Patent Application
20050032756
1. Field of the Invention
The present invention relates to a multistage preparation for contraception based on natural estrogen in combination with synthetic gestogen.
2. Description of the Related Art
Oral contraceptives were first marketed about 70 years ago. By continuous research the required dosages of the administered hormones have been reduced in a stepwise manner. Currently low dosage oral contraceptive preparations exist, which comprise an estrogen ingredient and a gestogen ingredient.
Multistage contraceptive preparations based on natural estrogen in combination with gestogens are known, for example from EP 0 770 388 B1, and its U.S. equivalent, U.S. Pat. No. 6,133,251. These latter preparations provided reduced intervening bleeding rates, while maintaining contraceptive effectiveness.
EP 0 770 388 B1 describes a multistage contraceptive preparation having
In example 5 of EP 0 770 388 B1 the contraceptive preparation is based on a combination of estradiol valerate and dienogest. The first stage consists of three daily dosage units of 3 mg estradiol valerate as the sole active ingredient. The second stage consists of four daily dosage units of 2 mg estradiol valerate and 1 mg dienogest, with a first group of 4 daily dosage units consisting of 2 mg estradiol valerate plus 2 mg dienogest and a second group of 16 daily dosage units consisting of 2 mg estradiol valerate plus 2 mg dienogest. The third stage consists of two daily dosage units consisting of 1 mg estradiol valerate. The final stage includes 3 daily dosage units of a pharmaceutically acceptable placebo.
The serum concentration of progesterone was measured radio-immunologically to obtain the information regarding conceptive reliability. A limiting value of 4.0 ng/ml of progesterone resulted from the measurements. The average rate of intervening bleeding (break-through bleeding and spotting) dropped about 45 to 53% from the first to the last cycle.
It is also known that the contraceptive reliability of combination preparations is based on the action of both ingredients, the estrogen and the gestogen.
Furthermore it is known that the ovulation inhibiting dosage for dienogest amounts to 1.0 mg daily: see “Dienogest: Pre-Clinical and Clinical [Results for] the new Gestogen”, by A. T. Teichmann; Walter de Gruyter, Berlin/New York, p. 101 (1995). The ovulation inhibiting dosage for drospirenone amounts to 2.0 to 3.0 mg (see P. Rosenbaum, W. Schmidt, F. M. Helmerhorst, et al, “Inhibition of Ovulation by a Novel Progestogen (drospirenone)” . . . , Eur. Contracept. Reprod. Health Care 5: pp. 16-24 (2000)).
Also H.-D. Taubert and H. Kuhl (“Contraception with Hormones”, by H.-D. Taubert, et al, Georg Thieme Press, Stuttgart/New York, p. 160 (1995)) show that there is scarcely any connection or interrelation between the occurrence of intervening bleeding and lower serum concentration of estrogen, here ethinyl estradiol, or the respective gestogen.
It is an object of the present invention to provide an agent or means for hormonal contraception based on a natural estrogen, which has a higher contraceptive reliability over the entire cycle, improved cyclic bleeding behavior and minimizes or prevents side effects, such as breast tension, headaches, depressive moods and libido changes.
According to the invention this object is attained by a multi-stage preparation for contraception comprising
In advantageous preferred embodiments of the invention dienogest, drospirenone or a gestogen with at least two times its known ovulation-inhibiting dosage is used as the gestogen ingredient.
The multi-stage preparation according to the invention is especially suitable for oral administration, but it is also conceivable that the method of administration could be intravaginal, parenteral, topical, rectal, intranasal, intrabuccal or sublingual.
The multi-stage preparation is made in a known way with the conventional solid or liquid carriers or diluents and contains the conventional pharmaceutical auxiliary ingredients according to the desired method of administration in a suitable dosage.
Preferably tablets, film tablets, dragees or hard gelatin tablets can be used for oral administration.
The invention will be demonstrated with a few examples hereinbelow. The contraceptive reliability, the cyclic bleeding behavior of women and the compatibility of the administration regime are demonstrated.
Contraceptive Reliability
In order to make a judgment regarding contraceptive reliability the Hoogland Score was determined. The follicle size, the estradiol level and the progesterone values were used to determine the Hoogland score. In the present case the serum concentration of progesterone was measured radio-immunologically on selected days. The number of ovulations (Hoogland score 6) and the lutinized, non-ruptured follicles (Hoogland score 5) were determined.
Cycle Stability
The cycle stability was evaluated with the help of the bleeding pattern determined for each cycle. In that connection the occurrence of intervening bleeding (spotting or break-through bleeding) is particularly interested. This sort of investigation was standardized. The evaluation of the data occurred descriptively.
Compatibility
The compatibility of the contraceptive preparation was evaluated with the help of subjective findings, such as headaches, depressive moods, breast tension, stomach complaints (nausea/vomiting), edemas and libido changes.
The following regimen was used for administration:
The studies were performed with 93 test subjects of ages 18 to 35 years. Administration duration amounted to three cycles each. However only the second and third cycles were observed. In the second cycle ovulation (primary target variable) took place in 3 of the 93 women (3.23%). In the third cycle ovulation occurred in 2 of the 92 women.
Thus a reliable ovulation inhibition of 96.77% as documented when the administration regime of the invention was employed. At the same time good compatibility is observed with all test subjects upon administration of the combination preparation according to the invention.
The following regimen was used for administration:
The studies were performed with 93 test subjects of ages 18 to 35 years. Administration duration amounted to three cycles each. However only the second and third cycles were observed. In the second cycle ovulation (primary target variable) took place in 2 of the 93 women (2.15%). In the third cycle ovulation occurred in 2 of the 92 women.
Thus a reliable ovulation inhibition of 97.85% as documented when the administration regime of the invention was employed. At the same time good compatibility is observed with all test subjects upon administration of the combination preparation according to the invention.
A sufficient ovulation inhibition of 97.85% and 96.77% can be documented for both examples. The latest tests of conventional ovulation inhibition according to R. A. Pierson, et al, “Ortho Evra/Evra versus oral contraceptives: follicular development . . . ”, Fertil. Steril. 80 (1), pp. 34-42 (2003) obtained with preparations, which have been available for a long time and have proven to be safe and reliable, attain a known percentage ovulation. In two treatment cycles, for example, ovulation occurred in 14% of the test subjects (3 out of 22) with an oral contraceptive containing a three-stage levonorgestrel preparation, ovulation occurred in 24% of the test subjects (6 out of 25) with an oral contraceptive containing a one-stage levonorgestrel preparation and ovulation occurred in 16% of the test subjects (4 out of 25) with an oral contraceptive containing a three-stage norgestimate preparation. These values clearly lie well above that of the inventive preparation, so that the preparations according to the invention provide a higher contraceptive reliability than those tested in Pierson, et al.
While the invention has been illustrated and described as embodied in a multistage preparation for contraception based on natural estrogens, it is not intended to be limited the details shown, since various modifications and changes may be made without departing in any way from the spirit of the present invention.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 195 40 253.7 | Oct 1995 | DE | national |
This is a continuation-in-part of U.S. patent application Ser. No. 09/950,915, filed Sep. 12, 2001, which, in turn, is a divisional of U.S. patent application Ser. No. 09/648,858, filed Aug. 25, 2000, which, in turn, is a continuation of U.S. patent application, Ser. No. 08/738, 314, filed Oct. 25, 1996, which has been allowed as U.S. Pat. No. 6,133,251, issued Oct. 17, 2000.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09648858 | Aug 2000 | US |
| Child | 09950915 | Sep 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 08738314 | Oct 1996 | US |
| Child | 09648858 | Aug 2000 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 09950915 | Sep 2001 | US |
| Child | 10891729 | Jul 2004 | US |
