Specification PHARMACEUTICAL COMPOSITION FOR

Specification
PHARMACEUTICAL
COMPOSITION
FOR THERAPY
OF INTERSTITIAL
CYSTITIS
TECHNICAL
The
present
invention
disorder
drug
of
the
relates
of interstitial
lower
to
a
urinary
depressant
of
a
specifically
nerve,
sensory
capsaicin-sensitive
therapeutic
FIELD
cystitis,
tract,
hypersensitive
and/ or
abacterial
prostatitis.
BACKGROUND
Interstitial
primarily
as
is sterile cystitis
in women and is a disease exhibiting
severe
nocturia,
cystitis
ART
pain
and
urinary
frequency,
that occurs
symptoms
urinary
and a sense of suprapubic pressure
urgency,
or pain when the
bladder is filled, which is alleviated after urination
Opinion
on Invest Drug,
The abacterial
prostatitis
is sterile prostatitis
on the basis
of white
quantitative
determination
of bacteria
(1978),
to the
and
interstitial
is
blood
cell
in urine
counts
classification
of Drach,
thought
as
of
a
variant
(Expert Opinion
1
and
et al.
condition
on Invest
that
specimens
disease
cystitis
(Expert
10: p.521).
is diagnosed
according
such
Drug,
of
10:
p.521).
Hypersensitive
referred
to herein
hypersensitivity
occurs
even
disorder
means
of the lower urinary
the state of exhibiting
in anyone
in the absence
of the bladder
wall and urethra.
a pain by
or urethra
of infectious
urinary tract or apparent pathological
tract as
diseases
and
in the
changes in the bladder
During the infusion period of cytometrogram,
there is no increase in the intravesical
15 cm H20): nonetheless,
pressure
the physiological
(lower than
bladder volume is
small, and these finding are characteristics
for this disorder
(Diagnostic
Disorders
Criteria
of the Hypersensitive
by NJR
George in Sensory Disorders of the Bladder and Urethra, edited
by NJR George and JA Gosling, Springer-Verlag,
Berilin,
1986,
pp.17-29).
With respect
the intravesical
is approved
States,
to drugs to treat interstitial
administration
of dimethyl sulfoxide
by Food and Drug Administration
and
its mechanism
desensitization
of
of
cystitis,
action
is
in the United
considered
capsaicin-sensitive
(DMSO)
sensory
to be
nerves
(Expert Opinion on Invest Drug, 10: p.521 and J. Urol., 158:
pp.1989-1995).
instillation
Also, , it is reported
of capsaicin or resiniferatoxin,
same pharmacological
of interstitial
Suppl: p.254
that the intravesical
that is wi th the
action, improves pain or other symptoms
cystitis in clinical testing
(J. Urol., 157,
(1997) and J. Urol., 163, Suppl: p.60
2
(2000)).
In addition,
effective
against
bladder
pain,
urinary
tract
it is suggested
that resiniferatoxin
symptoms,
as
such
due to hypersensitive
that
is
not
accompanied
Accordingly,
having
a depressant
nerves
are
effective
interstitial
urinary
action
tract,
and/or
improving
pain
hypersensitive
abacterial
of improving
cystitis, hypersensitive
and
abacterial
extensive
a
result,
line-2-carboxylate
or
a
salt
the
lower
urinary
the
in
of the lower
in interstitial
present
inventors
on a compound
sensory
made
having
nerves.
OF THE INVENT'ION
present
inventjLon has
(hereinafter abbreviated
a
has
sensory
therapy of interstitial
the
symptoms
found
that
I-phenyl-l,2,3,4-tetrahydroisoquino-
thereof
capsaicin-sensitive
sensory
a novel therapeutic
on capsaicin-sensit:Lve
quinuclidin-3'-yl
that drugs
prostatitis.
investigations
DISCLOSURE
As
and
disorder
pain and symptoms
prostatitis,
action
(J. Urol., 164:
disorder of the lower urinary tract,
and intensive
a depressant
interstitial
it is considered
Thus, for the purpose of creating
drug capable
with
change
and
of the lower
on capsaicin-sensitive
for
cystitis,
urgency
disorder
cystitis nor the typical pathological
pp. 676 -679 (2000».
urinary
is
nerves
as "Compound A")
depressant
and
is useful
cystitis, hypersensitive
tract,
and/or
3
effect
abacterial
for
on
the
disorder of
prostatitis,
leading
to accomplishment
Compound
International
A
or
a
Patent
of the invention.
salt
thereof
Publication
disclosed
to have binding action
receptors
and
contraction
inhibitory
and indicated
for urogenital
diseases
pollakiuria/urinary
pain of urogenital
neither indicated
diseases
such
disorder
of
prostatitis
the
such
diseases
it
anticholinergic
has
on
exhibiting
painful
resul ts
of
excreted
giving
Test
Compound
symptoms
cystitis,
of
is
tract,
hypersensitive
and
abacterial
been
considered
have
only
of intersti tia.l cystitis
sensory
2.
and
at all.
and more.
Example
drug
and the therapy of specific
A is calculated
(Primary
later, Compound A,
a depressant
nerve
at
concentration
to be about
10 mg per day orally and about 3.6 ~
4
a minor
action
urinary
On the other hand, from the
the
mg per day orally.
that
2: pp.181-187).
instilled, exhibited
of 1 ~
M3
bladder
the improvement
urinary
capsaicin-sensitive
concentrations
rhythmic
However,
As shown in Test Example 1 described
when intravesically
is
incontinence
& Gyneco~ogy,
Care Update Obstetrics
and
as urinary
(antimuscarinics)
role in the drug therapy
in
for muscarine
on rat
hitherto
drugs
96/20194
selective
interstitial
is not disclosed
Also,
described
to be useful as a therapeutic
frequency.
lower
No.
effects
nor disclosed,
as
is
of
urinary
1 ..
9 ~
when
when giving 20
Accordingly,
thereof
it is considered
have an inhibitory
that Compound A or salts
activity
on capsaicin-sensitive
sensory nerves within the bladder by oral administration
and
are effective for improving pain and symptoms such as urinary
urgency in interstitial
the lower urinary
cystitis, hypersensitive
tract, and/or
Specifically,
abacterial
disorder of
prostatitis.
the invention relates to a pharmaceutical
composition
for
inhibition
nerve,
containing
of capsaicin-sensitive
sensory
quinuclidin-3'-yl
I-phen-
yl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate
pharmaceutically
ingredient,
acceptable
salt
and specifically
thereof
or
as
to a pharmaceutical
an
a
active
composition
for therapy of a urogenital disease selected from interstitial
cysti tis, hypersensitive
and abacterial
disorder of the :Lowerurinary tract,
prostatitis.
Also, the invention relates to use of quinuclidin- 3' -yl
I-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate
pharmaceutically
of a depressant
invention
acceptable
salt thereof for the production
of capsaicin-sensitive
relates
to
use
of
sensory
pharmaceutically
acceptable
of a therapeutic
drug of a urogenital
urinary
cystitis,
tract,
nerve.
qUinuclidin-3'-yl
yl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate
interstitial
or a
The
I-phenor
a
salt thereof for the production
hypersensitive
and abacterial
disease
disorder
prostatitis.
5
selected
from
of the lower
Also.
the invention
capsaicin-sensitive
a
patient
with
a
abacterial
incJ.uding administering
therapeutically
or
a
The invention
disease
hypersensitive
of depressing
effective
amount
pharmaceutically
relates
selected
disorder
prostatitis.
wi th a therapeutically
acceptable
to a method
from
of' the
including
effective
of therapy
interstitial
lower
salt
urinary
of a
cystitis.
tract.
administering
pharmaceutically
acceptable
The invention
amount of quinuclidin- 3' -yl
quinuclidin-3'-yl
Publication
of the drug of the invention
{compound
salt thereof.
described
below in more detail.
is
1-phenyl-1.2.3.4-tetrahydroisoquino-
line-2-carboxylate
salts
or a
salt thereof.
will be described
The active ingredient
and
a patient
1-phenyl-1.2.3.4-tetrahydroisoquinoline-2-carboxylate
acceptable
of
1-phenyl-1.2.3.4-tetrahydroisoquino-
line-2-carboxylate
urogenital
to a method
sensory nerves.
quinuclidin-3'-yl
thereof.
relates
in
A}
or
pharmaceutically
As such salts. are enumerated
the· foregoing
No. 96/20194.
a
Specific
International
examples
the
Patent
acid addition
salts of inorganic acid such as hydrochlor:ic acid. hydrobromic
acid.
hydroiodic
phosphoric
acid.
sulfuric
acid.
nitric
acid.
and
acid. or organic acids such as formic acid. acetic
acid. propionic acid. oxalic acid. malonic acid. succinic acid.
fumaric acid. maleic acid. lactic acid. malic acid. tartaric
acid. citric acid. methanesulfonic
6
acid. ethanesulfonic
acid.
aspartic
acid,
and glutamic
acid;
and quaternary
salts with halogen atom ions, triflates,
etc.
Above
all,
succinic
acid
ammonium
tosylates, mesylates,
salts
are
particularly
preferable.
Also,
since
aSYmmetric
carbon
the
active
atoms,
ingredient
an optically
active
existed, and hence the active ingredient
diastereomers
or enantiomers
Also, the active ingredient
hydrates
and
solvates
polymorphisms.
as
a succinic
thereof.
and
crystal
acid
salt of
1-phenyl-1,2,3,4-tetra-
hydroisoquinoline-2-carboxylate
particularly
is
includes all of
ethanol
quinuclidin-3'-yl
has
substance
isomers
of the invention
such
A)
includes mixtures of
and isolated
In the invention,
(+)-(lS,3'R)-
(Compound
(solifenacin)
is
preferable.
These compounds are readily available by the production
process
as described
Publication
No.
in the foregoing
96/20194
International
or according
to that
Patent
production
process.
The drug of the invention can be prepared as oral solid
preparations,
organic
or
oral liquid preparations
inorganic
carrier,
suitable
for
according
to
customary
ingredient
of the drug of the invention
absorbing property,
or
excipient,
additives
the
oral
an
or injections using an
parenteral
manner.
and
other
administration
Since
the
active
has excellent
oral
the drug of the invention is sui table for
7
oral preparations.
easily
take
conveyance
Oral solid preparations
themselves
and
are convenient
of oral
powders.
fine
sustained
release
solid preparations
granules.
least one active
granules.
products.
substance
cellulose.
such
starch.
corn
additives
as
(HPMC);
polyethylene
capsules.
tablets.
pills.
polyvinylpyrrol.idone.
The
composition
other than inert diluents
cel.lulose
lubricants
calcium
at
such
and
glycolate
and
may
such as binders
hydroxypropylmethyl
as magnesium
stearate.
glycol. starch. and talc; disintegrating
such as cellulose
and
glucose. microcrystalline
aluminate.
hydroxypropyl
cellulose
and
is mixed with at least one inert
starch.
metasilicate
include
In such solid compositions.
diluent such as lactose. mannitol.
contain
in storage
are the most preferable.
Examples
magnesium
that patients can
and carmellose
agents
calcium;
stabilizers such as lactose; dissolution aids such as glutamic
acid
and aspartic
glycol;
yellow
coloring
iron
desired.
coating
acid;
agents
oxide
plasticizers
such as titanium
according
the tablets
or pills
may
or intestinal
emulsJ..ons. solutions.
8
manner.
with
If
a sugar
cellulose phthalate.
soluble
The oral liquid preparations
acceptable
be coated
talc. and
agar. pectin. hydroxypropyl
and hydroxypropylmethyl
gastric-soluble
oxide.
to the customary
such as sugar. gelatin.
cellulose,
such as polyethylene
or a
f~lm.
include pharmaceutically
suspensions.
syrups
and
elixirs
and contain a generally
as purified water and ethanol.
an auxiliary
agent
such
employed
inert diluent
This composition
as wetting
agents
agents, a sweetener, a flavor, an aromatic,
in addition
The
may contain
and
suspending
or an antiseptic,
to the inert diluent.
injections
such
injections,
intramuscular
as
intravenous
and
and emulsions.
injections,
subcutaneous
include sterile aqueous or non-aqueous
injections
solutions, suspensions
Examples of diluents for aqueous solutions or
suspensions include distilled water and physiological
Examples of diluents for non-aqueous
glycol, vegetable oils
such as olive oil, alcohols such as ethanol,
such
Such a composition
as an antiseptic,
dispersant,
aid
(such
a stabilizer
as
composi tions
through
a
glutamic
are
a wetting
agent,
agents
an emulsifier,
a
(such as lactose), and a dissolution
acid
sterilized
and
aspartic
by,
for
filter,
agent, or irradiation.
used by producing
and Polysolvate
may further contain auxiliary
bacteria-holding
anti-bacterial
saline.
solutions or suspensions
include propylene glycol, polyethylene
80.
such
acid).
example,
filtration
compounding
Further,
a sterile solid composition
These
with
an
these can be
and dissolving
it in sterile water or a sterile solvent for injection before
use.
The
invention
dose
of
the
active
is properly determined
9
ingredient
depending
compound
of
the
on the individual
case
while
taking
into
symptom of a patient,
account
the
ingredient can be usually administered
1 to 100 mg/day, and preferably
once or dividedly
with
urogenital
the active
in a dose of from about
from 5 to 50 mg/day per adult
twice.
Incidentally,
combination
route,
age of the subject to be administered,
In the case of oral administration,
sex, etc.
while.
administration
the drug of the invention
other
diseases
drugs
that
simultaneously
are used
can be used in
for therapy
or after elapsing
Examples of drugs that can be used .incombination
the drug of the invention
injections
for a
with
include oral drugs such as pentosan
sulfate, anti-inflammatory
intravesical
of
steroids, and antihistamines;
such as Baci~~us
and
and
Ca~mette-Guerin
doxorubicin.
BRIEF EXPLANATIONB
Fig.
1
shows
capsaicin-induced
OF THE DRAWING
inhibitory
extravasation
effects
of
Compound
1
on
of Evans blue in the mouse
bladder.
BEST MODE FOR CARRYING
OUT THE INVENTION
The invention will be hereunder described in detail wi th
reference
to the following Examples and Test Examples, but it
should not be construed that the invention. is limited to these
Examples.
Incidentally,
Compound
10
1 as used in the following
Examples and so on means a succinic acid salt of (+) - (IS, 3'R)1-phenyl-1,2,3,4-tetrahydroisoquino-
quinuclidin-3'-yl
line-2-carboxylate
(solifenacin).
Example
preparation
Table
1: Capsule
1
--
Compound 1
Lactose
Total
Components
a capsule
10-mg Caps
ule
10.0 mg
190.0 m 9
200.0 m 9
.
1-mg Capsule
1.0 mg
199.0 mg
200.0 mg
J
g
loo.-m capSUl~
100.0 mg
100.0 mg
200.0 mg
as shown in Table 1 were mixed and filled in
to produce
capsule
preparations.
Test Example 1: Inhibitory action of Compound 1 aga.inst plasma
protein
induced
extravasation
by
capsaicin
in the mouse
bladder
(Method)
(l) Used animal:
In the
experiment,
four
or
five
female
Balb/c
mice
(Japan SLC, Inc.) per group were used.
(2)
Measurement
A catheter
anesthetized
of plasma protein
was
inserted
with urethane
extravasation:
into
the bladder
(intraperitoneally
with 0.15 ml of a 20 % solution
administered
per mouse) via the urethra,
and after emptying the bladder, a physiological
solution was injected.
of a mouse
saline or drug
This catheter was prepared by blunting
11
the tip of a 24-guage hypodermic needle and making a side hole
at 2 romfrom the newly prepared
instillation
plasma
into
proteins
stimulation
the
due
of
tip.
bladder,
to
the
About one hour after
extrava.scular
inflammatory
capsaicin-sensitive
according to the method of Maggi, et al.
Arch.
Pharmaco~.
(30 mg/kg)
killed
by cervical
After
removing urine
dye was extracted
of
!lL
from the bladder
overnight,
determined
by measuring
620 nm of
100 ilL
supernatant
addition,
the content
wet tissue
was calculated.
instilled
with
administered
light
by
nerve
5
Evans blue
(300
vein,
and
the mouse.was
then the bladder wa.sremoved.
and blood remaining
formamide
caused
and capsaicin
the administration,
dye in the organs was quantitatively
150
That is
to the mouse from the tail
dislocation,
of
(Nauny-Schmiedeberg'
a dye bound by plasma proteins
five minutes after
leakage
sensory
pp. 546- 555 (1987))..
, 336:
1l9/kg) were administered
precisely
reaction
the
in the tissue,
determined.
by placing
and
,~as
absorbance
the
Evans blue
the tissue
quantitatively
at a wavelength
in a 96-well
in
of
microplate.
of Evans blue dye ln one milligram
In
of
Moreover, the mouse intravesically
physiological
saline
with a capsaicin-free
and
intravenously
Evans blue solut.ion served
as a normal control.
(3) Test
drug and other
reagents:
Compound1 was dissolved
saline,
and then administered
and diluted
in physiological
into the bladder
12
at a volume of
100 !lLper mouse.
Wako
Pure
Capsaicin and formamide were purchased from
Chemical
Industries,
purchased from Aldrich.
blue,
physiological
Ltd.,
and
Evans
blue
was
As the vehicle for capsaicin and Evans
saline
containin9
0.1
%
dimethyl
sulfoxide and 0.1 % Tween 80 was used in a volume of 10 mL/kg.
(4) Statistic
processing:
Results were shown as [(mean values)
±
(standard errors
of the mean) ]. The Student's t -test was used to determine the
significance
of difference between the group of mice receiving
intravesicla
saline and stimulated
group
of normal
control
mice.
with capsaicin
With
respect
effects of Compound 1 in the mice administered
a significance
comparison
with
physiological
variance.
judged
was determined
the
saline
in the case where
wi th capsaicin,
intravesically
folloeing
In these tests,
to inhibitory
using the Dunnett's
group
the
t-test by
injected
one-way
the statistical
e and the
with
analysis
of
significance
was
the p value was less than 5 %.
(Results)
The experimental
value by comparison
physiological
0.0027;
the
(The p
between the normal control group and the
p value
of
the
analysis
groups
was
0.0033;
by the Dunnett's
physiological
are shown in Fig. 1.
saline group according to the Student t-test was
capsaicin-treated
determined
results
of variance
and
in
the p value,
t-test when comparing
the
as
with the
saline group, for 1, 10 and 100 !lM groups of
13
Compound
1 when was 0.043, 0.0053 and 0.0023. respect~vely.)
Capsa~c~n
mouse bladder
control
~ncreased
by about
group.
concentrat~ons
~ncreases
~n
respect~vely.
s~gn~f~cant
the Evans blue dye content
5 t~mes as compa.red w~ th the normal
Compound
1
dye
content
These changes
d~fference.
~ntraves~cally
extravascular
~njected
of 1, 10 and 100 ~
the
~ntraves~cally
52
brought
~~, 76
Compound
of 1 ~
capsa~c~n-sens~t~ve
sensory
and
80
%,
~nduced
1 as ~nfused
or more ~nh~b~ted the
of plasma prote~ns
react~on
%
about a stat~st~cally
Therefore,
to the ~nflammatory
at
reducE~d capsa~c~n-~nduced
by
at concentrat~ons
leakage
~n the
~n the bladder due
by st~mulat~on
of the
nerve.
Test Example 2: Amount (of compound 1) excreted to ur~ne after
oral adm~nistration
to humans
(Method)
For
Compound
of,
the
purpose
of
evaluat~ng
1 for the pharmacok~net~cs,
healthy
Compound
sUbjects
were
orally
adm~n~stered
tolerab~l~ ty and safety
repeatedlyadmin~stered
w~th
1 at a dose of 10 mg or 20 mg per day for 15 days.
To determine the amount compound 1 excreted ~nto ur~ne as the
non-metabolized
substance,
the~r ur~ne was collected
hours after the f~nal admin~strat~on.
added a sodium b~carbonate
substance,
for 24
To the ur~ne sample were
solut~on and an ~nternal standard
then, the m~xture
was extracted
14
w~th
tert-butyl
methyl
ether.
and
the organic
residue was dissolved
methanol,
layer
wa.s evaporated.
in a mixed solution
and Compound
1 was separated
liquid chromatog+aphy.
Detection
The
of acet~c acid and
by high-performance
of Compound
1 was carried
out by mass spectrometry.
(Results)
The results
are shown in Table
2.
Table 2
Dose of Compound
1
Male
Female
Male -Female
10 mg/day
20 mg/day
Assuming
(Review
that the daily urine volume is about one liter
of Medica~
concentration
was calculated
Excret ion amount in urine
(mg/day)
0.911
0.907
1. 844
1.690
Sex
13th Edition, p.643), the mean
Physio~ogy,
in urine of Compound
1 (mo:Lecular weight: 480)
to be about 1.9 ""Mfor oral administration
10 mg per day and about 3.6 !-tM for oral administration
of
of 20
mg per day.
From the results of Test Example
it
is considered
inflammation
that,
since
in the bladder
capsaicin-sensitive
sensory
1 and Test Example 2,
Compound
induced
nerve
1 can
by stimulation
when
orally
adult at doses from 10 to 20 mg per day, Compound
15
inhibit
given
the
of the
to an
1 is useful
for
the
therapy
interstitial
urinary
of
a
cystitis,
urogenital
disease
hypersensitive
tract, and abacterial
selected
disorder
from
of the lower
prostatitis.
Also, the effect of the invention can also be confirmed
by clinical
tests to a patient
hypersensitive
abacterial
pathology
disorder
prostatitis
of
and
According
oral
lower
animal
urinary
tests
cystitis,
tract
reflecting
or
the
APPLICABILITY
to the invention,
therapeutic
hypersensitive
abacterial
the
interstitial
of such a disease.
INDUSTRIAL
an
with
disorder
drug
of
it is possible
to provide
interstitial
cystitis,
of the lower urinary
prostatitis.
16
tract,
and/or
WE CLAIM:
1,
A process for preparing a pharmaceutical composition for depression
of
capsaicin-sensitive sensory
nerve,
which
comprises
mixing
qUinuclidin-3'-yt 1-phenyl-1,2,3,4-tetrahydroisoquinolin.2-carboxytate
or a salt thereof with a pharmaceutically acceptable excipient.
2.
A process for preparing a pharmaceutical composition for therapy of
interstitial cystitis, 'ltlhlch comprises mixing quinu(:lldln-3'-y11-phenyl1,2,3,4-tetrahydroisoquinolin.2-carboxylate
or a salt thereof' with a
pharmaceutically acceptable excipient.
3.
A process for preparing a pharmaceutical composition for therapy of
hypersensitive disorder of the 10'N8rurinary tract, 'ltlhich comprises
mixing
quinuclidin-3'-y1
1-phenyl-1,2,3,4-tetrahydroisoquinolin.2-
carboxylate or a salt thereof with a pharmaceutically acceptable
excipient.
•.
A
pmtl888
for prepal1ng a pharmaceutical composition for therapy of
abacterial prostatitis, which comprises mixing qUinuclidin-3'-y11·-
- It .-
phenyl-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylate
\Nith a pharmaceutically
acceptable
or a salt thereof
excipient.
Dated this 29ltl DAY OF DECEMBER,
2003.
f=R~
OF L,S. DAVAR & CO,
APPLICANTS'
AGENT
- I~
Abstract
,. ITLE
OF
A
:
PHARMA<:.EUT
"INTERSTITIAL
depressant
containing
of
I CA\.
interstitial
urinary
tract, and/or
or
specifically
cystitis,
~OR
-T\-\£ R A P't
a
a
hypersensitive
abacterial
18
sensory
nerve,
1-phenyl-1,2,3,4-tetra-
quinuclidin-3'-yl
ingredient,
T ION
capsaicin- sensi tive
hydroisoquinoline-2-carboxylate
active
COMPO~1
c'f~TITIS:
salt
thereof
therapeutic
disorder
prostatitis.
as
drug
an
of
of the lower
, _113SI
01677 lKOL.w1 2003
CI611/KOLNf!0'3
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Figure
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compound 1 (~)
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