U.S. patent application number 13/847683 was filed with the patent office on 2014-01-02 for treatment of vasomotor symptoms.
This patent application is currently assigned to Sprout Pharmaceuticals Inc.. The applicant listed for this patent is Sprout Pharmaceuticals Inc.. Invention is credited to Vladimir Hanes, Annelies Verbeek.
Application Number | 20140005203 13/847683 |
Document ID | / |
Family ID | 40019339 |
Filed Date | 2014-01-02 |
United States Patent
Application |
20140005203 |
Kind Code |
A1 |
Hanes; Vladimir ; et
al. |
January 2, 2014 |
Treatment of Vasomotor Symptoms
Abstract
The invention relates to a method for the treatment of vasomotor
symptoms comprising the administration of a therpeutically
effective amount of flibanserin.
Inventors: |
Hanes; Vladimir; (Tarrytown,
NY) ; Verbeek; Annelies; (Sandy Hook, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sprout Pharmaceuticals Inc.; |
|
|
US |
|
|
Assignee: |
Sprout Pharmaceuticals Inc.
Raleigh
NC
|
Family ID: |
40019339 |
Appl. No.: |
13/847683 |
Filed: |
March 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12675231 |
Jan 28, 2011 |
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PCT/EP2008/062011 |
Sep 11, 2008 |
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13847683 |
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60971605 |
Sep 12, 2007 |
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Current U.S.
Class: |
514/254.06 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 15/12 20180101 |
Class at
Publication: |
514/254.06 |
International
Class: |
A61K 31/496 20060101
A61K031/496 |
Claims
1. A method for the treatment of vasomotor symptoms comprising the
administration of a therapeutically effective amount of
flibanserin, or a pharmacologically acceptable acid addition salt,
hydrate, or solvate, thereof.
2. The method according to claim 1, wherein the vasomotor symptoms
are vasomotor symptoms associated with the menopause.
3. The method according to claim 1, wherein the vasomotor symptoms
are vasomotor symptoms associated with surgically induced
menopause.
4. The method according to claim 1, wherein the vasomotor symptoms
are vasomotor symptoms associated with iatrogenic induced
menopause.
5. The method according to claim 1, wherein the vasomotor symptoms
are vasomotor symptoms associated with the use of medication,
radiation, or chemotherapeutic agents.
6. The method according to claim 1, wherein the vasomotor symptoms
are selected from the group consisting of hot flashes, night
sweats, mood swings, and irritability.
7. The method according to claim 1, wherein the vasomotor symptoms
are moderate to severe vasomotor symptoms associated with a natural
or iatrogenic hypogonadal state in men.
8. The method according to claim 7, wherein the vasomotor symptoms
are vasomotor symptoms associated with the use of medication,
radiation, or chemotherapeutic agents.
9. The method according to claim 7, wherein the vasomotor symptoms
are hot flashes in men.
10. The method according to any one of the claim 1 to 9 or 13 or
14, wherein the flibanserin is administered as a pharmaceutically
acceptable acid addition salt selected from the salts formed by
succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic
acid, methanesulphonic acid, lactic acid, phosphoric acid,
hydrochloric acid, sulphuric acid, tartaric acid, citric acid, and
mixtures thereof.
11. The method according to any one of the claim 1 to 9 or 13 or
14, wherein the flibanserin is administered as flibanserin
polymorph A.
12. The method according to any one of the claim 1 to 9 or 13 or
14, wherein the flibanserin is administered in a dose range between
0.1 to 400 mg per day.
13. The method according to claim 4, wherein the vasomotor symptoms
are vasomotor symptoms associated with the use of medication,
radiation, or chemotherapeutic agents.
14. The method according to claim 8, wherein the vasomotor symptoms
are hot flashes in men.
Description
[0001] The present invention relates to methods for the treatment
of vasomotor symptoms associated with the menopause comprising the
administration of a therapeutically effective amount of
flibanserin.
DESCRIPTION OF THE INVENTION
[0002] The compound
1[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-ben-
zimidazol-2-one (flibanserin) is disclosed in form of its
hydrochloride in European Patent Application EP-A-526434 and has
the following chemical structure:
##STR00001##
[0003] Flibanserin shows affinity for the 5-HT.sub.1A and
5-HT.sub.2-receptor. It is therefore a promising therapeutic agent
for the treatment of a variety of diseases, for instance
depression, schizophrenia, and anxiety.
[0004] Women transitioning through the menopausal frequently
experience a variety of symptoms which have been attributed to
estrogen deprivation due to ovarian failure. Menopause is defined
as the cessation of menstruation in women. The timing of the
menopause is determenied with hind sight and is established after
twelve months of amenorrhoea. Most women experience menopause
between the ages of 40 and 55. Menopausal transition is
characterized by hot flashes, headaches, night sweats, atrophic
vaginitis, frequent urinary tract infections, cold hands and feet,
forgetfulness and an inability to concentrate. Emotional indicators
of menopause transitioning include anxiety, distress, irritability,
mood swings, depression and decreased sex drive. There are many
undesirable symptoms too numerous to articulate which are
attributed to changes in the female body as she transitions through
the menopause.
[0005] Some of the symptoms, e.g., vulvar and vaginal atrophy can
be clearly attributed to estrogen deficiency; however, hot flashes
are likely to arise as a result of an alteration in the CNS
thermoregulatory set-point located in the anterior portion of the
hypothalamus. Hot flashes, also known as "vasomotor flushes" or
"hot flushes" are very common in perk and postmenopausal women. The
dilation of peripheral blood vessels results in reddening and
warming of the skin during a hot flash. Further symptoms such as
increased heart rate, night sweats, headaches, dizziness, weight
gain, fatigue and insomnia may be associated with a hot flash. Hot
flashes may appear prior to the cessation of the menses and may be
the first sign that menopause is approaching. During the
perimenopausal period, appr. 75% of women complain of hot flashes.
In most of these women the symptoms will last appr. 1 year. About
one-third of postmenopausal women will report symptoms that last up
to 5 years after natural menopause, and hot flashes can persist for
up to 15 years in 20% or more of women. Menopause induced by
surgery is associated with about a 90% probability of hot flashes
during the first year, and hot flashes associated with surgical
menopause are often more abrupt and severe and can last longer than
those associated with a non-surgical menopause.
[0006] The US Bureau of Census estimates that currently 49 million
American women are over the age of 50 years. Thus, over 32 million
women in the USA today might have had hot flashes, and up to 6
million might have reported severe symptoms.
[0007] Now, experimental results from studies performed in patients
with major Depressive Disorder have shown that flibanserin may be
useful for the treatment of vasomotor symptoms (e,g, hot flashes,
night sweats, moodswings and irritability).
[0008] Accordingly, the instant invention relates to a method for
the treatment of vasomotor symptoms comprising the administration
of a therapeutically effective amount of flibanserin, optionally in
form of the free base, the pharmacologically acceptable acid
addition salts and/or optionally in form of the hydrates and/or
solvates thereof.
[0009] In an further aspect, the instant invention relates to a
method for the treatment of vasomotor symptoms associated with the
menopausal transition comprising the administration of a
therapeutically effective amount of flibanserin, optionally in form
of the free base, the pharmacologically acceptable acid addition
salts and/or optionally in form of the hydrates and/or solvates
thereof.
[0010] As vasomotors symptoms do not only occur due to naturally
occurring menopause but may also be also due to surgically (e.g.,
hysterectomy and bilateral ovarectomy) induced menopause or by the
use of medications (e.g. by selective estrogen receptor modulators,
GnRH analogues and Aromatase inhibitors), or induced by radioation
and chemotherapeutic agents, the present invention relates to a
method for the treatment or prevention of vasomotor symptoms
associated with iatrogenic induced menopause, comprising the
administration of a therapeutically effective amount of
flibanserin, optionally in form of the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof.
[0011] In another embodiment the present invention refers to a
method for the treatment of hot flashes, night sweats, moodswings
and irritability comprising the administration of a therapeutically
effective amount of flibanserin, optionally in form of the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof.
[0012] Another aspect of the present invention relates to the use
of flibanserin for the treatment of moderate to severe vasomotor
symptoms associated with a natural or iatrogenic hypogonadal state
in men.
[0013] Still further aspect of the present invention relates to use
of flibanserin for treatment of hot flushes in men, preferably in
hypogonadal men, men on androgen deprivation treatment or those who
underwent castration.
[0014] Another embodiment of the invention relates to the use of
flibanserin, optionally in form of the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof for the preparation
of a medicament for the treatment of any one of the above mentioned
conditions. As already mentioned above, Flibanserin may be used in
form of the free base, optionally in form of its pharmaceutically
acceptable acid addition salts and/or optionally in form of the
hydrates and/or solvates thereof. Suitable acid addition salts
include for example those of the acids selected from, succinic
acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid,
methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric
acid, sulphuric acid, tartaric acid and citric acid. Mixtures of
the abovementioned acid addition salts may also be used. From the
aforementioned acid addition salts the hydrochloride and the
hydrobromide, particularly the hydrochloride, are preferred. If
Flibanserin is used in form of the free base, it is preferably used
in form of Flibanserin polymorph A as disclosed in WO
03/014079.
[0015] Flibanserin, optionally in form of the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates, may be incorporated into
the conventional pharmaceutical preparation in solid, liquid or
spray form. The composition may, for example, be presented in a
form suitable for oral, rectal, parenteral administration or for
nasal inhalation: preferred forms includes for example, capsules,
tablets, coated tablets, ampoules, suppositories and nasal
spray.
[0016] The active ingredient may be incorporated in excipients or
carriers conventionally used in pharmaceutical compositions such
as, for example, talc, arabic gum, lactose, gelatine, magnesium
stearate, corn starch, acqueous or non acqueous vehicles, polyvynil
pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium
chloride, sodium phosphate , EDTA, polysorbate 80. The compositions
are advantageously formulated in dosage units, each dosage unit
being adapted to supply a single dose of the active ingredient. The
dosis range applicable per day is between 0.1 to 400, preferably
between 1.0 to 300, more preferably between 2 to 200 mg. Each
dosage unit may conveniently contain from 0.01 mg to 100 mg,
preferably from 0.1 to 50 mg.
[0017] Suitable tablets may be obtained, for example, by mixing the
active substance(s) with known excipients, for example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
disintegrants such as corn starch or alginic acid, binders such as
starch or gelatine, lubricants such as magnesium stearate or talc
and/or agents for delaying release, such as carboxymethyl
cellulose, cellulose acetate phthalate, or polyvinyl acetate. The
tablets may also comprise several layers.
[0018] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number or
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0019] Syrups or elixirs containing the active substances or
combinations thereof according to the invention may additionally
contain a sweetener such as saccharine, cyclamate, glycerol or
sugar and a flavour enhancer, e.g of. a flavouring such as
vanilline or orange extract. They may also contain suspension
adjuvants or thickeners such as sodium carboxymethyl cellulose,
wetting agents such as, for example, condensation products of fatty
alcohols with ethylene oxide, or preservatives such as
p-hydroxybenzoates.
[0020] Solutions for injection are prepared in the usual way, e.g
of. with the addition of preservatives such as p-hydroxybenzoates,
or stabilisers such as alkali metal salts of ethylenediamine
tetraacetic acid, and transferred into injection vials or
ampoules.
[0021] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0022] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0023] The Examples which follow illustrate the present invention
without restricting its scope:
EXAMPLES
[0024] Clinical Trial
[0025] In twelve Phase II clinical studies performed in patients
diagnosed with Major Depressive Disorder, more then 1500 male and
female subjects aged between 18 and 65 years received one or more
doses of flibanserin ranging from 2 mg to 100 mg b.i.d. A
preliminary analysis of safety database in these subjects showed
that flibanserin was associated with virtually no AEs coded as hot
flushes/flushing as compared to placebo (1.25%) or selective
serotonin reuptake inhibitors (2.1%). (see table 1).
TABLE-US-00001 TABLE 1 Flibanserin in mg Paroxetine Fluoxetine 20
50 100 20 50 100 2 in mg in mg Treatment Placebo bid bid bid qd qd
qd bid 20 20 N 718 225 521 154 63 64 63 120 275 145 flushing 5 2 0
0 1 0 0 1 2 2 Hot 4 2 1 0 0 0 0 1 3 2 flush
[0026] In Table 1 it is shown that 9 patients of 718 receiving
placebo (1.25%), 5 patients of 275 (1.8%) or 4 of 145 (2.75%)
receiving Paroxetine or Fluoxetine respectively suffered form
flushing or hot flushes. In stark contrast, in the group receiving
50 to 200 mg/day Flibanserin only one out of 802 patients suffered
from flushing. These data suggest that flibanserin is useful for
the treatment of vasomotor symptoms like hot flushes in menopausal
women.
[0027] Examples of Pharmaceutical Formulations
[0028] A) Tablets
TABLE-US-00002 per tablet flibanserin hydrochloride 100 mg lactose
240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg magnesium
stearate 15 mg 740 mg
[0029] The finely ground active substance, lactose and some of the
corn starch are mixed together. The mixture is screened, then
moistened with a solution of polyvinylpyrrolidone in water,
kneaded, wet-granulated and dried. The granules, the remaining corn
starch and the magnesium stearate are screened and mixed together.
The mixture is compressed to produce tablets of suitable shape and
size.
[0030] B) Tablets
TABLE-US-00003 per tablet flibanserin hydrochloride 80 mg corn
starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg
polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg
magnesium stearate 2 mg 400 mg
[0031] The finely ground active substance, some of the corn starch,
lactose, microcrystalline cellulose and polyvinylpyrrolidone are
mixed together, the mixture is screened and worked with the
remaining corn starch and water to form a granulate which is dried
and screened. The sodium-carboxymethyl starch and the magnesium
stearate are added and mixed in and the mixture is compressed to
form tablets of a suitable size.
[0032] C) Coated Tablets
TABLE-US-00004 per coated tablet flibanserin hydrochloride 5 mg
corn starch 41.5 mg.sup. lactose 30 mg polyvinylpyrrolidone 3 mg
magnesium stearate 0.5 mg 80 mg
[0033] The active substance, corn starch, lactose and
polyvinylpyrrolidone are thoroughly mixed and moistened with water.
The moist mass is pushed through a screen with a 1 mm mesh size,
dried at about 45.degree. C. and the granules are then passed
through the same screen. After the magnesium stearate has been
mixed in, convex tablet cores with a diameter of 6 mm are
compressed in a tablet-making machine . The tablet cores thus
produced are coated in known manner with a covering consisting
essentially of sugar and talc. The finished coated tablets are
polished with wax.
[0034] D) Capsules
TABLE-US-00005 per capsule flibanserin hydrochloride 150 mg Corn
starch 268.5 mg.sup. Magnesium stearate 1.5 mg 420 mg
[0035] The substance and corn starch are mixed and moistened with
water. The moist mass is screened and dried. The dry granules are
screened and mixed with magnesium stearate. The finished mixture is
packed into size 1 hard gelatine capsules.
[0036] E) Ampoule Solution
TABLE-US-00006 flibanserin hydrochloride 50 mg sodium chloride 50
mg water for inj. 5 ml
[0037] The active substance is dissolved in water at its own pH or
optionally at pH 5.5 to 6.5 and sodium chloride is added to make it
isotonic. The solution obtained is filtered free from pyrogens and
the filtrate is transferred under aseptic conditions into ampoules
which are then sterilised and sealed by fusion.
[0038] F) Suppositories
TABLE-US-00007 flibanserin hydrochloride 50 mg solid fat 1650 mg
1700 mg
[0039] The hard fat is melted. At 40.degree. C. the ground active
substance is homogeneously dispersed. It is cooled to 38.degree. C.
and poured into slightly chilled suppository moulds.
[0040] In a particular preferred embodiment of the instsnt
invention, flibanserin is administered in form of specific film
coated tablets. Examples of these preferred formulations are listed
below. The film coated tablets listed below can be manufactured
according to procedures known in the art (see hereto WO
03/097058).
[0041] G) Film Coated Tablet
TABLE-US-00008 Constituents mg/tablet Core Flibanserin 25.000
Lactose monohydrate 71.720 Microcrystalline cellulose 23.905 HPMC
(Methocel E5) 1.250 Carboxymethylcellulose sodium 2.500 Magnesium
stearate 0.625 Coating HPMC (Methocel E5) 1.440 Polyethylene Glycol
6000 0.420 Titanium dioxide 0.600 Talc 0.514 Iron oxide red 0.026
Total Film coated tablet 128.000
[0042] H) Film Coated Tablet
TABLE-US-00009 Constituents mg/tablet Core Flibanserin 50.000
Lactose monohydrate 143.440 Microcrystalline cellulose 47.810 HPMC
(e.g. Pharmacoat 606) 2.500 Carboxymethylcellulose sodium 5.000
Magnesium stearate 1.250 Coating HPMC (e.g. Pharmacoat 606) 2.400
Polyethylene Glycol 6000 0.700 Titanium dioxide 1.000 Talc 0.857
Iron oxide red 0.043 Total Film coated tablet 255.000
[0043] I) Film Coated tablet
TABLE-US-00010 Constituents mg/tablet Core Flibanserin 100.000
Lactose monohydrate 171.080 Microcrystalline cellulose 57.020 HPMC
(e.g. Methocel E5) 3.400 Carboxymethylcellulose sodium 6.800
Magnesium stearate 1.700 Coating HPMC (e.g. Methocel E5) 3.360
Polyethylene Glycol 6000 0.980 Titanium dioxide 1.400 Talc 1.200
Iron oxide red 0.060 Total Film coated tablet 347.000
[0044] J) Film Coated Tablet
TABLE-US-00011 Constituents mg/tablet Core Flibanserin 2.000
Dibasic Calciumphosphate, anhydrous 61.010 Microcrystalline
cellulose 61.010 HPMC (Methocel E5) 1.950 Carboxymethylcellulose
sodium 2.600 Colloidal silicon dioxide 0.650 Magnesium stearate
0.780 Coating HPMC (Methocel E5) 1.440 Polyethylene Glycol 6000
0.420 Titanium dioxide 0.600 Talc 0.514 Iron oxide red 0.026 Total
Film coated tablet 133.000
[0045] K) Film Coated Tablet
TABLE-US-00012 Constituents mg/tablet Core Flibanserin 100.000
Dibasic Calciumphosphate, anhydrous 69.750 Microcrystalline
cellulose 69.750 HPMC (e.g. Methocel E5) 2.750
Carboxymethylcellulose sodium 5.000 Colloidal silicon dioxide 1.250
Magnesium stearate 1.500 Coating HPMC (e.g. Methocel E5) 2.400
Polyethylene Glycol 6000 0.700 Titanium dioxide 1.043 Talc 0.857
Total Film coated tablet 255.000
[0046] L) Film Coated Tablet
TABLE-US-00013 Constituents mg/tablet Core Flibanserin 20.000
Lactose monohydrate 130.000 Microcrystalline cellulose 43.100
Hydroxypropyl Cellulose (e.g. Klucel LF) 1.900 Sodium Starch
Glycolate 4.000 Magnesium stearate 1.000 Coating HPMC (e.g.
Methocel E5) 2.400 Polyethylene Glycol 6000 0.700 Titanium dioxide
1.043 Talc 0.857 Total Film coated tablet 205.000
* * * * *