CA1318251C - Combined use of an antigestagen and a progesterone systhesis inhibitor of the trilostane and epostane type - Google Patents
Combined use of an antigestagen and a progesterone systhesis inhibitor of the trilostane and epostane typeInfo
- Publication number
- CA1318251C CA1318251C CA000569576A CA569576A CA1318251C CA 1318251 C CA1318251 C CA 1318251C CA 000569576 A CA000569576 A CA 000569576A CA 569576 A CA569576 A CA 569576A CA 1318251 C CA1318251 C CA 1318251C
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- Canada
- Prior art keywords
- antigestagen
- progesterone
- pharmaceutical composition
- epostane
- synthesis inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
ABSTRACT
A pharmaceutical agent contains a progesterone synthesis inhibitor (ProI) of the trilostane or epostane type and an antigestagen (AG). It can be used for inducing delivery at term in humans and animals, for terminating normal or pathological pregnancies therein or for treatment of hormone-dependent tumors, endometriosis or dysmenorrhea.
A pharmaceutical agent contains a progesterone synthesis inhibitor (ProI) of the trilostane or epostane type and an antigestagen (AG). It can be used for inducing delivery at term in humans and animals, for terminating normal or pathological pregnancies therein or for treatment of hormone-dependent tumors, endometriosis or dysmenorrhea.
Description
~3~2~
This invention relates to a pharmaceutical agent, which comprises a progesterone synthesis inhibitor (ProI) of the type of trilostane and epostane, and an antigestagen (AG).
It is sometimes necessary, in order to avert dangers to the mother and/or child, to induce labor artificially or terminate pregnancy prematurely. Surgical techniques and pharmacological methods are available for this purpose.
One possible pharmacological method is the vaginal or intramuscular administration of prostaglandins, which, in the 0 case of termination of pregnancy, i~ carried out in the first or second trimester of pregnancv (Contraception 1983, Vol.
27, 51-60 and Int. J. Gynaecol. Obstet. 1982 t Vol. 20, 383-386).
The advantage of prostaglandin use is the possibility of employing it over a long period of the pregnancy.
Disadvantages of prostaglandins which should be mentioned are acute side effects such as pain and nausea. In addition in the case of the termination of pregnancy in advanced phases of pregnancy, the success rate does not exceed 90%, even with 0 prolonged duration of prostaglandin treatment.
Another possibility for terminating pregnancy comprises administration of an antigestagen (Med. et Hyg. 1982, Vol.
40, 2087-2093). Antigestagens are better tolerated than are prostaglandins, but are less effective, and have a longer latency period and greater individual variability of the onset of action compared with prostaglandins. In addition, it has been observed clinically that they have a tendency to cause hemorrhages, which can be severe.
Although the conjoint use of prostaglandins and 0 antigestagens (EP 84730108O2) has uncontestable advantages over administration of the individual active substances alone (especially reduction in the amount of each active ~`~
13~82~
substance), it does not, for example, solve the problems which generally occur when prostaglandins are used:
undesired side effects, such as gastrointestinal effects or uterine pain, the necessity for inpatient treatment, the storage and shelf-life of the pharmaceutical, owing to a lack of stability, being limited and/or elaborate, the impossibility o~ the most user-friendly administration form, namely oral, and thus the impossibility of combining the two active substances in a tablet, pill or coated tablet.
It has also been suggested to use the combination of prostaglandins, glucocorticoids and antigestagens for the induction of labor or for termination of pregnancy. The antigestagens can be either receptor competitive progesterone antagonists or compounds which antagonize the effect of gestagens by a different route, e.g, the derivatives of trilostane of U.S. patent 4,160,027. (See U.S. S.N. 790,020, filed October 22, 1985; DOS 3438994.6, filed October 22 1984).
Another possibility which has been suggested for premature termination of pregnancy is treatment with progesterone synthesis inhibitors such as epostane derivatives (also US Patent 4,160,027). However, it has been found that it is impossible to induce abortion in guinea pigs in advanced pregnancy even with doses high enough to cause a marked reduction in the serum progesterone level~ In early human pregnancy, the success rate even with the maximum epostane doses is not 100%. Once again, clinical treatment is successful only in combination with prostaylandins, but very large amounts of active substances (30 mg of PGE2, 5 X
600 mg of epostane) are necessary for this. In addition to this disadvantage, the method is subject to the problems associated with the use of prostaglandins which have been discussed above.
Pharmaceutical compositions for post-coital fertility control, which contain a competitive progesterone antagonist (antigestagen~ as well as a progesterone and estrogen synthesis blocker are already generically described in US
patent 4,670,426. Typical representatives of the competitive . .
13182~
progesterone antagonists to be used are fluocinolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17-acetate with acetone and 17~-hydroxy-11~,l4-dimethylaminophenyl~ 7~ prop-lynyl-estra-4,9-dien-3-one and equivalent derivatives. The stated dosages for these compounds is between 20 and 100 mg per person per day. As examples for the progesterone and estrogen synthesis blocker there are cited aminogluthetimide, ~-cyano-4,4,17~-trimethyl-5-androst-5-ene-17B-ol-3-one, 20,25-0 diazacholesterol, and compounds with equivalent activity.Doses of 300 to 1000 mg are stated. The use of the agent according to US patent 4,670,426 has to take place as early as possible within the first week after sexual intercourse over a period of 3 days; the treatment should best be continued 2 to 6 days. Prevention of nidation and thus of a pregnancy is caused by the synergistic effect in the combined use of the two components of the composition, and with a success rate on the order of 90% or more.
More recently the use of antigestagens in the field of 0 tumor therapy, especially for treatment of mastocarcinoma, has also been discussed. A first phase II study with the already mentioned 17B-hydroxy-llB-(4-dimethylaminophenyl)-17~-prop-1-ynyl-estra-4,9-dien-3-one-on postmenopausal or ovariectomy endocrine-therapy-resistant patients with metastasizing mastocarcinoma is reported by Maudelonde et al in Hormonal Manipulation of Cancor, eds. J.G.M. Klijn, R.
Paridaens and J. A. Folkens in Raven Press, p.55 (1987).
This invention has found that the use of a combination of progesterone synthesis inhibitors of the trilostane and 0 ~postane type(s) and antigestagens (competitive progesterone antagonists), i.e. of substances which both act on the principle of inhibition of the action of progesterone, (and ~r 131~2~
each of which is, by itself, only incompletely effective or entirely ineffective, even at high dosages), is surprisingly completely effective even with a dramatic reduction in these doses.
Progesterone synthesis inhibitors (ProI) of the trilostane and epostane type and antigestagens (AG) can be administered conjointly for inducing labor i.e., at term, in humans and animals and for terminating normal or pathological pregnancies therein. Further, the combination according to 0 the invention of progesterone synthesis inhibitors and antigestagen is suitable for treatment of endometriosis, dysmenorrhea and hormone-dependent tumors, for example, carcinoma of the breast and durosarcoma.
A 100% effectiveness is absolutely necessary for the use of these compounds for terminating pregnancy or inducing labor, since an embryotoxic action of the involved compounds can never be ruled out with certainty in practice. In the treatment of hormone-dependent tumors, this invention proves superior to the sole use of antigestagen.
0 Fig. 1 shows a comparison of the effect of an antigestagen tRU-486) alone, a prostaglandin synthesis inhibitor (epostane) alone, and the combination together in inducing abortion in pregnant guinea pigs.
dpc = day post coitus /d s.c. = per day subcutaneously /d p.o. = per day by mouth Progesterone synthesis inhibitors of the type of 0 trilostane or epostane and antigestagens are used for all these purposes in one dose unit or separately, simultaneously "f,~f`, .,.i~.
~ 3 ~
and/or sequentially, In a ratlo by welght whlch Is essentlally 1:40 to 60:1, preferably 1:30 to 30:1. The treatment wlth pro-gesterone synthesls Inhlbltors and antlgestagens per thls Inven-tlon Is, as a rule, carrled out for 1 to 4, preferably 1 to Z, days. It Is possl~le and preferred for progesterone synthesls Inhlbltor and antlgestagen to be admlnlstered comblned In one dose unlt.
Sultable antlgestagens Include all compounds whlch have a strong afFlnlty for the gestagen receptor (progesterone recep-tor) and, moreover, have no Important Intrlnslc gestagenlc actlv-l~y. Non-llmltlng examples o~ sultable compet~tlve progesterone antagonlsts Include the followlng sterolds: 11~ -r l4-N,N-dlmethylamlno)-phenyl]-17~ -hydroxy-17~ ~propynyl-4,9(10)-estra-dlen-3-one (RU-486), 11~ -C(4-N,N-dlmethylamlno)-phenyl]-17 ~ -hydroxy-18-methyl-17 ~ -propynyl-4,9-(10)-estradlen-3-one, and ~ (4-N,N-dlmethylamlno)-phenyl]-17a ~ -hydroxy-17a-propynyl-D-homo-4,9(1n)16-estratrlen-3-one (European Patent ApplIcatlon 82,400,02~.1 - Publlcatlon No. 0,057,115); and furthermore 11~ -p-methoxyphenyl-17~ -hydroxy-17~ -ethynyl-4,9(10)-estradlen-3-one (Sterolds 37 (1981) 361-382) and 11 -[(4-N,N-dlmethylamlno)-phenyl)-17 ~-hydroxy-17 ~(3-hydroxypropyl)-13~ -methyl-4,9-gona-dlen-3-one (European Patent No. 0129 499 correspondlng to U.S.
Ser. No. 621,308).
~5 The foregolng llstlng Is exemplary only. Many other antlgestagens can be used, e.g., as dlsclosed In Fertlll tY and Sterlllty 40, 253 ~1982), Ste olds 37, 36~-382 ~1981) and EP0057115.
The amounts of antlgestagens used accordlng to the pre-sent Inventlon are thereby belo~ the amounts otherwlse customary for termlnatlon of pregnancy ~and, nevertheless often Insuffl-clent for a 100% success rate). In general, ~ to 200 mg oF 11~ -[(4-N,N-dlmethylamlno)-phenyl]--17~ -hydroxy-17 ~-propynyl-4,9(10)-estradlen-3-one per day Sand per dosls unlt), or a blo-~, , :
"
,, 1 3 ~
loglcally equlvalent amount of ano~her antlgestagen, Is suffl-cient. These bloavallably equlvalent amounts can be determlned routlnely and conventlonaliy, e.~., by per f ormlng dl~ferentlal potency studles uslng ~ully routlne pharmacologlcal protocols, e.g., as dlsclosed In Fertll Itv and Sterl I Ity 40, 253 (1982~, Stero/ds 37, 361 {19~
Progesterone synthesls Inhlbltors whlch can be used accordlng to the Inventlon Include all Inhlbltors of the 3~ -hydroxysterold dehydrogenase enzyme system whlch reduce the blood progesterone level and are of the type of trllostane (4 ~,5-epoxy-3,17 ~ -dlhydroxy-5 ~-androst-2-ene-2-carbonltrlle) and/or epostane (4 ~,5-epoxy-3,17~ -dlhydroxy-4 ~ ,17~ -dlmethyl-5-androst-2-ene-2-carbonltrlle). By compounds of the trllostane and/or epostane type, there arP Included, among others, 5-androstanes havlng the structural features: 2-cyano-4 ~ -5 ~ -epoxy, and 17 ~ -hydroxy or -alkanoyloxy (1-6 C atoms). See USP
`4,160,027. In an especlally preferred subgenus, there are Included such 5~ -androstanes whlch Includ~, Instead of a 3-one f eature, the structural unlt 2-ene-3-hydroxy. In addltlon, all of such compounds can have substltuents, e.~., those def,lned In USP 4,160,027.
The amounts of these progesterone synthesls Inhlbltors whlch are used are also far below the amounts otherwlse customary for the mentloned Indlcatlons. When epostane Is used as the pro-gesterone synthesls Inhlbltor, as a rule a total of 5 - 600 mg, preferably 30 - 300 mg, wl I I suff Ice. One dose unlt contalns about 5 - 300 mg of epostane or a blologlcally equlvalent amount of another such progesterone synthesls Inhlbitor. These blo-avallably equlvalent amounts can be determlned routlnely and conventlonally, e.g., by performlng dlfferential potency studles uslng fully routlne pharmacologlcal protocols, e.g., as dlsclosed In Am. J. Obstet. Gynecol., SupP/., 1987, 157, ~065-74. The actlvlty of the claImed comblnat30n In treatlng hormone-dependent tumours can be determlned accordlng to already known methods, 131~
e.g. as dlsclosed In the mentloned reference to Maude londe et al The a~ounts of antlgestagen and progesterone synthesls Inhlbltor can vary from 1:20 to 20:1 when treatlng a hormone-dependent tumour or treatlng endometrlosls (dally dosage un1t 10 to 200 mg of each) or from 1:30 ~o 30:1 Y~hen treatlng dysmenor-rhea (dally dosage unlt 10 to 300 mg of each). In every case the upper llmlt of the dosage depends of the constltutlon of the respectlve patlent and of ~he Intended duratlon of the respectlve treatment.
The antlgestagens and progesterone synthesls In Inhlbltors can be admlnlstered, for example, locally, toplcally, enterally or parenterally. For the preferred oral admlnlstratlon It Is posslble to use In partlcular, ~ablets, coated tablets, capsules, pllls, suspenslons or solutlons, whlch can be prepared In the customary manner uslng the addltlves and vehlcles custom-ary In pharmacy. See e.g., the several references mentloned above. Preparatlons sultable for local or toplcal admlnlstratlon Include, for example, vaglnal supposltorles or transdermal sys-tems such as skln plasters.
Accordlng to the present Inventlon for termlnatlng pregnancy or Induclng labour the comblnatlon Is admlnlstered In every case after nldatlon, preferably In the second or thlrd trlmester of pregnancy, In the case of Induclng labour shortly before or on the term of labour. The c~npounds can be admlnls-tered In any sequence, preferably slmultaneously, In the case of sequentlal admlnlstratlon the second may be admlnlstered at any tlme after the fIrs$ so long as It becomes bloavallable In the patlent at the same tlme as an effectlve dose of the fIrst Is stlll bloavallable. For example, the ProI can be adminlstered wlthln 1 or 2 days after AG.
131 82~
Wlthout further elaboratlon, It Is belleved that one skllled In the art can, uslng the precedlng descrlptlon, utlllze the present Inventlon to Its fullest extent. The followlng pre-ferred speclflc embodlments are, therefore, to be construed as 5 merely Illustratlve, and not llmltatlve of the remalnder of the dlsclosure In any way whatsoever.
Composltlon of a ta~let contalnlng 11~[(4 - N,N -dlmethyl-amlno)-phenyl]-17 ~-hydroxy-17~ -propynyl-4,9~10)-estra-dlen-3-one for oral admlnlstration _ 7a -2 ~ ~
10.0 mg of llB-[(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-17~-propynyl-4,9(10)-estradien-3-one 140.5 mg of lactose 69.5 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of Aerosil 0.5 mg of magnesium stearate 225.0 mg total weight EX~MPLE 2 Composition of a tablet containing 4~,5-epoxy-3,17B-dihy-droxy-4B,17~-dimethyl-~-androst-2-ene-2-carbonitrile (epostane) for oral administration mg of 4~,5-epoxy-3,17B-dihydroxy-4B,1~-dimethyl-5~-androst-2-ene-2-carbonitrile 201 mg of lactose 139 mg of corn starch 5.0 mg of polyvinylpyrrolidone 25 ~~~ 4.0 mg of Aerosil Trale ~ar~
1.0 mg of magnesium stearate 380.0 mg total weight .
EX~MPLE 3 Composition of a tablet containing 4~,5-epoxy-3,17~
dihydroxy-5~-androst-2-ene-2-carbonitrile (trilostane) for oral administration -20.0 mg of 4~,5-epoxy-3,17B-dihydroxy-5~-androst-2-ene-2-carbonitrile 281.0 mg of lactose 139.0 mg of corn starch 5.0 mg of polyvinylpyrrolidone 25 4.0 mg of Aerosil rra~e ~ar~
0 mg of magnesium stearate 450.0 mg total weight ~ 31 8%e~
Pharmacoloqical findinqs I'he model substances selected for experiments on pregnant guinea pigs were the progesterone synthesis inhibitor epostane and the antigestagen llB-[(4-N,N-dimethyl--- -amino)-phenyl]-17B-hydroxy-17~-propynyl-4,9(10t-estradién-3-one (RU 486). The dosages tested are shown in the figure.
Investiqations on preqnant Quinea ~ias Test of the combination Description of the experiment Pregnant guinea pigs weighing about 800 g were entered in the experiment on day 42 of pregnancy (the 2nd day of vaginal opening in the mating period was regarded as the first day of pregnancy). Pregnancy was checked by palpation before the start of the experiment. The treatment with the selected test substances and the combination was effected by oral (epostane) or subcutaneous (RU 486) administration each day on days 43 and 44 of pregnancy. For this purpose, the antigestagen was dissolved in benzyl benæoate + castor oil (mixing ratio 2 + 4.5), and the daily dose was injected s~c.
,, 20 in a volume of 1.0 ml. The daily dose of epostane was suspended as microcrystals in Myrj(R)/ saline solution and administered divided into two equal doses in the morning and afternoon. 'Any expulsion'of emhryos was checked-several times a day during and a,fter the treatment. The animals were, sacrificed on-day 50 of,pregnancy. The uteri were inspected, and the fetuses were examined.
Results The results of the experiments on the induction of abortion in pregnant guinea pigs on combined administration of antigestagens and progesterone synthesis inhibitors are shown in the figure.
Proqesterone sYnthesis inhibitors At an oral dose of 30.0 mg/day, epostane was totally inactive in terms of an abortive effect (see Fig. 1).
_ g 13182~
Antiqestagens With the antigestagen RU 486 an existent pregnancy was terminated with 10 mg/d s.c. in 3 of 9 treated animals. The abortions took place after a latency period-of 4 to 6 days after the start of treatment (see Fig.. 1).
Antigestagen~proaesterone svnthesis inhibitor combination 0 The combination of marginally effective antigestagen doses (10.0 mg of RU 486/d s.c.) with an ineffective epostane doses o~ 30 mg/d orally resulted in an abortion rate of 100%
and a far more rapid occurrence of the abortions. The latency period was shortened to a maximum of 2 days ~see Fig.
1).
This invention relates to a pharmaceutical agent, which comprises a progesterone synthesis inhibitor (ProI) of the type of trilostane and epostane, and an antigestagen (AG).
It is sometimes necessary, in order to avert dangers to the mother and/or child, to induce labor artificially or terminate pregnancy prematurely. Surgical techniques and pharmacological methods are available for this purpose.
One possible pharmacological method is the vaginal or intramuscular administration of prostaglandins, which, in the 0 case of termination of pregnancy, i~ carried out in the first or second trimester of pregnancv (Contraception 1983, Vol.
27, 51-60 and Int. J. Gynaecol. Obstet. 1982 t Vol. 20, 383-386).
The advantage of prostaglandin use is the possibility of employing it over a long period of the pregnancy.
Disadvantages of prostaglandins which should be mentioned are acute side effects such as pain and nausea. In addition in the case of the termination of pregnancy in advanced phases of pregnancy, the success rate does not exceed 90%, even with 0 prolonged duration of prostaglandin treatment.
Another possibility for terminating pregnancy comprises administration of an antigestagen (Med. et Hyg. 1982, Vol.
40, 2087-2093). Antigestagens are better tolerated than are prostaglandins, but are less effective, and have a longer latency period and greater individual variability of the onset of action compared with prostaglandins. In addition, it has been observed clinically that they have a tendency to cause hemorrhages, which can be severe.
Although the conjoint use of prostaglandins and 0 antigestagens (EP 84730108O2) has uncontestable advantages over administration of the individual active substances alone (especially reduction in the amount of each active ~`~
13~82~
substance), it does not, for example, solve the problems which generally occur when prostaglandins are used:
undesired side effects, such as gastrointestinal effects or uterine pain, the necessity for inpatient treatment, the storage and shelf-life of the pharmaceutical, owing to a lack of stability, being limited and/or elaborate, the impossibility o~ the most user-friendly administration form, namely oral, and thus the impossibility of combining the two active substances in a tablet, pill or coated tablet.
It has also been suggested to use the combination of prostaglandins, glucocorticoids and antigestagens for the induction of labor or for termination of pregnancy. The antigestagens can be either receptor competitive progesterone antagonists or compounds which antagonize the effect of gestagens by a different route, e.g, the derivatives of trilostane of U.S. patent 4,160,027. (See U.S. S.N. 790,020, filed October 22, 1985; DOS 3438994.6, filed October 22 1984).
Another possibility which has been suggested for premature termination of pregnancy is treatment with progesterone synthesis inhibitors such as epostane derivatives (also US Patent 4,160,027). However, it has been found that it is impossible to induce abortion in guinea pigs in advanced pregnancy even with doses high enough to cause a marked reduction in the serum progesterone level~ In early human pregnancy, the success rate even with the maximum epostane doses is not 100%. Once again, clinical treatment is successful only in combination with prostaylandins, but very large amounts of active substances (30 mg of PGE2, 5 X
600 mg of epostane) are necessary for this. In addition to this disadvantage, the method is subject to the problems associated with the use of prostaglandins which have been discussed above.
Pharmaceutical compositions for post-coital fertility control, which contain a competitive progesterone antagonist (antigestagen~ as well as a progesterone and estrogen synthesis blocker are already generically described in US
patent 4,670,426. Typical representatives of the competitive . .
13182~
progesterone antagonists to be used are fluocinolone acetonide, triamcinolone acetonide, steroids with a cyclic 16,17-acetate with acetone and 17~-hydroxy-11~,l4-dimethylaminophenyl~ 7~ prop-lynyl-estra-4,9-dien-3-one and equivalent derivatives. The stated dosages for these compounds is between 20 and 100 mg per person per day. As examples for the progesterone and estrogen synthesis blocker there are cited aminogluthetimide, ~-cyano-4,4,17~-trimethyl-5-androst-5-ene-17B-ol-3-one, 20,25-0 diazacholesterol, and compounds with equivalent activity.Doses of 300 to 1000 mg are stated. The use of the agent according to US patent 4,670,426 has to take place as early as possible within the first week after sexual intercourse over a period of 3 days; the treatment should best be continued 2 to 6 days. Prevention of nidation and thus of a pregnancy is caused by the synergistic effect in the combined use of the two components of the composition, and with a success rate on the order of 90% or more.
More recently the use of antigestagens in the field of 0 tumor therapy, especially for treatment of mastocarcinoma, has also been discussed. A first phase II study with the already mentioned 17B-hydroxy-llB-(4-dimethylaminophenyl)-17~-prop-1-ynyl-estra-4,9-dien-3-one-on postmenopausal or ovariectomy endocrine-therapy-resistant patients with metastasizing mastocarcinoma is reported by Maudelonde et al in Hormonal Manipulation of Cancor, eds. J.G.M. Klijn, R.
Paridaens and J. A. Folkens in Raven Press, p.55 (1987).
This invention has found that the use of a combination of progesterone synthesis inhibitors of the trilostane and 0 ~postane type(s) and antigestagens (competitive progesterone antagonists), i.e. of substances which both act on the principle of inhibition of the action of progesterone, (and ~r 131~2~
each of which is, by itself, only incompletely effective or entirely ineffective, even at high dosages), is surprisingly completely effective even with a dramatic reduction in these doses.
Progesterone synthesis inhibitors (ProI) of the trilostane and epostane type and antigestagens (AG) can be administered conjointly for inducing labor i.e., at term, in humans and animals and for terminating normal or pathological pregnancies therein. Further, the combination according to 0 the invention of progesterone synthesis inhibitors and antigestagen is suitable for treatment of endometriosis, dysmenorrhea and hormone-dependent tumors, for example, carcinoma of the breast and durosarcoma.
A 100% effectiveness is absolutely necessary for the use of these compounds for terminating pregnancy or inducing labor, since an embryotoxic action of the involved compounds can never be ruled out with certainty in practice. In the treatment of hormone-dependent tumors, this invention proves superior to the sole use of antigestagen.
0 Fig. 1 shows a comparison of the effect of an antigestagen tRU-486) alone, a prostaglandin synthesis inhibitor (epostane) alone, and the combination together in inducing abortion in pregnant guinea pigs.
dpc = day post coitus /d s.c. = per day subcutaneously /d p.o. = per day by mouth Progesterone synthesis inhibitors of the type of 0 trilostane or epostane and antigestagens are used for all these purposes in one dose unit or separately, simultaneously "f,~f`, .,.i~.
~ 3 ~
and/or sequentially, In a ratlo by welght whlch Is essentlally 1:40 to 60:1, preferably 1:30 to 30:1. The treatment wlth pro-gesterone synthesls Inhlbltors and antlgestagens per thls Inven-tlon Is, as a rule, carrled out for 1 to 4, preferably 1 to Z, days. It Is possl~le and preferred for progesterone synthesls Inhlbltor and antlgestagen to be admlnlstered comblned In one dose unlt.
Sultable antlgestagens Include all compounds whlch have a strong afFlnlty for the gestagen receptor (progesterone recep-tor) and, moreover, have no Important Intrlnslc gestagenlc actlv-l~y. Non-llmltlng examples o~ sultable compet~tlve progesterone antagonlsts Include the followlng sterolds: 11~ -r l4-N,N-dlmethylamlno)-phenyl]-17~ -hydroxy-17~ ~propynyl-4,9(10)-estra-dlen-3-one (RU-486), 11~ -C(4-N,N-dlmethylamlno)-phenyl]-17 ~ -hydroxy-18-methyl-17 ~ -propynyl-4,9-(10)-estradlen-3-one, and ~ (4-N,N-dlmethylamlno)-phenyl]-17a ~ -hydroxy-17a-propynyl-D-homo-4,9(1n)16-estratrlen-3-one (European Patent ApplIcatlon 82,400,02~.1 - Publlcatlon No. 0,057,115); and furthermore 11~ -p-methoxyphenyl-17~ -hydroxy-17~ -ethynyl-4,9(10)-estradlen-3-one (Sterolds 37 (1981) 361-382) and 11 -[(4-N,N-dlmethylamlno)-phenyl)-17 ~-hydroxy-17 ~(3-hydroxypropyl)-13~ -methyl-4,9-gona-dlen-3-one (European Patent No. 0129 499 correspondlng to U.S.
Ser. No. 621,308).
~5 The foregolng llstlng Is exemplary only. Many other antlgestagens can be used, e.g., as dlsclosed In Fertlll tY and Sterlllty 40, 253 ~1982), Ste olds 37, 36~-382 ~1981) and EP0057115.
The amounts of antlgestagens used accordlng to the pre-sent Inventlon are thereby belo~ the amounts otherwlse customary for termlnatlon of pregnancy ~and, nevertheless often Insuffl-clent for a 100% success rate). In general, ~ to 200 mg oF 11~ -[(4-N,N-dlmethylamlno)-phenyl]--17~ -hydroxy-17 ~-propynyl-4,9(10)-estradlen-3-one per day Sand per dosls unlt), or a blo-~, , :
"
,, 1 3 ~
loglcally equlvalent amount of ano~her antlgestagen, Is suffl-cient. These bloavallably equlvalent amounts can be determlned routlnely and conventlonaliy, e.~., by per f ormlng dl~ferentlal potency studles uslng ~ully routlne pharmacologlcal protocols, e.g., as dlsclosed In Fertll Itv and Sterl I Ity 40, 253 (1982~, Stero/ds 37, 361 {19~
Progesterone synthesls Inhlbltors whlch can be used accordlng to the Inventlon Include all Inhlbltors of the 3~ -hydroxysterold dehydrogenase enzyme system whlch reduce the blood progesterone level and are of the type of trllostane (4 ~,5-epoxy-3,17 ~ -dlhydroxy-5 ~-androst-2-ene-2-carbonltrlle) and/or epostane (4 ~,5-epoxy-3,17~ -dlhydroxy-4 ~ ,17~ -dlmethyl-5-androst-2-ene-2-carbonltrlle). By compounds of the trllostane and/or epostane type, there arP Included, among others, 5-androstanes havlng the structural features: 2-cyano-4 ~ -5 ~ -epoxy, and 17 ~ -hydroxy or -alkanoyloxy (1-6 C atoms). See USP
`4,160,027. In an especlally preferred subgenus, there are Included such 5~ -androstanes whlch Includ~, Instead of a 3-one f eature, the structural unlt 2-ene-3-hydroxy. In addltlon, all of such compounds can have substltuents, e.~., those def,lned In USP 4,160,027.
The amounts of these progesterone synthesls Inhlbltors whlch are used are also far below the amounts otherwlse customary for the mentloned Indlcatlons. When epostane Is used as the pro-gesterone synthesls Inhlbltor, as a rule a total of 5 - 600 mg, preferably 30 - 300 mg, wl I I suff Ice. One dose unlt contalns about 5 - 300 mg of epostane or a blologlcally equlvalent amount of another such progesterone synthesls Inhlbitor. These blo-avallably equlvalent amounts can be determlned routlnely and conventlonally, e.g., by performlng dlfferential potency studles uslng fully routlne pharmacologlcal protocols, e.g., as dlsclosed In Am. J. Obstet. Gynecol., SupP/., 1987, 157, ~065-74. The actlvlty of the claImed comblnat30n In treatlng hormone-dependent tumours can be determlned accordlng to already known methods, 131~
e.g. as dlsclosed In the mentloned reference to Maude londe et al The a~ounts of antlgestagen and progesterone synthesls Inhlbltor can vary from 1:20 to 20:1 when treatlng a hormone-dependent tumour or treatlng endometrlosls (dally dosage un1t 10 to 200 mg of each) or from 1:30 ~o 30:1 Y~hen treatlng dysmenor-rhea (dally dosage unlt 10 to 300 mg of each). In every case the upper llmlt of the dosage depends of the constltutlon of the respectlve patlent and of ~he Intended duratlon of the respectlve treatment.
The antlgestagens and progesterone synthesls In Inhlbltors can be admlnlstered, for example, locally, toplcally, enterally or parenterally. For the preferred oral admlnlstratlon It Is posslble to use In partlcular, ~ablets, coated tablets, capsules, pllls, suspenslons or solutlons, whlch can be prepared In the customary manner uslng the addltlves and vehlcles custom-ary In pharmacy. See e.g., the several references mentloned above. Preparatlons sultable for local or toplcal admlnlstratlon Include, for example, vaglnal supposltorles or transdermal sys-tems such as skln plasters.
Accordlng to the present Inventlon for termlnatlng pregnancy or Induclng labour the comblnatlon Is admlnlstered In every case after nldatlon, preferably In the second or thlrd trlmester of pregnancy, In the case of Induclng labour shortly before or on the term of labour. The c~npounds can be admlnls-tered In any sequence, preferably slmultaneously, In the case of sequentlal admlnlstratlon the second may be admlnlstered at any tlme after the fIrs$ so long as It becomes bloavallable In the patlent at the same tlme as an effectlve dose of the fIrst Is stlll bloavallable. For example, the ProI can be adminlstered wlthln 1 or 2 days after AG.
131 82~
Wlthout further elaboratlon, It Is belleved that one skllled In the art can, uslng the precedlng descrlptlon, utlllze the present Inventlon to Its fullest extent. The followlng pre-ferred speclflc embodlments are, therefore, to be construed as 5 merely Illustratlve, and not llmltatlve of the remalnder of the dlsclosure In any way whatsoever.
Composltlon of a ta~let contalnlng 11~[(4 - N,N -dlmethyl-amlno)-phenyl]-17 ~-hydroxy-17~ -propynyl-4,9~10)-estra-dlen-3-one for oral admlnlstration _ 7a -2 ~ ~
10.0 mg of llB-[(4-N,N-dimethylamino)-phenyl]-17~-hydroxy-17~-propynyl-4,9(10)-estradien-3-one 140.5 mg of lactose 69.5 mg of corn starch 2.5 mg of polyvinylpyrrolidone 25 2.0 mg of Aerosil 0.5 mg of magnesium stearate 225.0 mg total weight EX~MPLE 2 Composition of a tablet containing 4~,5-epoxy-3,17B-dihy-droxy-4B,17~-dimethyl-~-androst-2-ene-2-carbonitrile (epostane) for oral administration mg of 4~,5-epoxy-3,17B-dihydroxy-4B,1~-dimethyl-5~-androst-2-ene-2-carbonitrile 201 mg of lactose 139 mg of corn starch 5.0 mg of polyvinylpyrrolidone 25 ~~~ 4.0 mg of Aerosil Trale ~ar~
1.0 mg of magnesium stearate 380.0 mg total weight .
EX~MPLE 3 Composition of a tablet containing 4~,5-epoxy-3,17~
dihydroxy-5~-androst-2-ene-2-carbonitrile (trilostane) for oral administration -20.0 mg of 4~,5-epoxy-3,17B-dihydroxy-5~-androst-2-ene-2-carbonitrile 281.0 mg of lactose 139.0 mg of corn starch 5.0 mg of polyvinylpyrrolidone 25 4.0 mg of Aerosil rra~e ~ar~
0 mg of magnesium stearate 450.0 mg total weight ~ 31 8%e~
Pharmacoloqical findinqs I'he model substances selected for experiments on pregnant guinea pigs were the progesterone synthesis inhibitor epostane and the antigestagen llB-[(4-N,N-dimethyl--- -amino)-phenyl]-17B-hydroxy-17~-propynyl-4,9(10t-estradién-3-one (RU 486). The dosages tested are shown in the figure.
Investiqations on preqnant Quinea ~ias Test of the combination Description of the experiment Pregnant guinea pigs weighing about 800 g were entered in the experiment on day 42 of pregnancy (the 2nd day of vaginal opening in the mating period was regarded as the first day of pregnancy). Pregnancy was checked by palpation before the start of the experiment. The treatment with the selected test substances and the combination was effected by oral (epostane) or subcutaneous (RU 486) administration each day on days 43 and 44 of pregnancy. For this purpose, the antigestagen was dissolved in benzyl benæoate + castor oil (mixing ratio 2 + 4.5), and the daily dose was injected s~c.
,, 20 in a volume of 1.0 ml. The daily dose of epostane was suspended as microcrystals in Myrj(R)/ saline solution and administered divided into two equal doses in the morning and afternoon. 'Any expulsion'of emhryos was checked-several times a day during and a,fter the treatment. The animals were, sacrificed on-day 50 of,pregnancy. The uteri were inspected, and the fetuses were examined.
Results The results of the experiments on the induction of abortion in pregnant guinea pigs on combined administration of antigestagens and progesterone synthesis inhibitors are shown in the figure.
Proqesterone sYnthesis inhibitors At an oral dose of 30.0 mg/day, epostane was totally inactive in terms of an abortive effect (see Fig. 1).
_ g 13182~
Antiqestagens With the antigestagen RU 486 an existent pregnancy was terminated with 10 mg/d s.c. in 3 of 9 treated animals. The abortions took place after a latency period-of 4 to 6 days after the start of treatment (see Fig.. 1).
Antigestagen~proaesterone svnthesis inhibitor combination 0 The combination of marginally effective antigestagen doses (10.0 mg of RU 486/d s.c.) with an ineffective epostane doses o~ 30 mg/d orally resulted in an abortion rate of 100%
and a far more rapid occurrence of the abortions. The latency period was shortened to a maximum of 2 days ~see Fig.
1).
Claims (12)
1 A pharmaceutical composition comprising effective amounts of a progesterone synthesis inhibitor of the trilostane or epostane type, and an antigestagen.
2. A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor is trilostane.
3, A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor is epostane.
4. A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor and the antigestagen are in a ratio by weight of 1:40 to 80:1, respectively.
5. A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor and antigestagen are in sep-arate dose units.
6. A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor and antigestagen are in common dose unit.
7. A pharmaceutical composition of claim 1, wherein the progesterone synthesis inhibitor dose unit contains 5 to 600 mg of epostane or a biologically equivalent amount of another progesterone synthesis inhibitor of the epostane or trilostane type.
8. A pharmaceutical composition of claim 1, wherein the antigestagen dose unit contains 5 to 200 mg of 11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propynyl-4,9(10)-estra-dien-3-one or a biologically equlvalent amount of another antigestagen.
9. A pharmaceutical composition of claim 7, wherein the antigestagen dose unit contains 5 to 200 mg of 11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propynyl-4,9(10)-estradien-3-one or a biologically equivalent amount of another antigestagen.
10. A pharmaceutical composition of claim 9, wherein the progesterone synthesis inhibitor and the antigestagen are in a ratio by weight of 1:40 to 60:1 respectively.
11. A pharmaceutical composition of claim 10, wherein the antigestagen is 11.beta.-[(4-N,N-dimethylamino)-phenyl]-17.beta.-hydroxy-17.alpha.-propynyl-4,9(10-estradien-3-one and the progesterone synthesis inhibitor is trilostane or epostane.
12. Use of a composition according to any one of claim 1 to 11, for inducing labour, terminating pregnancy, treating a hormone-dependent tumour, treating endometriosis, or treating dysenorrhea.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3720420.3 | 1987-06-16 | ||
| DE19873720420 DE3720420A1 (en) | 1987-06-16 | 1987-06-16 | PROGESTERONE SYNTHESIS INHIBITOR AND ANTI-STAGE TO BEGINNING BIRTH OR FOR PREGNANCY |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1318251C true CA1318251C (en) | 1993-05-25 |
Family
ID=6329981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000569576A Expired - Fee Related CA1318251C (en) | 1987-06-16 | 1988-06-15 | Combined use of an antigestagen and a progesterone systhesis inhibitor of the trilostane and epostane type |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0296097B1 (en) |
| JP (1) | JP2716461B2 (en) |
| AT (1) | ATE94391T1 (en) |
| AU (1) | AU611160B2 (en) |
| CA (1) | CA1318251C (en) |
| DE (2) | DE3720420A1 (en) |
| DK (1) | DK327288A (en) |
| ES (1) | ES2059556T3 (en) |
| IE (1) | IE63453B1 (en) |
| IL (1) | IL86731A (en) |
| PH (1) | PH25728A (en) |
| ZA (1) | ZA884315B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2145539C (en) * | 1992-09-25 | 2003-07-29 | Clive Barnes | Preventing contaminant build-up in beer lines |
| GB2345851B (en) * | 2000-01-18 | 2004-05-26 | Gavin Paul Vinson | A combination of trilostane or keto-trilostane and an anti-oestrogen for the treatment of an oestrogen-dependent cancer or tumour |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4062954A (en) * | 1976-12-27 | 1977-12-13 | Sterling Drug Inc. | Process for using a steroid compound |
| IL68222A (en) * | 1983-03-24 | 1987-02-27 | Yeda Res & Dev | Contraceptive compositions comprising a progesterone antagonist and a blocker of progesterone activity |
-
1987
- 1987-06-16 DE DE19873720420 patent/DE3720420A1/en not_active Withdrawn
-
1988
- 1988-06-13 JP JP63143843A patent/JP2716461B2/en not_active Expired - Fee Related
- 1988-06-14 EP EP88730135A patent/EP0296097B1/en not_active Expired - Lifetime
- 1988-06-14 ES ES88730135T patent/ES2059556T3/en not_active Expired - Lifetime
- 1988-06-14 IL IL86731A patent/IL86731A/en not_active IP Right Cessation
- 1988-06-14 AT AT88730135T patent/ATE94391T1/en not_active IP Right Cessation
- 1988-06-14 DE DE88730135T patent/DE3884067D1/en not_active Expired - Fee Related
- 1988-06-15 DK DK327288A patent/DK327288A/en not_active Application Discontinuation
- 1988-06-15 PH PH37078A patent/PH25728A/en unknown
- 1988-06-15 CA CA000569576A patent/CA1318251C/en not_active Expired - Fee Related
- 1988-06-15 IE IE180488A patent/IE63453B1/en not_active IP Right Cessation
- 1988-06-16 AU AU17750/88A patent/AU611160B2/en not_active Ceased
- 1988-06-16 ZA ZA884315A patent/ZA884315B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0296097A3 (en) | 1990-04-04 |
| IL86731A0 (en) | 1988-11-30 |
| IE881804L (en) | 1988-12-16 |
| EP0296097A2 (en) | 1988-12-21 |
| IL86731A (en) | 1992-11-15 |
| IE63453B1 (en) | 1995-04-19 |
| DE3884067D1 (en) | 1993-10-21 |
| ATE94391T1 (en) | 1993-10-15 |
| DK327288D0 (en) | 1988-06-15 |
| PH25728A (en) | 1991-10-18 |
| AU1775088A (en) | 1988-12-22 |
| DK327288A (en) | 1988-12-17 |
| JP2716461B2 (en) | 1998-02-18 |
| ES2059556T3 (en) | 1994-11-16 |
| ZA884315B (en) | 1989-06-28 |
| DE3720420A1 (en) | 1988-12-29 |
| AU611160B2 (en) | 1991-06-06 |
| EP0296097B1 (en) | 1993-09-15 |
| JPS63316725A (en) | 1988-12-26 |
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