Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 2067173
Use of Antigestagens for the Production of Phar~aceutical Agents
This invention relates to the use of antigestagens
(competitive progesterone antagonists) for the production of
pharmaceutical agents for treating breast cancers with a content
of tumor cells that is increased and judged as high-risk in the S
phase of the cell cycle.
The previous medicinal treatment of breast cancer with
antiestrogens is based on the observation that the growth and the
increase of the corresponding tumor cells are induced by or are
dependent on estrogens.
The antiestrogen tamoxifen is used, for example, for
palliative treatment of nonoperable breast cancer as well as for
adjuvant treatment after primary treatment of breast cancer. But
the disease is not cured with tamoxifen. Gestagens or aromatase
inhibitors are used for the secondary treatment. Aromatase
inhibitors prevent the biosynthesis of estrogens from their
corresponding precursors, by inhibiting the enzyme aromatose
necessary for this purpose. In premenopause, ovariectomy,
tamoxifen or LHRH analogs (LHRH = luteinizing hormone-releasing
hormones) result in comparable response rates (lit. H. T.
Mouridsen and R. Paridaens, Eur. J. Cancer Clin. Oncol., Z4, pp.
99-105, 1988).
More recently, the use of antigestagens in the field of
tumor treatment, in particular for the indication of breast
cancer, is also discussed. A first phase II study with 17~-
hydroxy-ll~-(4-dimethylaminophenyl)-17~-(prop---inyl)-estra-4,9-
dien-3-one in patients with metastasizing breast cancer who are
.
.
:
2 2~67173
-
postmenopausal or whose ovaries have been removed and who are
resistant to endocrine treatment is reported by Maudelonde et al.
in Hormonal Manipulation of Cancer, Editors J. G. M. Klijn, R.
Paridaens and J. A. Folkens in Raven Press, p. 55 (1987).
The common use of an antigestagen with an antiestrogen for
the treatment of hormone-dependent tumors was also recently
proposed (EP-A-0 310 542; Biochem. Biophys. Res. Commun. 1987,
145(2), 706).
The individual stages of the cell cycle, through which the
tumor cells pass, or the individual contents of the cells in the
various stages are of decisive importance for the development and
the course of the disease as well as for the prospects of a
treatment. Here, a special importance is attributable to the S
phase content (Clark, G. M.; Dressler, L. G.; Owens, M. A.;
Pounds, G.; Oldaker, T.; McGuire, W. L.: Prediction of relapse
or survival in patients with node-negative breast cancer by DNA
flow cytometry, N. Engl. J. Med. 320: 627-633, 1989 and McGuire,
W. L.; Dressler, L. G.: Emerging impact of flow cytometry in
predicting recurrence and survival in breast cancer patients,
JNCI 75(3), 405-410, (198S)).
The object of this invention is to indicate a pharmaceutical
agent which is suitable for endocrine treatment of breast cancer,
whose tumor cells comprise at least a certain content of tumor
cells in the S phase of the cell cycle.
This object is achieved by using antigestagens (competitive
progesterone antagonists) for the production of such a
pharmaceutical agent.
~ ~ . . . . ~
,. -
3 2067173
It has been found that antigestagens (competitive
progesterone antagonists) have an especially favorable influence
on the inhibition of the growth of breast cancer tumor cells,
which comprise at least a certain S-phase content. In
particular, those breast cancers are to be therapeutically
treated with antigestagens which according to the level of
knowledge on the importance of the S-phase content in the
carcinoma are evaluated as high-risk patients according to
current treatment (Clark, G. M et al., 1989, see above).
Competitive progesterone antagonists show strong antitumor action
both in the MXT and in the MNU and DMBA tumor models. tMNU = N-
methylnitrosourea; DMBA = 7.12-dimethylbenzanthracene: Europ. J.
Cancer Clin. Oncol., Vol. 25, No. 4, 691 (1989), M. R. Schneider,
H. Michna, Y. Nishino and M. F. El Etreby).
In contrast both with tamoxifen and estrogen treatment as
well as with the ovariectomy, the data obtained after treatment
of mice or rats with progesterone antagonists indicates that only
progesterone antagonists are able to block the progression of
tumor cells in the GoG1 phase of the cell cycle. This follows
from the flow-cytophotometric measurements in tumors grown in
vivo described below. A clear reduction of the content of tumor
cells in the S phase accompanies this blocking.
No hormone-therapeutic pharmaceutical agent for treatment of
breast cancer that produces a reduction of the content of tumor
cells in the S phase was previously known.
~i 2067173
The influence of antigestagens on various cell cycle phases
of hormone-dependent tumors is determined as described below.
There are tested:
-[(4-N,N-dimethylamino)-phenyl]-17a-hydroxy-17p-(3-
hydroxypropyl)-13a-methyl-4,9(10)-gonadien-3-one (A); EP-A-
84730062.1;
11~-(4-acetylphenyl)-17~-hydroxy-17~-(prop-1-inyl)-4,9(10)-
estradien-3-one (B); EP-A-86101548.5;
tamoxifen and diethylstilbestrol (DES) are used as reference
substances.
a) Hormone-dependent MXT(+)-breast cancer of the mouse in the
prophylaxis model
As an MXT tumor, the MXT line M 3.2 made available as a
frozen sample by Dr. A. E. Bogden (EG + G Bogden Laboratories,
Worcester, MA, USA) is used. The inoculation of the tumor on the
test animals and the subsequent removal of the grown tumors is
performed as described in Europ. J. Cancer Clin. Oncol., Vol. 25,
No. 4, 691 (1989) of M. R. Schneider, H. Michna, Y. Nishino and
M. F. El Etreby. After removal, the tumors are cut into pieces
of a 2 mm average diameter in MEM (Minium Essential Medium) 199.
In each case, two of these pieces are implanted in BDFI mice s.c.
After the transplantation, the animals are assigned to groups of
9 to 10 animals each. On the next day, the treatment is begun.
Compounds _ and B to be tested are injected daily in a dose
of 5 mg/kg/animal each as an oily solution (10% in benzyl
benzoate) s.c. or an ovariectomy is performed. Tamoxifen is
administered in a dose of 5 mg/kg/animal. After a six-week
,
i 2067~73
treatment, the animals are killed and weighed. After removal of
the tumors and determination of their wet weights, the tumors are
frozen in liquid nitrogen.
b) Methylnitrosourea (MNU) -- induced breast cancer of the SD
rat
Tumors are induced in 50 days-old female SD-rats
(Zentralinstitut fur Versuchstierzucht [Central Institute for
Test Animal Breeding] Hannover, FRG) by one-time i.v. injection
of 50 mg of MNU in the caudal vein. On the thirtieth day after
induction palpation of the animals for tumors is started.
Animals with at least one tumor with a tumor area of more than
150 mm2 are divided into test groups. The tumors are treated
with compounds A or B with a dose of 20 mg/kg/day each, with
tamoxifen with a does of 5 mg/kg/day and with DES with a dose of
0.5 mg/kg/day.
The various phase contents of the tumors (S, Go~Gl and G2M
phase) are determined as described by Dressler et al. ~DNA flow
cytometry and prognostic factors in 1331 frozen breast cancer
specimens, Cancer 61(3), 420, (1988); Evaluation of a modeling
system for S-phase estimation in breast cancer by flow cytometry,
Canc. Res. 47(20), 5294-5382, (1987)).
The results can be seen from table 1 (MXT(+) tumor of the
mouse) and from table 2 (MNU-induced breast cancer of the rat~.
The change of the tumctr areas in the course of the treatment
with compound _ or B in comparison with the control, ovariectomy
and reference compounds are represented in fig. 1 (MXT tumor) and
fig. 2 (MNU-induced tumor).
., , . , ', ' . . . , . .; ,.
2067173
The tests for the cell cycle were performed by the tumors of
these two represented experiments (tables 1 and 2)
, The analyses of the cell cycle phases took place for the MXT
- tumor model after a treatment time of 4 weeks (cf. fig. 1) and
for the MNU tumor model after a -treatment time of 6 weeks (cf.
fig. 2).
:" 2067173
TABLE 1
MXT Tumor Test (Mouse)
Flow-Cytophotometric Measurements
Key:
Gruppe/Dosis = group/dose
Kontrolle = control
Verbindung (A~ = compound (A)
Verbindung (B) = compound ~B)
Tiere pro Gruppe(n) = animals per group(s)
Zellcyclusphase = cell cycle ~hase
M~l (Mittelwert) = average value
SD (Standardabweichung) = standard deviation
* = signifikant (p < 0.05) gegen Kontrolle im Kruskal-Wallis Test
= significant (p ~ 0.05) against the control in the Kruskal-
Wallis test
Gruppe/Dosis Tiere pro Z e l 1 c y c 1 u s p h a s e
Gruppe(n)S-Phase Go~G1 G2
-
~ontrolle 3 15,2Z 7~,21 10.57
21,89 71,06 7,0~
20,15 72,83 7,02
~W (Mittelwert) 19,09 72,70 B,Z1
SD (Standardabwei- ~ 3,~6 ~ 1,5B ~ 2.0
chunq)
Tamoxifen 3 16.7~ 69.B3 13.~3
13,53 73,02 13,~5
5 mglkg 16,95 73,38 9,67
MW 15,74 72,0B 12,lB
SD ~1,92 ~ 1,95 ~2.18
DES 2 1~,9~ 77,22 7,B~
2,5 mglkg 1~,85 77,27 7,a8
MW 1~,90 77,25 7,86
SD ~0,06 ~ 0,0~ ~0,03
Yerbindung (A) 3 0,53 97,51 1,96
18,D6 75,37 6,57
5 mglkg 18,67 75,~1 5,93
MW 12,~Z 82,76 ~,82
SD ~ 10,30 ~12,77 ~2,50
Verbindung (8) ~ 0.37 98,52 1,11
11,53 8~,31 ~,17
5 mg/kg 1~ 29 789 728o 55 9~31
~W 9,~7~ 86,~5* ~,08
SD ~6,20 ~ 8,27 ~2,11
-- .. . .
. ~ 9 signifik~nt (p< 0.051 gegcn r.ontrolle {~ Krusk~l-W~llis-Test
. . 8
2067173
TABLE 2
NMU Tumor Test (Rat)
Flow-Cytophotometric Measurements
Key:
Gruppe/Dosis = group/dose
Kontrolle = control
Ovariektomie = ovariectomy
Tie~e pro Gruppe(n) = animals per group(s)
Zellcyclusphase = cell cycle phase
GruppelDosis Tiere pro Z e l l c y c 1 u s p h a s e
Gruppe(n) S-Phase Go~G1 G2~
Kontrolle 6 2 529952 ~535 2~ 0t56
~,3691,82 3,83
S! ~,2891,70 ~,03
~,1092,93 2,98
2,7~95,20 2,06
HW 3,5593,27 3,19
SD ~ 0,81~ 1,65 ~0,97
Ovare~tomie 5 ~ 2t86 9930 ~6~ 25 2292
5.3791,61 3,02
Z,689~,36 2,97
Z,2395,25 3,52
HW 3,7~93,05 3,~0
SD ~ 1,28t 1,92 ~1,11
Tamoxifen 7 22 75~895 01 22 ~20
~,0893,23 2,69
5 mglkg 37 57698~7:66oZ 37
~,2891,70 ~,03
3,8Z92,61 3,57
HW ~,099Z,75 3,15
~ t,66~ 2,58 ~l,û2
3 i,8993,59 2,53
OES 8,9Z 83,~1 7,67
0,5 mg/kg ~,02 .92,25 3;73
HW 5 61 89,75 ~,6~
SO ~ 2 87 ~ 5,53 ~2,69
-
-
~ .
'`s -
2067173
CONTINUATION OF TABLE 2
NMU Tumor Test (Rat)
Flow-Cytophotometric Measurements
Key:
Gruppe/Dosis = group/dose
Verbindung (A) = compound (A)
- Verbindung (B) = compound (B)
Tiere pro Gruppe(n) = animals per group(s)
Zellcyclusphase = cell cycle phase
* = signifikant (p < 0.05) gegen Kontrolle im Kruskal-Wallis Test
= significant (p < 0.05) against the control in the Krus~al-
l~allis test
GruppelOosis Tiere pro Z e 1 l c y c l u s p h a s e
Gruppe(nl S-Phase Go~Gl 62M
Verbindung (A~ 5 l,91 96.17 1,92
3,9Z 9~,00 Z,Ol
20 mg/kg 0 97,7Z 2,2a
Z.Z1 95,63 2,16
0 98,22 1,78
MW l,61* 96,35 2,03S
SO ~ 1,66 ,1,69 ~ D,20
Verbindung tB~ 7 0,37 98,52 1,11
o,g~ 97,00 2,05
20 mg/kg 1,0~ 98,Z1 0,7
0,53 98,~3 1,0
0,18 98,37 1,~
O 97,08 2,92
0,~7 98,29 1,25
HW O,SO~ 97.99* 1,51
SD ~ 0,38 ~0,65 ~ 0,75
* = signifikant tp < 0,051 gegen Kontrolle im Kruskal-Wallis-Test
'l
1~
206717~
Fia. 1 KeY:
MXT(+)-MAMMACARCINOM (PROPHYLAXE-MODELL) = MXT(+)-BREAST CANCER
(PROPHYLAXIS MODEL)
KONTROLLE = CONTROL
OVARIEKTOMIE = OVARIECTOMY 2
TUMOR FLAECHE mm2 = TUMOR AREA mm
THERAPIEDAUER IN WOCHEN = TREATMENT TIME IN WEEKS
Abb. 1
MXT (+)-MAMMA CARCINOM
(PROPHYLAXE-MODELL)
00 - ~ KONTROLLE
-~- OVARIEKTOMIE
T -~- TAMOXIFEN
U 90 : 3< E I
R .
t ~
ll
2 0 6 717 3
Fiq 2 Kev CARCINOM = HORMONE-DEPENDENT MNU-
BREAST CANCER
AENDERUNG DER TUMORFLAECHE = CHANGE OF THE TUMOR AREA
THERAPIEDAUER IN WOCHEN = TREATMENT TIME IN WEEKS
KONTROLLE = CONTROL
OVARIEKTOMIE = OVARIECTOMY
Abb. 2
HORMONABHANGIGES
MNU - MAMMA CARCINOM
% 900-
D ~00- . /
E
R
N 700- .
G . /
D
E ~00-
T 500- .
U ~
M .
R 400-
F / .
A ~ .
H ~- /
E
200-
. /~=~
O ~ 2 - 3- 4 5
THERAPIEDAUER IN WOCHEN
KONTROLLE
OVARIE~IOMIE .
--t - DES
. . -5- A
. . . ,~
2067173
This selective inhibition of the cell division, thus far unique
for an endocrine treatment, by an intervention in the cell cycle
as well as the growing content of the mass of the tumor cells in
connection with the capability to accelerate the rate of necrosis
of the cells from the proliferative population represents a
highly innovative mechanism of the antitumor action of
antigestagens (competitive progesterone antagonists). The
antigestagens therefore offer a decisive advantage relative to
all other established endocrine treatment strategies in breast
cancer, if its tumor cells exhibit a content of tumor cells in
the S phase of the cell cycle.
But the established treatment for treating breast cancer
with tamoxifen does not result in a reduction of the S-phase
content of the tumor cells. The advantage of the proposed
treatment consists in that if the S-phase content of the breast
cancer to be treated is determined before determining the
treatment, the endocrine antigestagen treatment can be used
specifically and with avoidance of a possibly useless
chemotherapy or treatment with tamoxifen without a time delay in
those patients whose tumor or tumors shows or show tumor cells in
the S phase. Thus, valuable time for the treatment of the tumor
then still in an earlier stage is gained; if it is possible to
reduce the S-phase content of the tumor cells, as result the
chance of survival of the patient in question is markedly
increased (McGuire, W. L., Dressler, L. G., Emerging impact of
flow cytometry in predicting recurrence and survival in bre~st
cancer patients, JNCI, 75(3), 405-410, (1985); Dressler, L. G.,
. , . .. ~., , - , . .... .
13 2067173
,.
Seamer, L. C., Owens, M. A., Clark, G. M., McGuire, W. L.: DNA
flow cytometry and prognostic factors in 1331 frozen breast
cancer specimens: Cancer 61 (3), 420-427, 1988).
- But here the treatment proposed according to the invention
for the first time offers a chance for specific intervention by
direct treatment of those patients whose breast cancer exhibits a
high-risk S-phase content with antigestagens (competitive
progesterone antagonists).
The patients who are treatable according to the invention
represent about 50% of the total group of patients affected by
the disease of breast cancer.
It is also possible, according to the invention, for the
production of the pharmaceutical agent to use in addition to the
antigestagen (to the antigestagens) at least one more
antiestrogen, since most breast cancers exhibit both progesterone
and estrogen receptors.
The weight ratio of both components can be varied here
within wide limits. Thus, both the same amounts of antigestagen
and antiestrogen and an excess of one of the two components can
be used. Antigestagen and antiestrogen are used together,
separately, simultaneously and/or in intervals (sequentially), in
a weight ratio of basically l:S0 to 50:1, preferably 1:30 to
30:1, and especially 1:15 to 15:1.
Preferably, antigestagen and antiestrogen can be
administered combined in a dosage unit.
As antigestagens, all compounds are suitable which have a
great affinity to the gestagen receptor (progesterone receptor)
14
- ~- 2067173
and in this connection show no gestagen activity of their own.
As competitive progesterone antagonists, for example, the
following steroids are suitable:
~ [(4-N,N-Dimethylamino)-phenyl]-17p-hydroxy-17~-propinyl-
- 4,9(10)-estradien-3-one (RU-38486),
~ (4-N,N-dimethylamino)-phenyl]-17~-hydroxy-18-methyl-
17~-propinyl-4,9(10)-estradien-3-one and
11~-[(4-N,N-dimethylamino)-phenyl]-17a~-hydroxy-17a~-
propinyl-D-homo-4,9(10),16-estratrien-3-one (all EP-A 0 057 115);
also
ll~-p-methoxyphenyl-17~-hydroxy-17~-ethinyl-4,9(10)-
estradien-3-one (Steroids 37 (1981), 361-382),
11~-(4-dimethylaminophenyl)-17a-hydroxy-17~-(3-
hydroxypropyl)-13~-methyl-4,9-gonadien-3-one (EP-A 0129 499),
11~-(4-acetylphenyl)-17~-hydroxy-17a-(prop-1-inyl)-4,9(10)-
estradien-3-one (EP-A 0 190 759), as well as
the ll~-aryl-14~-estradienes and estra-trienes described in
EP-A 0 277 676,
the l9,11~-bridged steroids, which are the object of EP-A 0
283 428,
the ll~-aryl-6-alkyl (or 6-alkenyl or 6-alkinyl)-estradienes
and -pregnadienes known from EP-A 0 289 073 and the 11~-aryl-7-
methyl (or 7-ethyl)-estradienes known from EP-A 0 321 010.
This list is not final; also other antigestagens described
in the above-mentioned publications as well as those from
publications not mentioned here are suitable!
~. . - . . . .
~ 15
': ~ 2~67173
The antigestagens are used according to this invention in
amounts of 10 mg to 200 mg; generally it will be possible to
manage well 50 to 100 mg of 11p-~(4-N,N-dimethylamino)-phenyl]-
17-hydroxy-17~-(3-hydroxypropyl)-13a-methyl-4,9(10)-gonadien-3-
one per day or a biologically equivalent amount of another
antigestagen.
As compounds acting antiestrogenically, antiestrogens and
aromatase inhibitors are suitable. Antiestrogens and aromatase
inhibitors according to this invention can be derived both from
steroids or nonsteroidal compounds.
But by compounds acting antiestrogenically according to this
invention are to be understood only those compounds which act as
selectively as possible, i.e., which basically inhibit only the
action of estrogen and/or reduce its concentration. The
antiestrogens act as competitive estrogen antagonists, by
displacing estrogen from the receptor, while aromatase inhibitors
suppress the biosynthesis of the estrogen. Compounds of the type
of aminoglutethimide, 3-alkylated 3-(4-aminophenyl)-piperidine-
2,6-diones, which in addition to the estrogen level have a
lowering effect on other sexual hormone serum concentrations, are
unsuitable according to this invention as antiestrogenically
active compounds.
The antiestrogens can be used approximately in the same
amounts as the antiestrogens already on the market, i.a., the
daily dose is approximately 5-100 mg for tamoxifen or
biologically equivalent amounts of another antiestrogen.
16
~` ~06~173
As nonsteroidal antiestrogens, there can be mentioned, for
example:
Tamoxifen = (Z)-2-[p-(1,2-diphenyl-1-butenyl)-phenoxy]-N,N-
dimethyl-ethylamine
nafoxidine = 1-2-[4-(6-methoxy-2-phenyl-3,4-dihydro-1-
naphthyl)-~henoxy]-ethylpyrrolidine, hydrochloride and
2-(4-hydroxyphenyl)-3-methyl-1-[6-(1-pyrrolidinyl)-hexyl]-
indol-5-ol and other aminoalkyl indoles mentioned in EP-A-
0348341.
Also, as steroidal antiestrogens, the following are
suitable:
~ Methoxy-17~-ethinyl-1,3,5(10)-estratriene-3,17~-diol,
16~-ethylestradiol and
11-(3,17~-dihydroxy-1,3,5(10)-estratrien-7~-yl)-undecanoic
acid-(N-butyl-N-methyl)-amide (EP-A 0 138 504) as well as the
antiestrogens described in German patent application DE-P 39 25
507.7, especially 11-(3,17-dihydroxy-14a,17~-ethano-1,3,5(10)-
estratrien-7~-yl)-undecanoic acid-(N-butyl-N-methyl)-amide.
As aromatase inhibitors, all compounds are suitable which
inhibit the formation of estrogens from their precursors, such
as, for example, the 1-methyl-androsta-1,4-diene-3,17-dione
described in German laid-open specification 33 22 285, the
:- testolactone (17a-oxa-D-homoandrosta-1,4-diene-3,17-dione)
described in Journal of Clinical Endocrinology and Metabolism,
49, 672 (1979), the compounds
androsta-4,6-diene-3,17-dione,
androsta-4,6-dien-17~-ol-3-on-acetate,
:
` ( 2067173
androsta-1,4,6-triene-3,17-dione,
4-androstene-19-chloro-3,17-dione,
4-androstene-3,6,17-trione
. described in "Endocrinology~ 1973, Vol. 92, No. 3, page 874,
the l9-alkynylated steroids described in German laid-open
specification 31 24 780,
the 10-(1,2-propadienyl) steroids described in German laid-
open specification 31 24 719,
the l9-thio-androstane derivatives described in European
patent application EP-A 100 566,
the 4-androsten-4-ol-3,17-dione and its ester described in
"Endocrinology" 1977., Vol. 100, No. 6, page 1684 and US patent
specification 4,235,893,
the l~methyl-15~-alkyl-androsta-1,4-diene-3,17-diones
described in German laid-open specification 35 39 244,
the lO~_alkinyl_4,9(11~-estradiene derivatives described in
German laid-open specification 36 4.4 358,
- and the 1,2~-methylene-6-methylene-4-androstene-3,17-dione
described in European patent application 0250262.
As nonsteroidal aromatase inhibitors, for example, [4-
(5,6,7,8-tetrahydroimidazotl,5a]-pyridin-5-yl)benzonitrile-
monohydrochloride] (Cancer Res., 48, pp. 834-838, 1988) and the
triazole derivatives known from EP-A-0293978 can be mentioned.
The dosage is at 1-1000 mg of 1-methyl-androsta-1,4-diene-
3,17-dione per day or biologically equivalent doses of other
aromatase inhibitors.
., ,
~ ` 18
2067173
Antigestagenically and antiestrogenically active compounds
can be administered, for example, locally, topically,
subcutaneously, enterally or parenterally.
- For the enteral administration, especially tablets, coated
tablets, capsules, pills, suspensions or solutions are suitable,
which can be produced in the usual way with the additives and
vehicles usual in galenicals. For local or topical use, for
example, vaginal suppositories or transdermal systems such as
skin plasters are suitable.
The preferred subcutaneous injection is performed with an
oily solution of the respective component or components.
An antigestagen dosage unit contains about 10-200 mg of 11~-
t(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-17~-(3-hydroxypropyl)-
13~-methyl-4,9(10)-gonadien-3-one or a biologically equivalent
amount of another antigestagen.
An antiestrogen dosage unit contains 1-100 mg of tamoxifen
or 10-200 mg of 1-methyl-androsta-1,4-diene-3,17-dione or a
biologically equivalent amount of another antiestrogenically
active compound.
: . .
` ~ ~ 19
- 2067173
Example 1
10.0 mg of 11~-[(4-N,~-dimethylamino)-phenyl]-17a-hydroxy-
17~-(3-hydroxypropyl)-13~-methyl-4,9-gonadien-
.- 3-one
140.5 mg of lactose
69.5 mg of corn starch
2.S mg of polyvinylpyrrolidone 25
2.0 mg of aerosil
0.5 mq of magnesium stearate
225.0 mg total weight of the tablet
Example 2
50.0 mg of 1-methyl-androsta-1,4-diene-3,17-dione
115.0 mg of lactose
50.0 mg of corn starch
2.5 mg of poly-N-vinylpyrrolidone 25
2.0 mg of aerosil
0.5 mq of magnesium stearate
220.0 mg total weight of the tablet
