Note: Descriptions are shown in the official language in which they were submitted.
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USE OF CGRP ANTAGONISTS IN TREATMENT AND PREVENTION OF HOT
FLUSHES IN PROSTATE CANCER PATLENTS
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method of treatment or prevention of hot
flushes in
men who underwent castration, e.g. due to androgen ablation treatment~in
prostate
cancer therapy (orchiectomy), comprising administration of an efFective amount
of a
CGRP antagonist and/or of a CGRP release inhibitor to a person in need of such
treatment. The method according to the invention preferably comprises
monotherapy
with a single substance, but also includes combined therapy with a number of
substances from the specified groups of active substances.
In a second aspect, the invention relates to the use of a CGRP antagonist
and/or of a
CGRP release inhibitor for manufacture of a pharmaceutical composition for
prevention or treatment of hot flushes in men who underwent castration.
BACKGROUND OF THE INVENTION
Hot flushes and sweating, that is vasomotor symptoms, are reported by 43 to
77% of
prostate cancer patients after medical or surgical castration, usually
persisting for
many years, possibly impairing quality of life (Arch. Surg. 43: 209, 1941; J.
Urol. 152:
1170, 1994). Furthermore, hot flushes occur in 75% of women after menopause.
In
WO 01/10425 it has been proposed that the symptoms of menopausal hot flushes
can be effectively prevented or their distressing effects substantially
alleviated by
substances which antagonise the effects of CGRP (CGRP antagonists) or inhibit
or
reduce the release of CGRP from sensory nerve endings (CGRP release
inhibitors),
this therapeutic approach being superior to hormone replacement therapy in
particular because of its lack of side efFects.
Although it has been already reported that plasma calcitonin gene-related
peptide
was increased during hot flushes in six men who underwent castration therapy,
the
mechanism of hot flushes in men is not well known. For instance, it is unclear
up to
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now why some men have vasomotor symptoms whereas some do not and it was
suggested to discover more about the mechanism of these symptoms to develop
new treatment alternatives (J. Urol. 166: 1720-1723, 2001).
BRIEF SUMMARY OF THE INVENTION
There is a clear need for alternative approaches and improvement in -the
treatment
and prevention of hot flushes in men who underwent castration:
It is therefore an object of the invention to provide a method of treatment
and
prevention of hot flushes in men who underwent castration, comprising
administering
to a patient in need of such treatment an effective amount of a CGRP
antagonist
and/or of a CGRP release inhibitor.
A second object of the invention is the use of a CGRP antagonist andlor of a
CGRP
release inhibitor for manufacture of a pharmaceutical composition for
prevention or
treatment of hot flushes in men who underwent castration.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that the symptoms of hot flushes in men who underwent
castration can be effectively prevented or their distressing effects
substantially
alleviated by substances which antagonise the effects of CGRP (CGRP
antagonists)
or inhibit or reduce the release of CGRP from sensory nerve endings (CGRP
release
inhibitors), this therapeutic approach being superior to conventional therapy.
The present invention thus relates to the use of CGRP antagonists aridfor CGRP
release inhibitors for combating hot flushes in men who underwent castration,
including both prevention and acute treatment. The use according to the
invention
preferably comprises monotherapy wifih a single substance, but also includes
combined therapy with a number of substances from the specified groups of
active
substances. Moreover, the treatment according to the invention may be carried
out in
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addition to conventional therapy, thus. any aspect of the invention includes
combination with conventional therapy or those drugs used in conventional
therapy.
The expression "conventional treatment" is meant to comprise
hormonal therapies comprising oral and topical administration (although
especially
oral hormonal therapies are known to cause side effects), e.g. oral
diethylstilbestrol,
topical estrogens such as estrogen patches, oral medroxyprogesterone acetate,
megestrol acetate and cyproterone acetate,
oral central a2-agonists, e.g. oral clonidine,
selective 5-hydroxyfiryptamine (5-HT) reupfiake inhibitors, e:g. sertraline
(Zoloft~) and
venlafaxine (Effexor~), and
acupuncture, preferably electrostimulated acupuncture.
Suggested recommendations for conventional treatment of hot flushes in men
with
prostate cancer treated by castration are:
First-line treatments:
estrogen patches 0.05 mg/24 hours or 0.10 mg/24 hours (e.g. twice weekly for 4
weeks), transdermal estradiol 0.05 mg/24 hours or oral diethylstilboestrol
(DES) 1
mg/day.
Second-line treatments:
Oral progestagens, e.g. megestrol acetate 40 mg/day or
oral cyproterone acetate 50 to 300 mg/day, e.g. 50 mg orally twice a day or
300 mg
intramuscularly once every 2 weeks, preferably 150 mg/day.
Third-line treatments:
Oral clonidine 0.1 mg/day or
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oral sertraline; start on 25 mg/day, titrate individually (to approximately 75-
100 mg
daily) or
oral venlafiaxine 12.5 mg twice daily or
acupuncture.
The invention also includes the use of an active substance selected from CGRP
antagonists and CGRP release inhibitors for the preparation of a
pharmaceutical
composition for treatment or prevention of hot flushes in men who underwent
castration wherein the pharmaceutical composition comprises an active compound
used in conventional therapy selected from the group consisting of
hormonal drugs, e.g. oral diethylstilbestrol, an estrogen, medroxyprogesterone
acetate, megestrol acetate and cyproterone acetate, including other salt forms
of
these drugs,
oral central a2-agonists, e.g. oral clonidine, and
selective 5-hydroxytrypfamine (5-HT) reuptake inhibitors, e.g. sertraline
(~oloft~) and
venlafaxine (Effexor~).
Any pharmaceutically acceptable active substances which antagonise the known
effects of CGRP or inhibit the release of CGRP from sensory nerve endings may
be
used for the purposes of the present invention.
Examples of CGRP antagonists include the amino acid derivatives described in
WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 and WO 01/49676 as
well as the non-peptidic active substances described in WO 98/56779, WO
98/09630
sand WO 97/09046.
Examples of CGRP release inhibitors include serotonin 5-HT~B»p-agonists such
as
almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,
sumatriptan or
zolmitriptan, as well as 5-HT~F-agonists or NPY-agonists.
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Of the CGRP antagonists described in WO 98/11128, the following compounds, for
example, may be used for the treatment andlor prevention of hot flushes in men
who
underwent castration, or for the preparation of a corresponding pharmaceutical
composition:
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi-
nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1-[4-amino-3,5-,dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1,3-benzodi-
azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(C) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(D) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine,
(E) 1-[N2-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-
1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(F) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-
1-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-L-lysyl]-4-(4-pyridinyl)-
piperazine,
(G) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,4-d]pyrimidin-3-yl)-
1-piperidinyl]carbonyl]-D-tyrosyl]-4-( 1-piperidinyl)-piperidine,
(H) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperidine,
(I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine,
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(J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperazine,
(K) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxothieno[3,2-d]pyrimidin-
3-
yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(L) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(tri-fluoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-
piperi-
dinyl)-piperidine,
(M) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl}-piperidine,
(N) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-
piperidine,
(O) 1-[N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-
3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(P) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-
piperidine,
(Q) 1-[4-amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(R) 1-[4-amino-3,5-dibromo-N-[(4-(3,4-dihydro-2(1 H}-oxoquinazolin-3-yl)-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine,
(S) . 1-[4-amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-
benzothiadiazin-
2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl}-piperidine,
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(T) 1-[4-amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-
piperidinyl]carbonyl]-
D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(U) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine,
(V) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(W) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-
piperazine,
(X) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-
piperazine,
(Y) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-
piperazine,
(Z) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-
piperidine,
(AA) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-
piperidinyl]carbo-
nyl]-N'-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AB) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-
piperidinyl]carbo-
nyl]-N'-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-
piperidine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(3,5-di-
bromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-
piperidine,
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(AD) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(3,5-di-
bromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-
piperidine,
(AE) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl}-1-piperidinyl]-2-
[(3,4-di-
bromphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AF}. 1-[N2-[N-[[4-( 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-
piperidinyl]carbonyl]-
3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(AG) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimida-
zol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(AH) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-
pyridinyl)-pipera-
tine,
(AI) 1-[N2-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-
yl)_1-
piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-
pipera-
zine,
(AJ) (R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1 H)-oxoquina-
zolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl}-piperidine,
(AK) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-
benzothiadiazin-
3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(AL) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-
3-
yl]-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1~-piperidinyl)carbonyl]-
piperidine
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
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(AN)~ 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperi-
dinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine,
(AO) 1-[4-amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-
piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-
piperi-
dine,
(AP) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl]-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine,
(AQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-
piperidinyl)-
piperidine,
(AR) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-
methyl-8-
azabicyclo[3,2,1]oct-3-yl)-piperazine,
(AS) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi-
peridinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(AT) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-
pi-
peridinyl)-piperazine,
(AU) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl]-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1 H-1,4-diazepin-
1-yl)piperidine,
(AV) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]car-
bonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine,
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(AW) 1-[4-amino-3,5-dibromo-N-[[4-(1;3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AX) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-
imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-
pipe-
ridine, .
(AY) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]car-
bonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(AZ) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-
piperi-.
dinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1 ]oct-3-yl)-
pipera-
tine,
(BA) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(BB) 1-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-
imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tjrrosyl]-4-(1-piperidinyl)-
piperidine,
(BC) 1-[N6-acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-
yl)-
1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(BD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-
piperi-
dinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(BE) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-
1-
yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperidine,
(BF) 1-[4-amino-3,5-dibromo-_N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2.H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
pi-
peridinyl)-piperidine,
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(BG) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidi-
nyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-
piperidine,
(BH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-
piperidine,
(BI) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi-
nyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine,
(BJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine,
(BK) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)
oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
piperidinyl)
piperidine,
(BL) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]car-
bonyl]-D-tyrosyl]-4-(hexahydro=1 H-1-azepinyl)-piperidine,
(BM) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(BN) _ 1-[4-amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-
oxoimi-
dazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicy-
clo[3,2,1 ]oct-3-yl)-piperazine,
(BO) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine,
(BP) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine,
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(BQ) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-
oXOimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-
azabi-
cyclo[3,2,1]oct-3-yl)-piperazine,
(BR) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidi-
nyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropyl-methyl)-4-piperidinyl]-piperidine,
(BS) 1-(4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-piperidine,
(BT) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-
piperi-
dinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine,
(BU) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi-
peridinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine,
(BV) 1-[3,5-dibromo-N-([4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxo-
imidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-
piperazine,
(BW) 1-[N2-[3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-
oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-
piperazine,
(BX) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-
piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine,
(BY) 1-[4-amino-N-([4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-
1-
piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-
piperi-
dine,
(BZ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1
H-
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1-azepinyl)-piperidine,
(CA) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-
2(2H)-
oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-
piperidinyl)-
piperazine,
(CB) 1-[4-amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-
1-
piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-
piperidine,
(CC) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoirnidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine,
(CD) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-pi-
peridinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine,
(CE) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl]-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine,
(CF) 1-[3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-
piperidinyl]car-
bonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine,
(CG) 1-[4-amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimi-
dazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-
piperi-
' dine,
(CH) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1 H)-oxoquinazolin-3-yl]-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine,
(CI) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-
yl)-
1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1 H-1-azepinyl)-
piperidine and
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(CJ) 1-[4-amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-
1-
yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperazine,
the tautomers, the diastereomers, the enantiomers, the mixtures fihereof and
the
physiologically acceptable salts thereof, while the compounds
(A) 1-[N2-(3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperi-
dinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1,3-benzodi-
azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine,
(J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperazine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(3,5-
dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-
piperidine,
(AF) 1-[N2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-
piperidinyl]carbonyl]-
3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine and
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
the tautomers, the diastereomers, the enantiomers, the mixtures thereof and
the
physiologically acceptable salts thereof, and especially the compounds
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidi-
nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine and
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(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1 H)-oxo-1,3-benzodi-
~azepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
the tautomers, the diastereomers; the enantiomers, the mixtures thereof and
the
physiologically acceptable salts thereof are particularly preferred.
The dosage required to produce the desired effect is appropriately 0.0001 to 3
mg/kg
of body weight, preferably 0.01 to~ 1 mg/kg of body weight for intravenous or
subcutaneous administration and 0.01 to 10 mg/kg of body weight, preferably
0.1 to
10 mg/kg of body weight for administration by oral or nasal route or by
inhalation, 1 to
3 times a day in each case.
If the treatment with CGRP antagonists and/or CGRP release inhibitors is given
as a
supplement to conventional therapy, it is advisable to reduce the doses given
above,
and in this case the dosage may range from 1l5 of the lower limits specified
above up
to 1./1 of the upper limits specified above.
For this purpose, the CGRP antagonists and/or CGRP release inhibitors may be
formulated with one or more conventional inert carriers and/or diluents, e.g.
with corn
starch, lactose, glucose, microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol,
water/glycerol,
water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl
alcohol,
carboxymethylcellulose or fatty substances such as hard fat or suitable
mixtures
thereof in conventional galenic preparations such as plain or coated tablets,
capsules,
powders, suspensions, solutions, metering aerosols or suppositories.
Preparations which are particularly suitable for the.method of treatment or
prevention
according to the invention are those which contain one of the active
substances
(A) 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidi-
nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
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(B) 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiaze-
pin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(I) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine,
(J) 1-[4-amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-
2-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-
piperazine,
(AC) (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(3,5-di-
bromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-
piperidine,
(AF) 1-[N2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-
piperidinyl]carbonyl]-
3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine or
(AM) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-
piperi-
dinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
in one of the following pharmaceutical formulations:
capsules for powder inhalation containing 1 mg of active substance, preferably
active
substance (A) or (B),
inhalable solution for nebulisers containing 1 mg of active substance,
preferably
active substance (A) or (B),
propellant gas-operated metering aerosol containing 1 mg of active substance,
preferably active substance (A) or (B),
nasal spray containing 1 mg of active substance, preferably active substance
(A) or
(B),
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tablets containing 20 mg of active subsfiance, preferably active substance
(B),
capsules containing 20 mg of active substance, preferably active substance
(B),
aqueous solution for nasal application containing 10 mg of active substance,
preferably active substance (A) or (B),
aqueous solution for nasal application containing 5 mg of active substance,
preferably active substance (A) or (B), or .
suspension for nasal application containing 20 mg of active substance,
preferably
active substance (A) or (B).
In the method according to the invention and in any of the formulations given
above
active substance (A) may also be used in form of a physiologically acceptable
salt,
preferably in form of the hydrochloride salt which is available by reaction of
the free
base with hydrochloric acid by conventional methods. Amounts are given based
on
the free base.
CGRP is released by sensory nerves, e.g. the trigeminal nerve which innervates
part
of the skin of the face. It has already been shown that stimulation of the
trigeminal
ganglion in humans leads to an increase in the CGRP plasma level and causes
reddening of the face ([4]: P.J. Goadsby et al., Annals of Neurology, Vol. 23,
No. 2,
1988, 193-196,). .
To demonstrate that hot flushes can be successfully treated using CGRP
antagonists
and CGRP release inhibitors, an increased release of endogenous CGRP was
induced in marmosets by stimulating the trigeminal ganglion, leading to
increased
blood flow through the blood vessels of 'the skin. The efFicacy of the
following test
substances was characterised by determining the dose administered i.v. which
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reduces by 50% the increased blood flow through the skin of the face which has
been brought about by endogenous CGRP:
(A) = 1-[N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
piperidi-
nyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine,
(B) = 1-[4-amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-
benzodiaze-
pin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-
piperidine,
(AC) _ (R,S)-1-[4-[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-
[(3,5-di-
bromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-
piperidine,
(AM) = 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1 H)-oxoquinazolin-3-yl)-1-
pi-
peridinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine,
(DA = sumatriptan and
(DB) = zolmitriptan.
Description of method:
Marmosets of both sexes (300-400 g) are anaesthetised with pentobarbital
(initially
with 30 mg/kg, i.p., followed by infusion of 6mg/kg/h, i.m.). The body
temperafiure is
maintained at 37°C using a heating plate. Pancurmium is administered as
a muscle
relaxant (initially 1 mg/kg, 0.5 mg after each hour thereafter). The animal's
head is
secured in a stereotactical apparatus. After the skin on the head has been
opened
using a lengthwise incision, a small hole is drilled in the skull and a
bipolar electrode
(Rhodes SNES 100) is lowered into the trigeminal ganglion.
Locating the ganglion is made easier by the use of an X-ray which shows up the
bone structure of the skull. The petrous bone serves as a guide for placing
the
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electrode (CCX-Digital X-ray apparatus).,The position of the electrode in the
ganglion
is. monitored at the end of each experiment. The stimulation parameters are:
Hz, 2 mA, 2 msec, for 30 sec.
The blood flow in the micro-vessels of the facial skin is determined by laser
Doppler
5 flow measurement using a PeriFlux Laser Doppler System.
The animals are exposed to 2 to 3 stimulation periods at intervals of 30 min
in each
case. The first stimulation serves as a reference value for the other
stimulations. The
test substances are administered i.v. 5 min before the 2nd and 3rd stimulation
periods.
Table 1: "50% dose" = i.v, dose which reduces by 50% the increased blood flow
through the facial skin caused by endogenous CGRP
Substance ~0% dose
A 0.003 mg/kg
B 0.042 mg/kg
AC 0.018 mg/kg
AM 0.046 mg/kg
DA 0.280 mg/kg
DB 0.035 mg/kg
'I 5
The Examples which follow describe pharmaceutical preparations which contain
as
active substance a CGRP antagonist or CGRP release inhibitor for use according
to
the invention, preferably one of the amino acid derivatives described in
WO 98/11128, WO 00/55154, WO 01/32648, WO 01/32649 or WO 01/49676 , for
example one of the abovementioned active substances (A) or (B), most preferred
is
substance (A) hydrochloride.
Example I
Capsules for powder inhalation with 1 ma of active substance (A) or (B)
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Composition:
1 capsule for powder inhalation contains:
active substance (A) or (B) 01.0 mg
lactose ~ 20.0 mg
hard gelatine capsules ~ 50.0 ma
71.0 mg
Method of preparation:
The active substance is ground to the particle size needed for inhalation. The
ground
active substance is homogeneously mixed with the lactose. The mixture is
packed
into hard gelatine capsules.
Example II
Inhalable solution for Respimat~ with 1 mg of active substance (A) or (B)
Composition:
1 spray contains:
active substance (A) 1.0 mg
or (B)
benzalkonium chloride 0.002 mg
disodium edetate 0.0075 mg
purified water ad 15.0 ~ pl
Method of preparation:
The active substance and benzalkonium chloride are dissolved in water and
packed
in Respimat~ cartridges.
Example III
Inhalable solution for nebulisers with 1 ma of active substance (A) or (B)
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Composition:
1 vial contains:
active substance (A) or (B) 0.1 g
sodium chloride 0.18 g
benzalkonium chloride 0.002 g
purified water ad 20.0 ml
Method of preparation:
Active substance, sodium chloride and benzalkonium chloride are dissolved in
water.
'I 0
Example IV
Propellant gas-operated metering aerosol with 1 ma of active substance (A) or
(B)
~~Composition:
1 spray contains:
active substance (A) or (B) ~ 1.0 mg
lecithin 0.1
propellant gas ad ~ 50.0 pl
Method of preparation:
The micronised active substance is homogeneously suspended in the mixture of
lecithin and propellant gas. The suspension is transferred into a pressurised
container with a metering valve.
Example V
Nasal spray with 1 ma of active substance (A~or (B)
Composition:
1 spray jet contains
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active substance (A) or 1.0 mg
(B)
mannitol 5.0 mg
disodium edetate 0.05 mg
ascorbic acid ~ 1.0 mg
~
purified water ad 0.1 ml
Method of preparation:
The active substance and the excipients are dissolved in water and ransferred
into a
suitable container.
Example VI
Iniectable solution with 5 ma of active substance (A) or (B) per 5 ml
Composition:
active substance (A) or (B) in basic 5 mg
form
acid/salt-forming agent in the amount
needed
to form a neutral salt q.s.
glucose 250
mg
human serum albumin 10 mg
glycofurol ~ 250
mg
water for injections ad 5 ml
Preparation:
Dissolve the glycofurol and glucose in water for injections (Wfl); add human
serum
albumin; add salt-forming agent; dissolve active substance with heating; make
up to
specified volume with Wfl; transfer into ampoules under nitrogen gas.
Example VII
Injectable solution for subcutaneous administration containing 5 ma of active
substance (A) or (B) per 1 ml
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Composition:
active substance (A) or (B) 5 mg
glucose 50 mg
polysorbate 80 = Tween 80 2 mg
water for injections ad 1 ml
Preparation:
Dissolve glucose and polysorbate in water for injections; dissolve active
substance
with heating or using ultrasound; make up to specified volume with Wfl;
transfer into
ampoules under inert gas.
Examcle VIII
Iniectable solution containing 100 ma of active substance (A~ or (B) per 10 ml
Composition:
active substance (A) or (B) 100 mg
monopotassium dihydrogen phosphate
= KH2POq. 12 mg
disodium hydrogen phosphate '
= Na2HPOq.~2H20 2 mg
sodium chloride 180 mg
human serum albumin 50 mg
polysorbate 80 20 mg
water for injections ad 10 ml
Preparation:
Dissolve polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate
and disodium hydrogen phosphate in water for injections (Wfl); add human serum
albumin; dissolve active substance with heating; make up to specified volume
with
Wfl; transfer into ampoules.
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Example IX
Lyophifisate containing 10 mg of active substance (A) or (B~
Composition:
active substance (A) or (B) in 4~asic form 10 mg
acid/salt-forming agent in the amount needed
to form a neutral salt q.s.
mannitol 300 mg
water for injections ad 2 ml
Preparation:
Dissolve mannitol in water for injections (Wfl); add salt-forming agent;
dissolve active
substance with heating; make up to specified volume with Wfl; transfer into
vials;
freeze-dry.
Solvent for Iyophilisate:
polysorbate 80 = Tween 80 20 mg
mannitol 200 mg
wafer for injections ad 10 ml
Preparation:
Dissolve polysorbate 80 and mannitol in water for injections (Wfl); transfer
into
ampoules.
Example X
Lyophilisate containing 5 mg of active substance (A) or~B)
Composition:
active substance (A) or (B) in basic form 5 mg
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polar or nonpolar solvent (which can be removed
by freeze-drying) ad 1 ml
Preparation:
Dissolve active substance in suitable solvent; transfer into vials; freeze-
dry.
Solvent for Iyo~hilisate:
polysorbate 80 = Tween 80 5 mg
mannitol 100 mg
water for injections ad 2 mi
Preparation:
Dissolve polysorbate 80 and mannitol in water for injections (Wfl); transfer
into
ampoules.
Example XI
Tablets containing 20 mct of active substance (A) or (B)
Composition:
active substance (A) or (B) 20 mg
lactose 120 mg
maize starch 40 mg
magnesium stearate. 2 ,-ng
Povidone K 25 18 mg
Preparation:
Homogeneously mix the active substance, lactose and maize starch; granulate
with
an aqueous solution of Povidone; mix with magnesium stearate; press in a
tablet
press; weight of tablet 200 mg.
Example XII
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Capsules containing 20 ma of active substance (A) or (B)
Composition:
active substance (A) or (B) ~ 20 mg
maize starch 80 mg
highly dispersed silica 5 mg
magnesium stearate 2.5 mg
Preparation:
Homogeneously mix the active substance, maize starch and silica; mix with
magnesium stearate; transfer mixture into size 3 hard gelatine capsules in a
capsule
filling machine.
Example XIII
Suppositories containing 50 ma of active substance (A) or (B)
Composition:
active substance (A) or (B) 50 mg
hard fat (Adeps solidus) q.s. ad 1700 mg
Preparation:
Melt the hard fat at about 38°C; homogeneously disperse the ground
active
substance in the molten hard fat; after cooling to about 35°C, pour
into chilled
moulds.
E~;ample XIV
Agueous solution for nasal administration containing 10 ma of active substance
(A)
or B
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Composition:
active substance (A) or (B) 10.0 mg
hydrochloric acid in the amount needed to form a
neutral salt methyl parahydroxybenzoate (PHB) 0.01 mg
propyl parahydroxybenzoate (PHB) 0.005 mg
purified water ad 1.0 ml
Preparation:
The active substance is dissolved in purified water; hydrochloric acid is
added until
the solution is clear; methyl and ,propyl PHB are added; the solution is made
up to the
specified volume with purified water; the solution is filtered'sterile and
transferred into
a suitable container.
Example XV
Aaueous solution for nasal administration containing 5 ma of active substance
(A) or
Composition:
active substance (A) or (B) 5 mg
1,2-propanediol 300 mg
hydroxyethylcellulose 5 mg
sorbic acid 1 mg
purified water ad 1 ml
Preparation:
The active substance is dissolved in 1,2-propanediol; a hydroxyethyl-cellulose
solution in purified water containing sorbic acid is prepared and added to the
solution
of active
substance; the solution is filtered sterile and transferred into a suitable
container.
Example XVI
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Aaueous solution for intravenous administration containing 5 ma of active
substance
A or B
Composition:
active substance (A) or (B) 5 mg
1,2-propanediol 300 mg
mannitol 50 mg
water for injections (Vllfl) ad 1, ml
Preparation:
The active substance is dissolved in 1,2-propanediol; the solution is made up
to
approximately the specified volume with Wfl; the mannitol is added and made up
to
approximately the specifiec~ a~'olume with Wfl; the solution is filtered
sterile, transferred
into individual containers and autoclaved.
Example XVIi
Liposomal formulation for intravenous infection containinct 7.5 mct of active
substance
A 'or B
Composition:
active substance (A) or (B) 7.5 mg
egg lecithin, e.g. Lipoid E 80 ~ 100.0 mg
cholesterol 50.0 mg
glycerol 50.0 mg
water for injections ad 1.0 ml
Preparation:
The active substance is dissolved in a mixture of lecithin and cholesterol;
the solution
is added to a mixture of glycerol and Wfl and homogenised by high pressure
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homogenisation -or , by the Microfluidizer technique; the liposomal
formulation
obtained is transferred into a suitable container under aseptic conditions.
ExampIe.XVlll
Suspension for nasal administration containing 20 ma of active substance (A)
or (B)
Composition:
active substance (A) or (B) 20.0 mg
carboxymethylcellulose (CMC) 20.0 mg
sodium monohydrogen phosphate/sodium
dihydrogen phosphate buffer pH 6.8 q.s.
sodium chloride 8.0 mg
methyl parahydroxybenzoate 0.01 mg
propyl parahydroxybenzoate , 0.003
mg
purified water ad 1.0 ml
Preparation:
The active substance is suspended in an aqueous CMC solution; the other
ingredients are added successively to the suspension and the suspension is
topped
up to the specified volume with purified water.
Example XIX
Aaueous solution for subcutaneous administration with 10 ma of active
substance (A)
or B
Composition:
active substance (A) or (B) 10.0 mg
sodium monohydrogen phosphate/sodium
dihydrogen phosphate buffer q.s. ad pH 7.0
sodium chloride 4.0 mg
CA 02531407 2006-O1-05
WO 2005/004869 PCT/EP2004/007228
-30-
water for injections ad 0.5 ml
Preparation:
The active substance is dissolved ~in the phosphate buffer solution, after the
addition
of the common salt the solution is made up to the specified volume with water.
The
solution is filtered sterile, transferred into a suitable container and
autoclaved.
Example XX
Agueous suspension for subcutaneous administration containing 5 mg of active
substance (A) or (B)
Composition:
active substance (A) or (B) 5.0 mg
polysorbate 80 0.5 mg
water for injections 0.5 ml
Preparation:
The active substance is suspended in the polysorbate 80 solution and
comminuted to
~0 a particle size of about 1 ~,m using a suitable dispersing technique (e.g.
wet grinding,
high pressure homogenisation, microfluidisation, etc.). The suspension is
transferred
into a corresponding container under aseptic conditions.
