Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-01-03
2001-11-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C514S170000, C514S843000
Reexamination Certificate
active
06312722
ABSTRACT:
The present invention relates to a two-stage pharmaceutical combined preparation for hormonal contraception containing at least 30 daily unit doses, which preparation, in its first stage, comprises as hormonal active ingredient a combination of an oestrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in single stage form and, in the second stage comprises as hormonal active ingredient an oestrogen preparation only, wherein the first stage comprises a minimum of 25 and a maximum of 77 daily discrete or continuous unit doses and the second stage comprises 5, 6 or 7 daily discrete or continuous unit doses, and wherein the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days, and relates also to a corresponding pack (contraceptive kit) containing that combined preparation, and to a contraceptive method that uses the above contraceptive preparation.
Oral contraceptives in the form of combined preparations have been known since 1960 as so-called monophase preparations. Those preparations consist of 21 unit doses that comprise active ingredient and 7 tablets or dragées that are active ingredient-free. The daily unit dose is composed of an oestrogen and gestagen. In monophase preparations the dose of active ingredient to be administered daily is the same in each unit dose. If the dose that is to be administered daily of the active components in the individual unit doses is different in individual sections over the administration cycle, then the preparation is referred to as a so-called multi-phase preparation. Triquilar® may be mentioned as an especially well-known example (DE-AS 23 65 103).
As a result of the development of new, more active gestagens than those contained in the first oral contraceptives, a continuous reduction of the daily dose of gestagen has been possible. It has also been possible for the daily dose of oestrogen to be reduced although, as before, the oestrogen contained in hormonal contraceptives is usually ethynyloestradiol. In the development of new, improved oral contraceptives, the following three factors have been (and are) dominant:
(1) contraceptive reliability
(2) good cycle control, that is to say a low incidence of intermediate bleeding and
(3) a minimum of undesired side effects should be ensured.
The contraceptive reliability is effected in particular by the gestagenic component. The daily dosage amount of that component corresponds at least to the threshold dose considered necessary for the gestagen in question to inhibit ovulation. The ethynyloestradiol usually used as the oestrogen in combined preparations should increase the ovulation-inhibiting effect of the gestagen and in particular ensure stability of the cycle. In the case of administration of ethynyloestradiol alone, the daily dose that has to be used in order to inhibit ovulation is 100 &mgr;g.
Combined preparations with the most recent generation of gestagens are, for example, the monophase preparations Femovan (DE-PS 2 546 062) and Marvelon (DE-OS 2 361 120). Milvane® may be mentioned as an example of a multi-phase preparation in which the unit doses contain a gestagen of the most recent generation, namely gestodene (EP-0 148 724). In those three-phase preparations, usually 4-6 dragées are administered in the first phase, each dragée comprising a low dose of oestrogen and a low dose of gestagen. In the second phase of 4-6 dragées, each unit dose comprises an oestrogen in the same dose or a dose that is slightly increased (up to a maximum of twice) and a gestagen in the same dose or a in a dose that is slightly increased (up to a maximum of 1.5 times). In a third phase of 9-11 units, each dragée comprises an oestrogen in the same dose or a dose that is slightly reduced, at most reduced to the initial amount, and a gestagen in a dose that is further increased, to a maximum of 3 times the initial amount. 7 pill-free days then follow. Recently, multi-phase combined preparations have been proposed that may provide an extended administration of active ingredient-containing unit doses, that is to say of up to 24 days in the 28-day cycle. In those preparations the daily dose of gestagen either increases from the first, over the second, up to the third phase (EP-A 0 491 415) or decreases (EP-A 0 491 438). In order to complete the 28-day cycle, in the first case there follow 4 blind pill days, 4 placebos or 4 unit doses that contain gestagen only, and in the second case from 4 to 7 blind pill days or from 4 to 7 placebos.
The aim of the development of new oral contraceptives having a reduced daily hormone dose is to minimize the side effects described in epidemiological studies. More recent epidemiological data point towards a trend for the improved tolerability of low-dose preparations in respect of cardiovascular side effects [Thorogood M, Oral Contraceptives and Cardiovascular Disease: an Epidemiologic Overview; Pharmacoepidemiology and Drug Safety, Vol. 2: 3-16 (1993); Gerstman B. B., Piper J. M., Tomita D. K., Ferguson W. J., Stadel B. V., Lundin F. E.; Oral Contraceptive Estrogen Dose and the Risk of Deep Venous Thromboembolic Disease, Am. J. E., Vol.133, No. 1, 32-36 (1991); Lidegaard O., Oral contraception and the risk of a cerebral thromboembolic attack: results of a case-control study; BMJ Vol. 306, 956-63 (1993); Vessey M., Mant D., Smith A., Yeates D., Oral contraceptives and venous thromboembolism: findings in a large prospective study; BMJ, Vol. 292 (1986); Mishell D. R., Oral Contraception: Past, Present and Future Perspectives; Int. J. Fertil., 36 Suppl., 7-18 (1991)].
A connection between the level of the daily oestrogen dose and the frequency of cardiovascular complications is accepted.
The preparation currently having the lowest dose of oestrogen is marketed as Mercilon
R
and contains 20 &mgr;g of ethynyloestradiol in combination with 150 &mgr;g of desogestrel in each daily unit dose over a period of 21 days with a following pill-free period of 7 days. As is to be expected, the cycle control of that preparation by comparison with preparations having a higher dose of oestrogen is somewhat poorer. A further clinically significant problem is the observation, which has been made in several studies, of a lower ovarian suppression of the preparation containing 20 &mgr;g of ethynyloestradiol. Clearly, below that very low dose of oestrogen, ripening of follicles occurs in many women, which could be detected by ultrasound examinations and hormone tests [Lunell N. O., Carlström K., Zador G., Ovulation inhibition with a combined oral contraceptive containing 20 &mgr;g ethynyloestradiol and 250 &mgr;g levonorgestrel; Acta Obstet. Gynecol. Scand. Suppl. 88: 17-21 (1979); Mall-Haefeli M., Werner-Zodrow I., Huber P. R., Klinische Erfahrungen mit Mercilon und Marvelon unter besonderer Berücksichtigung der Ovar-Funktion (Clinical experiences with Mercilon and Marvelon with special consideration given to ovary function); Geburtsh. and Frauenheilk. 51, 35-38, Georg Thieme Verlag, Stuttgart-New York (1991); Strobel E., Behandlung mit oralen Kontrazeptiva (Treatment with oral contraceptives); Fortschr. Med. 110 Jg. No. 20 (1992); Letter to Editor, Contraception 45: 519-521 (1992); Teichmann A. T., Brill K., Can Dose Reduction of Ethynylestradiol in OCs Jeopardize Ovarian Suppression and Cycle Control? Abstract Book, VIIIth World Congress on Human Reproduction, Bali, Indonesia (1993)].
Until recently, several days' interruption of the administration of dragées containing active ingredient was considered necessary in order to trigger withdrawal bleeding and ensure adequate cycle control.
Other preparations have been described that contain an oestrogenic and gestagenic active ingredient and that are generally administered in constant amounts in each individual unit dose over a period of 21 days, the administration of those unit doses containing an oestrogenic and gestagenic active ingredient preceding the administration of unit doses contai
Klemann Walter
Schmidt-Gollwitzer Karin
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
Spear James M.
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