Note: Descriptions are shown in the official language in which they were submitted.
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DULOXETINE FOR TREATMENT OF HOT FLASHES
FIELD OF THE INVENTION
The invention relates to a method for using duloxetine
for the treatment of hot flashes.
BACKGROUND OF THE INVENTION
Hot flashes or flushing is characterized by a sudden
onset of warmth in the face and neck and often progressing
to the chest. Such an episode generally lasts several
minutes and is evidenced by a visible flushing of the skin.
Often such episodes are accompanied by sweating, dizziness,
nausea, palpitations and diaphoresis. Such symptoms can
disrupt sleep and interfere with the quality of life.
In general, menopause is associated with vasomotor
symptoms, manifested by hot flashes, which are variable in
frequency and severity, and may persist for several months
or a few years. Approximately 75% of menopausal women will
experience hot flashes during menopause (McKinlay, S.,
Jeffreys, M., "The Menopausal Syndrome," J. Prev. Soc. Med.,
28:108, 1974), with 80% experiencing them for greater than
one year and 25 to 50% for greater than 5 years. Judd,
H.L., Cleary, R.E., Creasman, W.T., et al., "Estrogen
Replacement Therapy," Obstet. Gynecol., 58-267, 1981. For
some of these women, the symptoms are disabling. Gambrell,
' R.D., Jr. "The Menopause: Benefits and Risks of Estrogen
Progestogen Replacement Therapy," Fertil. Steril., 37:457,
1982. The standard therapy for alleviating these symptoms
is estrogen replacement therapy (ERT). Many women,
unfortunately, are not candidates for ERT because such
therapy is medically contraindicated (e. g., estrogen
sensitive carcinoma and thromboembolic disease).
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Furthermore, this therapy, while effective, suffers from
poor patient compliance, due to unpleasant side-effects,
poor oral absorption, and poor bio-availability of the
natural estrogens 17(3-estradiol and estrone.
Men may also have hot flashes following androgen-
deprivation therapy (from bilateral orchiectomy or treatment
with a gonadotrophin-releasing-hormone agonist) for
metastatic prostate cancer.
Non-hormonal alternatives for hot-flashes are extremely
limited at present and have been associated with poor
response in many patients. The two most widely used no-
hormonal therapeutic modalities at present in the United
States are clonidine and Bellargal spacetabs. Neither has
gained wide clinical acceptance because of poor
effectiveness and side effects.
A recent report has established in a pilot study that
45% of venlafaxine treated menopausal women (survivors of
breast cancer) suffering from hot flashes reported a greater
than 50% decrease in hot flash frequency versus only 20% in
treatment with placebo. "venlafaxine in management of hot
flashes in survivors of breast cancer: a randomised
controlled trial," The Lancet (2000), 356(9247), 2059-2063.
The investigators hypothesized that the hot flash
activity may be alleviated via treatment with venlafaxine.
However, over 500 of venlafaxine treated menopausal women
did not report a 50% decrease in hot flash frequency. Id.
at 2059. In addition, the investigators noted that any
venlafaxine "efficacy must be balanced against the drug's
side-effects." Thus, although the hot flash mechanism may
indeed be mediated through serotonin and norepinephrine
reuptake inhibition, it can not be predicted a priori
whether a pharmaceutical that is classified as a SSRI is
effective at decreasing the incidence of hot flashes.
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Further, it would be optimal to find a method of treatment
for hot flashes with greater efficacy and/or greater safety.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, there is
provided a method of treating hot flashes in a mammal
comprising the administration to a patient in need of such
treatment an effective amount of duloxetine.
Another aspect of the invention is a method for
treating hot flashes in a human female undergoing ERT
comprising administering duloxetine to a human female in
need thereof an effective amount of duloxetine.
Another aspect of the invention is a method for
treating hot flashes comprising administering duloxetine to
a human female where estrogen replacement thereof is
contradicted.
Another aspect of the invention is a method for
treating hot flashes in a human female undergoing raloxifene
administration comprising administering duloxetine to a
human~female in need thereof an effective amount of
duloxetine.
Further aspects of the present invention include a use
of duloxetine for the manufacture of a medicament for
treating hot flashes in a human, use of duloxetine for the
manufacture of a medicament for treating hot flashes in a
human undergoing ERT and a use of duloxetine for the
manufacture of a medicament for treating hot flashes in a
human female undergoing raloxifene administration.
DETAINED DESCRIPTION AND PREFERRED EMBODIMENTS
Duloxetine is N-methyl-3-(1-naphthalenyloxy)-3-(2-
thienyl)propanamine. It is usually administered as the (+)
enantiomer, and as the hydrochloride salt. It was first
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taught by U.S. Patent 4,956,388, which teaches the synthesis
of the compound as well as its high potency as an uptake
inhibitor of both serotonin and norepinephrine. The word
"duloxetine" will be used here to refer to any acid addition
salt or the free base of the molecule, as well as to either
an enantiomer or the racemate. It is to be understood,
however, that the (+) enantiomer is preferred.
As used herein, the term "active ingredient" refers to
duloxetine as it is usually administered.
The term "treating" (or "treat") as used herein
includes its generally accepted meaning which encompasses
prohibiting, preventing, restraining, and slowing, stopping,
decreasing the incidences or reversing progression,
severity, of a resultant symptom. As such, the methods of
this invention encompass both therapeutic and prophylactic
administration.
As used herein the term "effective amount" refers to.
the amount or dose of the compound, upon single or multiple
dose administration to the patient, which provides the
desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the
attending diagnostician, as one skilled in the art, by the
use of known techniques and by observing results obtained
under analogous circumstances. In determining the effective
amount or dose of compound administered, a number of factors
are considered by the attending diagnostician, including,
but not limited to: the species of mammal; its size, age,
and general health; the specific disease involved; the
degree of or involvement or the severity of the disease; the
response of the individual patient; the particular compound
administered; the mode of administration; the
bioavailability characteristics of the preparation
administered; the dose regimen selected; the use of
concomitant medication; and other relevant circumstances.
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For example, a typical daily dose may contain from about 60
to about 80 mg of the active ingredient. The compounds can
be administered by a variety of routes including oral,
rectal, transdermal, subcutaneous, intravenous,
intramuscular, bucal or intranasal routes. Alternatively,
the compound may be administered by continuous infusion.
As used herein the term "patient" refers to a mammal,
such as a mouse, guinea pig, rat, dog or human. It is
understood that the preferred patient is a human.
The compound is particularly selective, having few if
any physiological effects besides those on norepinephrine
and serotonin processing, and therefore is free of side
effects and unwanted activities. Further, it is effective
at relatively low doses, as discussed below, and may safely
and effectively be administered once or twice per day.
Thus, difficulties created by the multiple dosing of
patients, who are children and disorganized adults, are
completely avoided.
The most preferred dose of duloxetine for the treatment
of a given patient with any particular disorder will vary,
depending on the characteristics of the patient, as all
clinicians and medical doctors are aware. Factors such as
other diseases from which the patient suffers, the patient s
age and size, and other medications which the patient may be
using will have an effect on the duloxetine dose and will be
taken into account. In general, however, the daily dose of
duloxetine is from about Z to about 80 mg. A more preferred
dose range is from about 60 to about 80 mg daily.
Another preferred dose is about 60mg taken once per
day. Another preferred dose is 40 mg taken twice per day.
Duloxetine is orally available and presently is orally
administered, in the form of a tablet or a capsule full of
enteric coated granules. Oral administration in such forms
is preferred in the practice of the present invention.
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However, other routes of administration are also practical
and may be preferred in certain cases. For example,
transdermal administration may be very desirable for
patients who are forgetful or petulant about taking oral
medicine. Sustained release formulations, oral or
percutaneous, may be prepared, but are not preferred because
duloxetine is quite effective when administered once or
twice daily and there is little benefit from the additional
effort of preparing the sustained action product.
In general, the formulation of duloxetine fox use in
the present invention follows the methods used in
formulating duloxetine for other purposes, and indeed
methods usual in pharmaceutical science are appropriate.
However, a preferred formulation of duloxetine comprises
enteric pellets, or granules, of which a number, are charged
in a gelatin capsule.
Raloxifene hydrochloride (raloxifene) is described in
U.S. Patent No. 4,418,068 and is known to be effective in
treating the symptoms of post menopausal syndrome,
particularly osteoporosis. Indeed, raloxifene was approved
for marketing as a preventive agent for osteoporosis by the
U.S. Food and Drug Administration in late 1997
Raloxifene has the following structure:
v HCl
N
OH
HO -
Clinical studies of raloxifen2 demonstrated a slight
increase in the number of women, relative to placebo, who
reported incidences of hot flashes during the clinical
trial. (24.60 for raloxifene vs. 18.3% for placebo).
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The preferred duloxetine enteric formulation comprises
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.
The duloxetine layer, was built up by suspending
duloxetine in a 4% w/w solution of the hydroxypropylmethyl-
cellulose in water, and milling the suspension with a CoBall
Mill (Fryma Mashinen AG, Rheinfelden, Switzerland) model MS-
12. A fluid bed dryer with a Wurster column was used to
make this product, at a batch size of 1.0 kg. The
separating layer was added from a 4% w/w solution of the
hydroxypropyl-methylcellulose in water, in which the sucrose
was also dissolved.
In order to prepare the enteric coating suspension,
purified water was cooled to 10°C and the polysorbate,
triethyl citrate and silicone emulsion were added and
dispersed or dissolved. Then the HPMCAS and talc were added
and agitated until homogeneity was obtained, and the HPMCAS
was fully neutralized by addition of ammonium hydroxide
until solution of the polymer was complete. To this
suspension, a carboxymethylcellulose aqueous solution, 0.50
w/w, was added and blended thoroughly. The enteric
suspension was maintained at 20°C during the coating
process. The enteric suspension was then added to the
partially completed pellets in the Wurster column at a spray
rate of about 15 ml/min, holding the temperature of the
inlet air at about 50°C. The product was dried in the
Wurster at 50°C when the enteric suspension had been fully
added, and then dried on trays for 3 hours in a dry house at
60°C. A finishing layer was then applied which consisted of
a 4.5% w/w/ hydroxypropylmethyl-cellulose solution
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containing titanium dioxide and propylene glycol as
plasticizer. The pellets were completely dried in the fluid
bed dryer and then were then filled in size 3 gelatin
capsules.
When duloxetine and raloxifene are both employed, they
may be administered sequentially, concurrently, or
simultaneously as a single composition to the subject. If
administered sequentially, the period between the
administration of duloxetine and raloxifene will typically
be one week to one month, and optimally, one day to one
week. In a preferred administration scheme, the human will
receive duloxetine and raloxifene concurrently or
simultaneously.
In accordance with one method of use, duloxetine and
raloxifene may be administered systemically orally.
The precise dosage necessary will vary with the age,
size, sex and condition of the subject, the nature and
severity of the disorder to be treated, and the like; thus,
a precise effective amount should be determined by the
caregiver. In general terms, an effective dose of
duloxetine will range between values described above.
When duloxetine is administered with raloxifene, the
total dosage (per day) of raloxifene will typically be in
the range from about 1 mg to 1000 mg per day, usually being
in the range from about 10 mg to 100 mg per day, preferably
being in the range from about 25 mg to 75 mg per day, more
preferably being in the range from about 55 mg to 65 mg per
day, and most preferably being 60 mg per day.
Example 1
The patient to be benefited by practice of the present
invention is a patient experiencing vasomotor symptoms such
as hot flashes, a sudden brief flushing and sensation of
heat caused by dilation of skin capillaries. Diagnosis of
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this disorder is to be made by a physician. It is presently
believed that duloxetine's potency in inhibiting the uptake
of serotonin and norepinephrine is the mechanism by which it
benefits such patients, by alleviating the effects of the
disorder from which the patient suffers, or even eliminating
the disorder completely.
The following description is put forth so as to provide
those of ordinary skill in the art with a complete
disclosure and description of the effectiveness of the
compositions and methods of the invention and are not
intended to limit the scope of what the inventors regard as
their invention.
Patients eligible for a clinical trial include women
who are either 1) naturally menopausal; or 2) pre-menopausal
but had undergone bilateral oophorectomy surgery within four
weeks prior to the commencement of the study. All the women
in the study experience a minimum of thirty five hot flashes
per week. Men considered for a clinical trial would have
androgen deprivation therapy for prostate cancer scheduled
to continue at least 6 weeks beyond the trial entry date.
Men have bothersome hot flashes for at least the previous
month a minimum of fourteen times weekly of sufficient
severity to desire therapeutic intervention. The women or
men are divided into two groups for a randomized double-
blind placebo controlled study.
The groups receive drug or placebo as illustrated
below':
Group 1: Duloxetine (60 mg QD) + Placebo
Group 2: Placebo + Placebo
Group 3: Raloxifene (60 mg QD) + Placebo
Group 4: Raloxifene (50 mg QD) + Duloxetine (30 mg QD)
For three weeks both groups are administered placebo
only. For eight to twelve weeks thereafter, each group is
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administered drug or placebo. Data is collected
(numbers/severity of hot flashes experienced) from each
participant during and at the end of the test period.
The treatment of the clinical trial participants with
dul.oxetine results in a decrease, relative to the placebo
groups (Groups 2 and 3), of the incidence of hot flashes in
the duloxetine only group (Group 1) and the
duloxetine/raloxifene group (Group 4). This decrease
indicates the utility of the invention.
The invention has been described with reference to the
preferred embodiment. Obviously, modifications and
alterations will occur to others upon a reading and
understanding of this specification. It is intended to
include all such modifications and alterations insofar as
l5 they come within the scope of the appended claims or the
equivalents thereof.
