FLUOXETINE HYDROCHLORIDE FOR DECREASING HOT FLASHES
This application claims the benefit of U.S. Provisional
Application No. 60/076,541, filed March 2, 1998, and U.S.
Provisional No. 60/116,570, filed January 21, 1999.
FIELD OF THE INVENTION
The instant invention relates to the use of fluoxetine
hydrochloride for decreasing hot flashes.
BACKGROUND OF THE INVENTION
In general, menopause is associated with vasomotor
symptoms, manifested by hot flashes, flushing, or night
sweats, which are variable in frequency and severity, and
may persist for several months or a few years.
Approximately 75% of menopausal women will experience
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 therapy because such therapy is
medically contraindicated (e.g., estrogen sensitive
carcinoma and thromboembolic disease). 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.
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 non-
hormonal therapeutic modalities at present in the United
States are transdermal 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
50% of tamoxifen treated menopausal women (survivors of
breast cancer) suffering from hot flashes reported a
significant improvement of their hot flashes during
tamoxifen therapy when sertraline, a selective serotonin
reuptake inhibitor (SSRI) of the formula:

was also administered. Plouffe, et aJ., "An Open Trial of
Sertraline for Menopausal Hot Flushes: Potential Involvement
of Serotonin in Vasomotor Instability", Del. Med. J.,
69(9):481-2, 1997. The investigators believed that the hot
flash mechanism of action may be mediated through serotonin.
However, the investigators also noted that "unpublished
clinical trials with various serotoninergic agents in
menopausal women have failed to show any relief from hot
flushes." Id. at 481. Thus, although the hot flash
mechanism may indeed be mediated through serotonin, 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.
SUMMARY OF THE INVENTION
The present invention includes a method for decreasing
hot flashes in a human female comprising administering an
effective amount of fluoxetine to a human female in need
thereof.
Another aspect of the invention is a method for
decreasing hot flashes in a human female undergoing
raloxifene administration comprising administrating
fluoxetine; to a human female in need thereof an effective
amount of fluoxetine.
Another aspect of the invention is a pharmaceutical
formulation comprising fluoxetine and raloxifene.
Further aspects of the present invention include a use
of fluoxetine for the manufacture of a medicament for
decreasing hot flashes in a human female and a use of
fluoxetine for the manufacture of a medicament for
decreasing hot flashes in a human female undergoing
raloxifene administration.
DETAILED DESCRIPTION OF THE INVENTION
Fluoxetine hydrochloride (fluoxetine) is a well known
SSRI. See, e.g., U.S. Patent No. 4,590,213. Relative to
clonidine and bellargal, fluoxetine has a favorable side
effect profile. Fluoxetine has the following structure:

The carbon atom designated above with an asterisk (*)
is a chiral center. Thus, fluoxetine is enantiomeric, i.e.,
has an "R" and "S" enantiomer both of which are shown below:

The present invention envisions the use of a racemic
mixture of fluoxetine, the (R)-enantiomer, the (S)-
enantiomer, or a mixture enhanced with one enantiomer. An
"enhanced" mixture is where one enantiomer makes up between
50% and 99% of the total enantiomeric mixture. A preferred
embodiment of the present invention is the use of a racemic
mixture or a mixture 90%-99% enhanced with the (R)-
enantiomer. Most preferred is the use of substantially pure
(R)-enantiomer. As used in the present application,
"substantially pure" means that the enantioimeric mixture
contains at least 99% by weight (R)-fluoxetine and 1% or
less of (S)-fluoxetine.
Raloxifene hydrochloride (raloxifene) is described in
US 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 preventative agent for osteoporosis by
the U.S. Food and Drug Administration in late 1997.
Raloxifene has the following structure:

Clinical studies of raloxifene demonstrated a slight
increase in the number of women, relative to placebo, who
reported incidences of hot flashes during the clinical
trial. (24.6% for raloxifene vs. 18.3% for placebo).
Thus, another aspect of this invention, is a method for
decreasing hot flashes in a human female undergoing
raloxifene administration by administration of fluoxetine.
When "fluoxetine" and/or "raloxifene" are referred to
it is understood that such terms refer to fluoxetine
hydrochloride (the racemate, individual enantiomers, or
mixtures thereof) and raloxifene hydrochloride,
respectively, and includes other salts and solvates thereof.
The term "effective amount of fluoxetine" refers to an
amount of fluoxetine that is capable of decreasing hot
flashes. "Decreasing hot flashes" is defined to include
either reducing the occurrences or severity of the hot
flashes. The effective amount (per day) of fluoxetine will
typically be in the range from about 1 mg to 200 mg per day,
usually being in the range from about 5 mg to 80 mg per day,
preferably being in the range from about 10 mg to 60 mg per
day, and more preferably being in the range from about 15 mg
to 4 0 mg per day.
The term "effective amount of raloxifene" refers to an
amount which inhibits bone loss or an amount which is used
for any other medical therapeutic reason. When fluoxetine
is administered with raloxifene, the effective amount (per
day) of raloxifene will typically be in the range from about
10 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 2 5 mg to 7 5 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.
The term "effective term" refers to the period of time
that a human female suffers from incidences of hot flashes
and is usually for greater than 6 months. The effective
term should be determined by the caregiver in consult with
the caregiver's human female patient.
The term "human female" as used herein refers to a
human female who is suffering from hot flashes. These hot
flashes are typically associated with the natural onset of
menopause (and, thus, includes menopausal and post
menopausal women) but can also occur in "non-natural"
settings, e.g., when an oophorectomy has been performed. A
human female "undergoing raloxifene administration" includes
females who are ingesting raloxifene.
The need for the inhibition of bone loss in the context
of the present invention may arise locally in cases of bone
fracture, defect, prosthesis implantation, and the like.
Such need may also arise in cases of systemic bone disease,
such as osteoporosis, osteoarthritis, Paget's disease,
multiple myeloma and other forms of cancer, bone loss
resulting from side effects of other medical treatment (such
as steroids), and age-related loss of bone mass.
Raloxifene may be made by established procedures, such
as those detailed in U.S. Patent No.'s 4,418,068 and
5,62 9,42 5, the teachings of which are herein incorporated by
reference. Fluoxetine, as a racemic mixture, may also be
made by established procedures, such as those detailed in
U.S. Patent No.'s 4,314,081 and 4,194,009, the teachings of
which are herein incorporated by reference. Substantially
pure, individual enantiomers of fluoxetine may be prepared
by known procedures such as those taught in U.S. Patent No.
5,708,035, the teachings of which are herein incorporated by
reference, and references cited therein. See also,
Robertson, et al., J. Med. Chem., 31:1412-1417, 1988 for a
synthesis of (S)-fluoxetine.
Pharmaceutical formulations of the invention which
include fluoxetine, or fluoxetine and raloxifene, for
administration will generally include an effective amount of
fluoxetine and an effective amount of raloxifene, when
applicable, in addition to a pharmaceutically acceptable
excipient. Formulations containing fluoxetine, without
raloxifene, are taught in U.S. Patent No. 4,194,009, the
teachings of which are herein incorporated by reference.
Formulations containing raloxifene, without fluoxetine, are
taught in U.S. Patent No. 4,418,0 68 and European Patent
Application 95/301291.1, the teachings of which are herein
incorporated by reference.
Suitable excipients include most carriers approved for
parenteral administration, including water, saline, Ringer's
solution, Hank's solution, and solutions of glucose, lactose
dextrose, ethanol, glycerol, albumin, and the like. These
compositions may optionally include stabilizers,
antioxidants, antimicrobials, preservatives, buffering
agents, surfactants, and other accessory additives.
Fluoxetine, or fluoxetine and raloxifene, may also be
delivered in an iontophoretic patch. A thorough discussion
of suitable vehicles for parenteral administration may be
found in E.W. Martin, "Remington's Pharmaceutical Sciences"
(Mack Pub. Co., current edition sections relating to the
excipient vehicles and formulating being incorporated herein
by reference to disclose such). Such formulations are
generally known to those skilled in the art and are
administered systemically to provide systemic treatment.
If a combination of fluoxetine and raloxifene is
administered as a single composition, the molar ratio of
raloxifene to fluoxetine will be about 10:1 to 1:10,
preferably about 4:1 to 1:3, and most preferably about 2.1:1
to 1.9:1.
The following formulation examples are illustrative
only and are not intended to limit the scope of the present
invention. The term "active ingredients" refers to
fluoxetine and raloxifene.
The active ingredients, starch, and cellulose are
passed through a No. 45 mesh U.S. sieve and mixed
thoroughly. The solution of polyvinylpyrrolidone is mixed
with the resultant powders which are then passed through a
No. 14 mesh U.S. sieve. The granules so produced are dried
at 50°C-60°C and passed through a No. 18 mesh U.S. sieve.
The sodium carboxymethyl starch, magnesium stearate, and
talc, previously passed through a No. 6 0 U.S. sieve, are
then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets.
The active ingredients are passed through a No. 60 mesh
U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimal necessary
heat. The mixture is then poured into a suppository mold of
nominal 2 g capacity and allowed to cool.
An intravenous formulation is prepared as follows:

The solution of the above ingredients is intravenously
administered to a patient at a rate of about 1 mL per
minute.
When fluoxetine 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 fluoxetine and raloxifene will typically
be one week to one month, and optimally, one day to one
week. In a preferred administration scheme, the human
female will receive fluoxetine and raloxifene concurrently
or simultaneously.
In accordance with one method of use, fluoxetine and
raloxifene may be administered systemically orally and/or
parenterally,, including subcutaneous or intravenous
injection, and/or intranasally.
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
fluoxetine will range from about 0.001 mg/kg to about 5
mg/kg of body weight, per day. An effective dose for
raloxifene is about 0.001 mg/kg to 10 mg/kg of body weight,
per day. The total dosage (per day) of fluoxetine will
typically be in the range from about 1 mg to 200 mg per day,
usually being in the range from about 5 mg to 80 mg per day,
preferably being in the range from about 10 mg to 60 mg per
day, and more preferably being in the range from about 15 mg
to 40 mg per day.
When fluoxetine 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 2 5 mg to 7 5 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.
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.
A total of 120 - 160 women are gathered for a clinical
trial. These women 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. The women are divided
into four groups for a randomized double-blind placebo
controlled study. The groups receive drug or placebo as
illustrated below:
Group 1:Fluoxetine (20mg racemic mixture QD) + Placebo
Group 2:Placebo + Placebo
Group 3:Raloxifene (60mg QD) + Placebo
Group 4:Raloxifene (60mg QD) + Fluoxetine (2 0mg racemic
mixture QD)
For three weeks all four groups are administered
placebo only. For eight to twelve weeks thereafter, each
group is administered drug, placebo, or some combination as
outlined above. 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
fluoxetine results in a decrease, relative to placebo groups
(Groups 2 and 3), of the incidence of hot flashes in the
fluoxetine only group (Group 1) and fluoxetine/raloxifene
group (Group 4). This decrease indicates the utility of the
invention.
WE CLAIM:
1. A method for decreasing hot flashes in a human
female comprising administering an effective amount of
fluoxetine to a human female in need thereof for an
effective term.
2 . The method according to Claim 1 where the
fluoxetine is a racemic mixture of fluoxetine hydrochloride.
3. The method according to Claim 2 where the
effective amount of fluoxetine hydrochloride is between 5 mg
and 80 mg per day.
4. The method according to Claim 3 where the
effective amount of fluoxetine hydrochloride is between 10
mg and 60 mg per day.
5. The method according to Claim 4 where the
effective amount of fluoxetine hydrochloride is between 15
mg and 4 0 mg per day.
6. The method according to Claim 2 where the human
female is menopausal.
7 . The method according to Claim 2 where the human
female is post-menopausal.
8. The method according to Claim 1 where the
fluoxetine is substantially pure (R)-fluoxetine
hydrochloride.
9. A method for decreasing hot flashes in a human
female undergoing raloxifene administration comprising
administrating an effective amount of fluoxetine to a human
female in need thereof for an effective term.
10. The method according to Claim 9 where the
fluoxetine is a racemic mixture of fluoxetine hydrochloride
and the raloxifene is raloxifene hydrochloride.
11. The method according to Claim 10 where the
effective amount of fluoxetine hydrochloride is between 5 mg
and 8 0 mg per day.
12. The method according to Claim 11 where the
effective amount of fluoxetine hydrochloride is between 10
mg and 60 mg per day.
13. The method according to Claim 12 where the
effective amount of fluoxetine hydrochloride is between 15
mg and 4 0 mg per day.
14. The method according to Claim 10 where the human
female is menopausal.
15. The method according to Claim 10 where the human
female is post-menopausal.
16. The method according to Claim 9 where the
fluoxetine is substantially pure (R)-fluoxetine
hydrochloride and the raloxifene is raloxifene
hydrochloride?.
17. The method according to Claims 10 where the
administration of fluoxetine and raloxifene is concurrent.
18. The method according to Claim 17 where the
administration of fluoxetine and raloxifene is simultaneous.
19. The method according to Claim 10 where the
raloxifene administration arises from the existence of
osteoporosis, or probable onset of osteoporosis.
20. The method according to Claim 10 where the
raloxifene administration arises from the prevention of
osteoporosis.
21. A pharmaceutical formulation comprising fluoxetine
and raloxifene in a pharmaceutically acceptable excipient.
22. The formulation according to Claim 21 where the
fluoxetine is a racemic mixture of fluoxetine hydrochloride
and the raloxifene is raloxifene hydrochloride.
23. The formulation according to Claim 21 where the
fluoxetine is substantially pure (R)-fluoxetine
hydrochloride and the raloxifene is raloxifene
hydrochloride.
24. The formulation according to either Claim 22 or
Claim 23 where the molar ratio of raloxifene to fluoxetine
is 3:1 to 1:2.
25. The formulation according to either Claim 22 or
Claim 23 where the molar ratio of raloxifene to fluoxetine
is 2.1:1 to 1.9:1.
26. A use of fluoxetine for the manufacture of a
medicament for decreasing hot flashes in a human female.
27. The use according to Claim 26 where the fluoxetine;
is a racemic mixture of fluoxetine hydrochloride.
28. The use according to Claim 26 where the fluoxetine
is substantially pure (R)-fluoxetine hydrochloride.
29. The use according to either Claim 27 or Claim 28
where the human female is menopausal.
30. The use according to either Claim 27 or Claim 28
where the human female is post-menopausal.
31. A use of fluoxetine for the manufacture of a
medicament for decreasing hot flashes in a human female
undergoing raloxifene administration.
32. The use according to Claim 31 where the fluoxetine
is a racemic mixture of fluoxetine hydrochloride and the
raloxifene is raloxifene hydrochloride.
33. The use according to Claim 31 where the fluoxetine
is substantially pure (R)-fluoxetine hydrochloride and the
raloxifene is raloxifene hydrochloride.
34. The use according to either Claim 32 or Cia:::- 33
where the human female is menopausal.
35. The use according to either Claim 32 or Claim 33
where the human female is post-menopausal.
36. The use according to Claim 31 where the raloxifene
administration arises from the existence of osteoporosis, or
probable onset of osteoporosis.
37. A pharmaceutical formulation adapted for
decreasing hot flashes in human females comprising
fluoxetine and raloxifene.
38. The formulation according to Claim 37 where the
fluoxetine is a racemic mixture of fluoxetine hydrochloride
and the raloxifene is raloxifene hydrochloride.
39. The formulation according to Claim 37 where the
fluoxetine is substantially pure (R)-fluoxetine
hydrochloride and the raloxifene is raloxifene
hydrochloride.
40. The formulation according to either Claim 38 or
Claim 3 9 where the molar ratio of raloxifene to fluoxetine
is 3:1 to 1:2.
41. The formulation according to either Claim 38 or
Claim 3 9 where the molar ratio of raloxifene to fluoxetine
is 2.1:1 to 1.9:1.

The present invention includes a method for decreasing hot flashes in a human female by administering fluoxetine to that female.
Another aspect of the invention is a method for decreasing hot flashes in a human female undergoing raloxifene administration by
administrating fluoxetine to that female. Another aspect of the invention is a pharmaceutical formulation comprising fluoxetine and
raloxifene.