Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-06-26
2003-11-04
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S170000, C514S171000, C514S169000
Reexamination Certificate
active
06642219
ABSTRACT:
The invention relates to a contraceptive kit (drug delivery system) comprising means (a) for the daily administration of a progestogen and means (b) for the administration of an anti-progestogen, providing a contraceptive regimen of the estrogen-free, i.e. progestogen-only type.
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 minimise 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 minimise the amounts of estrogens and progestogens used. Preparations that fulfil many of these requirements are disclosed in WO 93/21927, wherein a contraceptive regimen free from estrogens is described, the active, ovulation-inhibiting ingredient being a progestational agent. This agent is combined, particularly intermittently, with an anti-progestogen in a dosage amount equivalent to 10 mg to 250 mg of RU 486 per dose. The regimen used is a regimen wherein only levonorgestrel 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 therefore 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 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, N.Y. 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.
Surprisingly a contraceptive regimen satisfying the above need has now been found in that a progestogen is administered at a dose sufficient to inhibit ovulation and an anti-progestogen is administered at a dose not affecting ovulation, but sufficient to retain good cycle control and almost completely decreasing the amount of spotting and bleeding, i.e. in general a dose sufficient to prevent irregular bleeding and which leads to an improved, more predictable and more acceptable, bleeding pattern as compared to a progestogen-only regimen with or without intermittent anti-progestogen administration.
The invention thus resides in a contraceptive kit of the type mentioned in the opening paragraph, wherein said means (a) and (b) are designed to constitute a combined means (c) for the simultaneous daily administration of the progestogen and the anti-progestogen, the daily dosage amount of the anti-progestogen being below the lower boundary indicated in WO 93/21927, i.e. below the equivalent of 10 mg of RU 486.
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 involving administering to a woman the above-mentioned regimens.
Progestogens for use with the invention are 3-keto-desogestrel (etonogestrel), desogestrel, gestodene, levonorgestrel, norgestrel and other progestogens commonly used for contraception. Desogestrel has the chemical name 13-ethyl-11-methylene-18,19-di-nor-17&agr;-pregn-4en-20-yn-17-ol, and is the preferred progestogen. Desogestrel is believed to be metabolised in the body into 3-ketodesogestrel (etonogestrel). Preferably the dosage units contain 75 &mgr;g of desogestrel or 3-ketodesogestrel, or an amount of other progestogens having an effect equivalent with that of 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. Highly suitable are also progestogens of a newer generation, a preferred example of which is Org 30659, known from EP 210 678, the IUPAC name of which is (17&agr;)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one.
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. Such compounds are widely known, e,g from EP 277 676, EP 289 073, EP 549 041, EP 582,338, and numerous other publications. Good examples are RU 486 (IUPAC name: (11&bgr;,17&bgr;)-11-[4-(demethylamino)-phenyl]-17-hydroxy-17-(1-propynyl)esta-4,9diene-3-one), 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], which are all particularly suited in the practice of the present invention.
The main requirement for the daily dose of anti-progestogen is that it is sufficient to prevent irregular bleeding. Preferably, said dose is as low as possible. Thus, the daily dose of anti-progestogen is generally chosen so as to be equivalent to a daily dose of the reference anti-progestogen RU 486 of from 0.05 to 5 mg, and preferably of from 0.1 mg to 2 mg. For most anti-progestogens this will mean the daily administration of the corresponding fixed dose. Thus in the case of Org 33628 and Org 31710, which are somewhat more potent anti-progestogens, the daily dosage amount will typically be in the range of from 0.02 to 4 mg, and preferably of from 0.05 to 2 mg. The average skilled person will appreciate that in some cases it is preferred to adapt the dosage regimen so as to have an exposure to the anti-progestogen which is equivalent with the above daily dose of reference. This can be routinely determined on the basis of the half-life of a given com
Akzo Nobel N.V.
Jiang S.
TraskBritt
Travers Russell
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