U.S. patent application number 12/306878 was filed with the patent office on 2009-12-17 for flibanserin for the treatment of urinary incontinence and related diseases.
Invention is credited to Ramiro Castro, Angelo Ceci.
Application Number | 20090312242 12/306878 |
Document ID | / |
Family ID | 38371077 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312242 |
Kind Code |
A1 |
Castro; Ramiro ; et
al. |
December 17, 2009 |
FLIBANSERIN FOR THE TREATMENT OF URINARY INCONTINENCE AND RELATED
DISEASES
Abstract
The invention relates to the use of Flibanserin for the
treatment or prevention of urinary incontinence and related
diseases. In a further embodiment, the instant invention is
directed to pharmaceutical combinations comprising flibanserin as
one active ingredient in combination with at least one additional
active ingredient for the treatment or prevention of urinary
incontinence and related diseases.
Inventors: |
Castro; Ramiro; (Barcelona,
ES) ; Ceci; Angelo; (Mittelbiberach, DE) |
Correspondence
Address: |
Michael P. Morris;Boehringer Ingelheim USA Corporation
900 Ridgebury Road
Ridgefield
CT
06877-0368
US
|
Family ID: |
38371077 |
Appl. No.: |
12/306878 |
Filed: |
June 27, 2007 |
PCT Filed: |
June 27, 2007 |
PCT NO: |
PCT/EP2007/056400 |
371 Date: |
August 20, 2009 |
Current U.S.
Class: |
514/1.1 ;
514/254.06 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 31/496 20130101; A61P 13/10 20180101; A61K 38/095 20190101;
A61K 45/06 20130101; A61K 38/22 20130101; A61K 31/138 20130101;
A61K 31/381 20130101; A61P 13/00 20180101 |
Class at
Publication: |
514/11 ;
514/254.06 |
International
Class: |
A61K 38/12 20060101
A61K038/12; A61K 31/497 20060101 A61K031/497 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 2006 |
EP |
06116393.7 |
Claims
1. A method for treating or preventing urinary incontinence
comprising administering a therapeutically effective amount of
Flibanserin 1, or a pharmacologically acceptable acid addition
salt, hydrate, or solvate thereof.
2. The method for treating or preventing urinary incontinence
according to claim 1, further comprising administering and an
active ingredient 2, or a pharmaceutically acceptable salt,
hydrate, or solvate thereof.
3. The method for treating or preventing urinary incontinence
according to claim 1, wherein the urinary incontinence is
overactive bladder syndrome.
4. The method for treating or preventing urinary incontinence
according to claim 2, wherein the urinary incontinence is
overactive bladder syndrome.
5. The method for treating or preventing urinary incontinence
according to claim 1, wherein the urinary incontinence is
urgency.
6. The method for treating or preventing urinary incontinence
according to claim 1, wherein the urinary incontinence is urge
urinary incontinence.
7. The method for treating or preventing urinary incontinence
according to claim 1, wherein the urinary incontinence is stress
urinary incontinence.
8. The method for treating or preventing urinary incontinence
according to claim 1, wherein the urinary incontinence is mixed
urinary incontinence.
9. The method for treating or preventing urinary incontinence
according to claim 2, wherein the active ingredient 2 is an
antimuscarinic agent 2a, vasopressin agonist 2b,
Serotonin/Noradrenaline modulator 2c, or .beta.3 agonist 2d.
10. The method for treating or preventing urinary incontinence
according to claim 9, wherein the active ingredient 2 is an
antimuscarinic agent 2a.
11. The method for treating or preventing urinary incontinence
according to claim 10, wherein the antimuscarinic agent 2a is
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin, or
Trospium, or a pharmaceutically acceptable acid addition salt,
hydrate or solvate thereof.
12. The method for treating or preventing urinary incontinence
according to claim 9, wherein the active ingredient 2 is a
vasopressin agonist 2b.
13. The method for treating or preventing urinary incontinence
according to claim 12, wherein the vasopressin agonist 2b is
desmopressin, a pharmaceutically acceptable acid addition salt,
hydrate, and/or solvate thereof.
14. The method for treating or preventing urinary incontinence
according to claim 9, wherein the active ingredient 2 is a
Serotonin/Noradrenaline modulator 2c.
15. The method for treating or preventing urinary incontinence
according to claim 14, wherein the Serotonin/Noradrenaline
modulator 2c is Venlafaxine, Duloxetine, Reboxetine, or
Cizoliritine, or a pharmaceutically acceptable acid addition salt,
hydrate, or solvate thereof.
16. The method for treating or preventing urinary incontinence
according to claim 9, wherein the active ingredient 2 is a .beta.3
agonist 2d.
17. The method for treating or preventing urinary incontinence
according to claim 16, wherein the .beta.3 agonist 2d is
AD9677/TAK677, CL 316,243, SB 418790, L-796568, BMS-196085,
BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecanidine, Zeneca
D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A, or CGP-12177A, or a
pharmaceutically acceptable acid addition salt, hydrate, or solvate
thereof.
18. A pharmaceutical composition comprising a therapeutically
effective amount of Flibanserin 1 and a therapeutically effective
amount of an active ingredient 2.
19. The pharmaceutical composition according to claim 18, wherein
the active ingredient 2 is an antimuscarinic agent 2a, vasopressin
agonist 2b, Serotonin/Noradrenaline modulator 2c, or .beta.3
agonist 2d.
20. The pharmaceutical composition according to claim 19, wherein
the active ingredient 2 is an antimuscarinic agent 2a.
21. The pharmaceutical composition according to claim 20, wherein
the antimuscarinic agent 2a is Tolterodine, Oxybutynin,
Darifenacin, Propiverine, Solifenacin, or Trospium, or a
pharmaceutically acceptable acid addition salt, hydrate, or
solvate.
22. The pharmaceutical composition according to claim 19, wherein
the active ingredient 2 is a vasopressin agonist 2b.
23. The pharmaceutical composition according to claim 22, wherein
the vasopressin agonist 2b is desmopressin, or a pharmaceutically
acceptable acid addition salt, hydrate, or solvate thereof.
24. The pharmaceutical composition according to claim 19, wherein
the active ingredient 2 is one or more, preferably one
Serotonin/Noradrenaline modulator 1c, optionally in combination
with a pharmaceutically acceptable excipient.
25. The pharmaceutical composition according to claim 24, wherein
the Serotonin/Noradrenaline modulator 2c is Venlafaxine,
Duloxetine, Reboxetine, or Cizoliritine, optionally in form of the
or a pharmaceutically acceptable acid addition salt, hydrate, or
solvate thereof.
26. The pharmaceutical composition according to claim 19, wherein
the active ingredient 2 is a .beta.3 agonist 2d.
27. The pharmaceutical composition according to claim 26, wherein
the .beta.3 agonist 2d is AD9677/TAK677, CL 316,243, SB 418790,
L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353,
Trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A, or CGP-12177A, or a
pharmaceutically acceptable acid addition salt, hydrate, or solvate
thereof.
28.-29. (canceled)
Description
[0001] The invention relates to the use of Flibanserin for the
treatment or prevention of urinary incontinence and related
diseases. In a further embodiment, the instant invention is
directed to pharmaceutical combinations comprising flibanserin as
one active ingredient in combination with at least one additional
active ingredient for the treatment or prevention of urinary
incontinence and related diseases.
DESCRIPTION OF THE INVENTION
[0002] The compound
1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-be-
nzimidazol-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-HT1A and
5-HT2-receptor. It is therefore a promising therapeutic agent for
the treatment or prevention of a variety of diseases, for instance
depression, schizophrenia, and anxiety.
[0004] Now, experiments provided evidence, that flibanserin can not
only be used for the aforementioned diseases but also for the
treatment or prevention of urinary incontinence.
[0005] In one embodiment the present invention relates to the use
of a therapeutically effective amount of Flibanserin 1, optionally
in form the free base, the pharmacologically acceptable acid
addition salts and/or optionally in form of the hydrates and/or
solvates thereof for the manufacture of a medicament for the
treatment or prevention of urinary incontinence.
[0006] With regard to the present invention the term "urinary
incontinence" includes stress urinary incontinence, urge urinary
incontinence, urgency, mixed urinary incontinence and overactive
bladder syndrome.
[0007] Urinary Incontinence (UI), as other Lower Urinary Tract
Dysfunctions, can be described as a symptom, as a sign, as an
urodynamic observation or as a condition as a whole. The symptom of
UI is defined as "the complaint of any involuntary leakage of
urine" (Abrams P, Cardozo Neurourol Urodyn 2002; 21:167-178).
[0008] Stress urinary Incontinence (SUI) is defined as the
complaint of involuntary leakage on effort or exertion, or on
sneezing or coughing. It occurs because a positive urethral
pressure gradient over bladder pressure cannot be maintained during
abrupt increases in abdominal pressure. This insufficient urethral
closure pressure can be the consequence of anatomical defects in
the pelvic floor muscles leading to urethral hypermobility,
intrinsic deficiency of the external urethral sphincter or a
combination of both.
[0009] SUI is more prevalent in women than in men. In women
pregnancy, childbirth and parity are the most important inciting
factors. In men SUI is infrequent and mainly referred as a sequale
after prostate surgery (Transurethral Prostate Resection for Benign
Prostate Hyperplasia or Radical Prostatectomy for Prostate Cancer).
Stress Urinary Incontinence is the most common type of UI in women,
with 78% of women presenting with the symptom of SUI in either pure
(49%) or mixed (29%) forms.
[0010] Urge urinary Incontinence (UUI) is defined as the complaint
of involuntary leakage accompanied by or immediately preceded by
urgency. Urgency is the complaint of a sudden compelling desire to
pass urine, which may be difficult to defer.
[0011] Urge urinary incontinence is one of the symptoms which is
categorised under the syndrome of Overactive Bladder (OAB).
According to the ICS definition, OAB is characterised by an
irresistible imperative need to urinate, which may or may not be
associated with urge urinary incontinence, usually with increased
frequency of micturition and nocturnal urination.
Pathophysiologically, this complaint may be based on involuntary
detrusor contractions during the filling phase, the cause of which
may be neurogenic or non-neurogenic (idiopathic) by nature. Urgency
and urge urinary incontinence are extremely unpleasant and
troublesome to those affected, leading to considerable impairment
of their quality of life and psychological, professional, domestic,
physical and sexual problems.
[0012] Mixed urinary incontinence is defined as the complaint of
involuntary leakage associated with urgency and also with exertion,
effort, sneezing or coughing. Again more women are affected than
men.
[0013] In another embodiment the present invention relates to the
use of a therapeutically effective amount of Flibanserin 1,
optionally in form the free base, the pharmacologically acceptable
acid addition salts and/or optionally in form of the hydrates
and/or solvates thereof for the manufacture of a medicament for the
treatment or prevention of overactive bladder syndrome.
[0014] In another embodiment the present invention relates to the
use of a therapeutically effective amount of Flibanserin 1,
optionally in form the free base, the pharmacologically acceptable
acid addition salts and/or optionally in form of the hydrates
and/or solvates thereof for the manufacture of a medicament for the
treatment or prevention of urge urinary incontinence.
[0015] In another embodiment the present invention relates to the
use of a therapeutically effective amount of Flibanserin 1,
optionally in form the free base, the pharmacologically acceptable
acid addition salts and/or optionally in form of the hydrates
and/or solvates thereof for the manufacture of a medicament for the
treatment or prevention of urgency.
[0016] In another embodiment the present invention relates to the
use of a therapeutically effective amount of Flibanserin 1,
optionally in form the free base, the pharmacologically acceptable
acid addition salts and/or optionally in form of the hydrates
and/or solvates thereof for the manufacture of a medicament for the
treatment or prevention of stress urinary incontinence.
[0017] In another embodiment the present invention relates to the
use of a therapeutically effective amount of Flibanserin 1,
optionally in form the free base, the pharmacologically acceptable
acid addition salts and/or optionally in form of the hydrates
and/or solvates thereof for the manufacture of a medicament for the
treatment or prevention of mixed urinary incontinence.
[0018] Another embodiment of the present invention relates to
methods of treating or preventing of any of the aforementioned
disorders, comprising the administration of a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof.
[0019] As Flibanserin 1 can not only be used as a monotherapy but
also in combination with other active ingredients useful for
treatment of urinary incontinence, another embodiment of the
invention relates to new pharmaceutical compositions comprising a
therapeutically effective amount of Flibanserin 1, optionally in
form the free base, the pharmacologically acceptable acid addition
salts and/or optionally in form of the hydrates and/or solvates
thereof, as one active ingredient in combination with a
therapeutically effective amount one or more, preferably one active
ingredient 2 useful for treatment of urinary incontinence.
[0020] The compositions according to the invention may contain
Flibanserin 1 and the one or more additional active ingredient 2 in
a single formulation or in separate formulations (multiple dosage
form). If Flibanserin 1 and the one or more, preferably one active
ingredient 2 are present in separate formulations these separate
formulations may be administered simultaneously or
sequentially.
[0021] In a further embodiment, the present invention is directed
to pharmaceutical compositions comprising a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof, as one
active ingredient in combination with a therapeutically effective
amount of one or more, preferably one active ingredient 2 useful
for treatment of urinary incontinence, wherein 2 is selected from
the group consisting of antimuscarinic agents 2a, vasopressin
agonists 2b, Serotonin/Noradrenaline modulators 2c and .beta.3
agonists 2d.
[0022] In a further embodiment, the present invention is directed
to pharmaceutical compositions comprising a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof, as one
active ingredient in combination with a therapeutically effective
amount of one or more, preferably one antimuscarinic agent 2a,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof and optionally in combination with
a pharmaceutical acceptable excipient. Preferred antimuscarinic
agents 2a include Tolterodine, Oxybutynin, Darifenacin,
Propiverine, Solifenacin and Trospium.
[0023] In a further embodiment, the present invention is directed
to pharmaceutical compositions comprising a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof, as one
active ingredient in combination with a therapeutically effective
amount of one or more, preferably one vasopressin agonist 2b,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof and optionally in combination with
a pharmaceutical acceptable excipient. A preferred vasopressin
agonist 2b is Desmopressin.
[0024] In a further embodiment, the present invention is directed
to pharmaceutical compositions comprising a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof, as one
active ingredient in combination with a therapeutically effective
amount of one or more, preferably one Serotonin/Noradrenaline
modulator 2c, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof and optionally in
combination with a pharmaceutical acceptable excipient. Preferred
Serotonin/Noradrenaline modulators 2c include Venlafaxine,
Duloxetine, Reboxetine and Cizoliritine.
[0025] In a further embodiment, the present invention is directed
to pharmaceutical compositions comprising a therapeutically
effective amount of Flibanserin 1, optionally in form the free
base, the pharmacologically acceptable acid addition salts and/or
optionally in form of the hydrates and/or solvates thereof, as one
active ingredient in combination with a therapeutically effective
amount of one or more, preferably one .beta.3 agonist 2d,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof and optionally in combination with
a pharmaceutical acceptable excipient. Preferred .beta.3 agonists
include AD9677/TAK677, CL 316,243, SB 418790, L-796568, BMS-196085,
BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecanidine, Zeneca
D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]a-
mino]ethyl)phenoxy]-2-methylpropionic acid, BRL37344A and
CGP-12177A
[0026] Flibanserin 1 can optionally be used in form of its
pharmaceutically acceptable acid addition salts. 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.
[0027] The active ingredients 2 which are suitable to be combined
with 1 within the teaching of the instant invention and which are
mentioned hereinbefore may also be capable of forming acid addition
salts with pharmaceutically acceptable acids. Representative salts
include the following: Acetate, Benzenesulfonate, Benzoate,
Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Camsylate,
Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,
Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate,
Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate,
Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate,
Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate,
Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,
Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine
ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate,
Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate,
Teoclate, Tosylate, Triethiodide and Valerate.
[0028] Furthermore, where the compounds 2 carry an acidic moiety,
suitable pharmaceutically acceptable salts 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.
[0029] The compounds 2 may have chiral centers and occur as
racemates, racemic mixtures and as individual diastereomers or
enantiomers with all isomeric forms being included in the present
invention. Therefore, where a compound is chiral, the separate
enantiomers, substantially free of the other, are included within
the scope of the invention. Further included are all mixtures of
the two enantiomers. Also included within the scope of the
invention are polymorphs and hydrates of the compounds of the
instant invention.
[0030] The present invention includes within its scope prodrugs of
the compounds 1 and 2. In general, such prodrugs will be functional
derivatives of the compounds of this invention which are readily
convertible in vivo into the required compound.
[0031] The term "therapeutically effective amount" shall mean that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought by a researcher or clinician.
[0032] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0033] According to the present invention Flibanserin 1 may be
administered as a monotherapy or together with component 2 as a
combination therapy. If Flibanserin 1 is administered in
combination with component 2, 1 and 2 may be administered
separately or together in one pharmaceutical composition. In
addition, the administration of one element of the combination of
the present invention may be prior to, concurrent to, or subsequent
to the administration of the other element of the combination.
[0034] Flibanserin 1 or the elements of the combination of 1 and 2
may be administered by oral, parenteral (e.g., intramuscular,
intraperitoneal, intravenous or subcutaneous injection, or
implant), buccal, nasal, vaginal, rectal, sublingual, or topical
(e.g. ocular eyedrop) routes of administration and may be
formulated, alone or together, in suitable dosage unit formulations
containing conventional non-toxic pharmaceutically acceptable
carriers, adjuvants and vehicles appropriate for each route of
administration.
[0035] The pharmaceutical compositions, dosage forms, kit of parts
for the administration of 1 or 1 and 2 of this invention may
conveniently be presented in dosage unit form and may be prepared
by any of the methods well known in the art of pharmacy. All
methods include the step of bringing the active ingredient into
association with the carrier which is constituted of one or more
accessory ingredients. In general, the pharmaceutical compositions,
dosage forms, kit of parts are prepared by uniformly and intimately
bringing the active ingredients into association with a liquid
carrier or a finely divided solid carrier or both, and then, if
necessary, shaping the product into the desired dosage form. In the
pharmaceutical compositions the active compounds are included in an
amount sufficient to produce the desired pharmacologic effect.
[0036] The pharmaceutical formulations, compositions, dosage forms
or kit of parts containing 1 and/or 2, separately or together, that
are suitable for oral administration may be in the form of discrete
units such as hard or soft capsules, tablets, troches or lozenges,
each containing a predetermined amount of the active ingredients;
in the form of a dispersible powder or granules; in the form of a
solution or a suspension in an aqueous liquid or non-aqueous
liquid; in the form of syrups or elixirs; or in the form of an
oil-in-water emulsion or a water-in-oil emulsion.
[0037] Dosage forms intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical formulations and such compositions.
[0038] The excipients used may be for example, (a) inert diluents
such as mannitol, sorbitol, calcium carbonate, pregelatinized
starch, lactose, calcium phosphate or sodium phosphate; (b)
granulating and disintegrating agents, such as povidone,
copovidone, hydroxypropylmethylcellulose, corn starch, alginic
acid, crospovidone, sodiumstarchglycolate, croscarmellose, or
polacrilin potassium; (c) binding agents such as microcrystalline
cellulose or acacia; and (d) lubricating agents such as magnesium
stearate, stearic acid, fumaric acid or talc.
[0039] In some cases, formulations for oral use may be in the form
of hardgelatin or HPMC capsules wherein the active ingredients 1
and/or 2, separately or together, are mixed with an inert solid
diluent, for example pregelatinized starch, calcium carbonate,
calcium phosphate or kaolin, or dispensed via a pellet formulation.
They may also be in the form of soft gelatin capsules wherein the
active ingredient is mixed with water or an oil medium, for example
peanut oil, liquid paraffin, medium chain triglycerides or olive
oil.
[0040] The tablets, capsules or pellets may be uncoated or they may
be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
delayed action or sustained action over a longer period. For
example, a time delay material such as celluloseacetate phthalate
or hydroxypropylcellulose acetate succinate or sustained release
material such as ethylcellulose or ammoniomethacrylate copolymer
(type B) may be employed.
[0041] 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.
[0042] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Besides such inert diluents, compositions can
also include adjuvants, such as wetting agents, emulsifying and
suspending agents, and sweetening, flavoring, perfuming and
preserving agents.
[0043] Aqueous suspensions normally contain the active materials 1
and/or 2, separately or together, in admixture with excipients
suitable for the manufacture of aqueous suspensions. Such
excipients may be (a) suspending agents such as hydroxy
ethylcellulose, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; (b) dispersing
or wetting agents which may be (b.1) a naturally-occurring
phosphatide such as lecithin, (b.2) a condensation product of an
alkylene oxide with a fatty acid, for example, polyoxyethylene
stearate, (b.3) a condensation product of ethylene oxide with a
long chain aliphatic alcohol, for example
heptadecaethyleneoxycetanol, (b.4) a condensation product of
ethylene oxide with a partial ester derived from a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or (b.5) a
condensation product of ethylene oxide with a partial ester derived
from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0044] The aqueous suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents, such as sucrose or saccharin.
[0045] Oily suspensions may be formulated by suspending the active
ingredients 1 and/or 2, separately or together, in a vegetable oil,
for example arachis oil, olive oil, sesame oil or coconut oil, or
in a mineral oil such as liquid paraffin. The oily suspensions may
contain a thickening agent, for example beeswax, hard paraffin or
cetyl alcohol. Sweetening agents and flavoring agents may be added
to provide a palatable oral preparation. These compositions may be
prepared by the addition of an antioxidant such as ascorbic
acid.
[0046] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient 1 and/or 2, separately or together in admixture with a
dispersing or wetting agent, a suspending agent and one or more
preservatives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those already mentioned above. Additional
excipients, for example, those sweetening, flavoring and coloring
agents described above may also be present.
[0047] The pharmaceutical formulations, compositions, dosage forms
or kit of parts of the invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil such
as olive oil or arachis oils, or a mineral oil such as liquid
paraffin or a mixture thereof.
[0048] Suitable emulsifying agents may be (a) naturally-occurring
gums such as gum acacia and gum tragacanth, (b) naturally-occurring
phosphatides such as soybean and lecithin, (c) esters or partial
esters derived from fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, (d) condensation products of said
partial esters with ethylene oxide, for example polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0049] Syrups and elixirs may be formulated with sweetening agents,
for example, glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a preservative and flavoring and
coloring agents.
[0050] The pharmaceutical formulations, compositions, dosage forms
or kit of parts containing 1 and/or 2, separately or together may
be in the form of a sterile injectable aqueous or oleagenous
suspension or solution. The suspension may be formulated according
to known methods using those suitable dispersing or wetting agents
and suspending agents which have been mentioned above. The sterile
injectable preparation may also be a sterile injectable solution or
suspension in a non toxic parenterally-acceptable diluent or
solvent, for example as a solution in 1,3-butane-diol. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables.
[0051] Preparations according to this invention containing 1 and/or
2, separately or together, for parenteral administration include
sterile aqueous or non-aqueous solutions, suspension, or
emulsions.
[0052] Examples of non-aqueous solvents or vehicles are propylene
glycol, polyethylene glycol, vegetable oils, such as olive oil and
corn oil, gelatin, and injectable organic esters such as ethyl
oleate. Such dosage forms may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents. They may
be sterilized by, for example, filtration through a
bacteria-retaining filter, by incorporating sterilizing agents into
the compositions, by irradiating the compositions, or by heating
the compositions. They can also be manufactured in the form of
sterile solid compositions which can be reconstituted in sterile
water, or some other sterile injectable medium immediately before
use. The combination of this invention may also be administered in
the form of suppositories for rectal administration. This
composition can be prepared by mixing the drugs with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials are cocoa butter, hard
fat, and polyethylene glycols. Compositions for buccal, nasal or
sublingual administration are also prepared with standard
excipients well known in the art.
[0053] For topical administration the formulations, compositions,
dosage forms or kit of parts of this invention containing 1 and/or
2, separately or together may be formulated in liquid or
semi-liquid preparations such as liniments, lotions, applications;
oil-in-water or water-in-oil emulsions such as creams, ointments,
jellies or pastes, including tooth-pastes; or solutions or
suspensions such as drops, and the like.
[0054] The dosage of the active ingredients in the compositions of
this invention may be varied. However, it is necessary that the
amount of Flibanserin 1 for the administration as a monotherapy or
the active ingredients 1 and 2, for the administration as a
combination therapy, be such that a suitable dosage form is
obtained. The selected dosage and the dosage form depend upon the
desired therapeutic effect, on the route of administration and on
the duration of the treatment. Dosage ranges in the combination are
approximately one tenth to one times the clinically effective
ranges required to induce the desired therapeutic effect,
respectively when the compounds are used singly.
[0055] The beneficial effects of Flibanserin 1, optionally in form
the free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
can be observed regardless of whether the disturbance existed
lifelong or was acquired, and independent of etiologic origin
(organic--both, physically and drug induced--, psychogen, a
combination of organic--both, physically and drug induced--, and
psychogen, or unknown).
[0056] Within the instant invention Flibanserin 1 is preferably
administered in such an amount that per single dosage between 5 to
200 mg of Flibanserin 1 are applied. Preferred are ranges of
between 10 to 150 mg, particular preferred 20 to 100 mg of
Flibanserin 1. Suitable dosage forms may contain for instance 20,
25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100
mg of Flibanserin 1. The aforementioned values are based on
Flibanserin 1 in form of the free base. If Flibanserin 1 is applied
in form of one of its acid addition salts, the corresponding values
are readily calculable from the aforementioned values.
[0057] Within the instant invention the antimuscarinic agents 2a
are preferably administered in such an amount that per day between
0.01 to 200 mg are applied. Preferred are ranges of between 0.5 to
100 mg, particular preferred 1 to 50 mg of the antimuscarinic
agents 2a. Suitable dosage forms may contain for instance 0.01,
0.05, 0.5, 1, 2, 5, 10, 20, 25, 50, 100 or 200 mg of the
antimuscarinic agents 2a. Advantageously, the compounds 2a of the
present invention may be administered in a single daily dose, or
the total daily dosage may be administered in divided doses of two,
three or four times daily.
[0058] Within the instant invention the vasopressin agonist 2b are
preferably administered in such an amount that per day between 0.01
to 100 mg are applied. Preferred are ranges of between 0.5 to 100
mg, particular preferred 1 to 50 mg of the vasopressin agonist 2b.
Suitable dosage forms may contain for instance 0.01, 0.05, 0.5, 1,
2, 5, 10, 20, 25, 50 or 100 mg of the vasopressin agonist 2b.
Advantageously, the compounds 2b of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times
daily.
[0059] Within the instant invention the Serotonin/Noradrenaline
modulators 2c are preferably administered in such an amount that
per day between 0.1 to 200 mg are applied. Preferred are ranges of
between 0.5 to 150 mg, particular preferred 1 to 100 mg of the
Serotonin/Noradrenaline modulators 2c. Suitable dosage forms may
contain for instance 0.1, 0.5, 1, 2, 5, 10, 20, 25, 50, 100 or 200
mg of the Serotonin/Noradrenaline modulators 2c. Advantageously,
the compounds 2c of the present invention may be administered in a
single daily dose, or the total daily dosage may be administered in
divided doses of two, three or four times daily.
[0060] Within the instant invention the .beta.3 agonists 2d are
preferably administered in such an amount that per day between 0.01
to 1000 mg are applied. Preferred are ranges of between 0.1 to 500
mg, particular preferred 1 to 200 mg of the .beta.3 agonists 2d.
Suitable dosage forms may contain for instance 0.1, 0.5, 1, 2, 5,
10, 20, 25, 50, 100 or 200 mg of the .beta.3 agonists.
Advantageously, the compounds 2d of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times
daily.
[0061] In another embodiment the invention relates to a method for
the treatment or prevention of urinary incontinence, comprising the
administration of a therapeutically effective amount of Flibanserin
1, optionally in form the free base, the pharmacologically
acceptable acid addition salts and/or optionally in form of the
hydrates and/or solvates thereof, in combination with a
therapeutically effective amount of one or more, preferably one
active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0062] In another embodiment the invention relates to a method for
the treatment or prevention of overactive bladder syndrome,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0063] In another embodiment the invention relates to a method for
the treatment or prevention of urge urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0064] In another embodiment the invention relates to a method for
the treatment or prevention of urgency, comprising the
administration of a therapeutically effective amount of Flibanserin
1, optionally in form the free base, the pharmacologically
acceptable acid addition salts and/or optionally in form of the
hydrates and/or solvates thereof, in combination with a
therapeutically effective amount of one or more, preferably one
active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0065] In another embodiment the invention relates to a method for
the treatment or prevention of stress urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0066] In another embodiment the invention relates to a method for
the treatment or prevention of mixed urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one active ingredient 2, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0067] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one active ingredient 2, optionally
in form of the pharmaceutically acceptable salts, in form of the
hydrates and/or solvates and optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates thereof, for the manufacture of a medicament for the
treatment of any of the aforementioned disorders.
[0068] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of any of the
aforementioned disorders in combination with one or more,
preferably one active ingredient 2, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof.
[0069] In another embodiment the invention relates to a method for
the treatment or prevention of one of the aforementioned diseases
selected from the group consisting of urinary incontinence,
overactive bladder syndrome, urge urinary incontinence, urgency,
stress urinary incontinence and mixed urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one antimuscarinic agents 2a, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof, separately or together within one pharmaceutical
composition. Preferred antimuscarinic agents 2a include
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin and
Trospium.
[0070] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one antimuscarinic agent 2a,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof, for the manufacture of a
medicament for the treatment of any of the aforementioned
disorders. Preferred antimuscarinic agents 2a include Tolterodine,
Oxybutynin, Darifenacin, Propiverine, Solifenacin and Trospium.
[0071] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of any of the
aforementioned disorders in combination with one or more,
preferably one antimuscarinic agent 2a, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof. Preferred antimuscarinic agents 2a include Tolterodine,
Oxybutynin, Darifenacin, Propiverine, Solifenacin and Trospium.
[0072] In another embodiment the invention relates to a method for
the treatment or prevention of one of the aforementioned diseases
selected from the group consisting of urinary incontinence,
overactive bladder syndrome, urge urinary incontinence, urgency,
stress urinary incontinence and mixed urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one vasopressin agonist 2b, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof, separately or together within one pharmaceutical
composition. A preferred vasopressin agonist 2b is
Desmopressin.
[0073] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one vasopressin agonist 2b,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof, for the manufacture of a
medicament for the treatment of any of the aforementioned
disorders. A preferred vasopressin agonist 2b is Desmopressin.
[0074] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of any of the
aforementioned disorders in combination with one or more,
preferably one vasopressin agonist 2b, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof. A preferred vasopressin agonist 2b is Desmopressin.
[0075] In another embodiment the invention relates to a method for
the treatment or prevention of one of the aforementioned diseases
selected from the group consisting of urinary incontinence,
overactive bladder syndrome, urge urinary incontinence, urgency,
stress urinary incontinence and mixed urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one Serotonin/Noradrenaline modulator 2c, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof, separately or together within one pharmaceutical
composition. Preferred Serotonin/Noradrenaline modulators 2c
include Venlafaxine, Duloxetine, Reboxetine and Cizoliritine.
[0076] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one Serotonin/Noradrenaline
modulator 2c, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof, for the manufacture of
a medicament for the treatment of any of the aforementioned
disorders. Preferred Serotonin/Noradrenaline modulators 2c include
Venlafaxine, Duloxetine, Reboxetine and Cizoliritine.
[0077] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of any of the
aforementioned disorders in combination with one or more,
preferably one Serotonin/Noradrenaline modulator 2c, optionally in
form of the pharmaceutically acceptable salts, in form of the
hydrates and/or solvates and optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates thereof. Preferred Serotonin/Nor-adrenaline modulators
2c include Venlafaxine, Duloxetine, Reboxetine and
Cizoliritine.
[0078] In another embodiment the invention relates to a method for
the treatment or prevention of one of the aforementioned diseases
selected from the group consisting of urinary incontinence,
overactive bladder syndrome, urge urinary incontinence, urgency,
stress urinary incontinence and mixed urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one .beta.3 agonist 2d, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition. Preferred .beta.3
agonists 2d include AD9677/TAK677, CL 316,243, SB 418790, L-796568,
BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecanidine,
Zeneca D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A.
[0079] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one .beta.3 agonist 2d, optionally
in form of the pharmaceutically acceptable salts, in form of the
hydrates and/or solvates and optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates thereof, for the manufacture of a medicament for the
treatment of any of the aforementioned disorders. Preferred .beta.3
agonists 2d include AD9677/TAK677, CL 316,243, SB 418790, L-796568,
BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecanidine,
Zeneca D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A.
[0080] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of any of the
aforementioned disorders in combination with one or more,
preferably one .beta.3 agonist 2d, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof. Preferred .beta.3 agonists 2d include AD9677/TAK677, CL
316,243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A,
BTA-243, GW 427353, Trecanidine, Zeneca D7114, SR 59119,
solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A.
[0081] In a preferred embodiment the invention relates to a method
for the treatment or prevention of overactive bladder syndrome,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one antimuscarinic agents 2a, selected from the group consisting of
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin and
Trospium, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof, separately or together
within one pharmaceutical composition.
[0082] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one antimuscarinic agent 2a,
selected from the group consisting of Tolterodine, Oxybutynin,
Darifenacin, Propiverine, Solifenacin and Trospium, optionally in
form of the pharmaceutically acceptable salts, in form of the
hydrates and/or solvates and optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates thereof, for the manufacture of a medicament for the
treatment of the overactive bladder syndrome.
[0083] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of overactive bladder
syndrome in combination with one or more, preferably one
antimuscarinic agent 2a, selected from the group consisting of
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin and
Trospium, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof.
[0084] In a preferred embodiment the invention relates to a method
for the treatment or prevention of urge urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one antimuscarinic agents 2a, selected from the group consisting of
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin and
Trospium, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof, separately or together
within one pharmaceutical composition.
[0085] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one antimuscarinic agent 2a,
selected from the group consisting of Tolterodine, Oxybutynin,
Darifenacin, Propiverine, Solifenacin and Trospium, optionally in
form of the pharmaceutically acceptable salts, in form of the
hydrates and/or solvates and optionally in the form of the
individual optical isomers, mixtures of the individual enantiomers
or racemates thereof, for the manufacture of a medicament for the
treatment of urge urinary incontinence.
[0086] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of urge urinary
incontinence in combination with one or more, preferably one
antimuscarinic agent 2a, selected from the group consisting of
Tolterodine, Oxybutynin, Darifenacin, Propiverine, Solifenacin and
Trospium, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof.
[0087] In a preferred embodiment the invention relates to a method
for the treatment or prevention of overactive bladder syndrome,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of the vasopressin agonist
2b Desmopressin, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0088] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of the vasopressin agonist 2b Desmopressin, optionally in form
of the pharmaceutically acceptable salts, in form of the hydrates
and/or solvates and optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates thereof, for the manufacture of a medicament for the
treatment of the overactive bladder syndrome.
[0089] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of the overactive
bladder syndrome in combination with the vasopressin agonist 2b
Desmopressin, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof.
[0090] In a preferred embodiment the invention relates to a method
for the treatment or prevention of urge urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of the vasopressin agonist
2b Desmopressin, optionally in form of the pharmaceutically
acceptable salts, in form of the hydrates and/or solvates and
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates thereof, separately or
together within one pharmaceutical composition.
[0091] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of the vasopressin agonist 2b Desmopressin, optionally in form
of the pharmaceutically acceptable salts, in form of the hydrates
and/or solvates and optionally in the form of the individual
optical isomers, mixtures of the individual enantiomers or
racemates thereof, for the manufacture of a medicament for the
treatment of urge urinary incontinence.
[0092] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of urge urinary
incontinence in combination with the vasopressin agonist 2b
Desmopressin, optionally in form of the pharmaceutically acceptable
salts, in form of the hydrates and/or solvates and optionally in
the form of the individual optical isomers, mixtures of the
individual enantiomers or racemates thereof.
[0093] In a preferred embodiment the invention relates to a method
for the treatment or prevention of stress urinary incontinence,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one Serotonin/Noradrenaline modulator 2c, selected from the group
consisting of Venlafaxine, Duloxetine, Reboxetine and Cizoliritine,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof, separately or together within one
pharmaceutical composition.
[0094] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one Serotonin/Noradrenaline
modulator 2c, selected from the group consisting of Venlafaxine,
Duloxetine, Reboxetine and Cizoliritine, optionally in form of the
pharmaceutically acceptable salts, in form of the hydrates and/or
solvates and optionally in the form of the individual optical
isomers, mixtures of the individual enantiomers or racemates
thereof, for the manufacture of a medicament for the treatment of
stress urinary incontinence.
[0095] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of stress urinary
incontinence in combination with of one or more, preferably one
Serotonin/Noradrenaline modulator 2c, selected from the group
consisting of Venlafaxine, Duloxetine, Reboxetine and Cizoliritine,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0096] In a preferred embodiment the invention relates to a method
for the treatment or prevention of overactive bladder syndrome,
comprising the administration of a therapeutically effective amount
of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, in combination
with a therapeutically effective amount of one or more, preferably
one .beta.3 agonist 2d, selected from the group consisting of
AD9677/TAK677, CL 316,243, SB 418790, L-796568, BMS-196085,
BRL-35135A, CGP12177A, BTA-243, GW 427353, Trecanidine, Zeneca
D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof, separately or together within one
pharmaceutical composition.
[0097] Another embodiment of the present invention relates to the
use of the combinations of Flibanserin 1, optionally in form the
free base, the pharmacologically acceptable acid addition salts
and/or optionally in form of the hydrates and/or solvates thereof,
and of one or more, preferably one .beta.3 agonist 2d, selected
from the group consisting of AD9677/TAK677, CL 316,243, SB 418790,
L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353,
Trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof, for the manufacture of a
medicament for the treatment of the overactive bladder
syndrome.
[0098] Another embodiment of the present invention relates to the
use of Flibanserin 1, optionally in form the free base, the
pharmacologically acceptable acid addition salts and/or optionally
in form of the hydrates and/or solvates thereof, for the
manufacture of a medicament for the treatment of overactive bladder
syndrome in combination with one or more, preferably one .beta.3
agonist 2d, selected from the group consisting of AD9677/TAK677, CL
316,243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A,
BTA-243, GW 427353, Trecanidine, Zeneca D7114, SR 59119,
solabegron, CL616243,
2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-
)phenoxy]-2-methylpropionic acid, BRL37344A and CGP-12177A,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0099] The Examples which follow illustrate the present invention
without restricting its scope:
Examples of Pharmaceutical Formulations
TABLE-US-00001 [0100] A) Tablets per tablet Flibanserin 100 mg
lactose 240 mg corn starch 340 mg polyvinylpyrrolidone 45 mg
magnesium stearate 15 mg 740 mg
[0101] 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.
TABLE-US-00002 B) Tablets per tablet Flibanserin 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
[0102] 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.
TABLE-US-00003 C) Coated tablets per coated tablet Flibanserin 5 mg
corn starch 41.5 mg.sup. lactose 30 mg polyvinylpyrrolidone 3 mg
magnesium stearate 0.5 mg 80 mg
[0103] 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.
TABLE-US-00004 D) Capsules per capsule Flibanserin 1 50 mg Corn
starch 268.5 mg.sup. Magnesium stearate 1.5 mg 420 mg
[0104] 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.
TABLE-US-00005 E) Ampoule solution Flibanserin 50 mg sodium
chloride 50 mg water for inj. 5 ml
[0105] 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.
TABLE-US-00006 F) Suppositories Flibanserin 50 mg solid fat 1650 mg
1700 mg
[0106] 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.
TABLE-US-00007 G) Film coated tablet: Combination of Flibanserin
with 2a Constituents mg/tablet Core Flibanserin 50.000 Tolterodine
70.225 Anhydrous dibasic calcium phosphate 100.000 Microcrystalline
cellulose 203.090 HPMC (Methocel E5) 6.615 Croscarmellose sodium
8.820 Magnesium stearate 2.250 Coating HPMC (Methocel E5) 4.320
Polyethylene Glycol 6000 1.260 Titanium dioxide 1.800 Talc 1.542
Iron oxide red 0.078 Total Film coated tablet 450.000
TABLE-US-00008 H) Film coated tablet: Combination of Flibanserin
with 2b Constituents mg/tablet Core Flibanserin 50.000 Desmopressin
10.000 Lactose monohydrate 133.750 Microcrystalline cellulose
40.000 Hydroxypropylcellulose 2.500 Corn starch 12.500 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 yellow 0.043 Total Film coated tablet 255.000
TABLE-US-00009 I) Film coated bilayer tablet: Combination of
Flibanserin with 2c Constituents mg/tablet Core Flibanserin 50.000
Duloxetine 24.000 Lactose monohydrate 143.490 Microcrystalline
cellulose 47.810 HPMC (e.g. Pharmacoat 606) 2.500
Carboxymethylcellulose sodium 5.000 Mannitol 60.000 Corn starch
36.500 Povidone 1.000 Colloidal silicon dioxide 1.000 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 bilayer tablet 380.000
* * * * *