Progestogen-anti-progestogen regimens

Details Progestogen-anti-progestogen regimens Progestogen-anti-progestogen regimens

2001-01-08

2003-01-14

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S423000, C424S464000, C424S465000, C424S451000, C424S456000, C514S169000, C514S170000

Reexamination Certificate

active

06506390

ABSTRACT:

FIELD OF THE INVENTION
The invention relates generally to progestogen-anti-progestogen regimens for use in contraception and hormone replacement therapy, and more specifically for contraception to progestogen-anti-progestogen regimens involving only the administration of a progestogen and an anti-progestogen.
BACKGROUND OF THE INVENTION
It has been known for some time that contraception can be achieved by the oral administration of sufficient quantities of a progestogen to a female of child-bearing age. Contraceptive preparations that minimize the incidence of menstrual spotting, break through bleeding, variations in menstrual cycle length and amenorrhea are preferred. It is further preferred to use contraceptive regimens that minimize the amounts of estrogens and progestogens used. Preparations that fulfill many of these requirements are disclosed in WO 93/21927, wherein a contraceptive regimen free from estrogens is described, the active ingredient being a progestational agent and intermittently an anti-progestogen. The regimen used is a regimen wherein only levonorgestel is administered as the progestogen, except that on days 1, 30, 60, 90, 120, 150, and 180 a dosage of the anti-progestogen RU 486 is administered. In fact the regimen is a progestogen-only regimen, interrupted by anti-progestogen administration at the beginning of each cycle. Although this regimen is a considerable improvement over existing regimens comprising estrogens, the bleeding profile is still not perfect since it recurs slowly after an almost bleeding-free interval, and further improvement is therefor desirable.
“Progestogen-only pills” are a preferred method of contraception for breast-feeding mothers, older women, women for whom estrogen is contraindicated, women who are hypertensive, and women who develop migraine headaches when taking a combined pill (i.e. one containing an estrogen and progestogen component). See, e.g. “Contraception for women over the age of 35”,
IPPF Medical Bulletin
, 22: 3-4 (1988) and P. W. Howie “The progestogen-only pill”,
Brit. J. Obstet. Gynaecol.
, 92: 1001-2 (1985). While different progestogen-only regimens have been described, they are still associated with incomplete ovulation inhibition, and relatively high failure rates. Vessey et al “Progestogen-only oral contraception. Findings in a large prospective study with special reference to effectiveness”,
Brit. J. Family Planning
, 292: 526-30 (1986). It has been suggested to increase the daily dosage of progestogen in order to induce complete ovulation inhibition, however such an increase in dosage also increases the frequency of intermenstrual bleeding (i.e. “spotting”), which is clearly not desired. E. Diczfalusy et al,
Progestogens in Therapy
, p. 150 (Raven Press, NY 1983).
Moreover, a high prevalence of functional ovarian cysts have been reported with progestogen-only contraceptive regimens, which resolve after discontinuation of the progestogen-only contraceptive. Fotherby, K. “The Progestogen-pill”, in: Filshie et al eds.
Contraception: Science and Practice
, pp. 94-108 (1989), and Howie, supra. A need exists for a progestogen-only contraceptive regimen which more effectively inhibits ovulation, while still not increasing the frequency of intermenstrual bleeding, or leading to persistent functional ovarian cysts. The solution to this need by adding intermittently an anti-progestogen needs further elaboration.
SUMMARY OF THE INVENTION
Surprisingly, it has now been found that apart from administering an anti-progestagen at the beginning of a cycle, by selecting one or more additional days during the cycle, preferably one day in the middle of the cycle, on which the anti-progestogen is administered, whereas over the rest of an entire menstrual cycle (e.g. 28 days) desogestrel or 3-ketodesogestrel is administered as the progestogen at certain specified dosages, complete ovulation inhibition is achieved, while retaining good cycle control and almost completely decreasing the amount of spotting.
The invention thus includes a drug delivery system for contraceptive use containing daily oral dosage units, each unit containing a progestogen, and two or more units comprising an anti-progestogen, one of which is administered at the end and the others orderly divided through the cycle (if one: in the middle of the cycle).
The invention also includes a drug delivery system for HRT (hormone replacement therapy) containing daily oral dosage units, each unit comprising a progestogen with or without an estrogen or an estrogen only, and two or more dosage units comprising an anti-progestogen, one of which is preferably administered at the beginning and the others orderly divided through the cycle (if one: in the middle of the cycle).
In general terms the invention relates to a contraceptive and/or HRT (hormone replacement therapy) kit comprising sequential daily dosage units for oral administration each comprising as the sole contraceptively effective ingredient a progestogen, or as effective ingredient for HRT a progestogen with or without an estrogen or an estrogen alone, and further two or more units comprising an anti-progestogen.
If desired the kits may contain placebo pills to bridge two periods of administration of active ingredients. This is usual for contraceptive regimens containing less than 28 dosage units, in order to obtain a kit still having 28 pills (the usual cycle).
The invention also includes a pharmaceutical product (i.e. the dosage units or the package containing the dosage units), a method of using the product, and a process of manufacturing the pharmaceutical product.
The invention also includes a method of providing contraception and/or HRT for a pre-, peri-, or post-menopausal woman involving administering to the woman the above-mentioned regimens.
DETAILED DESCRIPTION OF THE INVENTION
Progestogens for use with the invention are 3-keto-desogestrel (etonogestrel), desogestrel, gestodene, levonorgestel, norgestrel and other progestogens commonly used for contraception and HRT. Desogestrel has the chemical name 13-ethyl-11-methylene-18,19-di-nor-17&agr;-pregn-4-en-20-yn-17-ol, and is the preferred progestogen. Desogestrel is believed to be metabolized in the body into 3-ketodesogestrel. Preferably the dosage units contain 75 &mgr;g of desogestrel or 3-ketodesogestrel, or an amount of other progestogens having the equivalent effect as 75 &mgr;g of desogestrel. Based on practically applied doses, levonorgestrel, desogestrel, and 3-keto-desogestrel are relatively equipotent in progestogenic activity. Gestodene is approximately 1.5 times as potent as these compounds. Norgestrel is about one-half as potent as levonorgestrel.
The anti-progestogen can be an inhibitor of progesterone synthesis, such as epostane, azastene or trilostane (Creange, Contraception 24, 289, 1981; Drugs of the Future 7, 661, 1982, van der Spuy et al., Contraception 35, 111, 1987; U.S. Pat. No. 3,296,255) or a progesterone receptor antagonist, or any such pharmaceutically suitable agent that counteracts the normal biological activity of progesterone, such as antibodies or ligands bindable to progestogens or to the progesterone receptor.
A suitable anti-progestogen is a progesterone receptor antagonist. For example RU486, Onapristone, Org 31710 [(6&agr;,11&bgr;,17&bgr;)-11-(4-dimethylaminophenyl)-6-methyl-4′, 5′-dihydrospiro[estra-4.9-diene-17,2′-(3′H)-furan]-3-one], and Org 33628 [11&bgr;,17&agr;)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one] are particularly suitable in the practice of the present invention.
Suitable amounts of anti-progestogen are for example 0.1 to 300 mg, and preferably 0.5 to 150 mg of Org 31710 or such amounts of other anti-progestogens which have equivalent activity. The anti-progestogen is administered at the beginning of the cycle, preferably on day 1, and in the middle of the cycle, preferably day 14. More generally, the first of the anti-progestogen dosage units may be administered between days 1 and 3 (the beginning of the cycle), a

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