Note: Descriptions are shown in the official language in which they were submitted.
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COb~INATION THERAPY FOR TREATMENT OF DEPRESSION
Depression in its many variations has recently
become much more visible to the general public than it has
previously been. It is now recognized as an extremely
damaging disorder, and one that afflicts a surprisingly
large fraction of the population. Suicide is the most
extreme symptom of depression, but millions of people, not
quite so drastically afflicted, live in misery and partial
or complete uselessness, and afflict their families as well
by their affliction. The introduction of fluoxetine, a
serotonin reuptake inhibitor (SRI), was a breakthrough in
the treatment of depression, and depressives are now much
more likely to be diagnosed and treated than they were only
a decade ago.
Depression is often associated with other diseases
and conditions, or caused by such other conditions. For
example, it is associated with Parkinson's disease; with
HIV; with Alzheimer's disease; and with abuse of anabolic
steroids. Depression may also be associated with abuse of
any substance, or may be associated with behavioral problems
resulting from or occurring in combination with head
injuries, mental retardation or stroke.
A side effect sometimes associated with serotonin
reuptake inhibitors concerns the gastrointestinal system
wherein symptoms are often manifested as nausea and
occasional vomiting. An additional troubling side effect
associated with serotonin reuptake inhibitors is sexual
dysfunction. It has been estimated that such sexual
dysfunction is as high as 34%. [See F.M. Jacobsen, J.
Clin. Psychiatry, ,5",~, 119, (1992) ] . These side effects
often result in depressed patients not maintaining the SRI
therapy for a period that is long enough in duration to
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recognize any significant improvement in the patient's
condition.
A benefit of the present adjunctive therapy is a
reduction of the above-noted gastrointestinal side effects
and/or improvement of the sexual dysfunction known to be
associated with the administration of serotonin reuptake
inhibitors. It is believed that such a reduction in
gastrointestinal side effects and/or improvement of sexual
dysfunction will result in increased patient compliance with
the SRI therapy, and ultimately, an improvement in
lifestyle.
The present invention provides a method for
treating a patient suffering from depression, comprising
administering to said patient an effective amount of a first
component which is a 5-HT3 receptor antagonist, in
combination with an effective amount of a second component
which is a serotonin reuptake inhibitor.
The invention further provides a method for
treating a patient suffering from anxiety disorders,
premenstrual syndrome (PMS) and anorexia nervosa, comprising
administering to said patient an effective amount of a first
component which is a 5-HT3 receptor antagonist, in
combination with an effective amount of a second component
which is a serotonin reuptake inhibitor.
The invention also provides a pharmaceutical
composition which comprises a first component which is a 5-
HT3 receptor antagonist, and a second component which is a
serotonin reuptake inhibitor.
The above adjunctive therapies of the present
invention result in a reduction of gastrointestinal side
effects and/or improvement of sexual dysfunction. Thus, the
present invention provides the advantage of treatment of
depression with a serotonin reuptake inhibitor with a
reduction in gastrointestinal side effects or improvement in
sexual dysfunction observed with such treatment, conferring
a marked and unexpected benefit on the patient.
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The Compounds_
The first component is a compound which functions
as a 5-HT3 receptor antagonist. 5-HT3 receptor antagonists
include but are not limited to the following compounds:
Zatosetron, endo-5-chloro-2,3-dihydro-2,2-
dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-7-
benzofurancarboxamide, which has the following structure:
a
i
-.' ' O
N
~'~~~ N O
U.S. Patent No. 5,563,148, issued October 8, 1996 which is
incorporated herein by reference, discloses a preparation of
Zatosetron; Olanzapine, a preparation of which is disclosed
in U.S. Patent No. 5,229,382, issued July 20, 1993 which is
incorporated herein by reference. Also included as 5-HT3
receptor antagonists are Ondansetron; Granisetron;
Bemesetron; Tropiaetron; FK1052; YM-060; and MDL 72222. In
addition, see EP 0 781 561, published July 2, 1997 and WO
92/00103, published January 9, 1992, which are incorporated
herein by reference, for further examples of 5-HT3 receptor
antagonists which are included within the scope of the
present invention.
The second component is a compound which functions
as a serotonin reuptake inhibitor. The measurement of a
compound's activity in that utility is now a standard
pharmacological assay. along, et al.,
Neuro~sycho~armacol~av, 8, 337-344 (1993) . Many compounds,
including those discussed at length above, have such
activity, and no doubt many more will be identified in the
future. In the practice of the present invention, it is
intended to include reuptake inhibitors which show 50%
effective concentrations of about 1000 nM or less, in the
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protocol described by Wong supra. Serotonin reuptake
inhibitors include, but are not limited to:
Fluoxetine, N-methyl-3-(p-trifluoromethylphenoxy)-
3-phenylpropylamine, is marketed in the hydrochloride salt
form, and as the racemic mixture of its two enantiomers.
U.S. Patent 4,314,081 is an early reference on the compound.
Robertson et al., J. Med. Chem. 31, 1412 (1988), taught the
separation of the R and S enantiomers of fluoxetine and
showed that their activity as serotonin uptake inhibitors is
similar to each other. In this document, the word
"fluoxetine" will be used to mean any acid addition salt or
the free base, and to include either the racemic mixture or
either of the R and S enantiomers;
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-
thienyl)propanamine, is usually administered as the
hydrochloride salt and as the (+) enantiomer. It was first
taught by U.S. Patent 4,956,388, which shows its high
potency. The word "duloxetine" will be used here to refer
to any acid addition salt or the free base of the molecule;
Venlafaxine is known in the literature, and its
method of synthesis and its activity as an inhibitor of
serotonin and norepinephrine uptake are taught by U.S.
Patent 4,761,501. Venlafaxine is identified as compound A
in that patent;
Milnacipran (N,N-diethyl-2-aminomethyl-1-
phenylcyclopropanecarboxamide) is taught by U.S. Patent
4,478,836, which prepared milnacipran as its Example 4. The
patent describes its compounds as antidepressants. Moret et
al., Neuropharmacolocrv 24, 1211-19 (1985), describe its
pharmacological activities as an inhibitor of serotonin and
norepinephrine reuptake;
Citalopram, 1- (3- (dimethylamino)propyl] -1- (4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, is
disclosed in U.S. Patent 4,136,193 as a serotonin reuptake
inhibitor. Its pharmacology was disclosed by Christensen et
al., Eur J Pharmacol. 41, 153 (1977), and reports of its
clinical effectiveness in depression may be found in Dufour
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et al., Int. Clin. Psychopharmacol. 2, 225 (1987), and
Timmerman et al., ibid., 239;
Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)-
phenyl]-1-pentanone 0-(2-aminoethyl)oxime, is taught by U.S.
~ Patent 4,085,225. Scientific articles about the drug have
been published by Claassen et ~1., Brit. J. Pharmacol. 60,
505 (1977); and De Wilde et al., J. Affective Disord. 4, 249
(1982); and Benfield et al., Druas ~2, 313 (1986);
Paroxetine, trans-(-)-3-[(1,3-benzodioxol-5-
yloxy)methyl]-4-(4-fluorophenyl)piperidine, may be found in
U.S. Patents 3,912,743 and 4,007,196. Reports of the drug's
activity are in Lassen, Eur. J. Pharmacol. 47, 351 (1978);
Hassan ~t al., Brit. J. Clin. Pharmacol. 1~, 705 (1985);
Laursen g~ ~1., Acta Psychiat. Scand. 71, 249 (1985); and
Battegay ~t al., Neuro~sychobiolosv 1~, 31 (1985); and
Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-
1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride,
is a serotonin reuptake inhibitor which is marketed as an
antidepressant. It is disclosed by U.S. Patent 4,536,518.
All of the U.S. patents which have been mentioned
above in connection with compounds used in the present
invention are incorporated herein by reference. It is
understood that all of the 5-HT3 receptor antagonists and
serotonin reuptake inhibitors mentioned hereinabove for use
in the present invention are readily prepared by one of
ordinary skill in the art using known techniques and
procedures.
It will be understood that while the use of a
single 5-HT3 receptor antagonist as a first component is
preferred, combinations of two or more 5-HT3 receptor
antagonists may be used as a first component if necessary or
desired. Similarly, while the use of a single serotonin
reuptake inhibitor as a second component is preferred,
combinations of two or more serotonin reuptake inhibitors
may be used as a second component if necessary or desired.
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While all combinations of first and second
components are useful and valuable, certain combinations are
particularly valued and are preferred, as follows:
Zatosetron/fluoxetine
Zatosetron/venlafaxine
Zatosetron/citralopram
Zatosetron/fluvoxamine
Zatosetron/paroxetine
Zatosetron/sertraline
Zatosetron/milnacipran
Zatosetron/duloxetine
Ondansetron/fluoxetine
Granisetron/fluoxetine
In general, combinations and methods of treatment
using Zatosetron as the first component are preferred.
Furthermore, combinations and methods of treatment using
fluoxetine or duloxetine as the second component are
preferred. Especially preferred are combinations and
methods of treatment using Zatosetron as the first component
and fluoxetine as the second component.
It will be understood by the skilled reader that
most or all of the compounds used in the present invention
are capable of forming salts, and that the salt forms of
pharmaceuticals are commonly used, often because they are
more readily crystallized and purified than are the tree
bases. In all cases, the use of the pharmaceuticals
described above as salts is contemplated in the description
herein, and often is preferred, and the pharmaceutically
acceptable salts of all of the compounds are included in the
names of them.
Many of the compounds used in this invention are
amines, and accordingly react with any of a number of
inorganic and organic acids to form pharmaceutically
acceptable acid addition salts. Since some of the free
amines of the compounds of this invention are typically oils
at room temperature, it is preferable to convert the free
amines to their pharmaceutically acceptable acid addition
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salts for ease of handling and administration, since the
latter are routinely solid at room temperature. Acids
commonly employed to form such salts are inorganic acids
such as hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulfuric acid, phosphoric acid, and the like, and
organic acids, such as g-toluenesulfonic acid,
methanesulfonic acid, oxalic acid, p-bromophenylsulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic
acid, acetic acid and the like. Examples of such
pharmaceutically acceptable salts thus are the sulfate,
pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate,
propionate, decanoate, caprylate, acrylate, formate,
isobutyrate, caproate, heptanoate, propiolate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate,
butyne-1,4-dioate, hexyne-1,6-dioate, benzoate,
chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxyben-
zoate, methoxybenzoate, phthalate, sulfonate, xylenesulfon-
ate, phenylacetate, phenylpropionate, phenylbutyrate,
citrate, lactate, (3-hydroxybutyrate, glycollate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate and the like. Preferred
pharmaceutically acceptable salts are those formed with
hydrochloric acid, oxalic acid or fumaric acid.
Preferred pathological conditions to be treated by
the present method of adjunctive therapy include depression,
bulimia, obsessive-compulsive disease, premenstrual
dysphoric disorder, anxiety and obesity. Another preferred
condition more specific to combinations including preferably
duloxetine but also venlafaxine and milnacipran is urinary
incontinence. Depression in all its variations is an
especially preferred target of treatment with the present
adjunctive therapy and compositions.
Anxiety and its frequent concomitant, panic
disorder, may be particularly mentioned in connection with
the present compounds. The subject is carefully explained
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by the Diagnostic and Statistical Manual of Mental
Disorders, published by the American Psychiatric
Association, which classifies anxiety under its category
300.02.
Obsessive-compulsive disease appears in a great
variety of degrees and symptoms, generally linked by the
patient's uncontrollable urge to perform needless,
ritualistic acts. Acts of acquiring, ordering, cleansing
and the like, beyond any rational need or rationale, are the
outward characteristic of the disease. A badly afflicted
patient may be unable to do anything but carry out the
rituals required by the disease. Fluoxetine is approved in
the United States and other countries for the treatment of
obsessive-compulsive disease and has been found to be
effective.
Obesity is a frequent condition in the American
population. It has been found that fluoxetine will enable
an obese patient to lose weight, with the resulting benefit
to the patient's circulation and heart condition, as well as
general well being and energy.
Urinary incontinence is classified generally as
stress or urge incontinence, depending on whether its root
cause is the inability of the sphincter muscles to keep
control, or the overactivity of the bladder muscles.
Duloxetine controls both types of incontinence, or both
types at once, and so is important to the many people who
suffer from this embarrassing and disabling disorder.
The present combination is useful for treating
many other diseases, disorders and conditions as well, as
set out below. In many cases, the diseases to be mentioned
here are classified in the International Classification of
Diseases, 9th Edition (ICD), or in the Diagnostic and
Statistical Manual of Mental Disorders, 3rd Version Revised,
published by the American Psychiatric Association (DSM). In
such cases, the ICD or DSM code numbers are supplied below
for the convenience of the reader.
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depression, TCD 296.2 & 296.3, DSM 296, 294.80, 293.81,
293.82, 293.83, 310.10, 318.00, 317.00
migraine
pain, particularly neuropathic pain
bulimia, ICD 307.51, DSM 307.51
premenstrual syndrome or late luteal phase syndrome,
DSM 307.90
alcoholism, ICD 305.0, DSM 305.00 & 303.90
tobacco abuse, ICD 305.1, DSM 305.10 & 292.00
panic disorder, ICD 300.01, DSM 300.01 & 3'00.21
anxiety, ICD 300.02, DSM 300.00
post-traumatic syndrome, DSM 309.89
memory loss, DSM 294.00
dementia of aging, ICD 290
social phobia, ICD 300.23, DSM 300.23
attention deficit hyperactivity disorder, ICD
314.0
disruptive behavior disorders, ICD 312
impulse control disorders, ICD 312, DSM 312.39 & 312.34
borderline personality disorder, ICD 301.83, DSM 301.83
chronic fatigue syndrome
premature ejaculation, DSM 302.75
erectile difficulty, DSM 302.72
anorexia nervosa, ICD 307.1, DSM 307.10
disorders of sleep, ICD 307.4
autism
mutism
trichotillomania
As used herein the term "sexual dysfunction"
refers to a decrease in sexual functioning or a decrease in
sexual interest or desire, or a combination of both a
decrease in sexual functioning and a decrease in sexual
interest or desire. For example, sexual dysfunction
includes the following symptoms alone or in any combination;
a decrease in the ability to become sexually excited, an
increased latency of time to achieve orgasm, an inability to
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achieve orgasm, a decrease in the male's ability to get an
erection or to maintain an erection, failure of the male to
obtain an erection, decreased libido, and the like.
It is understood that the term "sexual
dysfunction" includes within its scope "substance-induced
sexual dysfunction". The term "substance-induced sexual
dysfunction" as defined by the DSM-IVT"", American
Psychiatric Association, page 519-521, 1994, incorporated
herein by reference, refers to a clinically significant
sexual dysfunction that results in marked distress or
interpersonal difficulty. The sexual dysfunction is judged
to be fully explained by the direct physiological effects of
a substance (i.e., a drug of abuse, a medication, or toxin
exposure). In addition, the sexual dysfunction is not
better accounted for by a sexual dysfunction that is not
substance-induced.
Thus, an improvement in sexual dysfunction means
there has been an increase in sexual functioning or an
increase in sexual interest or desire, or a combination of
both an increase in sexual functioning and an increase in
sexual interest or desire. For example, an improvement in
sexual dysfunction includes the following symptoms alone or
in any combination; an increase in the ability to become
sexually excited, a decreased latency of time to achieve
orgasm, an increased ability to achieve orgasm, an increase
in the male's ability to get an erection or to maintain an
erection, increased libido, and the like.
As used herein the term "gastrointestinal side
effect" includes but is not limited to nausea, vomiting or
diarrhea, or any combination thereof.
Administration
The dosages of the drugs used in the present
invention must, in the final analysis, be set by the
physician in charge of the case, using knowledge of the
drugs, the properties of the drugs in combination as
determined in clinical trials, and the characteristics of
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the patient, including diseases other than that for which
the physician is treating the patient. As used herein the
term "effective amount" is the amount or dose of the
compound which provides the desired effect in the patient
under diagnosis or particular treatment, such as treatment
for depression. General outlines of the dosages, and some
preferred dosages, can and will be provided here. Dosage
guidelines for some of the drugs will first be given
separately; in order to create a guideline for any desired
combination, one would choose the guidelines for each of the
component drugs.
Zatosetron: about 0.25 to 200 mg, once/day;
preferred, about 0.5 to 100 mg, once/day; most preferably
about 0.5 to 50 mg once/day; and most especially preferred
about 0.5 to 10 mg once/day.
Olanzapine: about 0.25 to 200 mg, once/day;
preferred, about 1 to 40 mg, once/day; most preferably about
2.5 to 30 mg once/day; and most especially preferred about 5
to 25 mg once/day.
Fluoxetine: from about 1 to about 80 mg,
once/day; preferred, from about 10 to about 40 mg once/day;
preferred for bulimia and obsessive-compulsive disease, from
about 20 to about 80 mg once/day;
Duloxetine: from about 1 to about 30 mg once/day;
preferred, from about 5 to about 20 mg once/day;
Venlafaxine: from about 10 to about 150 mg once-
thrice/day; preferred, from about 25 to about 125 mg
thrice/day;
Milnacipran: from about 10 to about 100 mg once-
twice/day; preferred, from about 25 to about 50 mg
twice/day;
Citalopram: from about 5 to about 50 mg once/day;
preferred, from about 10 to about 30 mg once/day;
Fluvoxamine: from about 20 to about 500 mg
once/day; preferred, from about 50 to about 300 mg once/day;
Paroxetine: from about 20 to about 50 mg
once/day; preferred, from about 20 to about 30 mg once/day.
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Sertraline: from about 20 to about 500 mg
once/day; preferred, from about 50 to about 200 mg once/day;
In more general terms, one would create a
combination of the present invention by choosing a dosage of
first and second components according to the spirit of the
above guideline.
As used herein the term "patient" refers to a warm-
blooded mammal such as a dog, rat, mouse, human and the like.
The preferred patient is a human.
The adjunctive therapy of the present invention is
carried out by administering a first component together with
the second component in any manner which provides effective
levels of the compounds in the body at the same time. All
of the compounds concerned are orally available and are
normally administered orally, and so oral administration of
the adjunctive combination is preferred. They may be
administered together, in a single dosage form, or may be
administered separately.
However, oral administration is not the only route
or even the only preferred route. For example, transdermal
administration may be very desirable for patients who are
forgetful or petulant about taking oral medicine. One of
the drugs may be administered by one route, such as oral,
and the others may be administered by the transdermal,
percutaneous, intravenous, intramuscular, intranasal or
intrarectal route, in particular circumstances. The route
of administration may be varied in any way, limited by the
physical properties of the drugs and the convenience of the
patient and the caregiver.
The adjunctive combination may be administered as
a single pharmaceutical composition, and so pharmaceutical
compositions incorporating both compounds are important
embodiments of the present invention. Such compositions may
take any physical form which is pharmaceutically acceptable,
but orally usable pharmaceutical compositions are
particularly preferred. Such adjunctive pharmaceutical
compositions contain an effective amount of each of the
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compounds, which effective amount is related to the daily
dose of the compounds to be administered. Each adjunctive
dosage unit may contain the daily doses of all compounds, or
may contain a fraction of the daily doses, such as one-third
of the doses. Alternatively, each dosage unit may contain
the entire dose of one of the compounds, and a fraction of
the dose of the other compounds. In such case, the patient
would daily take one of the combination dosage units, and
one or more units containing only the other compounds. The
amounts of each drug to be contained in each dosage unit
depends on the identity of the drugs chosen for the therapy,
and other factors such as the indication for which the
adjunctive therapy is being given.
The inert ingredients and manner of formulation of
the adjunctive pharmaceutical compositions are conventional,
except for the presence of the combination of the present
invention. The usual methods of formulation used in
pharmaceutical science may be used here. All of the usual
types of compositions may be used, including tablets,
chewable tablets, capsules, solutions, parenteral solutions,
intranasal sprays or powders, troches, suppositories,
transdermal patches and suspensions. In general,
compositions contain from about 0.5% to about 50% of the
compounds in total, depending on the desired doses and the
type of composition to be used. The amount of the
compounds, however, is best defined as the effective amount,
that is, the amount of each compound which provides the
desired dose to the patient in need of such treatment. The
activity of the adjunctive combinations do not depend on the
nature of the composition, so the compositions are chosen
and formulated solely for convenience and economy. Any of
the combinations may be formulated in any desired form of
composition. Some discussion of different compositions will
be provided, followed by some typical formulations.
Capsules are prepared by mixing the compound with
a suitable diluent and filling the proper amount of the
mixture in capsules. The usual diluents include inert
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powdered substances such as starch of many different kinds,
powdered cellulose, especially crystalline and
microcrystalline cellulose, sugars such as fructose,
mannitol and sucrose, grain flours and similar edible
powders.
Tablets are prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations
usually incorporate diluents, binders, lubricants and
disintegrators as well as the compound. Typical diluents
include, for example, various types of starch, lactose,
mannitol, kaolin, calcium phosphate or sulfate, inorganic
salts such as sodium chloride and powdered sugar. Powdered
cellulose derivatives are also useful. Typical tablet
binders are substances such as starch, gelatin and sugars
such as lactose, fructose, glucose and the like. Natural
and synthetic gums are also convenient, including acacia,
alginates, methylcellulose, polyvinylpyrrolidine and the
like. Polyethylene glycol, ethylcellulose and waxes can
also serve as binders.
A lubricant is necessary in a tablet formulation
to prevent the tablet and punches from sticking in the die.
The lubricant is chosen from such slippery solids as talc,
magnesium and calcium stearate, stearic acid and
hydrogenated vegetable oils.
Tablet disintegrators are substances which swell
when wetted to break up the tablet and release the compound.
They include starches, clays, celluloses, algins and gums.
More particularly, corn and potato starches,
methylcellulose, agar, bentonite, wood cellulose, powdered
natural sponge, cation-exchange resins, alginic acid, guar
gum, citrus pulp and carboxymethylcellulose, for example,
may be used, as well as sodium lauryl sulfate.
Enteric formulations are often used to protect an
active ingredient from the strongly acid contents of the
stomach. Such formulations are created by coating a solid
dosage form with a film of a polymer which is insoluble in
acid environments, and soluble in basic environments.
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Exemplary films are cellulose acetate phthalate, polyvinyl
acetate phthalate, hydroxypropyl methylcellulose phthalate
and hydroxypropyl methylcellulose acetate succinate. It is
preferred to formulate duloxetine and duloxetine-containing
combinations as enteric compositions, and even more
preferred to formulate them as enteric pellets.
A preferred duloxetine enteric formulation is a
pellet formulation comprising a) a core consisting of
duloxetine and a pharmaceutically acceptable excipient; b)
an optional separating layer; c) an enteric layer comprising
hydroxypropylmethylcellulose acetate succinate (HPMCAS) and
a pharmaceutically acceptable excipient; d) an optional
finishing layer. This enteric formulation is described in
U.S. Patent No. 5,508,276, herein incorporated by reference
in its entirety.
Tablets are often coated with sugar as a flavor
and sealant. The compounds may also be formulated as
chewable tablets, by using large amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now
well-established practice. Instantly dissolving tablet-like
formulations are also now frequently used to assure that the
patient consumes the dosage form, and to avoid the
difficulty in swallowing solid objects that bothers some
patients.
When it is desired to administer the combination
as a suppository, the usual bases may be used. Cocoa butter
is a traditional suppository base, which may be modified by
addition of waxes to raise its melting point slightly.
Water-miscible suppository bases comprising, particularly,
polyethylene glycols of various molecular weights are in
wide use, also.
Transdermal patches have become popular recently.
Typically they comprise a resinous composition in which the
drugs will dissolve, or partially dissolve, which is held in
contact with the skin by a film which protects the
composition. Many patents have appeared in the field
recently. Other, more complicated patch compositions are
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also in use, particularly those having a membrane pierced
with innumerable pores through which the drugs are pumped by
osmotic action.
The following typical formulae are provided for
the interest and information of the pharmaceutical
scientist.
Formulation 1
Hard gelatin capsules are prepared using the
following ingredients:
Quantity
~mg/capsule)
Zatosetron 25 mg
Fluoxetine, racemic, hydrochloride 20
Starch, dried 150
Magnesium stearate
Total 210 mg
Formulation 2
A tablet is prepared using the ingredients below:
Quantity
(mg/capsule)
Zatosetron 10
Fluoxetine, racemic, hydrochloride 10
Cellulose, microcrystalline 275
Silicon dioxide, fumed 10
Stearic acid 5
Total 310 mg
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Formulation 3
Capsules are made as follows:
Zatosetron 70 mg
Fluoxetine, racemic, hydrochloride 30 mg
Starch 39 mg
Microcrystalline cellulose 39 mg
Magnesium stearate 2 ma
Total 180 mg
F9rmulation 4
Suppositories are made as follows:
Zatosetron 75 mg
(+)-Duloxetine, hydrochloride 5 mg
Saturated fatty acid glycerides 2,000 ma_
Total 2,080 mg
The active ingredient is passed through a No. 60
mesh U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2 g capacity and allowed to cool.
Formu~.ation 5
Suspensions are made as follows:
Zatosetron 20 mg
Sertraline 100 mg
Sodium carboxymethyl cellulose
50 mg
Syrup 1.25 ml
Benzoic acid solution 0.10 ml
Flavor q.v.
Color q.v.
Purified water to total 5 ml
CA 02332253 2000-11-14
WO 99/59593 PCT/US99/10092
-18-
The active ingredient is passed through a No. 45
mesh U.S. sieve and mixed with the sodium carboxymethyl
cellulose and syrup to form a smooth paste. The benzoic acid
solution, flavor and color are diluted with a portion of the
water and added, with stirring. Sufficient water is then
added to produce the required volume.
Formulation 6
An intravenous formulation may be prepared as
follows:
Zatosetron 20 mg
Paroxetine 25 mg
Isotonic saline 1,000 ml
