JP2003511399A - Mesoprogestin (progesterone receptor modulator) as a component of female contraceptives - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of mesoprogestin for the production of a female contraceptive drug, a female contraceptive pharmaceutical formulation, and a female contraceptive method in which an effective amount of mesoprogestin is administered to a woman desiring contraception. Optionally said mesoprogestin can be used in combination with estrogen. Mesoprogestin is defined as a compound that possesses both agonistic and antagonistic activity for the progesterone receptor (PR) in vivo. They balance the effects of PR with intermediate levels of agonistic and antagonistic activity. A corresponding mode of action cannot be achieved with progestins or anti-progestins. J867, J912, J956, and J1042 are the preferred mesoprogestins according to the present invention.

Description

Detailed Description of the Invention

The present invention relates to the field of contraception. More particularly it relates to the use of mesoprogestin for the manufacture of a female contraceptive drug, a female contraceptive pharmaceutical composition, and a method of female contraception in which an effective amount of mesoprogestin is administered to a woman who desires contraception.

[0002]   Alternative pharmaceutical formulations are available for female oral contraception.

The most prevalent form of oral contraceptive method is the pill, a so-called mixed oral contraceptive formulation in which both estrogen and progestin are used in combination. Apparently,
Progestins block gonadotropin release (inhibition of ovulation); the estrogenic component results in endometrial control that reduces non-physiologic uterine bleeding.

Alternatively, there are contraceptive formulations that include only progestin. However, the progestin-only formulation (= progestin-only pill = POP) has a wider range of side effects than the combined formulation, especially more non-physiologic uterine bleeding. That is, a mixed formulation is the preferred oral contraceptive currently used (Sheth et al., Contrace
ption, 25: 243, (1982)).

Anti-progestins (also called “progesterone antagonists” or “antigestagens”) are a class of compounds that block progesterone receptors. For example, RU 486 (mifepristone) is a progesterone receptor antagonist. RU 486 binds to the progesterone receptor and interferes with progesterone binding to that receptor. When administered in the luteal phase of the menstrual cycle, RU 486 induces vaginal bleeding.

The prior art has shown either inhibition of the ovulatory menstrual cycle or delayed maturation of the endometrium. Both a single dose of antiprogestin RU 486 (5 mg / kg in muscle) or a weekly oral RU 486 dose of 25 mg in late follicle phase was shown to prevent ovulation in a primate model (Collins et al. ., J. Clin. Endocrinol. Metab. 19
86, 63: 1270-1276; Danforth et al., Contraception 1989, 40: 195-200)
.

By using various test protocols with different dosing regimens and doses, RU
It has been demonstrated by several groups of investigators that 486 also inhibits female ovulation (Shoupe et al., Am. J. Obstet. Gynecol. 1987, 157: 1421-1426.
; Liu et al., J. Clin. Endocrinol. Metab. 1987, 65: 1135-1140; Luukkain
en et al., Fertii. Steril. 1988, 49: 961-963). Ovulation inhibitory activity is RU 4
86 as well as other progesterone antagonists (Zeli
nski-Wooten.MB, Slayden, OD, Chwalisz, K., Hess, DL, Brenner. RM
., Stoufer, RL (1998a) Chronic treatment of female cycling rhesus monk
eys with low-doses of the antiprogestin ZK 137 316: Establishment of a
regimen that permits normal menstrual cyclicity.Hum Reprod 13: 259-267
).

As a result, several methods have been shown for non-ovulatory strategies to achieve contraception with progesterone antagonists.

A method of contraception in which RU 486 acts through implantation inhibition is also shown. So-called "L
H + 2 ”treatment (Swahn et al., ,, The luteal effect of RU 486 admini
stration during the early luteal phase on bleeding pattern, hormonal par
ameters and endometrium ”, Human Reproduction 5, 4: 402-408 (1990)), L
Two days after the appearance of the H peak (LH = luteinizing hormone), the ovulation inhibiting dose of RU 486 is administered once. The active compounds are administered only during the luteal phase of the physiological cycle after ovulation (luteal contraception).

A contraceptive method using a competitive progesterone antagonist is WO93 / 230.
20. Those ovulation-inhibiting and miscarriage doses of progesterone antagonists described below achieve female contraception by inhibition of implantation, preferably after oral administration. The method does not act against the female's menstrual cycle and does not carry the risk of aborting a previously implanted fertilized egg or fetus. Application of the progesterone antagonist should be at least 1 during the follicular phase of the female menstrual cycle (ie, before ovulation).
Happens every time. Preferred administration frequencies are daily or at regular intervals of several days, for example weekly or at intervals of 3 or 4 days between single administrations of the active compound.

WO 94/18982 describes a method of inhibiting fertilization of an oocyte which comprises administering a fertilization inhibiting amount of an anti-progestin to a ovulating mammal. The above amounts are either insufficient to prevent ovulation or to prevent the regularity of the female ovarian menstrual cycle. The preferred dosing frequency is daily.

According to one aspect of the invention mesoprogestin is used as an ingredient for the manufacture of a female contraceptive medicament. They can be used either as the sole pharmaceutically active ingredient in female contraceptives or with estrogen.

Mesoprogestin, according to one aspect of the invention alone or in combination with estrogen, is used in a regular, cyclical dosing regimen. This is because mesoprogestin
It will mean to be given in the same and repeated dosing cycles while contraception is desired. The cycle begins with the administration of mesoprogestin or mesoprogestin / estrogens, including the dosage units that follow daily with those additional dosage units. Each cycle is completed with a period of administration of inactive dose units (“pill free” days) or placebo.

Alternatively, in the case of mesoprogestin / estrogen administration, the dosing cycle is completed with a further administration of a dosage unit containing only estrogen. The new application cycle begins on the first day after completion of "pill-free" or placebo, respectively, or after the stage where a dose unit containing only estrogen is administered. In all cases, Day 1 of the first dosing cycle is the first day of bleeding in the woman's menstrual cycle at which contraceptive treatment is initiated.

One embodiment of mesoprogestin alone administration provides for administration of mesoprogestin comprising a dosage unit of up to 180 days. Reversible amenorrhea is induced and maintained upon repeated daily treatment (1-25 mg mesoprogestin / day). The contraceptive effect is due to the effect of mesoprogestin on the endometrium (endometrium inhibition). As a result, the endometrium does not prepare for implantation of the fertilized egg. It is sufficient to administer mesoprogestin at a dose that prevents implantation to achieve a contraceptive effect.
The dose of mesoprogestin may also inhibit ovulation, but this is not essential for achieving a contraceptive effect and for inducing and maintaining amenorrhea. Preferably said mesoprogestin alone is administered for a maximum of 3 months, which allows the reliability of the contraceptive agent of this method to be checked. Compared to other contraceptive regimens using only progestin, said regimen leads to better bleeding properties. Mini-pill (progesterone alone pill) and subcutaneous implant mixed with progestin (Norpl
A smaller amount of non-physiologic uterine bleeding is observed compared to ant). WO93 / 2
The normal cycle was maintained by the method using the progesterone antagonist described in 3020 and WO94 / 18982.

The next mode of mesoprogestin single administration is continuous for more than 3 months, for example 1 to 3 years. Mesoprogestin suppresses endometrial maturation and prevents the weakening of the endometrial duct and can therefore be used for a long time. In addition to chronic conditions, other reversible amenorrhea is achieved.

The next aspect of mesoprogestin alone administration is for a period of 7, 6, 5, 4 or 3 days during which the inactive compound is administered or placebo pill of 7, 6, 5, 4 or 3 days. 21, 22, 23, 24 including dose units, followed by any of the administrations
Alternatively, administration of up to 25 days of mesoprogestin is provided to complete a 28 day long cycle. On the next day, the next cycle begins with the administration of mesoprogestin, including dosage units, etc. In the last-mentioned dosing regimen, mesoprogestin acts like progestin by blocking ovulation and inducing amenorrhea and bleeding arrest.
Non-physiologic uterine bleeding is not induced. Non-physiological uterine bleeding is due to mesoprogestin-induced changes in the endometrium. As a result, in this aspect,
Mesoprogestin should be administered at an ovulation-inhibiting dose at least during the luteal phase of the female's menstrual cycle. A modification (not yet claimed) of the last-mentioned embodiment is the administration of a dose unit comprising mesoprogestin at an ovulation-inhibiting dose, except in the luteal phase of the female's menstrual cycle (not in the follicular phase).

The amenorrhagic-inducing dose of mesoprogestin can be determined by methods known to those skilled in the art, such as clinical studies. In general, the daily dose of mesoprogestin will range from 1 to 25 mg.

When estrogen is administered in addition to mesoprogestin, both active ingredients are administered from day 1 (see above) to day 21, 22, 23, 24 or 25 of the female's menstrual cycle, Then, in order to complete the long dosing cycle of 28 days each,
, 6, 5, 4 or 3 days inactive compound is administered or 7, 6,
Doses containing estrogen alone for 5, 4 or 3 days or 7, 6, 5
, Followed by either 4 or 3 days of placebo pill. The next day, the next cycle is initiated by the administration of mesoprogestin / estrogen, etc. in dosage units.

Estrogens are used in daily doses of 10 to 30 μg ethinyl estradiol or their bioequivalent amounts.

Mesoprogestins can be used sequentially for progestins. The mesoprogestin component in this contraceptive regimen prevents the non-physiologic uterine bleeding commonly associated with long-term progestin treatment. The progestin component in the doses used for so-called "mini pills" is administered for a period of 30-180 days, whereas mesoprogestin is administered for a period of 1-30 days. Physiological hemorrhage may or may not occur during mesoprogestin treatment. Nevertheless, the number of unscheduled bleedings is significantly reduced as a result of sequential progestin / mesoprogestin treatment.

A regular, cyclic dosing regimen of mesoprogestin, optionally in combination with estrogen, is illustrated in detail in FIG.

The use of mesoprogestin in a discontinuous, aperiodic dosing regimen is the so-called demand, which should be administered only near the time of intercourse where contraception is desired.
Use as a pill. Preferably the administration is
Before sexual intercourse ("medical condom").
See WO93 / 23020 for details.

A further aspect of the invention relates to a pharmaceutical combination product (composition) comprising mesoprogestin with estrogen.

A further aspect of the invention relates to a pharmaceutical combination product (composition) comprising mesoprogestin with progestin.

Yet another aspect of the invention relates to a female contraceptive pharmaceutical formulation comprising a daily dose unit of mesoprogestin. All aspects of the pharmaceutical formulation according to the invention are apparent from claims 25-38.

As mesoprogestins, in particular DE 43 32 283 and DE 43 3
The compounds described in 2284 are suitable for the purposes of the present invention. These aforementioned compounds, such as these aforementioned J867 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E) -oxime] and J912 [4- [17β-hydroxy-17
α- (Methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E) -oxime] (both DE 43 32 283).
And J900 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E)-.
[O- (ethoxy) carbonyl] oxime], J914 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene-11]
β-yl] benzaldehyde- (1E)-(O-acetyl) oxime] and J9
56 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E)-[O- (
Ethylamino) carbonyl] oxime] (all DE 43 32 284)
It has been described as a compound with strong anti-progesterone-inducing activity and has been compared to RU 486, which has a significantly reduced anti-glucocorticoid activity. Moreover, it is mentioned that these compounds have (indirectly) antiestrogenic potency, which is reflected by a decrease in uterine weight in guinea pigs with a physiological cycle. These effects must be committed to exerting a good effect specific to the pathologically altered tissues where estrogen stimulates maturation (lesions of endometriosis, fibroids, etc.). The disclosure of these applications does not relate to the use of the novel compounds in pharmaceutical formulations for or for the purpose of female contraception. Also, the progestagen activity of the compounds that are advantageous with respect to contraceptive efficacy claimed herein is not mentioned in any of these applications. Furthermore, the above mentioned application does not mention any of the mentioned conditions or any of the active doses to be used for treatment.

According to the present invention, mesoprogestin is a progesterone receptor (in vivo
PR) is defined as a compound with both agonist and antagonist activity. As a progestin and anti-progestin, mesoprogestin shows a high binding affinity for PR. However, mesoprogestin exhibits different pharmacological properties when compared to either progestin or antiprogestin. The presence of progesterone agonist activity in mesoprogestin was reported in PR
It was measured by commonly used in vivo biological tests that represent the major properties of this new class of Ms. However, this activity remains lower than that of progesterone in the plateau of the dose response curve. Mesoprogestin is unable to maintain ovariectomized pregnant rodents such as mice and rats.

The McFile test (Selye H., Textbook of Endo to evaluate progestinergic and antiprogestinergic effects using a classical bioassay, rabbit.
crinology, 1947, pp. 345-346), progesterone produces the highest McFile score of 4 (as a matter of course). However, treatment with mesoprogestin in the presence of progesterone resulted in a higher McFile score than that at all doses of RU 486, ie above 0.5-1.0, preferentially below 2.0-3.0. But a clinically relevant dose for the claimed indication (
That is, 0.01 mg to 30 mg / rabbit) results in a score clearly lower than 4 on the plateau of the dose response curve.

The ability of mesoprogestin to antagonize progesterone action is also tested by the McFile test with a dose of progesterone producing a McFile score ranging from 3-4. Mesoprogestin inhibits the effects of progesterone to a significant extent, but the maximal inhibition is below that of RU 486 or other single antiprogestins (eg, onapristone).

Thus, mesoprogestin balances the action of PR at intermediate levels of activity, which provides rationale for new clinical applications in gynecological therapy. Corresponding modes of action cannot be achieved by progestins or antiprogestins.

[0032] The PR antagonistic properties and agonist properties RESULTS Mesopurogesuchin as medicaments to demonstrate the utility of Mesopurogesuchin in indications claimed Selye (Tex
tbook of Endocrinology, 1947, pp. 345-346) to evaluate estrogen-primed rabbits.

A) Evaluation of PR agonist properties of mesoprogestin in rabbits (FIG. 1A) J867, J956, J1042 [4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4,9-diene-] 11β-yl] benzaldehyde- (1E)-[O- (ethylthio) carbonyl] oxime (German Patent Application No. 198 09 845.6)], and RU 486 (dose range: 0.0).
03-100 mg / rabbit) in the absence of progesterone,
Evaluation was performed using estradiol primed immature rabbits 4 days after subcutaneous (sc) treatment. The progestinergic effect of the mesoprogestin is 0.03 mg.
/ Rabbit or higher dose was observed. Progesterone causes endometrial changes at doses of 0.1 mg and above and reaches maximal effect at 1 mg / rabbit (generally McFfile score 4). Tested mesoprogestin (J1042, J867,
J956) did not reach the maximum effect of progesterone. J956 is
In this test, 0.3-1 mg / rabbit showed a biphasic response with a maximal effect with a McFile score of 1.5.

B) Evaluation of PR antiprogestin properties of mesoprogestin in rabbits (FIG. 1
B) Similarly, J867, J956, J1042, and RU 486 (dose range: 0
． (001-100 mg / rabbit) was evaluated using istradiol-primed immature rabbits 4 days after subcutaneous (sc) treatment in the presence of progesterone (1 mg / rabbit, subcutaneous). The anti-progestinergic effects of said mesoprogestin and RU 486 were first observed using a dose of 0.3-1 mg / rabbit (McFile index 0 = no change; 4 = complete change). The antiprogestin agonistic activity of mesoprogestin at higher clinically relevant doses (ie 3-30 mg / rabbit) was lower than that of RU 486.

In a guinea pig model that allows good prediction of human effects on abortion activity (Elger W, Beier S., Chwalisz K, Faehnrich M, Hasan SH, Henderson D, N
eef G, Rohde R (1986): Studies on the mechanism of action of progesteron
e antagonists. J Steroid Biochem 25: 835-845) Said mesoprogestin, J8
67, J912, J956, J1042 reach a maximum abortion rate of 20% at 100 mg / kg / day.

C) Evaluation of the abortion effect Physiological background: The guinea pig is considered as a relevant model for human gestation and birth (Elger W.
Faehnrich M, Beier S, Quing SS, Chwalisz K (1987). Endometrial and myom
etrial effects of progesterone antagonists in pregnant guinea pigs. Am J
Obstet Gynecol 157: 1065-1074; Elger W, Neef G, Beier S, Faehnrich M,
Gruendel M, Heermann J, Malmendier A, Laurent D, Puri CP, Singh MM, Hasa
n SH, Becker H (1992). Evaluation of antifertility activities of antiges
tagens in animal model.In: Puri CP and Van Look PFA (eds), Current Con
cepts in Fertility Regulation and Reproduction. Wiley Eastem Limited, Ne
w Delhi, pp. 303-328; Elger W, Faehnrich M, Beier S, Qing SS, Chwalisz K
(1986). Mechanism of action of progesterone antagonists in pregnant gui
nea pigs. Contraception 6: 47-62; Elger W, Chwalisz K, Faehnrich M, Has
an SH, Laurent D, Beier S, Ottow E, Neef G, Garfield RE (1990). Studies
on labor-conditioning and labor-inducing effects of antiprogesterones in
animal model, In: Garfield RE (eds), Norwell, pp. 153-175.). The anti-progestin abortion mechanism in this species is the onset of labor and ultimately the delivery of the fetus. The abortion effect during the very early pregnancy in the rat reflects an inhibitory effect on implantation rather than onset of uterine contractions. Studies in the rat model have led to a "overestimation" of the potential of antiprogestins to end pregnancy in humans. Conversely, in the guinea pig model, there is a high rate of pregnancy progression similar to the condition in humans, regardless of antiprogestin dose (Elger et al., Current Co
ncepts in Fertility Regulation and Reproduction (cited above)). Furthermore, in both humans and guinea pigs, there is a strong interaction between antiprogestins and prostaglandins with respect to induction of labor (cited above, and Elger W, Bei.
er S (1983) .Prostaglandine und Antigestagene fuer den Schwangerschaftsa
bbruch (Prostaglandins and antigestagens for pregnancy termination). Ger
man Patent DE 3337450 12; Van Look P, Bygdeman M (1989). Antiprogestatio
nal steroids: a new dimension in human fertility regulation. Oxford rev
See iews of reproductive medicine 11: 2-60).

[0037]   Evaluation of labor-inducing activity: FIG.

Pregnant guinea pigs were treated on day 43 and 44 of gestation and were observed until day 50 of gestation. See Table 1 and Figure 3 for the effects of various treatments. It is typical for this model that delivery occurs with a delay of several days after treatment. It can be found that mesoprogestin has a much lower abortion activity than RU 486. Following: RU 486>J956> J867, J912> J10
42 abortion activity rankings were obtained. The differences regarding abortion activity appear to be qualitative. It is not possible to overcome the low abortive activity of mesoprogestin by using higher doses.

[0039]

[Table 1]

The mesoprogestin is preferably a compound J867, J9 for the purposes of the present invention.
12, J956, J1042. More preferably mesoprogestin is: 4- [17β-hydroxy-17α- (ethoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E) -oxime; 4- [17β-methoxy -17α- (Ethoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E) -oxime; 4- [17β-Hydroxy-17α- (chloromethyl) -3-oxoestra-4 , 9-Dien-11β-yl] benzaldehyde- (1E) -oxime; 4- [17β-methoxy-17α- (methoxymethyl) -3-oxooestra-4,9-dien-11β-yl] benzaldehyde- (1E )-(O-Methyl) oxime (all DE 43 32 283); and 4- [17β-methoxy-1 α- (methoxymethyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E)-[O- (phenylamino) carbonyl] oxime; 4- [17β-methoxy-17α- (methoxy Methyl) -3-oxoestra-4,9-dien-11β-yl] benzaldehyde- (1E)-[propionyl] oxime; 4- [17β-methoxy-17α- (methoxymethyl) -3-oxoestra-4, 9-diene-11β-yl] benzaldehyde- (1E)-[benzoyl] oxime (all DE 43 32 284).

[0041]   The daily dose ranges from 1 to 25 mg mesoprogestin.

As estrogens, all estrogen agonistically active compounds are suitable for the purposes of the present invention.

Estrogen which may be used within the scope of the present invention include, for example, ethinyl estradiol, 17β-estradiol, as well as its esters such as estradiol-3-benzoate, estradiol-17-valerate, -cypionate, -undecylate,- Enanthate, and / or other estradiol
Esters (US-PS 2,611,773, US-PS 2,990,414
, US-PS 2,054,271, US-PS 2,225,419, and U.
S-PS 2,156,599) as well as conjugated estrogens.

-Estradiol-, ethinyl estradiol-, and estrone-3-
Sulfamate, such as estrone-N, N-dimethylsulfamate, estrone-N, N-diethylsulfamate, ethinyl estradiol-3-N,
N-dimethylsulfamate, ethinylestradiol-3-N, N-diethylsulfamate, ethinylestradiol-3-N, N-tetramethylenesulfamate, estrone sulfamate, estradiol-3-sulfamate, estradiol-3- N, N-dimethylsulfamate, estradiol-3-N, N-diethylsulfamate, ethinyl estradiol-3
-Sulfamate, all corresponding prodrugs of the corresponding 3-hydroxy compound (W. Elger et al., In J. Steroid Biochem. Molec. Biol., Vol. 55, No.
3/4, 395-403, 1995; DE 44 29 398 A1 and DE 44 29 397 A1) can also be used in the medicament according to the invention.

Suitable progestins useful in the present invention are all compounds that are suitable for use in oral contraceptives because of their progestin activity. For a representative list of the aforementioned compounds, see B. Runnebaum et al., “Female Contraception Update an
d Trends, ”Springer-Veriag, Berlin. 1988, pages 64-90, 109-121, 122-128
and found in 129-140. Preferred progestins within the scope of the invention are:
Guest den (gestodene), progesterone (progesteron)
e), levonorgestrel, cyproterone acetate, chlormadinone acetic acid (chl)
ormadinone acetate, drospirenone
none), (dihydrospirorenone
)), Northisterone, northisterone acetate, norgestimate (no).
rgestimate), desogestrel or 3
-3-ketodesogestrel. In the embodiment comprising the progestin according to the present invention, the progestin may be present in a dosage form suitable for oral administration called tablets, coated tablets, capsules or pills. In this case, the incorporation of the progestin is carried out in a manner similar to the preparation of progestins for hormonal contraception with the use of adjuvants which are commonly used for this purpose. The daily dose unit of the progestin is 0.6
-6.0 mg levonorgestrel, 2-20 mg cyproterone acetic acid, 0.3-3
． The latter is included at 0 mg Gestodene or 0.2-2.0 mg desogestrel or at other progestin doses in amounts that are comparable in activity to these doses.

The determination of equivalently acting doses of various progestins is carried out by known methods; further details can be found in eg the document “Probleme der Dosisfindung: Sexu in 2”.
alhormone [Problems of Dose-Finding: Sex Hormones] ”; F. Neumann et al.
in “Arzneimittelforschung [Drug Research]” 27, 2a, 296-318 (1977) as well as “Aktuelle Entwicklungen in der hormonalen Kontrazeption [Current Develo
pments in Hormonal Contraception] ”; H. Kuhl in“ Gynaekologe [Gynecologi
sts] ”25: 201-240 (1992).

According to all embodiments, the mesoprogestin may be present in a dosage unit intended for daily oral administration.

[0048]   The estrogen can also be present in daily oral dosage units.

When the dose unit of mesoprogestin is provided as an administration for a period of more than 7 days,
These dosage units may advantageously be present in the form of dosage units, which may be administered once a week.

In the aforementioned dosage units, which are to be administered once a week, the mesoprogestin should preferably be prepared in a formulation which results in a delayed release of the active ingredient.

The delayed release of said mesoprogestin may be formulated as a unit dosage form to be administered orally, eg as a complex tablet, or orally administered with a time-degradable coating well known to those skilled in the art. This can be accomplished by providing the dosage unit exactly as it should be.

By derivatization, for example by esterification of the free hydroxyl groups in the effective precursor, the mesoprogestin to be used according to the invention for the manufacture of a medicament has a longer half-life than this precursor. You can also As a result, a long lasting effect is also realized.

For the purposes of the present invention, the formulation of mesoprogestin, and optionally estrogen, is described for J867 in DE 43 32 283 and for their individual use as estrogen therapy, eg Cyclo-Progynova. It is carried out in a completely customary manner already known for the formulation of these compounds.

[0054]   In particular, reference is also made to the information contained in the mentioned prior art documents.

In addition to oral administration of estrogen and mesoprogestin, it is similar to administering one or both components transdermally, for example in a dermal patch (Climara Patch), which is the best known method of administering estrogen. Is possible.

Furthermore, administration can be effected by the use of an intrauterine release system (ie Mirena), but this modification is not within the scope of the present invention.

[0057]   It is also possible to formulate a sustained release formulation as the administration of one or both components.

Finally, all administration types mentioned above can be combined. For example, estrogen can be administered transdermally via a skin patch, and the progesterone antagonist can be administered daily orally or as one or more sustained release pharmaceutical formulations.

Estrogen is included according to the invention in the form of 10 to 30 mg ethinyl estradiol or a bioequivalent amount of other estrogen per daily dosage unit.

As a medicament according to the invention, mesoprogestin is included in each dosage unit, preferably in an amount sufficient to cause amenorrhea when used over the intended period.

In a preferred embodiment of the medicament according to the invention, mesoprogestin is included in each dose unit in an amount equivalent to 1 to 25 mg of J867. The bioequivalent dose of mesoprogestin can be evaluated by the McFile test.

The packages containing the pharmaceutical preparations according to the invention may be orally or dermally in the form of individually intended dosage forms (pills, coated tablets, etc. which may be suitable for mesoprogestin and / or estrogen in blister packs). Estrogen as a patch and one or two components, mesoprogestin, and estrogen in the form of pills, coated tablets, etc. in blister packs or capsules of sustained release formulations to be administered only once. In addition, the package will include instructions for use (package insert) for the use of the drug.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Schubert, Gerd             Federal Republic of Germany, 07753 Jena, Ka             ET-COL-BITZ-STRACE 13 F-term (reference) 4C084 AA17 MA52 NA14 ZA86                 4C086 AA01 AA02 DA08 MA01 MA02                       MA04 MA52 NA14 ZA86

Claims (38)

[Claims] 1. Use of mesoprogestins as an ingredient for the manufacture of a female contraceptive drug. 2. Use of mesoprogestin according to claim 1, which is otherwise free of pharmaceutically active compounds. 3. Use of mesoprogestin according to claim 1 or 2 according to a regular and a cyclical dosing regimen. 4. The method of claim 3, wherein the administration of mesoprogestin lasts from about day 1 to a maximum of 180 days, where day 1 is counted as the first day of bleeding in the female menstrual cycle. the method of. 5. The method of claim 4, whereby the daily dose of mesoprogestin is selected to induce and maintain amenorrhea. 6. The administration of the mesoprogestin is at least 21 from day 1.
Use according to claim 5, characterized in that it lasts up to the day and up to the 25th day, wherein the 1st day is counted as the first day of bleeding in the female menstrual cycle. 7. The method of claim 6, wherein the daily dose is selected to achieve reversible amenorrhea. 8. The mesoprogestin is J867, J912, J956, J.
Use according to any one of claims 1 to 7, which is 1042. 9. Use according to any one of claims 1 to 8, characterized in that the daily dose of the mesoprogestin is 1 to 25 mg. 10. Use according to any one of claims 1 and 3 to 9, characterized in that estrogen is used as an additional ingredient for the manufacture of a medicament. 11. Use according to claim 10, characterized in that the additional component is ethinyl estradiol, estradiol, estradiol ester or 17β-ethinyl estradiol or 3-sulfamate of 17β-estradiol. 12. The daily dose of estrogen, which is an additional component, is 10 to 30 μm.
Use according to claim 10 or 11, characterized in that it is g-ethinyl estradiol or a bioequivalent amount of another estrogen. 13. Use according to any one of claims 1 to 12, characterized in that the medicament is formulated for oral administration. 14. Use according to any one of claims 1 to 12, characterized in that the medicament is formulated as an intrauterine system. 15. The method according to claim 10, 11 or 12, characterized in that each at least one mesoprogestin and the additional component estrogen are formulated for oral administration. use. 16. At least one mesoprogestin and the additional component estrogen are each formulated as an intrauterine system,
Use according to any one of claims 10, 11 or 12. 17. Use according to claim 2 according to a non-continuous, aperiodic dosing regimen. 18. The use according to claim 17, wherein the mesoprogestin-containing medicament is administered on demand when contraception is actually desired for one case. 19. The use according to claim 18, wherein said administration is for a period of up to 4 days. 20. The use according to claim 19, wherein at least the first administration within a period of 4 days is before sexual intercourse for which contraception is desired. 21. The method according to claim 2, wherein the administration is once and before intercourse.
The method described in 0. 22. A pharmaceutical composition comprising mesoprogestin and estrogen. 23. The mesoprogestin is a compound J867, J912, J.
23. The pharmaceutical composition according to claim 22, selected from the group consisting of 956, J1042. 24. The estrogen is ethinyl estradiol, estradiol, estradiol ester or 17β-ethinyl estradiol or 3-sulfamate of 17β-estradiol.
The pharmaceutical composition according to. 25. A female contraceptive pharmaceutical formulation comprising a daily dose unit of mesoprogestin, wherein said pharmaceutical formulation provides a dosage unit for up to 180 days. 26. The pharmaceutical formulation of claim 25, wherein a means is provided that indicates placebo for up to 7 days or pill-free for up to 7 days following administration of the mesoprogestin. 27. A daily dose unit of said mesoprogestin of 21, 22, 23, 24 or 25 days and a placebo of 7, 6, 5, 4 or 3 days and also a pill-free of 7, 6, 5, 4 or 3 days. 27. The pharmaceutical formulation according to claim 26, which provides a means for indicating. 28. The pharmaceutical formulation according to claim 26 or 27, wherein a dosage unit comprising estrogen is provided in addition to the dosage unit comprising mesoprogestin. 29. The pharmaceutical formulation of claim 28, comprising the mesoprogestin and the estrogen in a common dosage unit. 30. The pharmaceutical formulation of claim 28, comprising the mesoprogestin and the estrogen in individual dosage units. 31. A pharmaceutical formulation comprises a daily dose unit comprising mesoprogestin and estrogen or a mixture of estrogen, wherein these dosage units are 21,2.
Administration given only for 2, 23, 24 or 25 days, and where these mesoprogestin / estrogen dosage units are followed for 7, 6, 5, 4 or 3 days containing only estrogen or estrogen mixture Units offered, resulting in 2
The above pharmaceutical preparation provided as a total dosage unit for administration for 8 days. 32. The pharmaceutical formulation of claim 31, comprising the mesoprogestin and the estrogen in a common dosage unit. 33. The pharmaceutical preparation according to claim 31, comprising the mesoprogestin and the estrogen in individual dosage units. 34. The mesoprogestin is J867, J912, J956.
, J1042. The pharmaceutical formulation according to any one of claims 25 to 33. 35. The estrogen is ethinyl estradiol, estradiol, estradiol ester or 17β-ethinyl estradiol or 3-sulfamate of 17β-estradiol.
34. The pharmaceutical preparation according to any one of claims 34 to 34. 36. The daily dosage unit comprises 1 to 25 mg mesoprogestin.
The pharmaceutical preparation according to any one of claims 25 to 35. 37. The daily dosage unit comprises 10-30 μg ethinyl estradiol or a bioequivalent amount of another estrogen, 28-33,35.
37. The pharmaceutical preparation according to any one of, and 36. 38. The pharmaceutical formulation of any one of claims 25-27, wherein the daily dosage unit comprises an amenorrhea-inducing and amenorrhea-inducing amount of mesoprogestin.