Hormonal contraceptive containing a combination of ethinyloestradiol and chlormadinone acetate

This application claims priority from German Patent Application No. 10 2004 026 670.0 filed on May 28, 2004.

1. Field of the Invention

The present invention relates to a hormonal contraceptive consisting of 21 to 25 hormone-containing daily units containing a combination of ethinyloestradiol in amount less than or equal to 25 μg and chlormadinone acetate in amounts of less than or equal to 5 mg, and optionally 7 to 3 daily units for oral administration to women.

In contraceptives, a combination of an oestrogen and a gestagen is conventionally administered per daily unit, wherein the amount of oestrogen should be kept as low as possible.

For all women, but in particular for women over 35 and in particular for women in the pre- and perimenopause, a hormonal contraceptive with the lowest possible amount of oestrogen is desirable, since from the age of 35 women have a greater risk of suffering complications caused by oestrogen-containing contraceptives, such as heart attack, stroke and lower limb thrombosis, followed by pulmonary embolisms.

2. Brief Description of Related Developments

It is already known from the prior art to use a combination of 30 μg of ethinyloestradiol and 2 mg of chlormadinone acetate for contraception and optionally for simultaneous treatment of acne. There is additionally a need to reduce still further the amount of ethinyloestradiol, which is combined with chlormadinone acetate, provided that reliable contraceptive action is nevertheless still guaranteed.

Furthermore, the contraceptive action of combined preparations of 15 μg of ethinyloestradiol and 60 μg of gestodene, which are administered for 24 days per cycle, is already known (Sullivan et al, Fertility and Sterility 72 (1999) 115-120; Gestodene Study Group 322, The European Journal of Contraception and Reproductive Health Care 4 (Suppl. 2) (1999) 9-15). However, gestodene does not ensure the advantageous properties of chlormadinone acetate.

Further combined preparations for hormonal contraception and for simultaneous treatment of complaints in the pre- and perimenopause are known from EP 0 398 460 and EP 0 253 607; these do not contain any chlormadinone acetate as the gestagen, however.

It was therefore the object of the present invention to provide a hormonal contraceptive containing chlormadinone acetate as the gestagen combined with a smaller amount of ethinyloestradiol compared with the prior art, but nonetheless guaranteeing a reliable contraceptive action.

This object is achieved by the hormonal contraceptive according to the invention, which consists of 21 to 25, preferably 21 to 24, hormone-containing daily units, which contains ethinyloestradiol in amounts of less than or equal to 25 μg, preferably of less than or equal to 20, and chlormadinone acetate in amount of less than or equal to 5 mg, preferable of less than or equal to 3 mg, and optionally 7 to 3, preferably 7 to 4, hormone-free daily units for oral administration to women.

The use of chlormadinone acetate ensures a high level of a contraceptive reliability and is distinguished by its pronounced antiandrogenic properties, which is suitable for all women of reproductive age since many women suffer androgen-dependent symptoms, such as acne, hirsutism (e.g. unwanted facial hair), androgenetic alopecia and seborrhoea. In addition, women with period problems (dysmenorrhoea) may be helped with the contraceptive according to the invention. The contraceptive according to the invention is also suitable in particular for contraception in women over 35, since it reduces the risk of thrombosis.

The hormonal contraceptive according to the invention comprises chlormadinone acetate in amount of less than or equal to 5 mg, preferable of 1 to 4 mg, very particularly preferably of 1 to 3 mg, and ethinyloestradiol in an amount of 25 μg, preferably of 10 to 20 μg, very particularly preferably of 15 to 20 μg.

Very particularly preferably, all the hormone-containing daily units of the contraceptive according to the invention each contain 2 mg of chlormadinone acetate and 20 μg of ethinyloestradiol and are taken by a woman as a monophasic contraceptive on 21 to 24 consecutive days of her cycle, followed by an interval in taking or the taking of hormone-free daily units for 7 to 4 days.

However, the contraceptive according to the invention may also take the form of a multiphasic contraceptive. In the case of a multiphasic contraceptive, a two-phase or a three-phase pill may be present.

The hormone-containing daily units of a multiphasic contraceptive according to the invention preferably comprise ethinyloestradiol in an amount of 20 μg and chlormadinone acetate in an amount of 1 or 3 mg. In the case of a two-phase contraceptive, the cycle preferably starts with taking daily a daily unit containing 1 to 2 mg of chlormadinone acetate in addition to EE for 7-12 days and ends with taking daily a daily unit of 2 to 3 mg of chlormadinone acetate for 9-18 days. In the case of a three-phase contraceptive, the tablet-taking cycle preferably starts with taking chlormadinone acetate daily in an amount of 1 to 2 mg for 6-7 days followed by taking chlormadinone acetate daily in an amount of 2 mg for 5-9 days and ends with taking chlormadinone acetate daily in an amount of 2 to 3 mg for 5-14 days.

The hormonal daily units each contain 20 μg of ethinyloestradiol.

In addition, to achieve maximum reliability of contraceptive action, it is particularly important to continue taking the hormone-containing daily units for 21 to 25 consecutive days per cycle.

In a tablet-taking cycle, there may be an interval in taking of 7 to 3 days or 7 to 3 hormone-free daily units may be taken daily before or after a tablet-taking phase of 21 to 25 hormone-containing daily units.

The daily units of the hormonal contraceptive according to the invention may preferably assume the form of tablets. Production methods for such daily units are known to the person skilled in the art. Known auxiliary substances may be used as additives in addition to the combination of chlormadinone acetate and ethinyloestradiol.

Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) were dissolved in 600 ml of ethanol. Chlormadinone acetate (particle size 90%<50 μm), lactose and maize starch were mixed in a mixer/pelletiser (Diosna P25) for 5 mins and then moistened thoroughly and mixed with the ethanolic EE/PVP solution. The moist composition was forced through a 3 mm screen and dried in a vacuum drying cabinet. The dried granular product was disagglomerated through a 0.6 mm screen, mixed with magnesium stearate and highly disperse silicon dioxide and pressed on a tablet press with 5 mm punches into tablets with a weight of 50 mg.

b) As indicated under a), hormone-free, folic acid-containing tablets with a weight of 50 mg were produced, wherein the sodium salt of the folic acid was dissolved in 600 ml of aqueous ethanol.

The tablets were coated with a methylhydroxypropylcellulose-based coating (e.g. Opadry YS-1-2184 made by Colorcon), coating composition 2 mg per tablet, and packaged into a dosage form comprising 120 hormone-containing daily units without folic acid and 7 hormone-free daily units with folic acid.