclics such as zirpasidone, pharmaceutically
acceptable salts there, or prodrugs thereof, or pharmaceutically acceptable
salts of prodrugs
thereof, associated with (or at levels even greater than) immediate release
can be fabricated
into depot formulations. For example, a pharmaceutical kit comprising
ziprazidone,
ziprasidone salts or prodrugs thereof, or pharmaceutically acceptable salts of
ziprasidone
prodrugs, which can be solubilized or unsolubilized; and a constituting liquid
vehicle
CA 02617420 2008-02-01
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comprised of a viscosity agent with the proviso that when the ziprasidone
compound is
unsolubilized, the aqueous liquid further comprises a solubilizer.
Ziprazidone depot formulation in the form of a suspension are described in
U.S.
Patent Application Serial No. 60/42195, filed October 25, 2002 and
incorporated herein by
reference in its entirety. Novel injectable depot formulations of ziprasidone
are described in
U.S. Patent Application Serial No. 60/421473, filed October 25, 2002 and
incorporated herein
by reference in its entirety.
For oral administration a pharmaceutical composition can take the form of
solutions,
suspensions, tablets, pills, capsules, powders, and the like. Tablets
containing various
excipients such as sodium citrate, calcium carbonate and calcium phosphate are
employed
along with various disintegrants such as starch and preferably potato or
tapioca starch and
certain complex silicates, together with binding agents such as
polyvinylpyrrolidone, sucrose,
gelatin and acacia. Additionally, lubricating agents such as magnesium
stearate, sodium
lauryl sulfate and talc are often very useful for tabletting purposes. Solid
compositions of a
similar type are also employed as fillers in soft and hard-filled gelatin
capsules; preferred
materials in this connection also include lactose or milk sugar as well as
high molecular
weight polyethylene glycols.
Alternatively, the compounds of the present invention can be incorporated into
oral
liquid preparations such as aqueous or oily suspensions, solutions, emulsions,
syrups, or
elixirs, for example. Moreover, formulations containing these compounds can be
presented as
a dry product for constitution with water or other suitable vehicle before
use. Such liquid
preparations can contain conventional additives, such as suspending agents,
such as sorbitol
syrup, synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium
carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin,
glucose/sugar
syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum
stearate gel,
emulsifying agents, such as lecithin, sorbitan monooleate, or acacia;
nonaqueous vehicles
(which can include edible oils), such as almond oil, fractionated coconut oil,
oily esters,
propylene glycol, and ethyl alcohol; and preservatives, such as methyl or
propyl p-
hydroxybenzoate and sorbic acid. The liquid forms in which the compositions of
the present
invention may be incorporated for administration orally or by injection
include aqueous
solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored
emulsions with
edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as
well as elixirs and
similar pharmaceutical vehicles.
When aqueous suspensions and/or elixirs are desired for oral administration,
the
compounds of this invention can be combined with various sweetening agents,
flavoring
agents, coloring agents, emulsifying agents and/or suspending agents, as well
as such
diluents as water, ethanol, propylene glycol, glycerin and various like
combinations thereof_
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Suitable dispersing or suspending agents for aqueous suspensions include
synthetic and
natural gums such as tragacanth, acacia, alginate, dextran, sodium
carboxymethylcellulose,
methyicellulose, polyvinyl-pyrrolidone or gelatin.
The combinations of this invention can also be administered in a controlled
release
formulation such as a slow release or a fast release formulation. Such
controlled release
formulations of the combinations of this invention may be prepared using
methods well known
to those skilled in the art. The method of administration will be determined
by the attendant
physician or other person skilled in the art after an evaluation of the
patient's condition and
requirements.
The pharmaceutical compositions of the present invention can consist of a
combination of immediate release and controlled release characteristics. Such
compositions
can take the form of combinations of the active ingredients that range in size
from
nanoparticles to microparticles or in the form of a plurality of pellets with
different release
rates. The tablet or capsule composition of the present invention can contain
an atypical
antipsychotic in sustained or controlled release form and, a second
therapeutic agent in an
immediate release form. Alternatively, the atypical antipsychotic can be in
immediate release
form and the second therapeutic agent can be in sustained or controlled
release form.
The combinations of this invention can also be administered in parenteral
form. For
parenteral administration, solutions in sesame or peanut oil or in aqueous
propylene glycol
can be employed, as well as sterile aqueous solutions of the corresponding
water-soluble
salts. Such aqueous solutions can be suitably buffered, if necessary, and the
liquid diluent
first rendered isotonic with sufficient saline or glucose. These aqueous
solutions are
especially suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal injection
purposes. In this connection, the sterile aqueous media employed are all
readily obtainable by
standard techniques well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain amount
of
active ingredient are known, or will be apparent in light of this disclosure,
to those skilled in
this art. For examples, methods of preparing pellets are described in
Remington: The
Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th
Edition
(1995). Prolonged release pellets are prepared by either coating immediate
release pellets or
via matrix systems. Coating may be carried out, for example, in coating pans
or in fluid bed
coater-driers. Extrusion and subsequent spheronization is a long-known method
for the
preparation of pharmaceutical pellets (J. W. Conine et al., Drug & Cosmetic
Ind. 106, 38-41
(1970)). However, other methods such as pelletization may be utilized.
Particles may be
agglomerated to form spherical granules or pellets, in a high speed mixer
granulator, or rotary
fluid bed agglomerator. These methods are described by K. W. Olson and A. M.
Mehta,
Int.J.Pharm.Tech&.Prod.Mfr. 6 18-24, 1985. Pellets may be also prepared by
extrusion of wet
CA 02617420 2008-02-01
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masses or melts followed by spheronisation, for example as described in C.
Vervaet, L. Baert
& J. P. Remon Int.J.Pharm. 116 (1995) 131-146. Excipients used are typically
those with
plastic qualities such as microcrystalline cellulose, but also mannitol. Small
quantities of a
polymeric binder are generally added. Surfactants such as sodium dodecyl
sulphate may also
be incorporated to give easier extrusion.
Pharmaceutical compositions according to the invention can contain 0.1 %-95%
of the
therapeutic agents of this invention, preferably 1%-70%. In any event, the
composition or
formulation to be administered wiil contain a quantity of therapeutic agent(s)
according to the
invention in an amount effective to treat the condition or disease of the
subject being treated.
The two different compounds of this invention can be co-administered
simultaneously
or sequentially in any order, or as a single pharmaceutical composition
comprising, for
example, ziprasidone and a GABA modulator, or ziprasidone and an
anticonvulsant, or
ziprasidone and a benzodiazepine as described above.
Since the present invention has an aspect that relates to the treatment of the
disease/conditions described herein with a combination of active ingredients
which canbe
administered separately, the invention also relates to combining separate
pharmaceutical
compositions in kit form. The kit comprises two separate pharmaceutical
compositions:
ziprasidone and a GABA modulator, a prodrug thereof or a pharmaceutically
acceptable salt
of said GABA modulator or prodrug; or ziprasidone and an anticonvulsant, a
prodrug thereof
or a pharmaceutically acceptable salt of said GABA modulator or prodrug;
ziprasidone and a
benzodiazepine, a prodrug thereof or a pharmaceutically acceptable salt of
said GABA
modulator or prodrug. The kit includes a container for containing the separate
compositions
such as a divided bottle or a divided foil packet. Typically the kit includes
directions for the
administration of the separate components. The kit form is particularly
advantageous when
the separate components are preferably administered in different dosage forms
(e.g., oral and
parenteral), are administered at different dosage intervals, or when titration
of the individual
components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well
known in
the packaging industry and are being widely used for the packaging of
pharmaceutical unit
dosage forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of
relatively stiff material covered with a foil of a preferably transparent
plastic material. During
the packaging process recesses are formed in the plastic foil. The recesses
have the size and
shape of the tablets or capsules to be packed. Next, the tablets or capsules
are placed in the
recesses and the sheet of relatively stiff material is sealed against the
plastic foil at the face of
the foil which is opposite from the direction in which the recesses were
formed. As a result,
the tablets or capsules are sealed in the recesses between the plastic foil
and the sheet.
Preferably the strength of the sheet is such that the tablets or capsules can
be removed from
CA 02617420 2008-02-01
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the blister pack by manually applying pressure on the recesses whereby an
opening is formed
in the sheet at the place of the recess. The tablet or capsule can then be
removed via said
opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of
numbers
next to the tablets or capsules whereby the numbers correspond with the days
of the regimen
which the tablets or capsules so specified should be ingested. Another example
of such a
memory aid is a calendar printed on the card, e.g., as follows "First Week,
Monday, Tuesday,
... etc .... Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will
be readily apparent to the skilled practitioner. A "daily dose" can be a
single tablet or capsule
or several pills or capsules to be taken on a given day. Also, a daily dose of
the ziprasidone
can consist of one tablet or capsule while a daily dose of the anticonvulsant,
benzodiazepine
or GABA modulator can consist of several tablets or capsules or vice versa.
The memory aid
should reflect this.
In another specific embodiment of the invention, a dispenser designed to
dispense
the daily doses one at a time in the order of their intended use is provided.
Preferably, the
dispenser is equipped with a memory-aid, so as to further facilitate
compliance with the
regimen. An example of such a memory-aid is a mechanical counter which
indicates the
number of daily doses that has been dispensed. Another example of such a
memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal readout, or
audible reminder
signal which, for example, reads out the date that the last daily dose has
been taken and/or
reminds one when the next dose is to be taken.
In another embodiment of the present invention, the treatment of treatment-
resistant
anxiety disorder in a patient the method of the present invention can include
administering a
triple combination pharmaceutical composition containing an amount of a first
therapeutic
agent, said first therapeutic agent being ziprasidone;
an amount of a second therapeutic agent, said second therapeutic agent being a
GABA modulator, a prodrug thereof or a pharmaceutically acceptable salt of
said GABA
modulator or said prodrug; and
an amount of a third therapeutic agent, said third therapeutic agent being a
benzodiazepine, a prodrug thereof or a pharmaceutically acceptable salt of
said
benzodiazepine or said prodrug.
In still another embodiment of the present invention, for the treatment of
psychotic
disorders or conditions in a subjects, the method of the present invention can
include
administering a triple combination pharmaceutical composition containing
an amount of a first therapeutic agent, said first therapeutic agent being
ziprasidone;
CA 02617420 2008-02-01
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an amount of a second therapeutic agent, said second therapeutic agent being a
benzodiazepine, a prodrug thereof or a pharmaceutically acceptable salt of
said
benzodiazepine modulator or said prodrug; and
an amount of a third therapeutic agent, said third therapeutic agent being an
anticonvulsant, a prodrug thereof or a pharmaceutically acceptable salt of
said anticonvulsant
or said prodrug.
It will be understood that while the use of a single atypical antipsychotic as
a first
component compound is preferred, combinations of two or more atypical
antipsychotics may
be used as a first component if necessary or desired. Similarly, while the use
of a single
GABA modulator, anticonvulsant or benzodiazepine as a second component
compound is
preferred, combinations of two or more of these agents may be used as a second
component
if necessary or desired.
The atypical antipsychotic of the present invention is useful alone or in
combination
with a second antipsychotic agent, for example, an atypical antipsychotic such
as ziprasidone
mesylate, a typical antipsychotic such as haloperidol, or a dopamine system
stabilizer
antipsychotic such as aripiprazole. In addition, the combinations of the
present invention may
be used in combination with other therapeutic agents for anxiety, i.e. SSRIs ,
or buspirone or
agents for psychotic or mood disorders, i.e. lithium, tricyclic
antidepressants. It is preferred
that if a second antipsychotic agent is used that they both administered to
the patient in
synergistic effective amounts. It is preferred that the total amount ranges
from about 0.0001
to about 1000 mg/kg per day, more preferably from about 0.01 to about 100
mg/kg per day
and most preferably from about 0.1 to about 60 mg/kg per day.
Pharmaceutical compositions of use in the present invention will comprise one
or
both active compound(s) in association with a pharmaceutically acceptable
carrier. Preferably
these compositions are in unit dosage forms such as tablets, pills, capsules,
powders,
granules, sterile parenteral solutions or suspensions, metered aerosol or
liquid sprays, drops,
ampyules, auto-injector devices or suppositories; for oral, parenteral,
intranasal, sublingual or
rectal administration, or for administration by inhalation or insufflation.
For preparing solid
compositions such as tabiets, the principal active ingredients are mixed with
a pharmaceutical
carrier, e.g. conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol,
talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other
pharmaceutical diluents, e.g. water, to form a solid preformulation
composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically
acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, it is
meant
that the active ingredients is dispersed evenly throughout the composition so
that the
composition may be readily subdivided into equally effective unit dosage forms
such as
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tablets, pills and capsules. This solid preformulation composition is then
subdivided into unit
dosage forms of the type described above containing from 0.1 to about 2000 mg
of each of
the active ingredients of the present invention. Typical unit dosage forms
contain from I to
300 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
The tablets or pills
of the novel composition can be coated or otherwise compounded to provide a
dosage form
affording the advantage of prolonged action. For example, the tablet or pill
can comprise an
inner dosage and an outer dosage component, the latter being in the form of an
envelope
over the former. The two components can be separated by an enteric layer which
serves to
resist disintegration in the stomach and permits the inner component to pass
intact into the
duodenum or to be delayed in release. A variety of materials can be used for
such enteric
layers or coatings, such materials including a number of polymeric acids and
mixtures of
polymeric acids with such materials as shellac, cetyl alcohol and cellulose
acetate.
When administered in combination, either as a single or as separate
pharmaceutical
composition(s), the ziprasidone and the GABA modulator, anticonvulsant or
benzodiazepine
are presented in a ratio which is consistent with the manifestation of the
desired effect. In
particular, the ratio by weight of ziprasidone to the GABA receptor modulator
will suitably be
between 0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to
1.
The pharmaceutical combinations may be administered on a regimen of up to 6
times
per day, preferably 1 to 4 times per day, especially 2 times per day, and most
especially once
daily.
As used herein the term "subject" includes animals of economic importance such
as
bovine, ovine, and porcine animals, especially those that produce meat, as
well as domestic
animals (e.g. cats and dogs), sports animals (e.g. horses), zoo animals, and
humans, the
latter being most preferred.
EXAMPLE 1
A pharmaceutical composition could be prepared by combining ziprasidone with a
GABA modulator which is either: (a) gabapentin, (b) pregabalin or (c)
lamotrigine in a
pharmaceutically acceptable carrier. The composition contains respective
amounts of
ziprasidone and gabapentin, pregabalin or lamotrigine to deliver on a daily
basis between
about 20mg to about 160 mg ziprasidone and between about (a) 100 to 400 mg
gabapentin;
or (b) 1 to 500 mg pregabalin; or (c) 2 to 200 mg lamotrigine. The composition
could be
administered to a patient for the treatment of schizophrenia on a daily, twice
daily, three times
daily, or four times daily basis.
It should be understood that the invention is not limited to the particular
embodiments
described herein, but that various changes and modifications may be made
without departing
from the spirit and scope of this novel concept as defined by the following
claims.
