Source: http://www.patentsencyclopedia.com/app/20100130606
Timestamp: 2016-08-24 18:11:27
Document Index: 19630433

Matched Legal Cases: ['§119', 'art 0', 'art 0', 'art 0', 'art 0', 'art 0', 'art 0', 'art 1', 'art 1', 'art 0', 'art 0', 'art 0']

PHARMACEUTICAL COMPOSITIONS COMPRISING FESOTERODINE - Patent application
Patent application title: PHARMACEUTICAL COMPOSITIONS COMPRISING FESOTERODINE
Hans-Jürgen Mika (Bonn, DE)
Christoph Arth (Dusseldorf, DE)
Michael Komenda (Koln, DE)
Fatima Bicane (Rosrath, DE)
Kerstin Paulus (Ratingen, DE)
Meike Irngartinger (Frechen, DE)
Hans Lindner (Leichlingen, DE)
IPC8 Class: AA61K31222FI
Patent application number: 20100130606
The present application relates to a pharmaceutical granulate comprising
Fesoterodine or a pharmaceutically acceptable salt or solvate thereof and
a pharmaceutically acceptable stabilizer, which can be selected from the
group consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose,
and combinations thereof, and is preferably a sugar alcohol selected from
the group consisting of xylitol and sorbitol. The granulate is suitable
for incorporation into pharmaceutical compositions comprising a gel
matrix formed by at least one type of hydroxypropyl methylcellulose into
which the Fesoterodine is embedded and, optionally, further excipients.
In certain embodiments, the granulate is formed by a process of wet
granulation.Claims:
31. A pharmaceutical composition comprising Fesoterodine, or a
pharmaceutically acceptable salt, and a pharmaceutically acceptable
stabilizer, wherein said stabilizer is selected from the group consisting
of xylitol, sorbitol, polydextrose, isomalt, dextrose and combinations
32. The pharmaceutical composition according to claim 31, wherein said
stabilizer is xylitol, sorbitol or polydextrose.
33. The pharmaceutical composition according to claim 31, wherein said
stabilizer is xylitol.
34. A pharmaceutical composition according to claim 31, wherein the
Fesoterodine/stabilizer ratio is 1%-20% [w/w].
35. A pharmaceutical composition according to claim 34, which comprises a
salt of Fesoterodine which has an auto pH in water of 3-5.
36. A pharmaceutical composition according to claim 35, wherein the
Fesoterodine salt is a salt of a di- or tricarboxylic acid, or of a
partially hydrogenated di- or tricarboxylic acid.
37. A pharmaceutical composition according to claim 36, which comprises
Fesoterodine hydrogen fumarate.
38. A pharmaceutical composition according to claim 37, which is in unit
dosage form and characterized in that Fesoterodine hydrogen fumarate is
present in an amount of between 0.5 and 12 mg per dosage unit.
39. A pharmaceutical composition according to claim 31, which is
obtainable by a method involving at least one granulation step.
40. A pharmaceutical composition according to claim 39, wherein the
granulation is wet granulation.
41. A pharmaceutical composition according to claim 40, wherein the
granulation is performed in the presence of water.
42. A pharmaceutical composition according to claim 31, wherein the
pharmaceutical composition further comprises a sustained release agent.
43. A pharmaceutical composition according to claim 42, wherein the
sustained release agent is a cellulose ether or ester or a mixture
44. A pharmaceutical composition according to claim 43, wherein the
sustained release agent is hydroxypropylmethylcellulose.
45. A pharmaceutical composition according to claim 42, wherein the
sustained release agent is contained in an amount of about 20-80% [w/w],
46. A pharmaceutical composition according to claim 42, which exhibits a
cumulated Fesoterodine release (in weight percent based on the
theoretical amount of Fesoterodine in the formulation) in an in vitro
dissolution assay according to USP 711 (in phosphate buffer pH 6.8,
37.degree. C., at 75 rpm) as follows:about 5% to about 30% Fesoterodine
release after 1 hour,about 15% to about 40% Fesoterodine release after 2
hours,about 35% to about 65% Fesoterodine release after 4 hours, andat
least about 75% Fesoterodine release after 16 hours.
47. A pharmaceutical composition comprising Fesoterodine, or a
stabilizer, wherein said stabilizer is identifiable from
pharmacologically acceptable excipients of the group of polyols, sugars
and sugar alcohols by a method comprising the following steps:preparation
of a binary granulate of 1 part by weight of Fesoterodine and 9 parts by
weight of a polyol, sugar or sugar alcohol; storing said granulate under
the following three conditions:a) 25.degree. C. and 60% r.H. in closed
vials for 6 weeksb) 40.degree. C. and 75% r.H. in closed vials for 6
weeksc) 40.degree. C. and 75% r.H. in open vials for 6 weeksdetermining
the content of the active metabolite of formula (II) via HPLC by the
area-% method ##STR00009## and selecting from said polyols, sugars or
sugar alcohols a stabilizer which limit the formation of active
metabolite of formula (II) during storage under at least two of the above
conditions as follows:i) about 1 wt % or less under storage condition
a)ii) about 2 wt % or less under storage condition b)iii) about 2 wt % or
less under storage condition c).
48. A pharmaceutical composition according to claim 47, which comprises a
49. A pharmaceutical composition according to claim 47, which comprises a
Fesoterodine salt of a di- or tricarboxylic acid, or of a partially
hydrogenated di- or tricarboxylic acid.
50. A pharmaceutical composition according to claim 47, which comprises
51. The pharmaceutical composition according to claim 31, wherein the
Fesoterodine/stabilizer ratio [w/w] is:1:1 to 1:9
(Fesoterodine:xylitol);1:1 to 1:9 (Fesoterodine:sorbitol);1:9
(Fesoterodine:polydextrose);1:9 (Fesoterodine:isomalt); or1:9
(Fesoterodine:dextrose).
52. A pharmaceutical composition according to claim 31, wherein said
stabilizer is sorbitol.
53. A pharmaceutical composition according to claim 52, wherein the
Fesoterodine/sorbitol ratio [w/w] is 1:1 to 1:9.
54. A pharmaceutical composition according to claim 53, wherein the
55. A pharmaceutical composition according to claim 54, which comprises
56. A pharmaceutical composition according to claim 33, wherein the
Fesoterodine/xylitol ratio [w/w] is 1:1 to 1:20.
57. A pharmaceutical composition according to claim 56, wherein the
Fesoterodine/xylitol ratio [w/w] is 1:1 to 1:9.
58. The pharmaceutical composition according to claim 45, wherein the
sustained release agent is contained in an amount of about 25-65%, based
on the total composition.
59. The pharmaceutical composition according to claim 45, wherein the
sustained release agent is contained in an amount of about 30-65%, based
60. The pharmaceutical composition according to claim 45, wherein the
sustained release agent is contained in an amount of about 35-55%, based
61. The pharmaceutical composition according to claim 46, which exhibits a
37.degree. C., at 75 rpm) as follows:about 6% to about 26% Fesoterodine
release after 1 hour,about 18% to about 38% Fesoterodine release after 2
hours,about 36% to about 56% Fesoterodine release after 4 hours, andat
least about 80% Fesoterodine release after 16 hours.Description:
[0001]This application claims benefit and priority under 35 U.S.C.
§119(e) of U.S. Provisional Patent Application Ser. No. 60/812,149
filed on Jun. 9, 2006, the entirety of which is expressly incorporated
[0002]The present invention generally relates to a pharmaceutical
composition comprising Fesoterodine or a pharmaceutically acceptable salt
or solvate thereof and to a method for its preparation.
[0003]Fesoterodine of formula (I) can be chemically described as
2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl
[0004]Fesoterodine is an innovative drug for the treatment of overactive
bladder, urinary incontinence and other dysfunctions of the urinary
tract. It is disclosed, inter alia, in EP 1077912 B1, pertaining to novel
derivatives of 3,3-diphenylpropylamines. EP 1230209 B1 discloses stable
salts of novel derivatives of 3,3-diphenylpropylamines, including
[0005]Overactive bladder (OAB) is an extremely common disorder, affecting
17% of the adult population in major European countries. OAB can occur at
any age and in either gender, although its prevalence is higher in
geriatric and female populations.
[0006]OAB is a bladder function disorder resulting in symptoms of urgency,
with or without urge incontinence, and usually includes increased urinary
frequency and nocturia. The disorder is due to spastic contractions of
the detrusor muscle of the bladder, resulting in sustained high bladder
pressure and the urgent need to urinate. This can be caused by several
reasons, such as traumatic or toxic nerve damage (e.g., abdominal trauma,
pelvic trauma or surgery, bladder stones, adverse effects of drugs),
neurological diseases (e.g., spinal cord lesions, multiple sclerosis,
Parkinson's disease, excessive neurotransmitter release in the bladder)
or myogenic instability (e.g., bladder hypertrophy caused by outlet
obstruction or urinary tract infection).
[0007]In some cases, OAB can be managed without pharmacotherapy, using
exercise, pessaries, implants, biofeedback or behavioral therapy. But in
most cases, pharmacotherapy is the better option. Antimuscarinic agents
have been found to be particularly effective for treating OAB. During
normal micturition, acetylcholine released from postganglionic
parasympathetic neurons acts on the muscarinic receptors of the detrusor
smooth muscle in the bladder to stimulate contractions. Antimuscarinic
agents interfere with this action, thus reducing detrusor contractions.
However, despite the availability of different antimuscarinic drugs,
physicians and patients remain dissatisfied with current treatments due
to adverse events and/or insufficient efficacy. Furthermore, as a general
matter, it is desirable for pharmaceutical compounds to have as little
effect on QT intervals as possible. In particular, it is desirable that
there be no significant QT/QTc interval prolongation. Therefore, new
agents with improved safety and efficacy are needed for a more effective
treatment of OAB.
[0008]Fesoterodine is known in the art for its potency in treating urinary
incontinence. However, Fesoterodine may exhibit substantial degradation
under stress conditions, e.g., in a humid environment and at increased
temperature. It is believed that hydrolyzation and oxidation are among
the major mechanisms resulting in degradation. Therefore, it would be
desirable to develop new pharmaceutical compositions comprising
Fesoterodine that are more stable against degradation over an extended
period of time even under stress conditions. To that end, it has now been
found, surprisingly, that some pharmaceutical excipients are able to
significantly slow down the degradation of Fesoterodine under stress
[0009]In one aspect, disclosed is a pharmaceutical composition comprising
[0010]In another aspect, disclosed is a pharmaceutical composition for the
oral administration of Fesoterodine, the composition comprising
[0011]In another aspect, disclosed is a granulate of Fesoterodine and a
stabilizer, preferably a pharmaceutically acceptable stabilizer. In
another aspect, disclosed is a pharmaceutical composition comprising a
granulate of Fesoterodine and a stabilizer, preferably a pharmaceutically
acceptable stabilizer.
[0012]Also disclosed is a pharmaceutical composition, preferably a solid
pharmaceutical composition, comprising Fesoterodine or a pharmaceutically
acceptable salt or solvate thereof and a stabilizer selected from the
and combinations thereof and at least one further excipient, preferably
at least one type of hydroxypropyl methylcellulose.
[0013]In another aspect, disclosed is a granulate comprising Fesoterodine
or its pharmaceutically acceptable salt or solvate and a stabilizer
selected from the group consisting of sorbitol, xylitol, polydextrose,
isomalt, dextrose, and combinations thereof. In another aspect, disclosed
is a pharmaceutical composition comprising a granulate of Fesoterodine or
its pharmaceutically acceptable salt or solvate and a stabilizer selected
from the group consisting of sorbitol, xylitol, polydextrose, isomalt,
dextrose, and combinations thereof.
[0014]In yet another aspect, presently disclosed is a pharmaceutical
composition for the oral administration of Fesoterodine or a
pharmaceutically acceptable salt or solvate thereof that may be obtained
by granulating Fesoterodine with a suitable excipient, preferably a
stabilizer selected from the group consisting of sorbitol, xylitol,
polydextrose, isomalt, dextrose, and combinations thereof. Preferably,
the stabilizer is a sugar alcohol chosen from among xylitol and sorbitol,
and more preferably xylitol. The granulate then may be combined or mixed
with at least one further excipient, preferably at least one type of
hydroxypropyl methylcellulose, and optionally other excipients.
[0015]In another aspect, disclosed is a pharmaceutical composition
comprising Fesoterodine or a pharmaceutically acceptable salt or solvate
thereof, wherein the pharmaceutical composition can be solid, and may be
suitable for oral administration. Fesoterodine, or a salt thereof,
further can be embedded in a gel matrix formed by at least one type of
hydroxypropyl methylcellulose (hypromellose) and, optionally, further
excipients. More preferably, Fesoterodine and a stabilizer may be
embedded in a gel matrix formed by at least one type of hydroxypropyl
methylcellulose (hypromellose) and, optionally, further excipients.
[0016]In certain embodiments, the fesoterodine salt can be a salt of a
polybasic acid, preferably with an auto pH in water in the range of about
3-5 (measured in water at 25° C. at a concentration of 1 wt %).
Examples may be chosen from the group of polybasic mineral acids, such as
e.g. sulfuric acid and phosphoric acid, or of polybasic organic acids.
Preferred examples are salts of di- or tricarboxylic acids such as
fesoterodine maleate, fesoterodine oxalate, fesoterodine citrate,
fesoterodine phthalate, fesoterodine fumarate, fesoterodine succinate,
fesoterodine tartrate, fesoterodine malonate, fesoterodine malate, etc.
In particular embodiments, the fesoterodine salt may be a partially
hydrogenated di- or tricarboxylic acid salt, particularly a salt with an
auto pH of 3-5, particularly between 3 and 4, more preferably between
3.25 and 3.75, such as hydrogen fumarate or hydrogen maleate. A
particularly preferred salt is fesoterodine hydrogen fumarate.
[0017]In yet another aspect, disclosed is a pharmaceutical composition as
described above comprising Fesoterodine fumarate as a pharmaceutically
acceptable salt, and preferably, Fesoterodine hydrogen fumarate.
[0018]In another aspect, disclosed is a pharmaceutical composition as
described above comprising Fesoterodine or a pharmaceutically acceptable
salt, preferably Fesoterodine hydrogen fumarate, or the free base, in an
amount of about 0.5-28 mg, or about 0.5-20 mg, preferably about 1-16 mg,
about 1-12 mg, more preferably about 1-8 mg, and even more preferably
about 2, about 4 or about 8 mg per dosage unit (based on the content of
Fesoterodine or its salt, e.g., Fesoterodine hydrogen fumarate), or free
[0019]Also disclosed is a method of treating patients suffering from
overactive bladder and having symptoms such as urinary incontinence,
specifically urinary urge incontinence, urinary urgency and/or urinary
frequency by administering a therapeutically effective amount of any of
the compositions as described herein. In particular, disclosed is a
method of treating patients suffering from overactive bladder that may
have symptoms such as urinary incontinence, urinary urge incontinence,
urinary urgency and/or urinary frequency by administering a unit dosage
form of the Fesoterodine compositions described herein. A unit dosage
form may contain between about 0.5-28 mg or about 0.5-20 mg Fesoterodine,
preferably about 1-16 mg or about 1-12 mg, more preferably about 1-8 mg,
and even more preferably about 2, about 4 or about 8 mg per dosage unit
(based on the content of Fesoterodine or its salt, e.g., Fesoterodine
hydrogen fumarate), or the free base. The unit dosage form can be
administered once-daily to a patient or, in some cases, more than once
daily to a patient, as may be appropriate.
[0020]Moreover, presently disclosed is a method for the production of a
pharmaceutical composition as described above comprising producing a
mixture containing Fesoterodine or a pharmaceutically acceptable salt
thereof and a stabilizer selected from the group consisting of sorbitol,
xylitol, polydextrose, isomalt, dextrose, and combinations thereof.
Preferably, the stabilizer is a sugar alcohol chosen from among xylitol
and sorbitol, and preferably xylitol. These components then can be mixed
or combined with at least one type of hydroxypropyl methylcellulose, and
optionally other excipients. Optionally, the resultant composition may be
pressed into tablets and coated.
[0021]One preferred method for the production of a pharmaceutical
composition containing Fesoterodine comprises granulating Fesoterodine or
a pharmaceutically acceptable salt thereof and a stabilizer selected from
the group consisting of sorbitol, xylitol, polydextrose, isomalt,
dextrose, and combinations thereof, preferably a sugar alcohol chosen
from among xylitol and sorbitol, and more preferably xylitol, and then
mixing or combining the granulate thus formed with at least one type of
hydroxypropyl methylcellulose, and optionally other excipients. The
resultant composition then may be pressed into tablets and coated.
[0022]The granulation process may be performed in a dry granulation
procedure, without the addition of liquid or, preferably, in the presence
of a liquid, such as water ("wet granulation"). In wet granulation, for
example, Fesoterodine or a pharmaceutically acceptable salt thereof and a
polydextrose, isomalt, dextrose, and combinations thereof, preferably a
suitable sugar alcohol, preferably sorbitol or xylitol, and more
preferably xylitol, can be mixed or combined in the presence of water.
The granulate then can be dried. This dried granulate then may be mixed
or combined with at least one further excipient, preferably at least one
type of hydroxypropyl methylcellulose, and optionally other excipients.
[0023]It has been surprisingly found that wet granulation can be
accomplished without increasing the degradation of Fesoterodine due to
hydrolyzation of the ester bond. For the same reason, it was even more
surprising that Fesoterodine is more stable in a composition that is
produced in the presence of water, e.g., by wet granulation, than in a
composition that is produced by dry granulation (see, e.g., Table 9) or
by dry mixing and compressing the excipients (see, e.g., Table 8).
[0024]In another and more general aspect, the present invention relates to
a pharmaceutical composition comprising fesoterodine, or a
pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable stabilizer, wherein the stabilizer is
identified by a method comprising the following steps: [0025]preparing
a binary granulate of 1 part by weight of fesoterodine and 9 parts by
weight of the stabilizer; storing said granulate under the following
three conditions: [0026]a) 25° C. and 60% r.H. in closed vials
for 6 weeks [0027]b) 40° C. and 75% r.H. in closed vials for 6
weeks [0028]c) 40° C. and 75% r.H. in open vials for 6 weeks
[0029]determining the content of the Active Metabolite of Formula II
[0030]via HPLC by the area-% method; [0031]selecting a stabilizer from
those which limit the formation of Active Metabolite of Formula II during
storage under at least two of the above conditions as follows: [0032]i)
about 1 wt % or less under storage condition a) [0033]ii) about 2 wt % or
less under storage condition b) [0034]iii) about 2 wt % or less under
storage condition c)
[0035]Preferably, such stabilizer is selected from polyols, sugars or
sugar alcohols. Most preferably this stabilizer is xylitol, sorbitol,
polydextrose, isomalt, dextrose or combinations thereof, and even more
preferably xylitol, sorbitol or polydextrose. The composition containing
the stabilizer preferably comprises a salt of Fesoterodine which has an
auto pH in water of 3-5. Auto pH is the pH value which can be measured
after dissolving 1 wt-% Fesoterodine salt in water at 25° C.
[0036]The pharmaceutical compositions comprising Fesoterodine and a
stabilizer disclosed herein do not significantly increase QT intervals,
e.g., QTcF or QTcI. Therefore, also disclosed are pharmaceutical
compositions comprising Fesoterodine and a stabilizer, preferably a sugar
alcohol such as xylitol or sorbitol, which pharmaceutical compositions do
not significantly increase QT intervals such as QTcF or QTcI. Such
pharmaceutical compositions may exhibit a mean time average QTcF or QTcI
decrease of about 4.6 ms to about 5.0 ms after three days of treatment.
The pharmaceutical compositions having such QTcF or QTcI characteristics
may contain between about 4 mg and about 28 mg of Fesoterodine.
Preferably, the pharmaceutical compositions are solid compositions such
as tablets containing about 4 mg, about 5 mg, about 6 mg, about 7 mg,
about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 16 mg, about 20
mg, about 24 mg, or about 28 mg of Fesoterodine. In particular
embodiments, the pharmaceutical compositions contain between about 4 mg
and about 12 mg, preferably between about 4 mg and about 8 mg, of
Fesoterodine and have the effect on QTcF or QTcI described above and
furthermore may cause dry mouth in not more than about 22% to about 34%
of patients when administered once-daily. In preferred embodiments, the
pharmaceutical compositions have these effects with respect to QT
intervals and dry mouth and contain about 4 mg, about 5 mg, about 6 mg,
about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12 mg, about 16
mg, about 20 mg, about 24 mg, or about 28 mg of Fesoterodine.
[0037]Disclosed also is a method of treatment for overactive bladder and
related conditions comprising the administration to a patient in need
thereof of a pharmaceutical composition comprising Fesoterodine and a
stabilizer wherein the method does not lead to a significant increase in
QTcF or QTcI. In certain embodiments, the method leads to a mean time
average QTcF or QTcI decrease of about 4.6 ms to about 5.0 ms after three
days of treatment. In certain embodiments, between about 4 mg to about 28
mg of Fesoterodine per day is administered. Preferably, about 4 mg per
day, about 5 mg per day, about 6 mg per day, about 7 mg per day, about 8
mg per day, about 9 mg per day, about 10 mg per day, about 12 mg per day,
about 16 mg per day, about 20 mg per day, about 24 mg per day, or about
28 mg per day of Fesoterodine is administered.
[0038]Disclosed also is a method of treatment for overactive bladder and
thereof of a pharmaceutical compositions comprising Fesoterodine and a
QTcF or QTcI, in particular wherein the method leads to a mean time
days of treatment, and wherein the method causes dry mouth in not more
than about 22% of patients when about 4 mg of Fesoterodine is
administered once-daily or wherein the method causes dry mouth in not
more than about 34% of patients when about 8 mg of Fesoterodine is
administered once-daily. Preferably, the method comprises the
administration of about 4 mg to about 12 mg of Fesoterodine per day.
Especially preferred is the administration of about 4 mg, about 5 mg,
about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg,
or about 12 mg of Fesoterodine per day.
[0039]Also disclosed is a pharmaceutical composition comprising
Fesoterodine and a stabilizer that exhibits a low level of adverse
events. Disclosed is a pharmaceutical composition comprising about 4 mg
of Fesoterodine and a stabilizer selected from the group consisting of
sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations
thereof, preferably a sugar alcohol such as xylitol or sorbitol, which
pharmaceutical composition causes dry mouth in not more than about 22% of
patients when administered once-daily. Also disclosed is a pharmaceutical
composition comprising about 8 mg of Fesoterodine and a stabilizer
isomalt, dextrose, and combinations thereof, preferably a sugar alcohol
such as xylitol or sorbitol, which pharmaceutical composition causes dry
mouth in not more than about 34% of patients when administered
once-daily. Also disclosed is a method of treating overactive bladder or
related conditions comprising administering a pharmaceutical composition
comprising about 4 mg of Fesoterodine and a stabilizer selected from the
and combinations thereof, preferably a sugar alcohol such as xylitol or
sorbitol, which pharmaceutical composition causes dry mouth in not more
than about 22% of patients when administered once-daily.
[0040]Also disclosed are pharmaceutical compositions comprising
Fesoterodine and a stabilizer that exhibit favorable pharmacokinetics.
[0041]Disclosed is a pharmaceutical composition comprising about 4 mg of
Fesoterodine and a stabilizer, preferably a sugar alcohol such as xylitol
or sorbitol, which pharmaceutical composition exhibits the following
parameters upon once-daily administration:
(a) a Cmax of about 2.19±0.66 ng/mL, a tmax of about
5.17±0.75 hr, and an AUC0-24 of about 17.99±7.16 hr*ng/mL on
day one after the start of administration;(b) a Cmax of about
1.92±0.84 ng/mL, a tmax of about 5.67±0.82 hr, and an
AUC0-24 of about 21.39±9.60 hr*ng/mL on day two after the start
of administration; and/or(c) a Cmax of about 2.12±1.28 ng/mL, a
tmax of about 4.17±2.04 hr, and an AUC0-24 of about
20.26±11.44 hr*ng/mL on day three after the start of administration.
[0042]Also disclosed is a method of treatment for overactive bladder or
comprising about 4 mg of Fesoterodine and a stabilizer, preferably a
sugar alcohol such as xylitol or sorbitol, which pharmaceutical
composition exhibits the following parameters upon once-daily
[0043]In certain embodiments, the method described immediately above does
not lead to a significant increase in QTcF or QTcI. In certain
embodiments, the method leads to a mean time average QTcF or QTcI
[0044]Also disclosed is a pharmaceutical composition comprising about 4 mg
of Fesoterodine and a stabilizer, preferably a sugar alcohol such as
xylitol or sorbitol, which pharmaceutical composition exhibits the
following parameters when the pharmaceutical composition is administered
two times per day, the two administrations occurring at the same time:
(a) a Cmax of about 4.31±1.79 ng/mL, a tmax of about
4.83±0.76 hr, and an AUC0-24 of about 44.48±17.47 hr*ng/mL on
3.73±1.35 ng/mL, a tmax of about 5.67±0.62 hr, and an
AUC0-24 of about 44.62±17.00 hr*ng/mL on day two after the start
of administration; and/or(c) a Cmax of about 5.15±2.02 ng/mL, a
tmax of about 5.00 hr, and an AUC0-24 of about 52.03±21.76
hr*ng/mL on day three after the start of administration.
[0045]Also disclosed is a pharmaceutical composition comprising about 4 mg
three times per day, the three administrations occurring at the same
(a) a Cmax of about 6.88±3.21 ng/mL, a tmax of about 5.00 hr,
and an AUC0-24 of about 61.81±18.43 hr*ng/mL on day one after the
start of administration;(b) a Cmax of about 6.63±1.59 ng/mL, a
tmax of about 5.67±0.82 hr, and an AUC0-24 of about
63.97±16.11 hr*ng/mL on day two after the start of administration;
and/or(c) a Cmax of about 7.11±3.01 ng/mL, a tmax of about
5.67±1.21 hr, and an AUC0-24 of about 72.87±25.37 hr*ng/mL on
day three after the start of administration.
[0046]Also disclosed is a pharmaceutical composition comprising about 4 mg
five times per day, the five administrations occurring at the same time:
(a) a Cmax of about 12.36±6.07 ng/mL, a tmax of about
5.50±0.55 hr, and an AUC0-24 of about 126±49 hr*ng/mL on day
one after the start of administration;(b) a Cmax of about
12.01±5.86 ng/mL, a tmax of about 5.67±0.82 hr, and an
AUC0-24 of about 126±60.42 hr*ng/mL on day two after the start of
administration; and/or(c) a Cmax of about 13.25±7.26 ng/mL, a
tmax of about 5.33±0.52 hr, and an AUC0-24 of about
136±68.76 hr*ng/mL on day three after the start of administration.
[0047]Also disclosed is a pharmaceutical composition comprising about 4 mg
seven times per day, the seven administrations occurring at the same
(a) a Cmax of about 16.29±5.69 ng/mL, a tmax of about
5.50±0.55 hr, and an AUC0-24 of about 181±59.74 hr*ng/mL on
18.14±3.57 ng/mL, a tmax of about 6.00 hr, and an AUC0-24 of
about 204±50.74 hr*ng/mL on day two after the start of administration;
and/or(c) a Cmax of about 18.28±6.31 ng/mL, a tmax of about
5.17±0.41 hr, and an AUC0-24 of about 213±73.26 hr*ng/mL on
[0048]Also disclosed is a pharmaceutical composition comprising about 8 mg
following parameters upon once-daily administration:
[0049]Also disclosed is a method of treatment for overactive bladder or
related conditions comprising administering to a patient in need thereof
a pharmaceutical composition comprising about 8 mg of Fesoterodine and a
stabilizer, preferably a sugar alcohol such as xylitol or sorbitol, which
pharmaceutical composition exhibits the following parameters upon
once-daily administration:
[0050]In certain embodiments, the method described immediately above does
[0051]Also disclosed is a pharmaceutical composition comprising about 12
mg of Fesoterodine and a stabilizer, preferably a sugar alcohol such as
[0052]Also disclosed is a method of treatment for overactive bladder or
a pharmaceutical composition comprising about 12 mg of Fesoterodine and a
[0053]In certain embodiments, the method described immediately above does
[0054]Also disclosed is a pharmaceutical composition comprising about 20
[0055]Also disclosed is a method of treatment for overactive bladder or
a pharmaceutical composition comprising about 20 mg of Fesoterodine and a
[0056]In certain embodiments, the method described immediately above does
[0057]Also disclosed is a pharmaceutical composition comprising about 28
[0058]Also disclosed is a method of treatment for overactive bladder or
a pharmaceutical composition comprising about 28 mg of Fesoterodine and a
[0059]In certain embodiments, the method described immediately above does
[0060]FIG. 1 shows the in vitro dissolution profiles of
Fesoterodine-containing pharmaceutical compositions (A) based on a 4 mg
tablet and (B) based on an 8 mg tablet.
[0061]FIG. 2 shows the course of time-matched QTcF changes (±SD) from
baseline after once-daily administrations of 4 mg or 28 mg Fesoterodine,
400 mg moxifloxacin, or placebo on day one.
[0062]FIG. 3 shows the course of time-matched QTcF changes (±SD) from
400 mg moxifloxacin, or placebo on day three.
[0063]FIG. 4 shows the time-averaged changes (mean and 95% confidence
interval) from baseline in QTcF after once-daily administrations of 4 mg
or 28 mg Fesoterodine, 400 mg moxifloxacin, or placebo for three days.
[0064]FIG. 5 shows the time-averaged changes (mean and 95% confidence
interval) from baseline in QTcI after once-daily administrations of 4 mg
[0065]FIG. 6 shows the change from baseline in average frequency of
micturitions per 24 hours for the trial comparing Fesoterodine 4 mg/day,
Fesoterodine 8 mg/day, tolterodine 4 mg/day, and placebo.
[0066]FIG. 7 shows the change from baseline in average number of
incontinence episodes per 24 hours for the trial comparing Fesoterodine 4
mg/day, Fesoterodine 8 mg/day, tolterodine 4 mg/day, and placebo.
[0067]FIG. 8 shows the treatment benefit scale for the trial comparing
Fesoterodine 4 mg/day, Fesoterodine 8 mg/day, tolterodine 4 mg/day, and
[0068]Unless the content indicates otherwise, the term "Fesoterodine"
includes pharmaceutically acceptable solvates of
isobutyrate (formula I), particularly hydrates of Fesoterodine.
"Fesoterodine" also includes pharmaceutically acceptable salts of
isobutyrate (formula I), particularly the hydrogen fumarate salt, as well
as the free base.
[0069]Throughout this application, amounts indicated relate to
Fesoterodine in the form which is used, i.e., either the free base or the
[0070]Fesoterodine is an ester which is susceptible to hydrolyzation after
administration in vivo as well as during storage under stress conditions
to give a main product
(2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol)
(formula II), which is referred to herein as the "Active Metabolite" and
corresponds to the following structure:
[0071]Throughout this application the term "hydrolyzation product" refers
to the Active Metabolite of formula II. Other degradation products also
may result from the metabolism and/or degradation of Fesoterodine. As
used herein, "total degradation products" will include, at least in part,
hydrolyzation product.
[0072]"Stabilizer," as the term is used herein, means a substance,
particularly a pharmaceutically acceptable excipient, which inhibits,
prevents, slows down, or reduces the degradation of Fesoterodine as
compared to Fesoterodine in the absence of the substance. As used herein,
the term "stabilizer" also embraces a combination of two or more of the
stabilizers according to the invention. By way of example, a combination
of xylitol and sorbitol, or a combination of xylitol, sorbitol and
polydextrose, or a combination of xylitol and polydextrose may be
[0073]Whether a substance is a stabilizer can be determined by the
following procedure: about 10 g. of a mixture of Fesoterodine and a
substance suspected to be a stabilizer in a ratio of about 1:9 (by
weight) is manually crushed with a pestle and then stored for about 6
weeks in an open vial at about 40° C. and about 75% relative
humidity. A substance is a stabilizer if the purity of Fesoterodine in
the mixture with the substance is higher under the above storage
conditions than the purity of Fesoterodine that was stored in the absence
[0074]The value of Fesoterodine purity, as well as the relative amounts of
hydrolyzation product and total degradation products given, are
determined via HPLC by the area-% method. In this area-% method the
purity is determined by comparing the area of the respective HPLC peaks
with the total area of all signals in the HPLC profile that can be
related to Fesoterodine and its hydrolyzation and/or degradation
[0075]Whether a certain excipient is suitable as a stabilizer according to
the present invention can also for example be determined by the following
[0076]At first a granulate is prepared: [0077]1 mass equivalent
Fesoterodine or a salt thereof, preferably Fesoterodine hydrogen
fumarate, and 9 mass equivalents of the excipient are weighed separately.
If the excipient is agglomerated, it is passed through a sieve (1.5 mm).
[0078]Fesoterodine and the excipient are passed through a sieve (0.8 mm).
[0079]The fesoterodine and the excipient are transferred into a suitable
granulator (e.g., a high-shear mixer granulator such as those
manufactured by Lodige, Type Diosna P1/6) at a temperature of below about
35° C. and mixed for 1 minute. [0080]About 5.5 wt % of purified
water is added to the dry mixture while stirring. [0081]The mixture is
stirred with a chopper for about 90 to 120 seconds. [0082]The mixer is
emptied, and the contents are transferred to a sieving machine to form a
wet granulate, which then is passed through a sieve or a screen (4.0 mm).
[0083]The sieved granulate is dried on trays at about 45° C. for a
minimum of 8 h. in a drying chamber/oven until a water content of not
more than about 0.5%. [0084]The dried granulate is passed through a sieve
(0.5 to 1.0 mm). [0085]The dried granulate is then mixed (at a speed of
about 8 rpm) for 5 minutes. [0086]One part of the granulate is examined
to determine the initial amount of hydrolyzation and degradation product,
while another part is stored in open vials as described above and
subsequently examined to determine the final amount of hydrolyzation and
degradation product.
[0087]Batches of this granulate are then stored under three conditions,
respectively, as follows: [0088]a) 25° C. and 60% r.H. in closed
vials for 6 weeks [0089]b) 40° C. and 75% r.H. in closed vials for
6 weeks [0090]c) 40° C. and 75% r.H. in open vials for 6 weeks
[0091]The content of the active metabolite of Formula II is determined via
HPLC by the area-% method. In this area-% method, the amount of active
metabolite is determined by comparing the area of the respective HPLC
peak with the total area of all signals in the HPLC profile that can be
[0092]According to this procedure, a substance is a stabilizer if it
limits the formation of Active Metabolite of Formula II during storage
under at least two of the above conditions as follows: [0093]a) about 1
wt % or less, preferably 0.5 wt % or less, and particularly preferably
0.36 wt % or less [0094]b) about 2 wt % or less, preferably 1 wt % or
less, and particularly preferably 0.5 wt % or less [0095]c) about 2 wt %
or less, preferably 1.5 wt % or less, and particularly preferably 0.58 wt
[0096]In preferred embodiments, stabilizers prevent the degradation of
Fesoterodine to the extent that if a stabilizer is mixed with
Fesoterodine and stored for about 6 weeks at about 40° C. and
about 75% relative humidity in open vials, the difference
(PF+S-PF) between the Fesoterodine purity in the mixture with a
stabilizer (PF+S) and the Fesoterodine purity upon storage of
Fesoterodine alone (PF) is at least about 1%, preferably at least
about 1.5%, and more preferably at least about 2%.
[0097]Other preferred stabilizers are those that inhibit, prevent, slow
down, or reduce the degradation of Fesoterodine during the production and
storage of a granulate. Such a preferred stabilizer can be determined by
producing about 10 g. of a granulate of Fesoterodine and a substance
suspected to be a stabilizer in a ratio of about 1:9 (by weight) under
the conditions as described below, storing the granulate in an open vial
at about 40° C., about 75% relative humidity (r.H.) for about 6
weeks and measuring the relative amount of the total hydrolyzation and
degradation products via HPLC by the area % method under the conditions
as described in Example 6b and above. An excipient is a preferred
stabilizer if the difference (DF-D0) between the final amount
of total hydrolyzation and degradation products after about 6 weeks of
storage in an open vial at about 40° C., about 75% relative
humidity (r.H.) (DF) and the initial amount of hydrolyzation and
degradation products after the production of the granulate (D0) is
less than about 3%, preferably less than about 2%, or more preferably
even less than about 1.5%.
[0098]Stabilizers of the present invention include, but are not limited
to, sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations
thereof. Preferred stabilizers include sugar alcohols meeting the
aforementioned criteria and more specifically include, but are not
limited to, xylitol and sorbitol. Xylitol is one preferred stabilizer.
[0099]The ratio of the Fesoterodine to the stabilizer is preferably
between about 1%-20% (w/w) and, more preferably, between about 5% and
about 10% (w/w).
[0100]Particularly preferred are those stabilizers that are capable of
reducing the destabilizing effect of certain other excipients, such as,
e.g., lactose, on Fesoterodine.
[0101]Stabilizers may be added to the matrix of a suitable formulation, or
preferably can be used in granulates, optionally together with one or
more other excipients.
[0102]Granulates comprising Fesoterodine or a pharmaceutically acceptable
salt or solvate thereof and a stabilizer, and optionally further
excipients, can be formed by mixing the components either dry or,
preferably, with a liquid, e.g., with water, and then granulating the
[0103]A "pharmaceutically acceptable stabilizer" is a stabilizer which is
not biologically or otherwise undesirable, i.e., the stabilizer can be
administered to an individual without causing significant undesirable
biological effects or interacting in a deleterious manner with any of the
components of the composition in which it is contained.
[0104]In a preferred embodiment, the stabilizers disclosed herein inhibit,
prevent, slow down, or reduce the hydrolyzation of Fesoterodine into
Active Metabolite of formula (II). Thus, in one aspect, disclosed are
compositions, mixtures, granulates and other pharmaceutical compositions
comprising Fesoterodine and a stabilizer, wherein the Fesoterodine is
protected against hydrolyzation under various stress conditions (see,
e.g., Table 6 and Table 7).
[0105]The stabilizers of the present invention can also inhibit, prevent,
slow down, or reduce the degradation of further ester compounds that are
susceptible to hydrolysis. In particular, stabilizers of the present
invention are useful for the stabilization of esters of the Active
Metabolite of fesoterodine of Formula II.
[0106]Thus, another aspect of this invention relates to the use of a
substance selected from the group consisting of xylitol, sorbitol,
polydextrose, isomalt, and dextrose for the stabilization of a
pharmaceutical composition comprising as active ingredient an ester
compound that is susceptible to hydrolysis, particularly an ester of the
Active Metabolite of Fesoterodine of Formula II and preferably such an
ester as indicated below, or a pharmaceutically acceptable salt or
[0107]Esters of the Active Metabolite of Fesoterodine of Formula II that
can be stabilized in this way include the following compounds:
[0108]a) Phenolic Monoesters of Formula III
[0109]wherein R1 is C1-C6 alkyl or phenyl;
[0110]b) Identical Diesters of Formula IV
[0111]wherein each R1 is as defined above;
[0112]c) Mixed Diesters of Formula V
[0113]wherein R1 is as defined above, R2 is hydrogen,
C1-C6 alkyl or phenyl with the proviso that R1 and R2
[0114]d) Benzylic Monoesters of Formula VI
[0115]wherein R1 is as defined above;
[0116]e) Intramolecular Cyclic Diesters of Formula VII and Formula VIII
[0117]wherein o and p are the same or different and represent the number
of methylene units --(CH2)-- and may range from 0 to 6; and
[0118]f) inorganic esters such as (±)-Benzoic acid
2-(3-diisopropylamino-1-phenylpropyl)-4-sulphooxymethyl-phenyl ester;
[0119]and their salts with physiologically acceptable acids, their free
bases and, when the compounds can be in the form of optical isomers, the
racemic mixture and the individual enantiomers.
[0120]In yet another aspect, disclosed also is a pharmaceutical
composition comprising such an ester as defined above, or a
pharmaceutically acceptable stabilizer, wherein said stabilizer is
selected from the group consisting of xylitol, sorbitol, polydextrose,
isomalt, dextrose and combinations thereof.
[0121]Preferred pharmaceutical compositions are those comprising
(a) a phenolic monoester of Formula III as defined above, particularly
preferably a phenolic monoester wherein R1 is a linear or branched
C3-C6 alkyl, or a pharmaceutically acceptable salt or solvate
thereof, and(b) a pharmaceutically acceptable stabilizer, wherein said
stabilizer is selected from the group consisting of xylitol, sorbitol,
polydextrose, isomalt, dextrose and combinations thereof.
[0122]In one aspect of the present invention, the pharmaceutical
composition comprising the ester as described above, preferably the
phenolic monoester of Formula III, and the stabilizer, contains said
ester in the form of a salt, preferably a salt of a di- or tricarboxylic
acid, or a partially hydrogenated di- or tricarboxylic acid, wherein said
salt of said ester has an auto pH in water that is close to the pH
stability optimum of the respective ester, for example at about pH 3-5.
[0123]In another embodiment, provided are various compositions comprising
Fesoterodine and a stabilizer. Exemplary, non-exhaustive examples of
various compositions may be described as follows.
[0124]A pharmaceutical composition comprising Fesoterodine and a
stabilizer, wherein the Fesoterodine is stable against degradation at
about 40° C., about 75% r.H. in an open vial such that after about
6 weeks at about 40° C., about 75% r.H. in an open vial, the
pharmaceutical composition contains no more than about 7%, about 6%,
about 5%, about 4.9%, about 4.8%, about 4.7%, about 4.6%, about 4.5%, or
about 4.4% of Active Metabolite of Formula II.
[0125]A pharmaceutical composition comprising Fesoterodine and a
about 40° C., 75% r.H. in a closed vial such that after about 6
weeks at about 40° C., 75% r.H. in closed vial the pharmaceutical
composition contains no more than about 2.5%, about 2.2%, about 2.1%,
about 2%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%,
about 1.4%, about 1.3%, about 1.2%, about 1.1%, or about 1% of Active
Metabolite of formula (II). More preferably, such a pharmaceutical
composition contains no more than about 1.09% of Active Metabolite of
Formula II after storage under such conditions.
[0126]A pharmaceutical composition comprising Fesoterodine and a
stabilizer wherein Fesoterodine is stable against degradation at about
40° C., 75% r.H. in an open vial such that after about 12 weeks at
about 40° C., 75% r.H. in open vial the pharmaceutical composition
contains at least about 85%, about 86%, about 87%, about 88%, about 89%
or about 90% Fesoterodine. More preferably, such a pharmaceutical
composition contains at least about 89% of Fesoterodine after storage
[0127]A pharmaceutical composition comprising Fesoterodine and a
25° C., about 60% r.H. in a closed vial such that after about 6
weeks at about 25° C., about 60% r.H. in closed vial the
pharmaceutical composition contains no more than about 1%, about 0.9%,
about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%,
about 0.2%, or about 0.1% of Active Metabolite. More preferably, such a
pharmaceutical composition contains no more than about 0.18% of Active
Metabolite of Formula II after storage under such conditions.
[0128]In another embodiment, the pharmaceutical composition for the oral
administration of Fesoterodine or a pharmaceutically acceptable salt
thereof comprises Fesoterodine and at least one stabilizer selected from
dextrose, and combinations thereof, preferably a stabilizing sugar
alcohol, including a sugar alcohol chosen from xylitol and sorbitol. The
composition may include one or more further excipients.
[0129]At least one of the further excipients that may be included is a
sustained release agent, preferably a substituted cellulose derivative,
such as hydroxypropylmethyl cellulose (HPMC). The sustained release
agent, e.g. HPMC, facilitates the delayed release of Fesoterodine from
the formulation such that the formulation can be administered to a
patient less often, such as once daily.
[0130]Another embodiment is a pharmaceutical composition for the oral
thereof that is a granulate of Fesoterodine and at least one suitable
excipient, preferably a stabilizer selected from the group consisting of
thereof, and even more preferably a sugar alcohol chosen from xylitol and
[0131]In another embodiment is a pharmaceutical composition for the oral
thereof that comprises granulate(s) of Fesoterodine and at least one
suitable excipient, preferably a stabilizer selected from the group
consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose, and
combinations thereof, and even more preferably a sugar alcohol chosen
from xylitol and sorbitol. Optionally, at least one further excipient may
be included in such compositions.
[0132]Another embodiment is a pharmaceutical composition for the oral
thereof that can be produced by a method comprising wet granulating
Fesoterodine and at least one suitable excipient, preferably a stabilizer
isomalt, dextrose, and combinations thereof, and even more preferably a
sugar alcohol chosen from xylitol and sorbitol to form a granulate, and
optionally mixing the granulate with further excipients, such as for
example one or more types of HPMC.
[0133]A pharmaceutical composition made from Fesoterodine granulate
described herein was found to have about 90% of the original amount of
Fesoterodine remaining in undegraded form. (See Table 4).
[0134]The following exemplary, non-exhaustive examples of pharmaceutical
compositions made from granulates of Fesoterodine are thus described.
[0135]In further additional embodiments, the stabilizer used in
pharmaceutical compositions made from a granulate of Fesoterodine can be
xylitol. Thus, exemplary, non-exhaustive examples of such compositions
[0136]A pharmaceutical composition comprising Fesoterodine and xylitol,
wherein the Fesoterodine in the pharmaceutical composition is stable
against degradation at about 40° C., about 75% r.H. in a closed
vial such that after about 6 weeks at about 40° C., about 75% r.H.
in a closed vial the pharmaceutical composition contains no more than
Metabolite of Formula II. More preferably, such a pharmaceutical
[0137]Also provided is a pharmaceutical composition comprising
Fesoterodine and xylitol, wherein the Fesoterodine in the pharmaceutical
composition is stable against degradation at about 40° C., about
75% r.H. in an open vial such that after about 6 weeks at about
40° C., about 75% r.H. in an open vial the pharmaceutical
composition contains no more than about 5%, about 4.9%, about 4.8%, about
4.7%, about 4.6%, about 4.5%, or about 4.4% of Active Metabolite of
[0138]A pharmaceutical composition comprising Fesoterodine and xylitol,
about 2%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, or about 1.5%
of total degradation products of Fesoterodine. More preferably, such a
pharmaceutical composition contains no more than about 1.54% of total
hydrolyzation and degradation products of Fesoterodine after storage
[0139]A pharmaceutical composition comprising Fesoterodine and xylitol,
against degradation at about 40° C., about 75% r.H. in an open
in an open vial the pharmaceutical composition contains no more than
about 7%, about 6.9%, about 6.8%, or about 6.7% of total degradation
products of Fesoterodine. More preferably, such a pharmaceutical
composition contains no more than about 6.78% of total hydrolyzation and
degradation products of Fesoterodine after storage under such conditions.
[0140]A pharmaceutical composition comprising Fesoterodine and xylitol
vial such that after about 12 weeks at about 40° C., about 75%
r.H. in an open vial at least about 80%, about 85%, about 90%, or about
95% of the original amount of Fesoterodine in the composition remains,
i.e., is undegraded.
[0141]A pharmaceutical composition comprising Fesoterodine and xylitol,
against degradation at about 25° C., about 60% r.H. in a closed
vial such that after about 6 weeks at about 25° C., about 60% r.H.
about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%,
about 0.4%, about 0.3%, about 0.2%, or about 0.1% of Active Metabolite of
Formula II. More preferably, such a pharmaceutical composition contains
no more than about 0.18% of Active Metabolite of Formula II after storage
[0142]A pharmaceutical composition comprising Fesoterodine and xylitol,
about 0.4%, or about 0.3% of total degradation products of Fesoterodine.
More preferably, such a pharmaceutical composition contains no more than
about 0.31% of total hydrolyzation and degradation products of
Fesoterodine after storage under such conditions.
[0143]In further additional embodiments, the stabilizer used in
pharmaceutical composition comprising Fesoterodine can be sorbitol. Thus,
exemplary, non-exhaustive examples of such compositions include the
[0144]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 7%, about 6.9%, about 6.8%, or about 6.7% of Active Metabolite of
no more than about 6.71% of Active Metabolite of Formula II after storage
[0145]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 3%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%,
about 2.4%, about 2.3%, about 2.2%, or about 2.1% of Active Metabolite of
no more than about 2.14% of Active Metabolite of Formula II after storage
[0146]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 11%, about 10.9%, about 10.8%, about 10.7%, about 10.6%, about
10.5%, or about 10.4% of total degradation products of Fesoterodine. More
preferably, such a pharmaceutical composition contains no more than about
10.48% of total hydrolyzation and degradation products of Fesoterodine
after storage under such conditions.
[0147]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 4%, about 3.9%, about 3.8%, about 3.7%, or about 3.6% of total
degradation products of Fesoterodine. More preferably, such a
pharmaceutical composition contains no more than about 3.66% of total
[0148]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 0.4%, or about 0.3% of Active Metabolite of Formula II. More
0.39% of Active Metabolite of Formula II after storage under such
[0149]A pharmaceutical composition comprising Fesoterodine and sorbitol,
about 1%, about 0.9%, about 0.8%, about 0.7%, or about 0.6% of total
pharmaceutical composition contains no more than about 0.64% of total
[0150]In a further embodiment, provided is a granulate of Fesoterodine and
at least one suitable excipient, preferably a stabilizer selected from
dextrose, and combinations thereof, and even more preferably a sugar
alcohol chosen from xylitol and sorbitol. Optionally, at least one
further excipient may be included in such granulate.
[0151]Whereas Fesoterodine itself was found to have degraded after about
12 weeks at about 40° C., 75% relative humidity (r.H.) in open
vials to the extent that only about 50% of the original Fesoterodine
remained in undegraded form, a granulate of Fesoterodine and xylitol was
found to have about 93% of the original amount of Fesoterodine remaining
in undegraded form after about 12 weeks under the same conditions.
[0152]Thus, exemplary, non-exhaustive examples of Fesoterodine granulate
[0153]A granulate of Fesoterodine and a stabilizer such as xylitol,
wherein the Fesoterodine in the granulate is stable against degradation
at about 40° C., about 75% r.H. in an open vial such that after
about 12 weeks at about 40° C., about 75% r.H. in an open vial at
least about 80%, about 85%, about 90%, or about 95% of the original
amount of Fesoterodine in the granulate remains, i.e., is undegraded.
[0154]A granulate of Fesoterodine and a stabilizer such as xylitol,
about 6 weeks at about 40° C., about 75% r.H. in an open vial the
granulate contains no more than about 1%, about 0.9%, about 0.8%, about
0.7%, about 0.6%, or about 0.5% of Active Metabolite of Formula II by
weight. More preferably, such a granulate contains no more than about
0.58% of Active Metabolite of Formula II after storage under such
[0155]A granulate of Fesoterodine and a stabilizer such as xylitol wherein
the Fesoterodine in the granulate is stable against degradation at about
40° C., about 75% r.H. in a closed vial such that after about 6
weeks at about 40° C., about 75% r.H. in a closed vial the
0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, or about 0.2% of
Active Metabolite of Formula II. More preferably, such a granulate
contains no more than about 0.23% of Active Metabolite of Formula II
[0156]A granulate of Fesoterodine and a stabilizer such as xylitol,
granulate contains no more than about 2%, about 1.9%, about 1.8%, about
1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, or about 1.2% of
total degradation products of Fesoterodine. More preferably, such
granulate contains no more than about 1.25% of total hydrolyzation and
[0157]A granulate of Fesoterodine and a stabilizer, preferably xylitol,
at about 40° C., about 75% r.H. in a closed vial such that after
about 6 weeks at about 40° C., about 75% r.H. in a closed vial the
0.7%, about 0.6%, about 0.5%, about 0.4%, or about 0.3% of total
degradation products of Fesoterodine. More preferably, such granulate
contains no more than about 0.37% of total hydrolyzation and degradation
products of Fesoterodine after storage under such conditions.
[0158]A granulate of Fesoterodine and a stabilizer, preferably xylitol,
at about 25° C., about 60% r.H. in a closed vial such that after
about 6 weeks at 25° C., about 60% r.H. in a closed vial the
0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or
about 0.1% of Active Metabolite of Formula II. More preferably, such a
granulate contains no more than about 0.12% of Active Metabolite of
[0159]A granulate of Fesoterodine and a stabilizer, preferably xylitol,
about 6 weeks at about 25° C., about 60% r.H. in a closed vial the
total degradation products of Fesoterodine. More preferably, such a
granulate contains no more than about 0.22% of total hydrolyzation and
[0160]In further additional embodiments, the granulate includes sorbitol,
polydextrose, isomalt, or dextrose as the stabilizer. Exemplary,
non-exhaustive examples of such granulate include the following.
[0161]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
in the granulate is stable against degradation at about 40° C.,
about 75% r.H. in an open vial such that after about 6 weeks at about
40° C., about 75% r.H. in an open vial the granulate contains no
more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about
0.5%, or about 0.4% of Active Metabolite of Formula II. More preferably,
such granulate contains no more than about 0.48% of Active Metabolite of
[0162]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
about 75% r.H. in a closed vial such that after about 6 weeks at about
40° C., about 75% r.H. in a closed vial the granulate contains no
more than about 2%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about
1.5%, or about 1.4% of Active Metabolite of Formula II. More preferably,
such granulate contains no more than about 1.47% of Active Metabolite of
[0163]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, or
about 0.9% of total degradation products of Fesoterodine. More
preferably, such granulate contains no more than about 0.91% of total
[0164]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
more than about 3%, about 2.9%, about 2.8%, or about 2.7% of total
contains no more than about 2.79% of total hydrolyzation and degradation
[0165]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
in the granulate is stable against degradation at about 25° C.,
about 60% r.H. in a closed vial such that after about 6 weeks at about
25° C., about 60% r.H. in a closed vial the granulate contains no
0.5%, about 0.4%, or about 0.3% of Active Metabolite of Formula II. More
preferably, such granulate contains no more than about 0.36% of Active
Metabolite of Formula II under such conditions.
[0166]A granulate of Fesoterodine and sorbitol, wherein the Fesoterodine
more than about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, or
about 0.5% of total degradation products of Fesoterodine. More
preferably, such granulate contains no more than about 0.51% of total
[0167]The stability of Fesoterodine in pharmaceutical compositions
comprising Fesoterodine and xylitol described herein has been tested for
up to 24 months in closed containers at about 25° C., about 60%
r.H. and found to be remarkably high. (See Table 3).
[0168]Accordingly, in another embodiment, provided is a pharmaceutical
composition comprising Fesoterodine and xylitol wherein the Fesoterodine
in the pharmaceutical composition is stable against degradation at about
25° C., about 60% r.H. in a closed vial such that after about 3
months at about 25° C., about 60% r.H. in a closed vial the
pharmaceutical composition contain no more than about 0.1% to about 0.6%
of Active Metabolite of Formula II. More preferably, such pharmaceutical
composition contains no more than about 0.16%, about 0.50%, or about
0.58% of Active Metabolite of Formula II when stored under such
[0169]Other, exemplary, non-exhaustive examples of such compositions are
[0170]A pharmaceutical composition comprising Fesoterodine and a
stabilizer, preferably xylitol, wherein the Fesoterodine in the
pharmaceutical composition is stable against degradation at about
pharmaceutical composition contains no more than about 0.2% to about 0.6%
composition contains no more than about 0.21%, about 0.53%, or about
0.69% of Active Metabolite of Formula II when stored under such
[0171]A pharmaceutical composition comprising Fesoterodine and a
25° C., about 60% r.H. in a closed vial such that after about 9
pharmaceutical composition contains no more than about 0.3% to about 0.7%
composition contains no more than about 0.31%, about 0.65%, or about
0.71% of Active Metabolite of Formula II when stored under such
[0172]A pharmaceutical composition comprising Fesoterodine and a
25° C., about 60% r.H. in a closed vial such that after about 12
pharmaceutical compositions contain no more than about 0.4% to about 0.9%
compositions contain no more than about 0.39%, about 0.75%, or about
0.88% of Active Metabolite of Formula II when stored under such
[0173]A pharmaceutical composition comprising Fesoterodine and a
25° C., about 60% r.H. in a closed vial such that after about 18
pharmaceutical composition contains no more than about 0.3% to about 1%
composition contains no more than about 0.37%, about 0.85%, or about
1.018% of Active Metabolite of Formula II when stored under such
[0174]A pharmaceutical composition comprising Fesoterodine and a
25° C., about 60% r.H. in a closed vial such that after about 24
pharmaceutical compositions contain no more than about 0.8% to about 1.1%
composition contains no more than about 0.78%, about 0.94%, or about
1.14% of Active Metabolite of Formula II when stored under such
[0175]A pharmaceutical composition comprising Fesoterodine and a
pharmaceutical composition contains no more than about 1% of total
degradation products of Fesoterodine. More preferably, such
pharmaceutical composition contains no more than about 1.05% of total
hydrolyzation and degradation products of Fesoterodine when stored under
[0176]A pharmaceutical composition comprising Fesoterodine and a
pharmaceutical composition contains no more than about 1.1% of total
hydrolyzation and degradation products of Fesoterodine.
[0177]A pharmaceutical composition comprising Fesoterodine and a
pharmaceutical composition contains no more than about 1.2% of total
[0178]A pharmaceutical composition comprising Fesoterodine and a
pharmaceutical composition contains no more than about 1.4% of total
pharmaceutical compositions contain no more than about 1.37% of total
[0179]A pharmaceutical compositions comprising Fesoterodine and a
pharmaceutical composition contains no more than about 1.3% of total
pharmaceutical composition contains no more than about 1.26% of total
[0180]A pharmaceutical composition comprising Fesoterodine and a
pharmaceutical composition which is stable against degradation at about
pharmaceutical composition contains no more than about 2% of total
pharmaceutical composition contains no more than about 1.95% of total
[0181]In another embodiment, the production of the pharmaceutical
pharmaceutically acceptable salt thereof comprises granulating
Fesoterodine with a stabilizer selected from the group consisting of
thereof, preferably a sugar alcohol like xylitol or sorbitol.
[0182]Thus, the production of granulates comprising granulating a mixture
of Fesoterodine or a salt thereof, with a suitable excipient such as a
sugar alcohol, preferably sorbitol or xylitol, and more preferably
xylitol, forms a further aspect of the disclosure herein.
[0183]Further provided are granulates of Fesoterodine formed by such a
process with a suitable excipient, such as a stabilizer selected from the
and combinations thereof, preferably a sugar alcohol, preferably sorbitol
or xylitol, and more preferably xylitol.
[0184]Granulate produced from such a granulation step preferably has a
Fesoterodine/stabilizer ratio of about 1-30% [w/w], more preferably about
1-20% [w/w], more preferably about 3-15% [w/w], and even more preferable
about 5-10% [w/w]. In a particularly preferred embodiment, granulate
includes a Fesoterodine/xylitol or Fesoterodine/sorbitol ratio of about
1-30% [w/w], preferably about 1-20% [w/w], more preferably about 3-15%
[w/w], and even more preferably about 5-10% [w/w].
[0185]The average size of the granulate can be controlled by usual
techniques such as sieving or milling, and typically may be below about 4
mm, preferably below about 2 mm, more preferably below about 1 mm, and
even more preferably below about 0.75 mm, e.g. about 0.5 mm.
[0186]Fesoterodine granulates as described herein, particularly if
produced in a wet granulation process, are surprisingly stable under
humid stress conditions. The granulates can be further processed and
incorporated into pharmaceutical compositions that are also surprisingly
[0187]It has been further surprisingly found that granulating Fesoterodine
with either xylitol or sorbitol provides for enhanced stability during
the granulation process as compared to granulating Fesoterodine with
either mannitol or maltitol. When Fesoterodine was granulated separately
with these four sugar alcohols and tested for the amount of hydrolyzation
or total degradation that occurred during granulation, it was found that
granulating with xylitol or sorbitol resulted in less degradation
products than granulating with mannitol or maltitol. Granulating with
xylitol or sorbitol led to the formation of about 0.06% to about 0.07% of
hydrolyzation products and total degradation products, while granulating
with mannitol or maltitol led to the formation of about 0.42% to about
0.73% of hydrolyzation products and total degradation products. (See
[0188]The surprisingly superior results observed for granulation with
xylitol or sorbitol were also observed when Fesoterodine granulates
including xylitol or sorbitol were used to prepare pharmaceutical
compositions. Pharmaceutical compositions in tablet form that were
prepared with granulates of Fesoterodine that included xylitol or
sorbitol exhibited far less hydrolyzation products and total degradation
products (about 0.06% to about 0.11%) than tablets prepared with
Fesoterodine granulates containing mannitol or maltitol (about 1.1% to
about 1.7%). (See Table 7).
[0189]The difference between sorbitol and mannitol is especially
surprising since these two sugar alcohols are isomers.
[0190]Accordingly, in another embodiment, provided is the use of
granulates comprising Fesoterodine and a stabilizer, such as sugar
alcohol described herein, for the treatment of urinary incontinence,
frequency and the preparation of a medicament for treating such
conditions. Preferably, the granulates which are used for preparing the
medicament (such as, e.g., a tablet) comprise a sugar alcohol (such as,
e.g., xylitol or sorbitol). The medicament may be in the form of, e.g., a
granulate, a capsule, a lozenge, a tablet or a coated tablet, or other
solid administration form.
[0191]In yet a further embodiment, provided is a pharmaceutical
pharmaceutically acceptable salt or solvate thereof, preferably
Fesoterodine hydrogen fumarate, that can be obtained by combining or
mixing the granulate described herein with at least one further
excipient, preferably with at least one type of sustained release agent,
such as hydroxypropyl methylcellulose, and optionally other excipients.
[0192]In another aspect, the active ingredient (Fesoterodine or a
pharmaceutically acceptable salt thereof) and a stabilizer are embedded
in a gel matrix formed by at least one type of hydroxypropyl
methylcellulose. More preferably, a granulate comprising the active
ingredient (Fesoterodine or a pharmaceutically acceptable salt thereof)
and a stabilizer, preferably a sugar alcohol selected from xylitol and
sorbitol, are embedded in a gel matrix formed by at least one type of
hydroxypropyl methylcellulose. Such a formulation comprising
Fesoterodine, a stabilizer and a gel matrix formed by at least one type
of hydroxypropyl methylcellulose is preferably designed to release
Fesoterodine over an extended period of time, preferably to allow for
once-daily oral administration. Suitably, such a once-daily formulation
contains at least about 20% hydroxypropyl methylcellulose by weight of
the total weight of the formulation, and more preferably at least about
25% (w/w), such as between 25% and 65%, and even more preferably at least
about 30% (w/w), such as between 30% and 65%, and particularly preferably
at least about 35% (w/w) such as between 35% and 55% HPMC.
[0193]It has been determined that the presently disclosed formulations
that are suitable for once-daily administration in humans exhibit a
particular Fesoterodine release profile in in vitro dissolution assays.
These formulations and their dissolution profiles form another embodiment
[0194]The particularly preferred formulations of the present disclosure,
such as for examples the formulations "A", "B", "C", "D", "E", "F", "G"
and "H" given in Tables 1 and 2 of the Experimental part of this
application, were shown in clinical studies and/or in bioequivalence
studies to be effective for the once-daily administration in man. They
all exhibit a particular Fesoterodine release profile in in-vitro
dissolution assays. These formulations and other formulations showing the
respective dissolution profiles form another embodiment of the present
[0195]Pharmaceutical compositions comprising Fesoterodine that show a
cumulative Fesoterodine release (in weight percent based on the
dissolution assay according to USP 711 (in phosphate buffer, about pH
6.8, about 37° C., at about 75 rpm) are disclosed as follows:
[0196](a) about 5 to about 30%, preferably about 6 to about 26%
Fesoterodine release after about 1 hour, [0197](b) about 15% to about
40%, preferably about 18% to about 38% Fesoterodine release after about 2
hours, [0198](c) about 35% to about 65%, preferably about 36% to about
56% Fesoterodine release after about 4 hours, and [0199](d) at least
about 75%, preferably at least about 80% Fesoterodine release after about
[0200]The gel matrix may optionally contain further ingredients. In
particular, a filler such as lactose and/or microcrystalline cellulose
also may be embedded in the matrix.
[0201]In another embodiment, a solid Fesoterodine composition comprises at
least two types of hydroxypropyl methylcellulose (HPMC). The two types of
hydroxypropyl methylcellulose (HPMC) may be chemically identical but
differ in their viscosity, when dissolved in water under standard
conditions. Alternatively, two types of HPMC which differ chemically may
[0202]A particularly advantageous composition can be obtained when one
type of hydroxypropyl methylcellulose has a nominal viscosity of about
100,000 mPas (i.e., 100,000±20,000 mPas), and the other has a nominal
viscosity of about 4,000 mPas (i.e., 4,000±1000 mPas) when dissolved
in water at about 22° C. in a concentration of about 2% by weight.
[0203]In one preferred embodiment, the ratio of Fesoterodine or the
pharmaceutically active salt or solvate thereof and hydroxypropyl
methylcellulose is between about 1:80 and about 1:5 [w/w]. Even more
preferred are weight ratios of between about 1:70 and about 1:10 [w/w]
and even more preferably between about 1:40 and about 1:15 [w/w].
[0204]Another preferred embodiment is a solid pharmaceutical composition
that comprises about 0.25 to about 10% [w/w] Fesoterodine or its
pharmaceutically acceptable salt or solvate. Most preferred compositions
include Fesoterodine in an amount between about 0.5 and about 4% [w/w]. A
preferred composition further may contain one or more additional
excipient(s), such as one or more filler(s), binder(s) and/or
lubricant(s), and among them lactose, microcrystalline cellulose, talc
and glycerol dibehenate are particularly preferred.
[0205]The pharmaceutical composition provided herein is preferably a
granulate, a tablet or a coated tablet.
[0206]A solid pharmaceutical composition, like those that described
herein, may comprise the active ingredient Fesoterodine or a
pharmaceutically acceptable salt or solvate thereof, at least one type of
hydroxypropyl methylcellulose, and optionally other excipients. In a
preferred embodiment, the pharmaceutical composition further comprises a
stabilizer, such as sugar alcohol chosen from xylitol and sorbitol,
particularly xylitol, as one of the excipients.
[0207]The compositions are preferably formulated in a unit dosage form.
Each unit dosage form can contain from about 0.5 to about 20 mg,
preferably about 1-8 mg, and more preferably about 2, about 4, or about 8
mg of Fesoterodine or a pharmaceutically acceptable salt thereof, such
as, e.g., the hydrogen fumarate salt. The term "unit dosage form" refers
to physically discrete units suitable as unitary dosages for human beings
or other mammals, each unit containing a predetermined quantity of
Fesoterodine or its salt calculated to produce the desired therapeutic
effect, in addition with suitable pharmaceutical excipients. Most
preferred are solid administration forms (such as tablets, coated
tablets, granulates and capsules) that only require a once-daily
administration to the patient to achieve the desired therapeutic effect.
[0208]Pharmaceutical excipients that may be present in the compositions
described herein include sustained release ("SR") agents, disintegrants,
fillers and lubricants. Other excipients can also be included.
Sustained Release ("SR") Agents
[0209]The hydroxypropyl methylcellulose (HPMC) or mixture of HPMCs that is
a component of the pharmaceutical composition may act as a binder and
sustained release agent. It is preferably present in an amount that
allows for the formation of a gel matrix from which the active ingredient
is gradually released.
[0210]In addition, the pharmaceutical composition may comprise further
sustained release agents, preferably those that swell upon contact with
water such as polyvinylpyrrolidone, hydroxyethylcellulose,
hydroxypropylcellulose, other cellulose ethers and esters like
methylcellulose, methylethylcellulose, hydroxypropylmethylcellulose,
carboxymethylcellulose, starch, pregelatinized starch, polymethacrylate,
polyvinylacetate, microcrystalline cellulose, dextrans or mixtures
[0211]In a preferred embodiment, two types of hydroxypropyl
methylcellulose of a different viscosity are used. In these mixtures, one
HPMC may have a high viscosity and one HPMC may have a low viscosity.
[0212]"High viscosity HPMCs" are those having at (22° C.) a nominal
viscosity (by Ubbelohde viscometers) of between about 70,000 and about
150,000, and preferably of about 100,000 (i.e., 100,000±20,000) mPas
when dissolved (about 2% by weight) in water. "Low viscosity HPMCs"
refers to HPMCs having at room temperature a nominal viscosity of between
about 3,000 and about 20,000, and preferably of about 4,000 mPas (i.e.,
4,000±1,000 mPas) when dissolved (about 2% by weight) in water.
Preferably the rate of substitution with methoxyl groups of the HPMCs
used is between about 15 and about 35%, and particular preferred between
about 18 and about 30%, while the rate of substitution with
hydroxypropoxy groups is preferably between about 5 and about 14%, and
more preferably between about 7 and about 12%. Suitable qualities are
found in, for example, METHOCEL® E4M, METHOCEL® K4M,
METHOCEL® K15M and METHOCEL® K100M which are obtainable from the
[0213]Particularly preferred brands are METHOCEL® K100M having a
nominal viscosity of about 100,000 mPas and METHOCEL® K4M having a
nominal viscosity of about 4,000 mPas. The weight ratios of METHOCEL®
K100M and K4M used in the compositions and formulations described herein
can be in the range of about 20:1 to about 1:2, and are preferably in the
range of about 10:1 to about 1:1.5, and are even more preferably in the
range of about 7:1 to about 1:1.3.
[0214]In one embodiment, one distinct type of hydroxypropyl
methylcellulose may be used, such as, e.g., HPMC with a nominal viscosity
of between about 50,000 and about 120,000 mPas, wherein HPMC with a
viscosity of between about 50,000 and about 100,000 mPas is preferred.
[0215]Further, the compositions and formulations described herein can also
contain disintegrants, such as pregelatinized starch, sodium starch
glycolate, microcrystalline cellulose, carboxymethylcellulose sodium
(CMC-Na), cross-linked CMC-Na, polacrilin potassium, low-substituted
hydroxypropylcellulose or mixtures thereof. The presence of a
disintegrant in compositions and formulations described herein is not
necessary, but may desirable.
[0216]The pharmaceutical compositions described herein can further contain
fillers and/or binders such as microcrystalline cellulose, powdered
cellulose, lactose (anhydrous or monohydrate), compressible sugar, starch
(e.g., corn starch or potato starch), pregelatinized starch, fructose,
sucrose, dextrose, dextrans, other sugars such as mannitol, maltitol,
sorbitol, lactitol and saccharose, siliconized microcrystalline
cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate
dihydrate, dicalciumphosphate dihydrate, tricalciumphophate, calcium
lactate or mixtures thereof.
[0217]Preferably, the excipients include at least one filler selected from
microcrystalline cellulose and lactose, such as lactose monohydrate. One
preferred embodiment includes as filler a combination of microcrystalline
cellulose and lactose, wherein the microcrystalline cellulose:lactose
ratio can be about 1:1 to about 1:3 [w/w]. A particularly preferred
excipient is MICROCELAC® 100, which is a co-processed mixture of
about 75% by weight lactose monohydrate and about 25% by weight
microcrystalline cellulose, both of pharmacopoeial quality, manufactured
by combined spray-drying. In MICROCELAC® 100, both the filling
properties of lactose and the binding capacity of microcrystalline
cellulose are synergistically co-processed to one excipient providing
improved flow properties and better tableting performance to the
[0218]The compositions described herein also can comprise binders, such as
cellulose derivatives (e.g., methylcellulose and sodium
carboxymethylcellulose), gelatin, glucose, lactose, sucrose, polyethylene
glycol, polymethacrylates, hydroxypropylcellulose, sugar alcohols (such
as, e.g., sorbitol or xylitol), pregelatinized starch and sodium
alginate, wherein xylitol and sorbitol are preferred, and wherein xylitol
is particularly preferred. These may be helpful to form granules.
[0219]If binders are used to form granulates, they preferably can be used
in mean particle size of about 1-300 μm, preferably about 1-200 μm,
and even more preferably about 5-100 μm. Most preferably, the binder
particles should be smaller than about 1 mm.
[0220]For example, if xylitol is used to form granules, suitable qualities
are provided by XYLITAB® 300 or XYLITOL® CM50 (both produced by
Xyrofin Oy, Kotka, Finland and commercialized by Danisco) and XYLITOL 90
(produced by Roquette GmbH, Germany)
[0221]The compositions and formulations disclosed herein also can comprise
lubricants, antiadherents and/or glidants such as stearic acid, magnesium
stearate, calcium stearate, sodium lauryl sulphate, hydrogenated
vegetable oil, hydrogenated castor oil, sodium stearyl fumarate,
macrogols, glycerol dibehenate, talc, corn starch, silicone dioxide or
[0222]The preferred lubricants are talc and glycerol dibehenate.
[0223]The term "glycerol dibehenate" as used herein shall be considered
synonymous with "glyceryl behenate".
[0224]Optionally, compositions and formulations described herein,
including cores/tablets, can be coated with conventional materials used
for film coating, e.g., as described in Pharmaceutical Coating
Technology, 1995, edited by Graham Cole. Film coating compositions
usually contain the following components: polymer(s), plasticizer(s),
colorant(s)/opacifier(s), vehicle(s). Minor quantities of flavours,
surfactants and waxes also can be used in the film coating solution or
suspension. The majority of the polymers used in film coatings are either
cellulose derivatives, such as the cellulose ethers, or acrylic polymers
and copolymers. Occasionally encountered are high molecular weight
polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol and waxy
[0225]Typical cellulose ethers are hydroxyethylcellulose,
hydroxypropylcellulose, hydroxypropyl methylcellulose and
methylcellulose. Acrylic polymers comprise a group of synthetic polymers
with diverse functionalities. Some of them can be further modified to
enhance swelling and permeability by the incorporation of materials such
as water soluble cellulose ethers and starches in order to ensure
complete disintegration/dissolution of the film.
[0226]The commonly used plasticizers can be categorized into three groups:
polyols (glycerol, propylene glycol, macrogols), organic esters
(phthalate esters, dibutyl sebacetate, citrate esters, triacetin),
oils/glycerides (castor oil, acetylated monoglycerides, fractionated
coconut oil).
[0227]Colorants/opacifiers are classified into several groups: organic
dyes and their lakes, inorganic colors, natural colors. Different
materials from each group can also be combined in defined ratios.
[0228]One suitable composition of a coating suspension (calculated on dry
material) comprises: [0229](a) about 1-99% by weight of polymer,
preferably about 1-95% of polymer, [0230](b) about 1-50% by weight of
plasticizer, preferably about 1-40% of plasticizer, [0231](c) about
0.1-20% of colorant/opacifier, preferably about 0.1-10% of
colorant/opacifier.
[0232]Film coats may be prepared from ready-to-make preparations which are
available on the market. One preferred film-coat material is OPADRY®,
particularly OPADRY® blue, which is a mixture of 6 components, i.e.,
polyvinyl alcohol (film forming agent), PEG (plasticizer), lecithin
(emollient), talc (lubricant), titanium dioxide (white pigment), indigo
carmine aluminium lake (dye). Depending on the desired opacity, the
preferred amount the coating is about 4-6% w/w of the tablet, preferably
[0233]A film coating dispersion or suspension can be prepared by using
different solvents (water, alcohols, ketones, esters, chlorinated
hydrocarbons), but water is preferred.
[0234]Preferred exemplary, non-exhaustive examples of solid pharmaceutical
compositions will now be described. All percentages are weight based
[w/w], relating to the total weight of the composition, unless indicated
[0235]In one embodiment is a pharmaceutical composition that comprises:
[0236](a) About 0.5-4.0% [w/w] of Fesoterodine or a salt thereof,
preferably Fesoterodine hydrogen fumarate. [0237](b) About 5-25% [w/w] of
a stabilizer, preferably sorbitol or xylitol. The stabilizer preferably
has a mean particle size of about 0.001-0.30 mm. [0238](c) About 20-40%
[w/w] of fillers and/or binders, such as lactose monohydrate and
microcrystalline cellulose. [0239](d) About 20-80% [w/w] hydroxypropyl
methylcellulose, and preferably about 25-65%, more preferably about
30-65%, and even more preferably about 35-55% [w/w] hydroxypropyl
methylcellulose. [0240](e) About 1-10% [w/w] lubricants, such as glycerol
dibehenate and/or talc.
[0241]More preferably is a pharmaceutical composition that comprises:
[0242](a) about 0.3-5.0% [w/w] of Fesoterodine or a salt thereof,
preferably Fesoterodine hydrogen fumarate; [0243](b) about 5-25% [w/w] of
a stabilizer, preferably sorbitol or xylitol (preferably having a mean
particle size of about 0.001-0.30 mm); [0244](c) about 20-40% [w/w] of a
mixture comprising about 45-80%, preferably about 75% [w/w] lactose
monohydrate and about 20-55%, preferably about 25% [w/w] microcrystalline
cellulose; [0245](d) about 20-80%, preferably about 25-65%, more
preferably about 30-65%, and even more preferably about 35-55% [w/w]
hydroxypropyl methylcellulose; [0246](e) about 1-10% [w/w] lubricants,
such as glycerol dibehenate and/or talc.
[0247]In another specific embodiment, a pharmaceutical composition
comprises [0248](a) about 0.5-4.0% [w/w] of Fesoterodine hydrogen
fumarate; [0249](b) about 5-25% [w/w] of a stabilizer, preferably
sorbitol or xylitol (preferably having a mean particle size of about
0.001-0.30 mm); [0250](c) about 20-40% [w/w] of a mixture comprising
about 75% (w/w) lactose monohydrate and about 25% [w/w] microcrystalline
cellulose; [0251](d) about 15-55%, and preferably about 15-40% [w/w] high
viscosity hydroxypropyl methylcellulose; [0252](e) about 5-30%, and
preferably about 5-25% [w/w] low viscosity hydroxypropyl methylcellulose;
[0253](f) about 1-5% [w/w] glycerol dibehenate; and [0254](g) about 1-5%
[w/w] talc.
[0255]A coating may optionally be applied to such a composition. One
preferred material for film-coating is OPADRY®, but other coatings
[0256]In yet another embodiment is a pharmaceutical composition that
comprises: [0257](a) about 0.1-10%, preferably about 0.2-7%, more
preferably between 0.3 and 5%, and even more preferably about 0.5-4.0%
Fesoterodine or a salt thereof, preferably the hydrogen fumarate salt,
[0258](b) about 20-80%, preferably about 25-65%, more preferably about
30-65%, and even more preferably about 35-55% HPMC, wherein the HPMC may
comprise two or more different types, such as a high-viscosity HPMC
(e.g., METHOCEL® K100M) and a low-viscosity HPMC (e.g., METHOCEL®
K4M). The ratio of high-viscosity HPMC to low-viscosity HPMC may be about
20:1 to about 1:2 [w/w], and preferably is about 10:1 to about 1:1.5
[w/w], and even more preferably is about 7:1 to about 1:1.3 [w/w].
[0259](c) about 1-45%, preferably about 2-35%, and more preferably about
5-25% xylitol or sorbitol, [0260](d) about 10-70%, preferably about
15-50%, and more preferably about 20-40% a filler, and [0261](e) about
0.5-10%, preferably about 1-8%, and more preferably about 2-7% a
[0262]A particularly preferred solid pharmaceutical composition comprises
[w/w]:
Fesoterodine hydrogen fumarate about 0.5-4.0%
Xylitol about 5-25%
MICROCELAC ® 100 about 20-40%
HPMC (high viscosity) about 15-40%
HPMC (low viscosity) about 5-25%
Glycerol dibehenate about 1-5%
Talc about 1-5%
and optionally a pharmaceutically acceptable coating.
In this particularly preferred embodiment the preferred mean particle size
of xylitol is about 1-300 μm, more preferably about 1-200 μm, and
even more preferably about 5-100 μm. In the most preferred embodiment,
all particles should preferably be less than about 1 mm.
[0263]Another preferred embodiment is a coated tablet comprising a core
that further comprises:
Fesoterodine hydrogen fumarate about 4.0 mg
Xylitol (preferably with a mean about 36.0 mg
particle size of about 0.001-0.30 mm)
MICROCELAC ® 100 about 121.5 mg
HPMC having a nominal viscosity about 70.0 mg
of about 100,000 mPa s when
dissolved (about 2% by weight) in
water, preferably METHOCEL ® K100M
HPMC having a nominal viscosity of about about 70.0 mg
4,000 mPa s when dissolved
(about 2% by weight) in water,
preferably METHOCEL ® K4M
Glycerol dibehenate about 10.0 mg
Talc about 8.5 mg
and a coating, preferably OPADRY ®, and more preferably about 15 mg
OPADRY ®.
[0264]The pharmaceutical compositions in addition may contain minor
amounts (less than about 3%, and more preferably less than about 1% by
weight) of impurities. Moreover, the compositions preferably contain no
more than about 5% by weight water which may be used during the
[0265]In yet another embodiment is a coated tablet comprising a core
Fesoterodine hydrogen fumarate about 8.0 mg
Xylitol (preferably with a mean about 72.0 mg
particle size of about 0.001-0.20 mm)
MICROCELAC ® 100 about 77.5 mg
HPMC having a nominal viscosity of about about 120.0 mg
100,000 mPa s when dissolved
preferably METHOCEL ® K100M
HPMC having a nominal viscosity of about about 24.0 mg
of OPADRY ®.
[0266]The present pharmaceutical compositions can be prepared by known
procedures, e.g., compression or granulation. In the preparation of the
pharmaceutical compositions, Fesoterodine or a pharmaceutically
acceptable salt or solvate thereof usually can be mixed with an excipient
or mixture of excipients, or diluted by an excipient or mixture of
excipients, or enclosed within an excipient or mixture of excipients.
[0267]Granulates comprising Fesoterodine or a pharmaceutically acceptable
salt or solvate thereof can be produced by granulation, for example by
dry granulation or, preferably, by wet granulation. Wet granulation is
usually performed by adding a liquid, e.g., water, to a mixture of the
active ingredient (i.e., Fesoterodine or its salts or solvates) and the
binder used to form granulates (e.g., a sugar alcohol selected from
sorbitol and xylitol) and then granulating the wet mixture.
[0268]In one embodiment, wetting a mixture of Fesoterodine and sorbitol or
xylitol can be performed in conventional granulation equipment, such as a
high shear mixer (e.g., Lodige MGT 250) or fluid bed spray dryer (e.g.,
Glatt GPCG 60/90), by spraying a liquid such as, e.g., ethanol,
isopropanol, aqueous solutions of ethanol or isopropanol, or preferably
water or an aqueous granulating liquid onto the mixture of Fesoterodine
and xylitol or sorbitol by conventional pharmaceutical techniques.
Wetting also can be performed by direct addition of a liquid, such as
water or an aqueous granulating liquid to the above mixture during a
mixing operation in a proper mixing device, e.g., a high-shear mixer
granulator. The term "aqueous granulating liquid" refers to an aqueous
dispersion which contains purified or demineralised water (Ph.Eur.) as a
liquid and a solid substance which is dispersed, suspended or dissolved
[0269]The mixing of excipients alone or with Fesoterodine may be effected
in conventional devices used for mixing of powders, e.g., motionless
(passive) mixers, fluidized bed, diffusion, biconic diffusion, biconic,
turbular, cubic, planetary, Y-, V-shaped or high-shear mixers.
[0270]For drying the wet granulate, conventional drying systems such as
fluid-bed dryers or drying chambers can be used.
[0271]In the processes as described above, compression, in particular to
tablets, can be effected using an automatic rotary tablet machine from
different manufacturers of equipment for use in the pharmaceutical
[0272]Conventional equipment can be used for applying a film coating, such
as the Driacoater 1200 coating system or other conventional coating pans
[0273]The process for preparing the pharmaceutical composition can be
carried out as a wet or dry granulation process or as a direct
[0274]It has been determined, surprisingly, that Fesoterodine is
particularly stable in a pharmaceutical composition that is produced in
the presence of a liquid, preferably water, and particularly if the
pharmaceutical composition comprising Fesoterodine is produced via a wet
granulation process, particularly preferably if water is used as the
liquid in the wet granulation process.
[0275]Since Fesoterodine contains an ester functional group, it was
expected that exposing Fesoterodine to water would lead to more
hydrolyzation of the ester than not exposing Fesoterodine to water. Thus,
prior to the Applicants' work, more hydrolyzation was expected from wet
granulation processes than from dry granulation processes. Instead,
surprisingly, for example, pharmaceutical compositions of Fesoterodine
and xylitol in the form of tablets that were produced by a process
including wet granulation were tested for stability for 6 weeks at
40° C., 75% r.H. in closed vials and were found to contain only
about 0.5% hydrolyzation product (i.e., Active Metabolite) and only about
0.7% total degradation products (see Table 8). In contrast, tablets
comprising Fesoterodine and xylitol that were produced by direct
compression (i.e., a process not including wet granulation), stored under
the same conditions, were found to contain about 1.3% hydrolyzation
product (i.e., Active Metabolite) and about 2.1% total degradation
products (see Table 8).
[0276]Accordingly, another embodiment provide is a pharmaceutical
composition comprising Fesoterodine and xylitol, which pharmaceutical
composition contains no more than about 0.5% (and in particular, no more
than about 0.48%) hydrolyzation product (i.e., Active Metabolite) and no
more than about 0.7% (and in particular, no more than about 0.68%) total
degradation products after storage for 6 weeks at about 40° C.,
about 75% r.H. in closed vials.
[0277]Pharmaceutical compositions of Fesoterodine and xylitol in the form
of tablets that were produced by a process including wet granulation were
tested for stability for 6 months at room temperature in closed vials,
and were found to contain only about 0.2% hydrolyzation product (i.e.,
Active Metabolite) (by weight as compared to Fesoterodine) and only about
1.3% total degradation products (see Table 9). In contrast, tablets
comprising Fesoterodine and xylitol that were produced by dry
granulation, stored under the same conditions, were found to contain
about 0.8% hydrolyzation product (i.e., Active Metabolite) and about 1.7%
total degradation products (by weight as compared to Fesoterodine) (see
[0278]Accordingly, also provided herein is a pharmaceutical composition
comprising Fesoterodine and xylitol, which pharmaceutical composition
contains no more than about 0.2% (and in particular, no more than about
0.27%) hydrolyzation product (i.e., Active Metabolite) and no more than
about 1.3% (and in particular, no more than about 1.33%) total
degradation products after storage for 6 months at room temperature in
closed vials.
[0279]Also provided is an improved process for producing a granulate of
Fesoterodine and a stabilizer, preferably xylitol or sorbitol comprising
the step of wet granulating Fesoterodine and the stabilizer. Similarly,
provided is a granulate of Fesoterodine and a stabilizer, preferably
xylitol or sorbitol produced by a process comprising the step of wet
granulating Fesoterodine and the stabilizer, preferably xylitol or
sorbitol, particularly preferably xylitol. In a preferred embodiment,
water is used in wet granulation.
[0280]The process of wet granulation may comprise: [0281](a) providing a
mixture of Fesoterodine and a stabilizer, such as a stabilizing sugar
alcohol, including a sugar alcohol selected from xylitol or sorbitol;
[0282](b) adding water to the mixture to form a wet mixture; and
[0283](c) granulating the wet mixture.
[0284]The ratio of Fesoterodine:stabilizer in the mixture of step (a) may
be from about 1:1 to about 1:20, and is more preferably from about 1:1 to
[0285]In a preferred embodiment, the wet aqueous granulation process
comprises: [0286](a) providing Fesoterodine that is optionally
micronized or a pharmaceutically acceptable salt or solvate thereof,
[0287](b) granulating the Fesoterodine or the salt or solvate thereof
together with suitable excipients such as, e.g., a stabilizer such as a
sugar alcohol selected from sorbitol or xylitol, using water or a
water-based dispersion as granulation liquid to obtain a granulate,
[0288](c) mixing the above, optionally with HPMC and/or other excipients
to give a compression mixture, [0289](d) compressing the compression
mixture to the desired form, and [0290](e) optionally applying a coating.
[0291]In yet another embodiment, a pharmaceutical composition comprising
Fesoterodine or pharmaceutically acceptable salts thereof is produced by:
[0292](a) providing a dry mixture of Fesoterodine and a sugar alcohol
selected from xylitol and sorbitol; [0293](b) adding a liquid, preferably
water, to the mixture obtained in (a) to form a wet mixture; [0294](c)
granulating the wet mixture; [0295](d) drying the granulates; [0296](e)
mixing the granulates with at least one type of hydroxypropyl
methylcellulose to form a mixture of granulates and hydroxypropyl
methylcellulose and optionally adding other excipients; [0297](f)
pressing the mixture of granulates and hydroxypropyl methylcellulose into
tablets; and [0298](g) coating the tablets.
[0299]The pharmaceutical compositions described herein in the form of a
tablet, or optionally a coated tablet, are surprisingly stable under
harsh conditions (40° C., 75% relative humidity). The shelf-life
of a preferred composition at room temperature can be as long as 2 years.
[0300]6.4 kg of Fesoterodine fumarate and 57.6 kg of xylitol were weighed
separately. If xylitol had agglomerated, it was passed through a sieve
(1.5 mm). Fesoterodine fumarate and xylitol were passed through a sieve
(0.8 mm). The materials were transferred into a suitable high-shear mixer
granulator (e.g., Lodige Diosna V25 or Lodige Diosna P1/6) and mixed for
1 minute. 3.6 L of purified water were added to the dry mixture while
stirring. The mixture was stirred with a chopper for 90 to 120 seconds.
The mixer was emptied, and the contents were transferred to a sieving
machine. The wet granulate was passed through a sieve or a screen (4.0
mm). The sieved granulate was dried on trays at 45° C. for a
minimum of 8 h in a drying chamber/oven until a water content of not more
than 0.5%. The dried granulate was passed through a sieve (0.5 to 1.0
mm). Mixing (speed: 8 rpm) was performed for 5 minutes.
[0301]16.0 kg of the granulate and 48.6 kg of MICROCELAC® 100 were
passed through a sieve (0.5 to 1.0 mm) (e.g., FREWITT), transferred into
a mixing container and mixed (speed: 8 rpm) for 10 minutes. 28.0 kg of
hypromellose (e.g., METHOCEL® K100M), 28.0 kg of hypromellose (e.g.,
METHOCEL® K4M), 4.0 kg of glycerol dibehenate and 3.4 kg of talc were
added to the pre-mixture and mixed (speed: 8 rpm) for 1 minute. The
mixture was passed through a sieve (0.5 to 1.0 mm) (e.g., FREWITT) into a
mixing container. Mixing (speed: 8 rpm) for 10 to 30 minutes was
[0302]32.0 kg of the granulate and 31.0 kg of MICROCELAC® 100 were
a mixing container and mixed (speed: 8 rpm) for 10 minutes. 48.0 kg of
hypromellose (e.g., METHOCEL® K100M), 9.6 kg of hypromellose (e.g.,
[0303]The finished press mixture was transferred to a rotary tablet
machine and compressed to oval biconvex tablets.
[0304]OPADRY® and purified water were added to a vessel under
stirring. The mixture was stirred for at least 1 h. Then the suspension
was passed through a sieve of a suitable size (e.g., 300 μm) and
transferred into the solution tank of the coating pan (e.g., Driacoater
1200). A film coating was applied on the cores under constant stirring of
the suspension until the weight per coated tablet was 335 mg.
[0305]TABLE 1
Fesoterodine hydrogen fumarate 4.0 4.0 4.0
Xylitol 36.0 36.0 36.0
Lactose monohydrate (75%)/ 124.5 121.5 121.5
MICROCELAC ® 100)
Hypromellose (e.g. METHOCEL ® K100M) 70.0 70.0 70.0
Hypromellose (e.g. METHOCEL ® K4M) 70.0 70.0 70.0
Glycerol dibehenate 8.0 10.0 10.0
Talc 7.5 8.5 8.5
Purified water q.s.* q.s.* q.s.*
Film-coat White White Blue
10.0 10.0 15.0
Total 330.0 330.0 335.0
*removed during drying of the wet granulate or during film-coating, to a
total residual moisture of approx. 2.5-3.5%
Fesoterodine hydrogen fumarate 8.0 8.0 8.0 8.0 8.0
Xylitol 72.0 72.0 72.0 72.0 72.0
Lactose monohydrate (75%)/ 80.5 140.0 80.5 77.5 77.5
(e.g. MICROCELAC ® 100)
Hypromellose (e.g. METHOCEL ® 120.0 165.0 120.0 120.0 120.0
Hypromellose (e.g. METHOCEL ® 24.0 33.0 24.0 24.0 24.0
Glycerol dibehenate 8.0 11.0 8.0 10.0 10.0
Talc 7.5 11.0 7.5 8.5 8.5
Purified water q.s.* q.s.* q.s.* q.s.* q.s.*
Film-coat 15.0 15.0 10.0 10.0 15.0
Total 335.0 455.0 330.0 330.0 335.0
total residual moisture of approx. 2.5-3.0%
[0306]The tablet compositions of Examples A, F, and G containing 4, 8, and
8 mg Fesoterodine hydrogen fumarate, respectively, were tested for
stability. The results are shown in Table 3 below.
[0307]The purity of the Fesoterodine in the tablets was measured under the
following HPLC conditions and taken as an indication of stability:
[0308]Column: Prontosil Spheribond CN, 5 μm, 250 mm×4 mm or
equivalent [0309]Component A: Water/trifluoroacetic acid 1000/1 (v/v)
[0310]Component B: Acetonitrile/trifluoroacetic acid 1000/1 (v/v)
[0311]Gradient profile:
[0311]Time (min) % A % B
0.0 75 25
10.0 75 25
10.1 50 50
19.0 50 50
[0312]Flow rate: 1.2 mL/min. [0313]Column temperature: 35° C.
[0314]Injection volume: 75 μL [0315]Detection wavelength: 220 nm
[0316]The retention time of the Active Metabolite was about 4.7 min;
response factor: 1.5.
[0317]Evaluation of the HPLC results was by the area percent method.
[0318]The average content of hydrolyzation or degradation product (% by
weight) observed after storage at 25° C., 60% r.H. in closed
containers (25 mL brown glass bottle sealed with a plastic cap and a
paraffin sealing, without any desiccant), for representative compositions
is shown in Table 3 below.
Ex. A Ex. F Ex. G Ex. G
4 mg 8 mg 8 mg 8 mg
Time of Storage % Hydr % Hydr % Hydr % Degr
Initial 0.47 0.51 0.11 0.69
3 months 0.50 0.58 0.16 1.05
6 months 0.53 0.69 0.21 1.10
9 months 0.70 0.65 0.31 1.20
12 months 0.88 0.75 0.39 1.37
18 months 0.85 1.01 0.37 1.26
24 months 0.94 1.14 0.78 1.95
% Hydr = Hydrolyzation product of Fesoterodine (Active Metabolite) [% by
[0319]Fesoterodine hydrogen fumarate, a granulate containing Fesoterodine
hydrogen fumarate and xylitol in a weight-ratio of 10:90, as well as a
composition comprising Fesoterodine hydrogen fumarate and xylitol were
stored in open vials (25 ml brown glass bottles) for up to 12 weeks at
40° C. and 75% r.H. The results are shown in Table 4 below.
[0320]The degradation of Fesoterodine was measured by HPLC. The following
conditions were used to measure degradation products in the stability
testing of Fesoterodine hydrogen fumarate: [0321]Column: Polaris
C18-Ether, 3 μm, 250 mm×4.6 mm [0322]Eluent A:
Water/methanesulfonic acid 1000:0.5 (v/v) [0323]Eluent B:
Acetonitrile/methanesulfonic acid 1000:0.5 (v/v) [0324]Typical gradient
[0324]Time (min) % A % B
0.0 67 33
16.0 38 62
[0325]Column temperature: 35° C. [0326]Flow rate: 1.2 mL/min
[0327]Detection wavelength: 220 nm [0328]Injection volume: 20 μL
[0329]The retention time of the Active Metabolite was about 4.1 min
(rrt=0.50); response factor: 1.4.
[0330]Evaluation of the HPLC results was by the area percent method.
[0331]A comparison of the observed average purity of a
Fesoterodine-containing granulate and a corresponding composition as
compared to pure Fesoterodine after open storage under stress conditions
is set out in Table 4, wherein values are indicated in % of Fesoterodine
hydrogen fumarate remaining at various times.
at 40° C. Granulate containing
and 75% Fesoterodine Fesoterodine/Xylitol Composition
r.H. (pure) 10%/90% (wt/wt) (Ex. B)
Initial 98.96% 99.04% 99.18%
1 week 98.56% 98.83% not measured
2 weeks 97.67% 98.61% 96.98%
4 weeks 94.32% 97.45% 94.79%
12 weeks 50.39% 92.83% 89.76%
[0332]Blends of Fesoterodine hydrogen fumarate with xylitol, sorbitol,
mannitol and maltitol were stored for 6 weeks and 3 months in closed
vials at 25° C. and 60% r.H., in closed vials at 40° C. and
75% r.H., or in open vials at 40° C. and 75% r.H. and then tested
for stability by measuring the purity of Fesoterodine. The initial purity
of the Fesoterodine in the blends was 99.7%.
[0333]Table 5a shows that while Fesoterodine is stabilized against
degradation in open vials when mixed with xylitol or sorbitol, it
decomposes more rapidly when mixed with mannitol and maltitol.
Blend closed vial closed vial open vial
Fesoterodine 25° C., 60% 40° C., 75% 40° C., 75%
with: r.H. r.H. r.H.
6 weeks 99.6 98.7 98.7
3 months 99.6 98.2
6 weeks 99.6 95.7 98.6
3 months 99.6 65.2
6 weeks 99.4 98.2 99.0
3 months 99.0 98.5
6 weeks 99.6 99.3 98.7
3 months 99.5 70.2
6 weeks 99.6 89.6 91.7
3 months 99.4 42.8
6 weeks 99.7 94.4 94.5
3 months 99.6 41.3
6 weeks 99.6 94.2 95.4
3 months 99.5 53.7
6 weeks 99.6 95.1 96.3
3 months 99.6 51.2
6 weeks 99.6 99.3 96.3
3 months 99.7 53.1
[0334]Table 5b shows that lactose destabilizes Fesoterodine, while xylitol
is capable of reducing the destabilizing effect of lactose
6 weeks 99.7 98.0 86.2
3 months 99.6 42.8
6 weeks 99.6 97.3 96.2
3 months 99.5 59.8
6 weeks 99.9 99.2 98.8
3 months 99.6 97.8
6 weeks 99.6 97.1 98.6
3 months 99.5 83.8
[0335]Granulates of Fesoterodine with various sugars, sugar alcohols,
polyols, or derivatives thereof were produced as described in Example 1.
After production of the granulates, and after six weeks and three months
of storage under various conditions, the purity of the Fesoterodine in
the granulates was determined. The results are given in Table 6.
Closed vial Closed vial Open vial
Feso-Granulate 25° C., 60% r.H 40° C., 75% r.H 40°
C., 75% r.H
with % Hydr % Degr % Hydr % Degr % Hydr % Degr
Start 0.45 0.87 0.45 0.87 0.45 0.87
6 weeks 6.08 8.03 10.40 18.86 28.14 40.72
3 months 10.37 12.83 28.15 57.64 40.52 63.62
Start 0.42 0.83 0.42 0.83 0.42 0.83
6 weeks 3.80 5.43 7.90 16.77 22.14 45.52
3 months 13.85 17.71 11.44 29.72 43.11 72.05
Start 0.06 0.06 0.06 0.06 0.06 0.06
6 weeks 0.12 0.22 0.23 0.37 0.58 1.25
3 months 0.23 0.28 7.04 14.77 1.14 4.01
Start 0.07 0.07 0.07 0.07 0.07 0.07
6 weeks 0.36 0.51 1.47 2.79 0.48 0.91
3 months 0.74 0.99 7.58 18.03 0.91 3.38
Start 0.35 0.63 0.35 0.63 0.35 0.63
6 weeks nd nd 19.67 46.23 20.69 44.73
3 months 20.90 27.90 17.32 92.55 21.14 88.25
Start 0.19 0.55 0.19 0.55 0.19 0.55
6 weeks nd nd 8.47 13.31 23.57 55.14
3 months 5.43 6.92 10.65 19.81 20.78 64.40
monohydr 1:9
3 weeks 0.36* 0.83* 0.73 1.3 nd nd
6 weeks 0.39* 0.81* 1.3 2.3
3 weeks 0.39* 0.79* 0.75 1.3 nd nd
6 weeks 0.73* 1.2* 1.0 1.8
dextrose 1:9
3 weeks 0.21* 0.58* 0.41 0.8 nd nd
6 weeks 0.25* 0.71* 0.42 0.9
[0336]Granulates of Fesoterodine with various sugars and sugar alcohols
were produced as described in Example 1. These granulates were then used
to produce 4 mg tablets according to Example 2.1 and with the composition
given as "Example C" in Table 1, as well as wherein the xylitol was
substituted with mannitol, maltitol, sorbitol, or lactose. After
production of the tablets, and after six weeks and three months of
storage under various conditions, the amount of degradation of the
Fesoterodine was determined by measuring the purity of the Fesoterodine.
Tablets 25° C., 60% r.H 40° C., 75% r.H 40° C., 75%
Fesoter. 6 weeks 6 weeks 6 weeks
Start 1.23 1.95 1.23 1.95 1.23 1.95
6 weeks 6.29 8.61 14.68 29.32 22.24 42.84
3 months 16.58 23.21 24.06 60.11 26.62 69.83
Start 1.11 1.78 1.11 1.78 1.11 1.78
6 weeks 5.31 7.68 11.46 23.67 22.38 40.38
3 months 11.16 15.95 26.87 68.52 26.65 69.94
Start 0.06 0.12 0.06 0.12 0.06 0.12
6 weeks 0.18 0.31 1.09 1.54 4.40 6.78
3 months 0.64 0.88 3.91 6.68 6.76 13.51
Start 0.11 0.21 0.11 0.21 0.11 0.21
6 weeks 0.39 0.64 2.14 3.66 6.72 10.48
3 months 1.03 1.29 9.81 18.54 10.79 20.49
Start 0.67 1.03 0.67 1.03 0.67 1.03
6 weeks 3.94 5.47 22.96 41.54 23.56 43.39
3 months 11.14 15.24 41.54 51.14 42.74 51.17
% Hydr. = Hydrolyzation product of Fesoterodine (Active Metabolite) [% by
(f) Stability of Fesoterodine in Tablets after Wet Granulation Vs. Direct
[0337]Tablets with the composition of "Example C" of Table 1 were obtained
either (a) by the process according to Examples 1 and 2.1., i.e., by wet
granulating Fesoterodine and xylitol or (b) by the direct compression of
all excipients. The tablets were then subjected to stability testing for
6 weeks and 3 months at 40° C., 75% r.H. in closed vials. The
% Hydrolyzation by % Total Degradation
Tablets produced by weight by weight
6 weeks 0.48 0.68
3 months 1.69 2.92
6 weeks 1.32 2.08
3 months 4.71 8.72
[0338]Hydrolyzation by weight refers to the percent by weight of Active
[0339]Total degradation by weight refers to the percent by weight of total
degradation products of Fesoterodine.
[0340]Tablets with the composition of "Example C" of Table 1 were prepared
[0341]3.5 kg Fesoterodine hydrogen fumarate was blended with 31.5 kg
xylitol and sieved through a 0.032'' sieve. The blend was dry compacted
with a roller compactor at a pressure of 1250 psi. The compacted ribbons
were granulated via a 20 mesh screen in an oscillator granulator. The
material was further screened through a 0.040'' grater screen. 33.91
MICROCELAC® 100 and 15.09 kg hypromellose K100M were added and
blended. After sieving over 0.040'', the blend was dry compacted at 700
psi. After compaction, the material was granulated via a 16 mesh
oscillating sieve and finally via a 0.062'' grater screen. 37.41 kg
hypromellose K100 M, 0.5 kg hypromellose K4M and 3.72 kg talc were added,
blended and the blend sieved via a 0.062'' grater screen. After
subsequent blending, 4.38 kg glyceryl behenate were added and the mixture
was blended to the press mixture.
[0342]The finished press mixture was transferred to a rotary tablet
[0343]OPADRY® and purified water were added to a vessel under
[0344]The tablets were subjected to stability testing at room temperature
for 6 months in closed vials.
[0345]Table 9 shows the result of the stability testing of the composition
produced by dry granulation compared to a composition produced by wet
granulation according to Example 1.
Composition Hydrolyzation by Total degradation
produced by weight by weight
Dry Granulation 0.83 1.79
Wet Granulation 0.27 1.33
[0346]Hydrolyzation by weight refers to the percent by weight of Active
[0347]Total degradation by weight refers to the percent by weight of total
7. In Vitro Dissolution Profile of Pharmaceutical Compositions Containing
Various Amounts of HPMC
[0348]The in-vitro dissolution profiles of Fesoterodine tablets with
different HPMC contents were determined. The composition of the tablets
is shown in Table 10 below.
4 mg 4 mg 4 mg 8 mg 8 mg 8 mg
[mg] [mg] [mg] [mg] [mg] [mg]
Fesoterodine/xylitol 40.00 40.00 40.00 80.00 80.00 80.00
MICROCELAC ® 100 121.50 165.50 197.50 77.50 125.50 157.50
METHOCEL ® K100M 70.00 48.00 32.00 120.00 80.00 53.00
METHOCEL ® K4M 70.00 48.00 32.00 24.00 16.00 11.00
Compritol 888 ATO 10.00 10.00 10.00 10.00 10.00 10.00
Talc 8.50 8.50 8.50 8.50 8.50 8.50
Total 320.00 320.00 320.00 320.00 320.00 320.00
[0349]The in-vitro dissolution profiles were determined by the following
[0350]Dissolution Tester: e.g. Erweka DT800 [0351]Dissolution method:
according to USP <711> Drug Release, App. 2 [0352]Temperature:
37° C.±0.5° C. [0353]RPM: 75 [0354]Sampling volume: 5 mL
(medium replacement after each sampling) [0355]Sinker: yes
[0356]Dissolution Medium: phosphate buffer pH 6.8
[0356] [0357]Column: Spherisorb CN, 5 μm, 250 mm×4 mm
[0358]Mobile phase: Acetonitrile/Water/Trifluoro acetic acid 550:450:1
(v/v/v) [0359]Flow rate: 0.8 mL/min [0360]Oven temperature: 35° C.
[0361]Autosampler temperature: 20° C. [0362]Injection volume: 50
μL [0363]Detection: UV at 220 nm [0364]Retention times:
[0364] Fesoterodine hydrogen fumarate approx. 4.4 min
Active Metabolite approx. 4.0 min
[0365]Run Time: 6.5 min
[0366]The dissolution results are shown in Table 11a (4 mg) and Table 11b
(8 mg) below and in FIGS. 1A (4 mg) and 1B (8 mg).
amount of HPMC
1 18 21 19
2 31 35 37
4 49 55 59
16 93 96 76
1 18 21 23
2 31 37 40
4 50 60 63
16 93 100 96
[0367]Numbers refer to the percent release of Fesoterodine fumarate. The
total amount of Fesoterodine fumarate in the tablets was 4 mg.
[0368]Based on these dissolution profiles the formulations having a HPMC
content of over 30% (formulations "I" and "L") are particularly
preferred. Another formulation matching the most preferred dissolution
profile was formulation "O" given in Table 11c below:
Fesoterodine hydrogen fumarate 4.0
Xylitol 76.0
Lactose monohydrate 43.0
Microcrystalline cellulose 41.5
Hypromellose (e.g. METHOCEL ® K100M) 70.0
Hypromellose (e.g. METHOCEL ® K4M) 70.0
Glycerol dibehenate 8.0
Purified water q.s.*
Film-coat --
8. Lack of Electrocardiographic Effects of Fesoterodine Formulations
[0369]Fesoterodine formulations were administered orally to steady state
at dosages of 4 mg and 28 mg per day to healthy male and female human
subjects and the effect of such administration on QT values was
[0370]The Fesoterodine 4 mg formulation was as follows. Higher dosage
levels were obtained by administering multiple 4 mg formulations.
Fesoterodine fumarate 4.0
Xylitol 36.0
Lactose monohydrate --
Microcryst. Cellulose --
Lactose monohydrate (75%)/ 121.5
Hypromellose (e.g. Methocel K100M) 70.0
Hypromellose (e.g. Methocel K4M) 70.0
Glycerol dibehenate/glyceryl 10.0
Talc 8.5
Purified water q.s.a
Film-coat White
aremoved during drying of the wet granulate or during film-coating,
to a residual moisture of approx. 2.5%
[0371]Steady state was determined by pharmacokinetic analysis of the
Active Metabolite. Assay sensitivity was shown by a significant increase
from baseline in QTcF and QTcI after multiple doses of moxifloxacin. The
mean time-averaged QTcF increased by 8.6 ms after three days of treatment
[0372]Multiple 4 mg and 28 mg doses of Fesoterodine did not exert an
effect on myocardial repolarization, as shown by similar decreases from
baseline in QTcF and QTcI between the Fesoterodine and placebo treated
groups. The mean time-averaged QTcF decreased by 4.7 ms, 4.6 ms, and 5.0
ms after three days of treatment with placebo, 4 mg Fesoterodine, and 28
mg Fesoterodine, respectively. Outlier analyses revealed no differences
between the Fesoterodine treatment groups and placebo. In contrast, a
higher incidence of QTc outliers was seen after treatment with
[0373]The study design was double-blind, single-site, randomized, placebo-
and positive controlled, parallel. Two hundred and fifty-six male and
female subjects were assigned to one of the following four treatment
groups (N=64 each; at least 50% female):
Fesoterodine 4 mg.day
[0374]Fesoterodine 28 mg/dayMoxifloxacin 400 mg/day
[0375]Subjects were administered 3 days of one of the above four
treatments. Three 12-lead ECGs were downloaded from an H-12 flash card
(data carrier) at each of the following time points on Days -1, 1, and 3:
1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, and 23.5 hours. Plasma samples for
the determination of Active Metabolite concentration (and the
concentration of further metabolites) were drawn on Day 1 and Day 3
predose and at 1, 2, 3, 4, 6, 8, 12, and 23.5 hours postdose.
[0376]FIG. 2 shows that results of the QTcF analyses on Day 1.
[0377]FIG. 3 shows that results of the QTcF analyses on Day 3.
[0378]FIG. 4 shows time-averaged changes in QTcF.
[0379]FIG. 5 shows time-averaged changes in QTcI.
[0380]Treatment with 4 mg or 28 mg Fesoterodine and with placebo resulted
in a slight decrease of QTcF and QTcI with no significant difference
between the active treatment groups and placebo. Assay sensitivity was
shown by an increase of QTcF and QTcI after treatment with moxifloxacin,
which was statistically significant as compared to Fesoterodine or
placebo treatments. Outlier analysis revealed no differences between the
Fesoterodine treatment groups and placebo, but a higher incidence after
treatment with moxifloxacin was seen.
9. Comparison of the Efficacy of Fesoterodine Fumarate and Tolterodine
[0381]A randomized, double-blind, double dummy, placebo and
active-controlled trial in adult male and female human subjects was
conducted. Once-daily 4 mg and 8 mg Fesoterodine fumarate was orally
administered to patients with overactive bladder and compared to placebo
and active-control (4 mg/day tolterodine 4 mg ER (extended release)).
[0382]The Fesoterodine formulations were as follows:
4 mg 8 mg 8 mg
Fesoterodine fumarate 4.0 8.0 8.0
Xylitol 36.0 72.0 72.0
Lactose monohydrate -- -- --
Microcryst. cellulose -- -- --
Lactose monohydrate (75%)/ 124.5 80.5 77.5
Hypromellose (e.g. Methocel 70.0 120.0 120.0
Hypromellose (e.g. Methocel 70.0 24.0 24.0
Glycerol dibehenate/glyceryl 8.0 8.0 10.0
Talc 7.5 7.5 8.5
Purified water q.s.a q.s.a q.s.a
Film-coat White White White
Total 330.0 330.0 330.0
to a residual moisture of approx. 2.5%.
[0383]The trial was conducted in 19 countries. A total of 1135 subjects
were randomized and 1103 subjects were included in the full analysis set:
279 in the placebo treatment group, 265 in the 4 mg Fesoterodine
treatment group, 276 in the 8 mg Fesoterodine treatment group, and 283 in
the 4 mg tolterodine ER treatment group. The mean age of subjects was 57
years. A total of 81% were female and 97% were white. There were no
notable differences among the treatment groups with respect to gender,
race, age, or weight/BMI.
[0384]The efficacy results demonstrated statistically significant (all
p≦0.001) improvements compared to placebo at the end of treatment
in the primary variables requested by both the USFDA (change in average
number of micturitions per 24 hours and change in the average number of
urge incontinence episodes per 24 hours) and European regulatory
authorities (change in average number of micturitions per 24 hours and
treatment response (Yes/No variable) derived from a 4-category Treatment
Benefit Scale). The decreases in the number of micturitions and urge
incontinence episodes per 24 hours in the Fesoterodine 8 mg/day and 4
mg/day groups were significantly higher than in the placebo group. The
treatment response rates also were higher at the end of treatment in both
Fesoterodine dose groups compared to placebo. For all primary variables,
Fesoterodine 4 mg/day demonstrated a slightly higher numerical change
compared to placebo than tolterodine ER. This numerical difference was
more pronounced for Fesoterodine 8 mg/day.
[0385]For the safety set, the number of patients were: 283 in the placebo
treatment group, 272 in the Fesoterodine 4 mg/day treatment group, and
287 in the Fesoterodine 8 mg/day treatment group. The most common adverse
events were typical of those observed in subjects taking marketed
antimuscarinics. Dry mouth occurred more frequently in
Fesoterodine-treated subjects compared to placebo-treated subjects
(Fesoterodine 4 mg/day 22%, Fesoterodine 8 mg/day 34%, placebo 7%).
Constipation occurred more frequently in Fesoterodine-treated subjects
compared to placebo-treated subjects (Fesoterodine 4 mg/day 3%,
Fesoterodine 8 mg/day 5%, placebo 1%). Keratoconjunctivitis sicca
occurred more frequently in Fesoterodine-treated subjects compared to
placebo-treated subjects (Fesoterodine 4 mg/day 2%, Fesoterodine 8 mg/day
4%, placebo 0%). The incidence of dry throat was low in all groups
((Fesoterodine 4 mg/day 1%, Fesoterodine 8 mg/day 3%, placebo 0%) as was
urinary retention (Fesoterodine 4 mg/day 1%, Fesoterodine 8 mg/day 1%,
placebo 0%) and blurred vision (Fesoterodine 4 mg/day 1%, Fesoterodine 8
mg/day 1%, placebo 2%).
[0386]Table 14 shows the changes from baseline to end of treatment for the
micturition and incontinence variables and the rates of treatment
Pbo Feso 4 mg/day Feso 8 mg/day Tolt 4 mg/day
N = 279 N = 265 N = 276 N = 283
Variable Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Number of micturitions -1.02 (2.97) -1.74 (2.66) -1.94 (3.15) -1.69 (2.42)
Urge incontinence per 24 -0.84 (2.94) -1.44 (2.75) -1.81 (2.35) -1.43
Treatment response 53% 75% 79% 72%
aEnd of treatment is the last on-treatment visit based on an LOCF
[0387]Table 15 shows an ANCOVA analysis of the micturition variable.
Treatment Endpoint Treatment ANCOVA 95% CI for
Variable [n] LS Mean Contrast difference p-value the difference
Number of Placebo -0.95
micturitions [279]
per 24 hours Feso 4 mg -1.76 4 mg vs Pbo -0.81 <0.001 (-1.26, -0.36)
Feso 8 mg -1.88 8 mg vs Pbo -0.93 <0.001 (-1.38, -0.49)
Tolt 4 mg -1.73 Tolt 4 mg -0.78 0.001 (-1.23, -0.34)
[283] vs Pbo
[0388]Table 16 shows an ANCOVA analysis of the urge incontinence variable.
Urge Placebo -1.14
incontinence [211]
per 24 hours Feso 4 mg -1.95 4 mg vs Pbo -0.81 0.001 (-1.26, -0.35)
Feso 8 mg -2.22 8 mg vs Pbo -1.08 <0.001 (-1.52, -0.64)
Tolt 4 mg -1.74 Tolt 4 mg -0.60 0.008 (-1.04, -0.16)
[223] vs Pbo
The decreases in the number of micturitions and number of urge
incontinence episodes per 24 hours in the Fesoterodine 8
[0389]The decreases in the number of micturitions and number of urge
treatment response rates were also higher at the end of treatment in both
Fesoterodine dose groups compared to placebo.
[0390]FIGS. 6, 7, and 8 illustrate the changes from baseline by treatment
visit for the three primary variables. Improvements in all three primary
variables were observed as early as after two weeks of treatment (Visit
3=first point of post-baseline measurement).
[0391]A summary of the results of the closed testing procedure is provided
variables using closed testing procedures (FAS with LOCF
Testing procedure p-valuea Significantb
Step 1: Number of micturitions per 24 hours <0.001 Yes
Step 2: Number of micturitions per 24 hours <0.001 Yes
Step 3: Number of urge incontinence episodes per <0.001 Yes
24 hours Feso 8 mg/day vs pbo
Step 4: Number of urge incontinence episodes per 0.001 Yes
24 hours Feso 4 mg/day vs pbo
European Regulatory Authorities p-valuea Significantc
Step 1: Feso 8 mg/day vs pbo Yes
a) Number of micturitions per 24 hours <0.001
b) Treatment response <0.001
Step 2: Feso 4 mg/day vs pbo Yes
aNumber of micturitions and urge incontinence episodes analysed with
an ANCOVA model with terms for treatment and region and baseline value as
a covariate. Treatment response is analyzed using a normal approximation
method for binary data.
bSignificant based on closed testing procedure. Each step tested at
0.05 two-sided (0.025 one-sided). If result was not significant at any
step, then all steps after that are considered not statistically
cSignificant based on closed testing procedure. If both p-values at
Step 1 are less than 0.05 two-sided (0.025 one-sided), then 8 mg results
are statistically significant. If Step 1 is statistically significant and
both p-values at Step 2 are less than 0.05 two-sided (0.025 one-sided),
then 4 mg results are statistically significant.
[0392]For the USFDA analysis, all 4 p-values in the closed testing
procedure were less than 0.05. Therefore, both Fesoterodine doses (4 mg
and 8 mg/day) showed statistically significant improvement over placebo
at end of treatment for the micturitions and urge incontinence variables.
[0393]Similarly, for the European regulatory authorities analysis, all 4
p-values in the closed testing procedure were less than 0.05. Therefore,
both Fesoterodine doses (4 mg and 8 mg/day) showed statistically
significant improvement over placebo at end of treatment for the
micturitions and treatment response variables.
[0394]Treatment-emergent adverse events were reported for 107/283 (38%) of
subject in the placebo group, 135/272 (50%) of subjects in the
Fesoterodine 4 mg/day group, and 167/287 (58%) of subjects in the
Fesoterodine 8 mg/day group.
[0395]Table 18 summarizes the most common adverse events during the
overall treatment period (i.e., adverse events with an incidence of
≧3% in a treatment group) and other relevant adverse events
Summary of subject with treatment-emergent adverse
events reported by ≧3% of subjects in at least one treatment
Feso Feso
Pbo 4 mg/day 8 mg/day
MedDRA system organ N = 283 N = 272 N = 287
class/preferred term n (%) n (%) n (%)
Any adverse event 107 (38) 135 (50) 167 (58)
Keratoconjunctivitis sicca 0 6 (2) 12 (4)
Mouth dry 20 (7) 59 (22) 97 (34)
Constipation 4 (1) 9 (3) 13 (5)
Fatigue 1 (<1) 1 (<1) 1 (<1)
Urinary tract infection 6 (2) 8 (3) 9 (3)
Nasopharyngitis 7 (3) 8 (3) 5 (2)
Influenza 6 (2) 9 (3) 2 (<1)
Headache 14 (5) 12 (4) 7 (2)
SS = safety set
[0396]A randomized, double-blind, placebo-controlled trial in adult,
healthy male human subjects was conducted in which the pharmacokinetics
of Fesoterodine fumarate formulations at 4 mg, 8 mg, 12, mg, 20 mg, and
28 mg once-daily for three days was determined.
[0397]The Fesoterodine 4 mg formulation used was as follows. Higher dosage
Microcryst. cellulose 41.5
Lactose monohydrate (75%)/ --
Glycerol dibehenate/glyceryl 8.0
[0398]40 subjects were randomized. The subjects were healthy Caucasian
males, aged from 18 to 50 years, with a normal body weight as determined
by body mass index ranging between 20 to 28 kg/m2 and having normal
laboratory findings with respect to blood pressure, heart rate, and ECG.
[0399]Non-compartmental pharmacokinetic parameters were derived from the
individual concentration time curves of Active Metabolite of Fesoterodine
based on scheduled blood sampling times as well as from the individual
amounts of Active Metabolite excreted into urine and based on actual
[0400]All statistical summaries and displays were done based on scheduled
sampling times unless there were significant deviations of actual
sampling times from scheduled sampling times.
[0401]Plasma concentrations of Active Metabolite were displayed as
individual plasma concentration-time curves after single dose as measured
and after log-transformation. Summaries and displays of plasma
concentrations of Active Metabolite were done according to the following
[0402]Mean concentration-time curves (means±SD) were generated
according to the following rules: Mean concentrations were only
calculated if at least 2/3 (this was 4 in this trial) of the
concentrations were above LOQ. This was done to avoid that means towards
the end of the measurement period were biased by only few values above
LOQ. All values below LOQ were discarded. Descriptive statistics
including geometric means and geometric SD, were calculated and tabulated
per scheduled sampling time.
[0403]For the calculation of individual pharmacokinetic profile
parameters, concentration values were handled as specified above.
Parameters were listed for all subjects and summarized by dose level and
period by means of descriptive statistics, including geometric mean,
geometric SD including 90% confidence intervals for the geometric means.
These confidence intervals were derived via exponential retransformation
of the corresponding confidence intervals for means of the
log-transformed data. For tmax, a frequency table was also provided.
[0404]For the assessment of dose linearity of Active Metabolite,
Cmax, and AUC were dose normalized. The resulting dose-adjusted
parameters were then subjected to a one-way ANOVA with dose as
"treatment" factor. The dose-adjusted parameters were log-transformed
prior to submission to the ANOVA. Dose dependency of these
pharmacokinetic parameters (without dose adjustment) were also assessed
[0405]An evaluation of the amounts of Active Metabolite excreted into
urine was done similarly to the procedures outlined above for the plasma
concentrations. Cumulative excretion time curves were generated. The
total amount excreted into urine and the amount excreted into urine on
Day 3 were subjected to the same statistical procedures as outlined for
the plasma concentrations.
[0406]Table 20 shows the pharmacokinetic results.
4 mg 8 mg 12 mg 20 mg 28 mg
Day Parameter Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
1 Cmax (ng/mL) 2.19 (0.66) 4.31 (1.79) 5.88 (3.21) 12.36 (6.07) 16.29
tmax (hr) 5.17 (0.75) 4.83 (0.75) 5.00 (0.00) 5.50 (0.55) 5.60 (0.66)
Ctrough (ng/mL) 0.01 (0.02) 0.00 (0.00) 0.00 (0.00) 0.00 (0.00) 0.00
Lambdaz (1/hr) 0.12 (0.03) 0.10 (0.02) 0.11 (0.03) 0.12 (0.02) 0.11
t1/2 (hr) 6.11 (1.15) 7.42 (2.03) 6.75 (2.57) 5.87 (0.79) 6.94 (3.13)
AUC0-24 (hr * ng/mL) 17.99 (7.16) 44.48 (17.47) 61.81 (18.43) 126 (49)
181 (59.74)
AUC0-inf (hr * ng/mL) 20.09 (8.60) 51.79 (20.66) 69.29 (18.20) 137
(54.28) 208 (68.96)
Ae (mcg) 263 (88.2) 662 (246) 1132 (479) 1678 (506) 1681 (640)
2 Cmax (ng/mL) 1.92 (0.84) 3.73 (1.35) 5.63 (1.59) 12.01 (5.86) 18.14
tmax (hr) 5.67 (0.82) 5.67 (0.82) 5.67 (0.82) 5.67 (0.82) 6.00 (0.00)
Ctrough (ng/mL) 0.22 (0.14) 0.62 (0.33) 0.73 (0.22) 1.31 (0.65) 2.26
AUC0-24 (hr * ng/mL) 21.39 (9.60) 44.62 (17.00) 63.97 (16.11) 126
(60.42) 204 (50.74)
Ae (mcg) 305 (127) 708 (305) 1178 (515) 1744 (420) 2542 (646)
3 Cmax (ng/mL) 2.12 (1.28) 5.15 (2.02) 7.11 (3.01) 13.25 (7.25) 18.28
tmax (hr) 4.17 (2.04) 5.00 (0.00) 5.67 (1.21) 5.33 (0.52) 5.17 (0.41)
Ctrough (ng/mL) 0.37 (0.19) 0.74 (0.33) 0.82 (0.37) 1.41 (0.72) 2.81
Lambdaz (1/hr) 0.12 (0.07) 0.11 (0.02) 0.11 (0.03) 0.12 (0.03) 0.09
t1/2 (hr) 7.76 (4.09) 6.54 (0.91) 6.37 (1.55) 6.07 (1.16) 8.04 (2.07)
AUC0-24 (hr * ng/mL) 20.26 (11.44) 52.03 (21.76) 72.87 (25.37) 136
(68.78) 213 (73.28)
CLtot/f (L/min) 5.81 (6.63) 3.41 (2.83) 3.10 (1.29) 2.89 (1.10) 2.42
MRT (hr) 12.97 (5.65) 10.79 (0.87) 11.26 (1.94) 10.99 (1.68) 13.39
Vz/f (L) 2749 (1447) 1639 (1154) 1756 (947) 1551 (624) 1683 (717)
Ae (mcg) 317 (184) 671 (307) 1364 (487) 1757 (363) 2426 (593)
Clren (L/min) 0.26 (0.07) 0.21 (0.04) 0.33 (0.10) 0.24 (0.06) 0.20 (0.07)
Patent applications by Fatima Bicane, Rosrath DE
Patent applications by Hans Lindner, Leichlingen DE
Patent applications by Kerstin Paulus, Ratingen DE
Patent applications by Meike Irngartinger, Frechen DE
Patent applications by Michael Komenda, Koln DE
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