DE2218831C3 - Use of hormones for contraception - Google Patents

Description

Hormonal methods of contraception are already known. The use of Estrogens and progestins in oral contraception. For example, from Pharmindex III (1971), Pages 300, 328 and 729, and from J. Reprod. Fert Suppl. 5 (1968), pages 109 to 116, known contraceptives which contain 0.05 mg ethinyl estradiol and 0.5 mg Have norgestrel. Except for the combination products that consist of the same combination of estrogen and progestin for daily intake exist, there are already sequential preparations that consistently use the contain the same amount of estrogen and some of which are unit doses for the first few days of the intake cycle (1st stage) no or a small amount of progestin and a few dose units for the following days of the intake cycle (2nd stage) an increased amount of progestin contain. A sequence preparation with 0.1 mg ethinyl estradiol and 0.1 mg (1st stage) or 1.0 mg Gestagen (2nd stage) is known from Pharmindex III (1971), page 450.

Although in "Hearings before the Subcommittee on Monopoly" of the US Senate, published as Competitive Problems in the Drug Industry, Part 15 (1970), Oral Contraceptives (Volume One), page 5929, required that the contraceptives should not contain more than 0.05 mg of an estrogenic component were in Sequence preparations always used higher amounts of estrogen than 0.05 mg. In example 1 of the US patent 35 68 828 is the lowest estrogen dose of a sequence preparation with 0.075 mg ethinyl estradiol and a gestagen content of 10 mg in the 1st stage and 50 mg in the 2nd stage. But also after the Proposals of the US patent exceed the recommended daily dose of 0.05 mg estrogen by 50%. Despite excessive amounts of estrogen, the known sequence preparations do not use the same contraceptive method Reliability achieved as with the proven, albeit relatively high-dose combination preparations. Disadvantages of the combination preparations are z. B. the relatively common gastrointestinal ones Discomfort, chest symptoms and weight gain, as well as other significant side effects known to be and risks.

It has now been found that you can get an estrogen-accentuated sequence preparation with a consistently low estrogen content of 0.05 mg ethinyl estradiol daily with safe conception protection and very low Side effects are obtained if you add 0.05 mg d-norgestrel and the estrogen daily for 11 days add 0.125 mg d-norgestrel daily in the 2nd stage of 10 days.

The invention thus relates to the use of daily

a) 0.05 mg each of 17 (\ - ethinyl estradiol and 0.05 mg d-norgestrel in stage I on 11 days and

b) 0.05 mg each of 17a-ethinyl estradiol and 0.125 mg

d-norgestrel in the 2nd stage for 10 days
in oral contraception.

It is surprising that by adding a very low amount of d-norgestrel, the amount of estrogen in both stages can be reduced to such an extent that the The recommended daily dose of 0.05 mg ethinyl estradiol is never exceeded. Due to the special nature of the Active ingredient distribution results in unforeseen advances in the use according to the invention of the new sequence preparation. During the clinical testing of the new preparation it was shown that in every case one safe conception protection is guaranteed The tolerance and acceptability of the preparation were good; There were fewer side effects than with other contraceptives. Despite months A physiological structure of the endometrium and the vaginal epithelium could be observed will.

Because of the low hormonal dosage, the low percentage of side effects and the The new preparation is particularly suitable for growing girls with a high degree of certainty

example 1

(Composition of a coated tablet per level)
fe

1st stage

0.050 mg

0.050 mg

33.150 mg

18,000 mg

2.100 mg

1,650 mg

17 "-ethinyloestradiol

d-norgestrel

Lactose

Cornstarch

Polyvinyl pyrrolidone

talc

55,000 mg Total weight, which with the usual ker mix supplemented to about 90 mg jfe will. 0.050 mg 17a-ethinyl estradiol 0.125 mg d-norgestrel 33.075 mg Lactose 18,000 mg Cornstarch 2.100 mg Polyvinyl pyrrolidone 1,650 mg talc

55,000 mg total weight, supplemented to around 90 mg with standard sugar mix will.

Clinical Investigations A.

254 women of reproductive age (Table 1) received daily (1st stage) and the for 11 days the following 10 days daily (2nd stage) for each woman a preparation according to Example 1; the subsequent 7 days during who had the withdrawal bleeding remained tablet-free. This form of administration (11 days / 1st stage and 10th Days / 2. Level and 7 days / tablet-free) was retained for up to 6 months for most women, resulting in this results in a total of 1441 treatment cycles.

No pregnancies occurred during the entire treatment period. The preparation was excellent tolerable, the number of intermenstrual bleeding and spotting was compared to that before the treatment significantly reduced (Table 2) the side effects were compared to the last cycle before the Treatment, also in some cases significantly reduced (Table 3).

Table 1

Age in years

Number of patients
Section. %

until 2010

21-25 59

26-30 76

31 - 35 49

36 - 40 40

41-45 17

46-50 2

over 50 -

Subtotal 253

No answer 1_

Total 254

4.0

23.2

29.9

19.3

15.7

6.7

0.8

99.6 0.4

100

Table 2

Juxtaposition Spotting
1st cycle (254 women)
% Breakthrough bleeding
1st cycle (254 women)
% Intermenstrual bleeding
before treatment
% Spotting
last unhealth. cycle
% 10.6 4.0 5.9 18.9 Spotting
Total number of
Behanüiuiigszykien (1,441;
% Breakthrough bleeding
Total number of
Treatment cycles (i.441)
% 8.1 2.4

Table 3

Juxtaposition last unhealth. Total number Side effects cycle the treatment (254 women) development cycles % (1,441) 7.9 1.8 Dysmenorrhea 6.3 5.7 Nausea and vomiting 4.7 1.3 dizziness 7.5 6.7 Other symptoms 7.9 6.8 Chest tension 13.8 8.2 headache 14.2 6.3 nervousness 6.3 3.5 depressions 13.4 8.8 Decreased libido 4.0 1.3 Aknc 0.4 0.4 Chloasma 0.4 0.2 Edema 3.2 1.8 Vari / s - - Thrombophlebitis - 0.1 llcnutonuthic

Clinical examinations B

275 girls in 2535 cycles received various contraceptives. The individual preparations and the Frequency of the occurring complaints due to intolerance to discontinuation of the intake are compiled as an overview in Table 4

Table 4

Incompatibility rate of various contraceptives

From this compilation it can be seen that the intolerance rates of the individual preparations between 30 and 46% were. The preparation according to Example 1 with a failure rate of only 16% was the best compatible.

Preparation type number of Cycles Incompatible Main complaints girl opportunity Mini pill 75 751 38 Amenorrhea or prolonged too (0.03 mg progestin) frequent bleeding Standard combination I 71 596 46 Oligomenorrhea or too frequent (0.1 mg progestin and Spotting 0.1 mg estrogen) Standard combination II 49 539 33 Various (typical of all (1.0 mg progestin and Ovulation inhibitors) 0.05 mg estrogen) Standard sequence 30th 244 30th Nausea, weight gain (16 x 0.1 mg estrogen and 5 x 1.0 mg progestin and 0.1 mg estrogen) Sequence according to example 1 50 405 16 Spotting, breakthrough bleeding total 275 2535

Claims (1)

Claim: Use daily a) 0.05 mg each of 17a-ethynyl estradioI and 0.05 mg d-norgestrel in the 1st stage on 11 days and b) 0.05 mg each of t7oc-ethinyl estradiol and 0.125 mg d-norgestrel in the 2nd stage for 10 days in oral contraception.