Note: Descriptions are shown in the official language in which they were submitted.
1.
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Medicament with delayed active constituent release
containing 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of
The present invention relates to a pharmaceutical
formulation with delayed active constituent release that
contains 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of or one of its pharmaceutically acceptable
salts in a matrix.
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of is
known from EP 0 693 475 B1 as an analgesically active
medicament and may be administered orally. The usual
formulations for oral administration of 1-dimethylamino-3-
(3-methoxyphenyl)-2-methylpentan-3-of lead to a rapid
release of the active constituent in the gastrointestinal
tract, resulting in a rapid onset of the analgesic effect.
At the same time it is observed that the effect rapidly
wears off. Accordingly the treatment of severe chronic
pain using 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of has hitherto required the medicament to
be administered at relatively short intervals, for example
4 to 6 times a day, in order thereby to ensure a sufficient
concentration of active constituent in the patient's blood
plasma. The necessity of a frequent dosage easily leads
however to mistakes in administration of the medicament as
well as to undesired plasma concentration fluctuations,
which has a deleterious effect as regards patient
compliance and therapeutic usefulness, especially in the
treatment of chronic pain conditions. A pharmaceutical
application form with delayed release (retard formulation)
for oral administration of the active constituent 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of is
therefore desirable.
' r .,
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In the prior art retard formulations are generally known
for a large number of various active constituents.
Conventional retard forms include, inter alia, coated
retard forms and matrix retard forms.
In the case of coated retard forms such as are described
for example in DE 36 25 456 A1, the core of a
pharmaceutical composition containing an active constituent
is provided with a coating of one or more hydrophilic
and/or hydrophobic polymers that delays the release of the
active constituent.
In matrix retard forms the active constituent is contained
in a matrix formed from one or more carrier materials,
which controls the release of the active constituent. Thus
for example, DE 33 09 516 A1 discloses a process for the
production of matrix formulations with hydroxypropylmethyl-
cellulose (HPMC) as carrier material and to some extent a
delayed release of the active constituent, wherein the
active material does not comprise more than one third of
the weight of the formulation and consists of at least one
hydroxypropylmethylcellulose that has a methoxy content of
16-24 wt.%, an hydroxypropyl content of 4-32 wt.% and a
number average molecular weight of at least 50,000. The
formulations disclosed in DE 33 09 516 A1 contain HPMCs
with viscosities (in 2 wt.% aqueous solution at 20°C)
between 15 and 30,000 cPs (15 to 30,000 mPa~s). A release
behaviour independent of the pH value of the dissolution
medium is not disclosed in DE 33 09 516 A1.
An object of the present invention is accordingly to
provide a pharmaceutical formulation with delayed active
V11~ 03/099267 CA 02488220 2004-11-26 pCT/~P03/05488
3
constituent release containing 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-ol.
This object is achieved by a pharmaceutical formulation
with delayed release that contains 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of or a pharmaceutically
acceptable salt thereof in a matrix with delayed release of
active constituent, wherein the matrix contains 1 to
80 wt.%, preferably 5 to 80 wt.%, of one or more
hydrophilic or hydrophobic polymers as pharmaceutically
acceptable matrix-forming agents, and has the following in
vitro release rate measured using the Ph. Eur. paddle
method at 75 rpm in a buffer (according to Ph. Eur.) at a
pH value of 6.8 at 37°C and with UV spectrometric
detection:
3-35 wt.% of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of (referred to 100 wt.% of active
constituent) released after 0.5 hour,
5-50 wt.% of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of released after 1 hour
10-75 wt.% of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of released after 2 hours
15-82 wt.% of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of released after 3 hours
30-97 wt.% of 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of released after 6 hours
more than 50 wt.% of 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of released after 12
hours,
more than 70 wt.% of 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of released after 18
hours,
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more than 80 wt.% of 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of released after 24
hours.
It has surprisingly been found that the formulation
according to the invention provides for the delayed release
of the active constituent 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of when administered orally
and is thus suitable for administration at intervals of at
least 12 hours. The formulation according to the invention
accordingly provides a treatment for pain as. well as a
treatment for increased urinary urgency or urinary
incontinence, in particular urgency incontinence and stress
incontinence, in connection with which 1-dimethylamino-3-
(3-methoxyphenyl)-2-methylpentan-3-of need be administered
only once daily, for example at intervals of 24 hours, or
twice daily, for example at intervals of 12 hours, in order
to ensure a sufficient plasma concentration of the active
constituent. A corresponding effect duration and the
maintenance of a sufficient blood plasma level is confirmed
by simulation studies and experimental investigations.
It is particularly surprising in this connection that the
formulation according to the invention not only guarantees,
due to the delayed release, a long-lasting therapeutic
effectiveness over a relatively long period (at least 12
hours), but at the same time on first administration of the
medicament permits a rapid build up of the active
constituent in the plasma, which leads to a rapid pain
relief in the patient (rapid onset effect). Thus, on
administration of the formulation according to the
invention to a patient suffering pain, the pain can be
rapidly alleviated without the analgesic effect also
rapidly attenuating. The formulation according to the
f ' r
WO 03/099267 CA 02488220 2004-11-26 pCT/gP03/05488
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invention thus combines properties of a formulation with
immediate release of active constituent - rapid relief of
pain due to sufficiently high active substance
concentration shortly after administration of the
medicament - with properties of a formulation with delayed
release - long-lasting analgesic effect on account of a
sufficiently high active constituent level over a prolonged
time. The patient suffering from pain can thus effectively
alleviate his/her pain by taking the analgesic in the
formulation according to the invention and at the same time
can, without further measures and simply by regular
administration of the medicament at intervals of 12 (or 24)
hours, effectively relieve the pain for a relatively long
period.
It is also convenient that, due to the constant and
sufficiently high active constituent level of the 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of
compound over a fairly long time that is achieved by the
formulations and at the same time without further measures
and simply by administration at intervals of 12 (or 24)
hours, it is possible effectively to treat, alleviate or
relieve over a relatively long time increased urinary
urgency or urinary incontinence, in particular urgency
incontinence and stress incontinence.
The active constituent of the formulation according to the
invention is contained in a matrix with delayed release.
It is however also conceivable for the active constituent
to be contained in a matrix exhibiting a conventional
release behaviour and to achieve the delayed release by a
retard coating.
.r . ,
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In the case where the formulation according to the
invention contains a matrix with delayed release, the
matrix comprises 1-80 wt.% of one or more hydrophilic or
hydrophobic polymers as pharmaceutically acceptable matrix-
forming agents, for example gums, cellulose ethers,
cellulose esters, acrylic resins, materials derived from
proteins, fats, waxes, fatty alcohols or fatty acid esters.
When using hydrophilic polymers as matrix-forming agent it
is preferred that the matrix contains 5 to 80 wt.% of
matrix-forming agent.
The present invention also provides a pharmaceutical
formulation that contains 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of or a pharmaceutically
acceptable salt thereof in a matrix with delayed active
constituent release, the matrix containing 1 to 80 wt.%, in
particular 5 to 80 wt.%, of one or more hydrophilic or
hydrophobic polymers as pharmaceutically acceptable matrix-
forming agent, and which is characterised in that it
comprises as pharmaceutically acceptable matrix-forming
agent cellulose ethers and/or cellulose esters that have a
viscosity of 3000 to 150,000 mPa~s in a 2 wt.% aqueous
solution at 20°C. (The viscosity determination is carried
out by means of capillary viscosimetry according to Pharm.
Eu.) The compositions have the release profile according
to the invention specified above.
Preferably cellulose ethers and/or cellulose esters that in
a 2 wt.% aqueous solution at 20°C have a viscosity between
10,000 mPa~s, in particular 50,000 mPa~s, and 150,000 mPa-s,
are used as pharmaceutically acceptable matrix-forming
agents.
.. ,
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Particularly suitable pharmaceutically acceptable matrix-
forming agents are selected from the group comprising
hydroxypropylmethylcelluloses (HPMC),
hydroxyethylcelluloses, hydroxypropylcelluloses (HPC),
methylcelluloses, ethylcelluloses and
carboxymethylcelluloses, and in particular are selected
from the group comprising HPMCs, hydroxyethylcelluloses and
HPCs. Most particularly preferred are HPMCs with a
viscosity of ca. 100,000 mPa.s measured in a 2 wt.% aqueous
solution at 20°C.
The active constituent 1-dimethylamino-3-(3-methoxyphenyl)-
2-methylpentan-3-of may be present as such, i,e. as free
base, but may also be present in the form of a
pharmaceutically acceptable salt, for example as the
hydrochloride. The preparation of the free base is known
from EP 0 693 475 A1. Insofar as the preparation of
pharmaceutically acceptable salts - such as the
hydrochloride - is also not disclosed in EP 0 693 475 A1,
these may be obtained from the free base by means of
methods generally known in the prior art.
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-o1 has
two asymmetry centres, with the result that the compound
may be present in the form of four different stereoisomers.
In the formulation according to the invention 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of may
be present as a mixture of all four diastereomers in an
arbitrary mixture ratio, but also as a mixture of two or
three of the four stereoisomers, or in stereoisomer-pure
form. Preferred stereoisomers are in this connection (+)-
(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-
3-0l and (-)-(1S,2S)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-ol, which may be present in the formulation
f .
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according to the invention as a mixture, in particular as a
1:1 mixture (racemate), or particularly preferably in
isomer-pure form. The term "active constituent" is
therefore understood for the purposes of the present
invention to denote 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of compound as a mixture of various of its
stereoisomers or as one of its pure stereoisomers, in each
case as a free base or in the form of a pharmaceutically
acceptable salt.
In the medicaments according to the invention the content
of delayed release active constituent is preferably between
0.5 and 85 wt.% and the content of pharmaceutically
acceptable matrix-forming agent is between 8 and 40 wt.%.
Particularly preferred are medicaments with a content of
delayed release active constituent of between 3 and
70 wt.%, in particular between 8 and 66 wt.%, and a content
of pharmaceutically acceptable matrix-forming agent of
between 10 and 35 wt.%, in particular between 10 and
30 wt.%. If the enantiomer-pure (+)-(2R,3R)-1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of (or a
mixture of the (+) and (-) enantiomers with a large excess
of the (+) enantiomer) is used as active constituent, it is
particularly preferred if the content of active constituent
is at the lower level, i.e. is between 0.5 and 25 wt.%
(referred to the total weight). If the enantiomer-pure
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of (or a mixture of the (+) and (-)
enantiomers with a large excess of the (-) enantiomer) is
used as active constituent, it is particularly preferred if
the content of active constituent is between 16 and
66 wt.%.
WO 03/099267 CA 02488220 2004-11-26 p~T/gP03/05488
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Further constituents of the matrix of the formulation
according to the invention may optionally include
digestible long-chain (i.e. with 8 to 50 C atoms,
preferably 12 to 40 C atoms) unsubstituted or substituted
hydrocarbons, such as for example fatty alcohols, fatty
acid glyceryl esters, mineral oils and vegetable oils, as
well as waxes, hydrocarbons with a melting point between
25° and 90°C being preferred. In particular fatty alcohols
are preferred, most particularly preferred being lauryl
alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol
and cetylstearyl alcohol. Their content in the matrix is
0 to 60 wt.%. Alternatively or in addition polyethylene
glycols may also be contained in the matrix in an amount of
0 to 60 wt.%.
The pharmaceutical formulations according to the invention
may in addition contain as further constituents
pharmaceutically conventioral s.uxiliary substances such as
fillers, for example lactose, microcrystalline cellulose
(MCC) or calcium hydrogen phosphate, as well as slip
agents, intestinal lubricants and flow regulating agents,
for example talcum, magnesium stearate, stearic acid and/or
highly dispersed silicon dioxide, whose total weight in the
tablet is between 0 and 80 wt.%, preferably between 5 and
65 wt.%.
In many cases the release rate of an active constituent
from an application form depends on the pH of the release
medium. This may vary in a pH range from below 1 to
about 8 during passage of the medicament through the
gastrointestinal tract. These variations may differ from
person to person taking the medicament. Also, there may be
a different pH value/time profile during passage through
the gastrointestinal tract in one and the same person from
1 1
WO 03/099267 CA 02488220 2004-11-26 pCT/gP03/05488
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one administration to the next. If the release rate of the
active constituent from the medicament depends on the pH,
this can lead to different release rates in vivo and thus
to different bioavailability behaviours. The release
profiles of the active constituent (in the form of the base
or one of its pharmaceutically acceptable salts) from a
pharmaceutical formulation according to the invention are
however surprisingly independent of the pH value, such as
may physiologically occur during passage through the
gastrointestinal tract. The release profiles at an ambient
pH value of 1.2, 4.0 and 6.8 are identical to one another
and also when compared to the release during a pH
value/time profile from pH 1.2 through pH 2.3 and pH 6.8 up
to pH 7.2.
It has been found that for achieving the delayed release of
active constituent from the formulation according to the
invention, preferably present in tablet form, it is
immaterial whether, under otherwise identical dimensions
and identical composition of the tablet as regards the
active constituent, the matrix-forming agent and the
optional constituents, a water-soluble filler, for example
lactose, is used as filler, or an insoluble filler that
does not swell in the aqueous medium, for example calcium
hydrogen phosphate, is used as filler, or an insoluble
filler that swells in aqueous medium, for example
microcrystalline cellulose, is used as filler. All such
medicaments exhibit a release behaviour corresponding to
one another.
It is furthermore surprising that in the compositions
according to the invention, for a given amount of active
constituent the amount of matrix-forming agent and the
amount of optional constituents may in each case vary over
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a relatively large range without the therapeutic
effectiveness of at least 12 hourly or twice daily
administration being compromised (as long as the
quantitative limits for active constituent, matrix-forming
agent and the further, optional constituents are
maintained). An effectiveness of at least 12 hours is
ensured for example with a content of active constituent of
ca. 32.25 wt.% (referred to the weight of the total
composition) in a composition comprising ca. 12.9 wt.% of
HPMC with a viscosity of 100,000 mPa~s as matrix-forming
agent and a content of for example MCC as filler of ca.
52.6 wt.%, as well as in a composition comprising ca.
25.8 wt.% of the same HPMC and ca. 39.7 wt.% of MCC (or
lactose monohydrate) with otherwise the same amounts of
slip agent, intestinal lubricant and flow regulating agent.
The same also applies to compositions according to the
invention with a higher or lower content of active
constituent within the specified limits.
Also extremely surprising is the observation that when
administering the pharmaceutical formulations according to
the invention with delayed release of active constituent to
human experimental subjects, despite the high first-pass
effect for the active constituent an unaltered
bioavailability is achieved, contrary to expectations,
compared to formulations with immediate release of active
constituent.
Those compositions according to the invention are
furthermore preferred whose tmax value in the plasma
concentrationitime diagram in vivo is between 2 and 10
hours, in particular between 3.5 and 6 hours and most
particularly preferably between 4 and 5.5 hours after oral
WO 03/099267 CA 02488220 2004-11-26 p~T/gP03/05488
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administration of the composition, i.e. whose peak plasma
level occurs in the aforementioned timeframes.
The formulation according to the invention contains the
active constituent 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of as such and/or as a pharmaceutically
acceptable salt in an amount of normally 2.5 to 800 mg, in
particular 5 to 400 mg, most particularly preferably 10 to
250 mg (weight of the active constituent 1-dimethylamino-3-
(3-methoxyphenyl)-2-methylpentan-3-of as hydrochloride) per
dosage unit, wherein the release behaviour of the
formulation according to the invention is not influenced by
the exact amount of the active constituent as long as the
quantitative limits specified above are maintained. It is
preferred if the more active (+)-(2R,3R)-1-dimethylamino-3-
(3-methoxyphenyl)-2-methylpentan-3-of is present in an
amount of 2.5 to 80 mg, in particular 5 to 40 mg and most
particularly preferably in an amount of 10 to 25 mg of
active constituent (referred to the hydrochloride) in the
formulations according to the invention, and specifically
with the proviso that the quantitative limits specified
above are maintained.
Pharmaceutically acceptable (or tolerable) salts of the
active constituent are, within the context of the present
invention, those salts of the active constituent that are
physiologically compatible in pharmaceutical use, in
particular for use in mammals and/or humans. Such
pharmaceutically acceptable salts may be formed for example
with inorganic or organic acids.
The pharmaceutical formulations according to the invention
may exist in the form of simple tablets as well as coated
tablets, for example as film tablets or sugar-coated
WO 03/099267 CA 02488220 2004-11-26 p~/$pp3 j05488
13
tablets. Usually the tablets are round and biconvex;
oblong tablet shapes that allow the tablet to be divided
are also possible. Furthermore granules, spheroids,
pellets or microcapsules are also possible, which may be
packed in sachets or capsules or compressed into
dispersible tablets.
one or more coating layers may be used for the coated
tablets. Suitable as coating material are known
hydroxypropylmethylcelluloses with a low viscosity of ca. 1
to 100 mPa~s and low molecular weight of <10,000 (e. g.
Pharmacoat 606 with a viscosity of 6 mPa~s in a 2 wt.%
aqueous solution at 20°C), which only slightly affect the
release profile of the medicaments according to the
invention. Diffusion coatings known to the person skilled
in the art, for example based on swellable but water-
insoluble poly(meth)acrylates, lead to a modulation of the
delay of the release of active constituent from
pharmaceutical formulations according to the invention.
The tablet core containing the active constituent and
releasing the latter in a delayed manner, with an active
constituent content preferably between 0.5 and 85 wt.%,
particularly preferably between 3 and 70 wt.% and most
particularly preferably between 8 and 66 wt.%, may be
coated by various methods known to the person skilled in
the arts for example sugar coating, spraying from solutions
or suspensions or by powder application methods, with
additional active constituent that is not released in a
delayed manner like the initial dose, although this is not
absolutely necessary for the desired delayed release with
simultaneous rapid build up of the active constituent for
the rapid relief of pain on first administration of the
pharmaceutical formulation according to the invention.
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Further modifications include multilayer tablets and
laminated tablets, in which 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of or one of its
pharmaceutically acceptable salts in one or more layers of
the multilayer tablet with a content of active constituent
preferably between 0.5 and 85 wt.%, particularly preferably
between 3 and 70 wt.% and most particularly preferably
between 8 and 66 wt.%, and in the core of the laminated
tablet with a content of active constituent preferably
between 0.5 and 85 wt.%, particularly preferably between 3
and 70 wt.% and most particularly preferably between 8 and
66 wt.%, is released in a delayed manner by a
pharmaceutically acceptable matrix-forming agent, and the
release of the active constituents in one or more layers of
the multilayer tablet or the outer lamination layer of the
laminated tablets takes place in an unretarded manner.
Multilayer tablets and laminated tablets may contain one or
more coatings free of active constituent.
Instead of a retard matrix it is also possible to use in
the pharmaceutical formulation with delayed release a
normal release matrix with a coating that delays the
release of the active constituent. In this connection the
active constituent may for example be contained in a
conventional matrix of microcrystalline cellulose and
optionally further pharmaceutical auxiliary substances such
as binders, fillers, slip agents, intestinal lubricants and
flow regulating agents, which are coated or covered with a
material that controls the delayed release of the active
constituent in aqueous medium. Suitable coating agents are
for example water-insoluble waxes and polymers such a5
polymethacrylates (Eudragit or the like) or water-insoluble
celluloses, in particular ethyl cellulose. Optionally the
coating material may also contain water-soluble polymers
WO 03/099267 CA 02488220 2004-11-26 peT/EP03/05488
such as polyvinylpyrrolidone, water-soluble celluloses such
as hydroxypropylmethylcellulose or hydroxypropylcellulose,
other water-soluble agents such as Polysorbate 80, or
hydrophilic pore-forming agents such as polyethylene
5 glycol, lactose or mannitol.
The compositions according to the invention may for example
be produced by the following general methods:
10 the constituents of the composition (active constituent,
matrix-forming agent and optional constituents) are weighed
out in turn and then screened on a conventional screening
machine. The Quadro Comil U10 screening machine may for
example be used for this purpose, a normal screen size
15 being ca. 0.813 mm. The screened material is then mixed in
a container mixer, for example in a Bohle container mixer,
under the following typical operating conditions: duration
ca. 15 minutes ~ 45 sec. at a rotational speed of
~ 1 rpm. The powder mixture that is obtained is then
20 compressed into tablets in a pelletising machine. A Korsch
EKO pelletising machine with a round 10 mm diameter stamp
having the contour of sugar-coated pills may for example be
used for this purpose. Alternatively a compaction of the
powder mixture and subsequent screening (Comil 3 mm
friction slicing screen followed by 1.2 mm round hole
screen) of the mouldings may be carried out, wherein the
resultant granules are then compressed as described above
with the addition of lubricant (e.g. magnesium stearate) on
for example an EKO pelletising machine with 10 mm round
stamps. The granulation may also be carried out by wet
granulation based on aqueous or organic solvents; aqueous
solvents with or without suitable binders are preferred.
The production process may be adapted without any
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difficulty to the respective requirements and to the
desired application form according to procedures that are
well known in the prior art.
The production of pharmaceutical formulations according to
the invention is characterised by a high reproducibility of
the release properties of the resultant compositions that
contain 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-
3-0l or one of its pharmaceutically acceptable salts. The
release profile of medicaments according to the invention
was found to be stable over a storage time of at least one
year under the conventional storage conditions according to
the ICH Q1AR Stability Testing Guideline.
A single or double daily administration of a pharmaceutical
formulation according to the invention to the patient
ensures a good therapeutic effectiveness not only in
chronically severe pain but also a good therapeutic
effectiveness in the treatment of increased urinary urgency
or urinary incontinence, in particular stress incontinence
and urgency incontinence.
Accordingly, the present invention also provides for the
use of a pharmaceutical formulation according to the
invention or a tablet according to the invention for the
production of a medicament for treating pain, in particular
chronic, visceral, neuropathic or acute pain or
inflammation pain.
The invention furthermore provides for the use of 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of for
the production of a medicament for treating pain, in
particular chronic, visceral, neuropathic or acute pain or
inflammation pain, in which 1-dimethylamino-3-(3-
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methoxyphenyl)-2-methylpentan-3-of is contained in a
pharmaceutical formulation according to the invention.
A further object of the present invention was to discover
substances or pharmaceutical formulations or medicaments
that are helpful in the treatment of increased urinary
urgency or urinary incontinence, and that in particular
release effective doses that exhibit fewer side effects
and/or analgesic effects than medicaments known from the
prior art.
Urinary incontinence is the involuntary voiding of urine.
This occurs in an uncontrolled manner if the pressure
within the bladder exceeds the pressure that is necessary
to close the ureter. Causes may include on the one hand an
increased internal bladder pressure (for example due to
detrusor instability) resulting in urgency incontinence,
and on the other hand a reduced sphincter pressure (for
example after childbirth or surgical intervention),
resulting in stress incontinence. The detrusor is the
collective term for the coarse bundles of multilayer
muscles of the bladder wall, whose contraction leads to
release of urine; the sphincter is the constrictor muscle
of the urethra. Mixed forms of these types of incontinence
as well as so-called overflow incontinence (e. g. in benign
prostatic hyperplasia) or reflex incontinence (e. g. after
spinal cord injury) occur. Further details can be found in
Chutka, D.S. and Takahashi, P.Y., 1998, Drugs 550: 587-595.
Urinary urgency is the state of increased bladder muscle
tension leading to voiding of urine (micturition) when the
bladder is almost full (or when its capacity is exceeded).
This muscle tone acts as a stimulus to pass urine.
Increased urinary urgency is understood in this connection
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to mean in particular the occurrence of premature or more
frequent and sometimes even painful urinary urgency up to
so-called dysuria. This consequently leads to a
significantly increased frequency of micturition. Causes
may include, inter alia, inflammation of the bladder and
neurogenic bladder disorders, as well as also bladder
tuberculosis. However, all causes have not yet been
elucidated.
Increased urinary urgency and also urinary incontinence are
regarded as extremely unpleasant and there is therefore a
clear need to achieve the greatest possible long-term
improvement in patients affected by these medical
conditions.
Increased urinary urgency and in particular urinary
incontinence are normally treated with substances that act
on the reflexes of the lower urinary tract (Wein A.J.,
1998, Urology 51 (Suppl. 21): 43-47). In general these are
medicaments that have a blocking effect on the detrusor
muscle, which is responsible for the internal bladder
pressure. These medicaments include for example
parasympatholytics such as oxybutynin, propiverine or
tolterodine, tricyclic antidepressants such as imipramine,
or muscle relaxants such as flavoxate. Other medicaments
that in particular increase the resistance of the urethra
or cervix of the bladder have similarities with a,-
adrenoreceptors such as ephedrine, with [3-adrenoreceptors
such as clenbutarol, or are hormones such as oestradiol.
Also, certain opioids, diarylmethylpiperazines and
diarylmethylpiperidines have been described for this
medical condition in WO 93/15062.
WO 03/099267 CA 02488220 2004-11-26 pCT/gP03/05488
19
In the medical conditions that are of interest here, it
should be noted that in general these involve the very
long-term use of medicaments and, in contrast to many
situations in which analgesics are used, patients suffer
very unpleasant but not intolerable discomfort.
Accordingly in this case - even more than with analgesics -
care should be taken to avoid side effects if the patient
does not wish to exchange one discomfort for another.
Furthermore, in the long-term treatment of urinary
incontinence analgesic effects are also largely
undesirable.
Yet another object of the present invention was accordingly
to find substances or pharmaceutical formulations or
medicaments that are helpful in the treatment of increased
urinary urgency or urinary incontinence.
It was now surprisingly found that 1-dimethylamino-3-(3-
methoxyphenyl)-2-methylpentan-3-of and in particular the
pharmaceutical formulations according to the invention
containing 1-dimethylamino-3-(3-methoxyphenyl)-2-
methylpentan-3-of have an outstanding effect on bladder
function and accordingly are ideally suitable for treating
the corresponding medical conditions.
The present invention accordingly also provides for the use
of a pharmaceutical formulation according to the invention
or a tablet according to the invention for producing a
medicament for treating increased urinary urgency or
urinary incontinence.
The invention in addition provides for the use of 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of for
the production of a medicament for treating increased
..
WO 03/099267 CA 02488220 2004-11-26 pCT/EP03/05488
urinary urgency or urinary incontinence, in which 1-
dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-of is
contained in a pharmaceutical formulation according to the
invention.
5
Examples
The examples serve to illustrate the present invention and
preferred embodiments, but are not intended to restrict the
10 scope thereof.
Example 1
Matrix tablets with the following composition per tablet
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol;5 mg
hydrochloride
Hydroxypropylmethylcellulose (Metolose 90 SH 100,000 80 mg
from the Shinetsu company), 100,000 mPa~s
Microcrystalline cellulose (Avicel PH 101 from the 50 mg
FMC
company)
Lactose monohydrate (Lactose 200 from the Meggie 169 mg
company)
Highly dispersed silicon dioxide 3 mg
Magnesium stearate 3 mg
Total amount 310 mg
were produced in the following way in a batch size of 2000
tablets:
All constituents were weighed out and screened on a Quadro
Comil U10 screening machine using a screen size of
0.813 mm, mixed in a container mixer (Bohle LM 40) for
15 minutes ~ 15 sec. at a rotational speed of 20 ~ 1 rpm,
and compressed on a Korsch EKO eccentric press into tablets
with a diameter of 10 mm having the contours of sugar-
WO 03/099267 CA 02488220 2004-11-26 pCT/EP03/05488
21
coated pills, a convex radius of 8 mm and a mean tablet
weight of 310 mg.
The in vitro release was measured using the Ph. Eur. paddle
method at 75 rpm in 900 ml of buffer pH 6.8 according to
Ph. Eur. at 37°C and with W spectrometric detection, and
is given in the following table.
Time [min] Released total amount
of the active
constituent [%)
0 0
30 17
240 75
480 95
720 100
Example 2
Matrix tables with the following composition per tablet
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol;50 mg
hydrochloride
Hydroxypropylmethylcellulose (Metolos~e 90 SH 100,000 80 mg
from the Shinetsu company), 100,000 mPa~s
Microcrystalline cellulose (Avicel PH 101 from the 174 mg
FMC
company)
Highly dispersed silicon dioxide 3 mg
Magnesium stearate 3 mg
Total amount 310 mg
were produced in the following way in a batch size of 2000
tablets:
All constituents were weighed out and screened on a Quadro
Comil U10 screening machine using a screen size of
TnTO 03/099267 CA 02488220 2004-11-26 p~/gpp3/05488
22
0.813 mm, mixed in a container mixer (Bohle LM 40) for
15 minutes ~ 15 sec. at a rotational speed of 20 ~ 1 rpm,
and compressed on a Korsch EKO eccentric press into tablets
with a diameter of 10 mm having the contours of sugar-
s coated pills, a convex radius of 8 mm and a mean tablet
weight of 310 mg.
The in vitro release was measured using the Ph. Eur. paddle
method at 75 rpm in 900 ml of buffer pH 6.8 according to
Ph. Eur. at 37°C and with W spectrometric detection, and
is given in the following table.
Time [mint Released total amount
of the active
constituent [
0 0
30 20
240 63
480 81
720 91
WO 03/099267 CA 02488220 2004-11-26 pCT/gP03/05488
23
Example 3
Matrix tables with the following composition per tablet
1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol;100 mg
hydrochloride
Hydroxypropylmethylcellulose (Metolose 90 SH 100,000 80 mg
from the Shinetsu company), 100,000 mPa~s
Microcrystalline cellulose (Avicel PH 101 from the 94 mg
FMC
company)
Lactose monohydrate (Lactose 200 from the Meggie 30 mg
company)
Highly dispersed silicon dioxide 3 mg
Magnesium stearate 3 mg
Total amount 310 mg
were produced in the following way in a batch size of 2000
tablets:
All constituents were weighed out and screened on a Quadro
Comil U10 screening machine using a screen size of
0.813 mm, mixed in a container mixer (Bohle LM 40) for
15 minutes ~ 15 sec. at a rotational speed of 20 ~ 1 rpm,
and compressed on a Korsch EKO eccentric press into tablets
with a diameter of 10 mm having the contours of sugar-
coated pills, a convex radius of 8 mm and a mean tablet
weight of 310 mg.
The in vitro release was measured using the Ph. Eur. paddle
method at 75 rpm in 900 ml of buffer pH 6.8 according to
Ph. Eur. at 37°C and with UV spectrometric detection, and
is given in the following table.
WO 03/099267 CA 02488220 2004-11-26 pCT/EP03/05488
24
Time [min] Released total amount
of the active
constituent [%]
0 0
30 22
240 69
480 88
720 96
Tablets according to Example 3 were stored for 3 months at
40°C and 75% relative atmospheric humidity, for 9 months at
25°C and 9 months at 30°C (storage conditions according to
ICH. The in vitro release was then redetermined using the
Ph. Eur. paddle method at 75 rpm in 900 ml buffer pH 6.8
according to Ph. Eur. at 37°C and with UV spectrometric
detection, and is shown in the following table:
Storage Conditions
9 Months/25C 9 Months/30C 3 Months/40C
Time [mint
75% relative
humidity
Released total
amount of the
active constituent
[%]
0 0 0 0
30 21 21 21
240 73 72 77
480 93 92 94
720 100 99 100
WO 03/099267 CA 02488220 2004-11-26 pOT/gp03/05488
Example 4
Matrix tablets with the following composition per tablet
(-)-(1R,2R)-1-dimethylamino-3-(3-methoxyphenyl)-2- 100 mg
methylpentan-3-ol; hydrochloride
Cellactose (Meggie) 72.5 mg
Hydroxyethylcellulose (Natrosol 250 HX from the Hercules12.5 mg
company)
Cutina HR (Henkel) 150 mg
Talcum 3 mg
Magnesium stearate 2 mg
Total amount 340 mg
5 were produced in the following way in a batch size of 200
tablets:
The active constituent, Cellactose, Natrosol and Cutina
were mixed, then heated in a drying cabinet to 80°C, and
granulated in a Kenwood Chef kitchen mixer. The cooled
10 granules were sieved through a 1 mm screen. After mixing
with magnesium stearate and talcum, the granules were
compressed in an EKO eccentric press (Korsch) into 6 x
15 mm large oblong tablets with a fracture notch.
15 The in vitro release was measured as in Example 1.
Time (min] Released total amount
of the active
constituent
0 0
10
240 53
480 69
720 80
900 98
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26
Example 5
Pellets with the following composition
(-)-(1R,2R)-1-dimethylamino-3-(3-methoxyphenyl)-2- 100 mg
methylpentan-3-ol; hydrochloride
Low-substituted hydroxypropylcellulose (L-HPC LH 75 mg
31
from the Shinetsu company)
Aquacoat (aqueous ethylcellulose dispersion from 20 mg
the
FMC company) (calculated as dry substance)
Microcrystalline cellulose (Avicel PH 101 from the 75 mg
FMC
company)
Dibutyl sebacate (DB5) 4 mg
Tween 80 0.4 mg
Total amount 274.4 mg
were produced in the following way:
The active constituent, Avicel and L-HPC were mixed in a
planetary mixer (Kenwood K mixer) for 10 minutes and then
granulated with water. The moist granules were extruded in
a Nica extruder with a 0.8 x 0.8 mm matrix and then rounded
for 10 minutes in a Nica spheroniser at 500 rpm (load
1 kg). The pellets were dried overnight in a drying
cabinet at 50°C and then graded in screening fractions.
Pellets of size 0.6-1.0 mm (yield ca. 95%) were coated in
the WSG (smooth GPCGl with Wurster insert) at feed air
temperatures of 60°C (product temperature 40°C) with an
aqueous dispersion of Aquacoat and DBS (20%, calculated in
terms of Aquacoat solids content), so as to produce a
weight increase of 9.8% (referred to the initial weight).
The dispersion was produced according to the manufacturer's
data (FA, FMC), and the DBS together with Tween 80 were
homogenised in part of the water and then added to the
diluted Aguacoat dispersion. The ready-for-use dispersion
WO 03/099267 CA 02488220 2004-11-26 pCT/gP03/05488
- 27
had a solids content of 20 wt.% and was stirred for at
least 3 hours. The coated pellets were dried in the WSG
and heat treated in the drying cabinet (2 hours at 60°C).
The release was determined similarly to Example 1, but
according to the basket method at 100 rpm.
Time [min] Released total amount
of the active
constituent [%]
0 0
30 2
240 29
480 67
720 78
900 89
1080 101
Example 6: List of tested substances:
A list of the compounds tested for their effectiveness is
given below:
Name Cmpd.
No.
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2- 1
methylpentan-3-ol; hydrochloride
(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2- 2
methylpentan-3-ol; hydrochloride
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2- 21
methylpentan-3-ol; hydrochloride
WO 03/099267 CA 02488220 2004-11-26 p~T/gP03/05488
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Example 8: Cystometry test system on conscious fresh rats
Cystometry investigations were carried out on fresh female
Sprague-Dawley rats according to the method of Ishizuka et
al. ((1997), Naunyn-Schmiedeberg's Arch. Pharmacol. 355:
787-793). Three days after implantation of bladder and
venous catheters the animals were investigated in the
conscious state while freely moving. The bladder catheter
was connected to a pressure gauge and an injection pump.
The animals were placed in metabolic cages that enabled the
volume of urine to be measured. Physiological saline
solution was infused (10 ml/hour) into the emptied bladder
and the bladder pressure and volume of urine were
continuously recorded. After a stabilisation phase a 20-
minute phase was recorded that was characterised by normal,
reproducible micturition cycles. The following parameters
among others were measured:
~ threshold pressure TP, bladder pressure immediately
before micturition,
~ bladder capacity BC, residual volume after prior
micturition plus volume of infused solution during the
filling phase,
intercontraction interval ICI, i.e, the time interval
between consecutive micturition.
An increase in the threshold pressure (TP) indicates an
important therapeutic effect in one of the medical
conditions covered by the invention. Also, the
intercontraction interval (ICI) is an important parameter
for measuring the physiological effectiveness of a
substance in the treatment of urinary incontinence, as is
the bladder capacity (BC). In this connection, on account
WO 03/099267 CA 02488220 2004-11-26 pCT/$P03/05488
29
of the widely differing causes of the symptoms of these
disease patterns it is not necessary to influence
positively all three parameters in order for a medicament
to be effective. It is therefore perfectly adequate if a
positive effect is demonstrated in only one of these
parameters in order for the medicament to be of use in
urinary incontinence or increased urinary urgency.
After recording three reproducible micturition cycles to
provide a baseline value, the test substances (1
(1.0 mg/kg), 2 (0.1; 0.3 and 0.5 mg/kg) and 21 (0.5 mg/kg),
in a vehicle comprising 0.9% NaCl were applied
intravenously and the effect on the cystometric parameters
was recorded at 90 to 120 minutes. In the effect maximum
the mean value of 3 micturition cycles was determined and
recorded as a percentage change compared to the baseline
value (Table 1).
Compound: TP BC ICI
(Concentration) Threshold Bladder Inter-
Pressure Capacity Contraction
Interval
1
1.0 mg/kg iv +94%** +31%*** +42%
(n=9)
2
0.1 mg/kg iv +28.5%** +7.8% +15.6%
(n=5)
0.3 mg/kg iv +122%** +33%* +28%*
(n=8)
0.5 mg/kg iv +77.5%** +20.6%* +28.6%**
(n=9)
21
0.5 mg/kg iv -1.1% +3% +10%
(n=8)
Table 1: Influencing of the cystometric parameters by the
test substances (change compared to the baseline value
(%)); n corresponds to the number of experimental animals;
WO 03/099267 CA 02488220 2004-11-26 p~T/8P03/05488
significance (Student T Test): * p < 0.05; ** p < 0.01;
*** p < 0.001.
The investigated substances exhibit a positive effect on
5 the bladder regulation and are therefore suitable for
treating urinary incontinence.
It was found inter alia that, of the enantiomers of the
racemic compound 1, the (+) enantiomer (compound 2) is very
10 effective (and thus is a particularly preferred compound of
the invention), while the (-) enantiomer (compound 21) does
not exhibit such a marked effect.
