HK1099701B - Multi-phase contraceptive preparation based on a natural estrogen - Google Patents

Description

Multi-segment contraceptive formulations based on natural estrogens

Technical Field

The invention relates to a multi-part contraceptive preparation based on natural estrogen and synthetic progestogen.

Compared to conventional products of contraception by ovulation inhibition, which have proven reliable and safe over long-term and widespread use, the multi-segment contraceptive of the present invention has a higher reliability over the entire cycle duration, improving periodic bleeding, while minimizing or eliminating side effects such as breast tenderness, headaches, mood swings and libido changes.

Background

The patent literature discloses multi-part contraceptive products based on a combination of natural estrogens and progestogens.

EP0770388B1 describes a multi-part contraceptive product wherein the first phase consists of 2 to 4 daily dosage units and the active ingredients contained in each daily dosage unit are all natural estrogens. The second phase of the multi-part product consists of two groups of daily dosage units containing at least one natural estrogen and at least one synthetic progestin. Here, the first group consists of 5 to 3 daily dosage units, while the second group consists of 17 to 13 daily dosage units. The third phase consists of 2 to 4 daily dosage units and the active ingredient contained in each daily dosage unit is entirely natural estrogen. The daily dosage of natural estrogen in each phase remains the same, but decreases from phase 1 to phase 3. In the second phase, the proportion of synthetic or natural progestagen in the second group is greater than the proportion in the first group. The last phase consists of 2 to 4 daily dosage units and the active ingredient in each daily dosage unit is a pharmaceutically acceptable placebo.

In example 5 a combination of estradiol valerate and dienogest is listed. In this case, the first phase is 3 daily dosage units containing 3mg of estradiol valerate, in the second phase the first group is 4 daily dosage units containing 2mg of estradiol valerate and 1mg of dienogest, the second group is 16 daily dosage units containing 2mg of estradiol valerate and 2mg of dienogest, and the third phase is 2 daily dosage units containing 1mg of estradiol valerate. The last phase was 3 daily dosage units containing a pharmaceutically acceptable placebo.

To obtain information on contraceptive reliability, the serum concentration of progesterone was measured by radioimmunoassay. The reported progesterone concentration of this patent is 4.0 ng/ml. From the first to the last dosing cycle, the average proportion of irregular bleeding (breakthrough bleeding and drip bleeding) dropped by 45 to 53%.

Furthermore, it has now been ascertained that the contraceptive reliability of the combined preparation results from the action of both the estrogen and the progestogen.

It has now been ascertained that inhibition of ovulation requires the daily administration of 1mg of Dienogest (Dienogest:und Klinik eines neuen Gestagens, edited by A.T. Terchmann, Walter de Gruyter Berlin/New York (1995), p.101) and 2.0-3.0mg drospirenone (Rosenbaum P, Schmidt W, Helmerhorst F M et al, Inhibition of infection by a novel progestogen (drospirenone), Eur conceptr. 16-24(2000)).

Furthermore, TAUBERT, H.D. and KUHL, H. (Kontrazepton mit Hormonen, editors TAUBERT, H.D.et. al., Georg Thieme Verlag Stuttgart/New York (1995), p.160) indicate that there is no inevitable link between the incidence of irregular bleeding and low serum concentrations of estrogens, such as ethinylestradiol or progestogens.

Disclosure of Invention

It is therefore an object of the present invention to provide a hormonal contraceptive composition based on natural estrogens which provides a higher contraceptive reliability over the duration of the whole cycle, improved cyclic bleeding, and at the same time minimizes or eliminates side effects such as breast tenderness, headaches, depressed mood and altered libido compared to conventional products for contraception by ovulation inhibition. This object is achieved with a multi-part contraceptive product in which the first phase consists of 2 daily dosage units containing 3mg of the natural estrogen estradiol valerate. The second phase consists of two groups of daily dosage units, wherein the first group comprises 5 daily dosage units containing a combination of 2mg of estradiol valerate and a synthetic progestogen in a dosage which is at least 2-fold or 3-fold the ovulation-inhibiting dosage. The second group of the second phase consists of 17 daily dosage units containing a combination of 2mg of estradiol valerate and a synthetic progestogen in a dosage which is at least 3-fold or 4-fold the ovulation-inhibiting dosage. The third phase comprises 2 daily dosage units containing 1mg of estradiol valerate. The last phase was 2 daily dosage units containing a pharmaceutically acceptable placebo.

Preferably, the dosage of the synthetic progestagen active ingredient, such as dienogest, drospirenone or a progestogen is at least 2 times the known ovulation-inhibiting dosage.

The multi-part contraceptive products of the present invention are particularly adapted for oral administration, but may also be administered intravaginally, parenterally, including topically, rectally, nasally, intraorally, or sublingually.

The multistage contraceptive product is prepared in the desired dosage by known methods using solid or liquid carriers or diluents and excipients conventionally used in pharmaceutical technology adapted to the desired form of administration.

Tablets, film-coated tablets, sugar-coated tablets or hard gelatin capsules are preferably used for oral administration.

Detailed Description

The present invention is illustrated by the following examples. In this section, the issues of contraceptive reliability, periodic bleeding and drug administration tolerance are discussed with emphasis.

Contraceptive reliability

Contraceptive reliability is mainly determined by the Hoogland score, which is given by follicle size, estradiol level and progestogen concentration. In the present invention, radioimmunoassay was used to determine the serum concentration of progesterone at a given point in the menstrual cycle, and the number of ovulations (Hoogland score of 6) and the number of etiolated non-ruptured follicles (Hoogland score of 5) were determined.

Stability of cycle

Cycle stability was evaluated based on the bleeding characteristics recorded in each cycle. The emphasis was to record the incidence of irregular bleeding (breakthrough bleeding and drip bleeding). The manner of recording is standardized. The data is analyzed descriptively.

Tolerance to stress

Tolerance was assessed by subjective sensations such as headache, mood depression, breast tenderness, stomach upset (nausea/vomiting), edema, and altered libido.

Example 1

The medication scheme is as follows:

days 1 to 2: estradiol valerate 3mg daily;

days 3 to 7: 2mg estradiol valerate +2mg dienogest daily;

day 8 to 24: 2mg estradiol valerate +3mg dienogest daily;

day 25 to 26: 1mg daily estradiol valerate;

day 27 to 28: a placebo.

93 women participated in the study, aged 18 to 35 years. Each person participated in 3 dosing cycles, and observations were made for the 2 nd and 3 rd dosing cycles.

In cycle 2 (main experiment period), 3 out of 93 women ovulated (3.23%), and 2 out of 93 women ovulated in cycle 3.

Thus, the reliability of the present dosing regimen to inhibit ovulation was 96.77%.

At the same time, the dosing regimen of the invention also exhibits good tolerability.

Example 2

The medication scheme is as follows:

days 1 to 2: estradiol valerate 3mg daily;

days 3 to 7: 2mg estradiol valerate +3mg dienogest daily;

day 8 to 24: 2mg estradiol valerate +4mg dienogest daily;

day 25 to 26: 1mg daily estradiol valerate;

day 27 to 28: a placebo.

93 women participated in the study, aged 18 to 35 years. Each person participated in 3 dosing cycles, and observations were made for the 2 nd and 3 rd dosing cycles.

In the 2 nd dosing cycle (main experiment period), 2 out of 93 women ovulated (2.15%), and in the 3 rd dosing cycle, 2 out of 92 women ovulated.

Thus, the dosing regimen of the present invention has 97.85% reliability in inhibiting ovulation.

At the same time, the dosing regimen of the invention also exhibits good tolerability.

The effective ovulation inhibition rates observed for the two examples were 97.85% and 96.77%, respectively. In recent studies on conventional ovulation inhibitors (Pierson R A et al, "OrthoEvra/Eva vertical concentrations," Fertil. Steril.80(1), pp.34-42(2003)), the results of the experiments demonstrate that ovulation constitutes a certain percentage even if the product has proven to be reliable and safe after long-term and widespread use. In the 2 nd cycle of administration, the ovulation rate was 14% (3 of 22 subjects ovulating) with the levonorgestrel-containing three-stage oral contraceptive, 6 of 25 subjects ovulating with the levonorgestrel-containing one-stage oral contraceptive, and 16% (4 of 25 subjects ovulating) with the norgestimate-containing three-stage oral contraceptive. These values are clearly different from the results obtained with the product of the invention above, indicating that the reliability of the product of the invention is higher than the contraceptive reliability discussed by Pierson et al.

Claims (1)

1. Multistage contraceptive product based on a combination of natural estrogens and synthetic progestogens, characterized in that

The first phase consists of 2 daily dosage units containing 3mg of the natural estrogen estradiol valerate,

the second phase consists of two groups of daily dosage units, wherein the first group consists of 5 daily dosage units containing 2mg of estradiol valerate in combination with dienogest or drospirenone in which the dosage of dienogest or drospirenone is at least 2 times or 3 times the ovulation-inhibiting dosage, and the second group consists of 17 daily dosage units containing 2mg of estradiol valerate in combination with dienogest or drospirenone in which the dosage of dienogest or drospirenone is at least 3 times or 4 times the ovulation-inhibiting dosage,

the third phase consists of 2 daily dosage units containing 1mg of estradiol valerate, and

the other phase consisted of 2 daily dosage units containing a pharmaceutically acceptable placebo.