Europäisches Patentamt *EP001462107A1* (19) European Patent Office Office européen des brevets (11) EP 1 462 107 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: A61K 31/565, A61K 31/57, 29.09.2004 Bulletin 2004/40 A61P 15/18 (21) Application number: 03075905.4 (22) Date of filing: 28.03.2003 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Coelingh Bennink, Herman Jan Tijmen HU IE IT LI LU MC NL PT RO SE SI SK TR 3971 BE Driebergen (NL) Designated Extension States: • Visser, Monique AL LT LV MK 3704 BB Zeits (NL) (71) Applicant: Pantarhei Bioscience B.V. (74) Representative: Jorritsma, Ruurd 3701 CH Zeist (NL) Nederlandsch Octrooibureau Postbus 29720 2502 LS Den Haag (NL) (54) Method of female contraception and kit for use in such method (57) The present invention is concerned with a dydrogesterone. method of contraception in a female mammal of child- Another aspect of the invention relates to a kit com- bearing capability, said method comprising orally ad- prising a plurality of oral dosage units, said plurality of ministering to the female a combination of estrogen and daily hormone units containing an estrogen in an progestogen continuously for at least 3 months, wherein amount equivalent to 2.2-5 mg 17β-estradiol and a pro- the estrogen is selected from the group consisting of gestogen in an amount equivalent to 5-50 mg dydroges- 17β-estradiol, precursors of 17β-estradiol and combina- terone, wherein the estrogen is selected from the group tions thereof, said estrogen being administered in an consisting of 17β-estradiol, precursors of 17β-estradiol amount equivalent to a daily oral dosage of 2.2-5 mg and combinations thereof. 17β-estradiol and said progestogen being administered in an amount equivalent to a daily oral dose of 5-50 mg EP 1 462 107 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 462 107 A1 2 Description progestogen and at least one estrogen is described in WO 99/12531. In contrast to the aforementioned com- TECHNICAL FIELD OF THE INVENTION bined and sequential contraceptive methods, no regular menses occur as the continuous administration of pro- [0001] The present invention is concerned with a new 5 gestogen in the indicated amounts induces amenor- method of contraception in mammalian females of child- rhoea. This so called continuous combined method of- bearing capability. More particularly the present inven- fers the advantage that it prevents withdrawal bleed- tion relates to such a method comprising orally admin- ings. In addition, the method gives rise to less subjective istering to the female a combination of estrogen and pro- complaints, such as the symptoms caused by hormone gestogen continuously for at least 3 months. 10 fluctuations, and is associated with a lower risk of VTE [0002] The invention also relates to a pharmaceutical than the well-known combined and sequential regi- kit comprising a plurality of oral dosage units, said plu- mens. Finally, it is believed that the avoidance of chronic rality of daily hormone units containing an estrogen and fluctuations in blood serum steroid levels may have a a progestogen. positive impact on the occurrence of premenstrual syn- 15 drome and the risk of breast cancer. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION [0003] Currently on the market there are a number of hormonal contraceptives for females which can be clas- [0007] As mentioned above, a continuous combined sified into two general types. The first are known as 20 contraceptive method that employs a combination of an monophasic preparations. These contain a constant estrogen and a progestogen is known from WO amount of an estrogen and a progestogen. Newer prep- 99/12531. The present inventors have unexpectedly arations known as bi- or triphasic preparations have var- discovered that significantly less unscheduled bleeding ying levels of estrogen and progestogen; in most cases and spotting is observed in such a continuous combined consisting of relatively constant levels of estrogen with 25 method if the estrogen 17β-estradiol (E2) is employed a step-wise increase in progestogen throughout the cy- and is administered in a dosage that is significantly high- cle. This pattern of estrogen and progestogen adminis- er than that advocated in the PCT-application. tration results in a relatively dominant estrogenic formu- [0008] In addition, it was surprisingly found that the lation at the beginning of the package with increasing prolonged use of a combination of a relatively high dose progestogenic activity toward the end of the package. 30 of E2 and a progestogen very effectively suppresses en- Mono-, bi- and triphasic contraceptives are commonly dometrial thickening. This finding indicates that a con- referred to as combined contraceptives. tinuous combined method employing a relatively high [0004] Virtually all combined contraceptives have in dose of E2 may be used advantageously as a contra- common that they are based on a regimen which in- ceptive method. volves an administration-free interval of about 7 days 35 [0009] It is very unexpected that, despite the use of a whereby withdrawal bleeding, simulating the natural high dose of E2, the present method does not give rise menses, occurs. Thus 21 day intervals of hormone ad- to significant endometrial thickening since E2, like other ministration alternate with 7 days during which no hor- estrogens, is usually associated with endometrial stim- mones are administered. ulation. [0005] As an alternative to the aforementioned com- 40 bined contraceptive methods, the so called sequential DETAILED DESCRIPTION OF THE INVENTION method has been proposed. Typical of the sequential contraceptive method is that it comprises two consecu- [0010] Accordingly, one aspect of the invention is con- tive phases, i.e. one phase during which estrogen and cerned with a method of contraception in a female mam- no progestogen is administered and another phase dur- 45 mal of childbearing capability, said method comprising ing which a combination of estrogen and progestogen orally administering to the female a combination of es- is administered. The first sequential methods, like the trogen and progestogen continuously for at least 3 aforementioned combined contraceptives, made use of months, wherein the estrogen is selected from the group an administration free interval of about 7 days. More re- consisting of 17β-estradiol, precursors of 17β-estradiol cently, sequential methods have been proposed which 50 and combinations thereof, said estrogen being admin- do not include such an administration-free (or placebo) istered in an amount equivalent to a daily oral dosage period, meaning that estrogen is administered through- of 2.2-5 mg 17β-estradiol and said progestogen being out the full cycle and that progestogen is co-adminis- administered in an amount equivalent to a daily oral tered during only part of that cycle. WO 95/17895 (Ehr- dose of 5-50 mg dydrogesterone. lich et al.) describes such an uninterrupted sequential 55 [0011] The combination of estrogen and progestogen method. is advantageously administered at least once daily so [0006] Yet another alternative contraceptive method as to maintain a relatively constant serum concentra- that employs continuous uninterrupted administration of tion. Most preferably the combination is administered 2 3 EP 1 462 107 A1 4 once daily. that can be obtained by reacting the hydroxyl groups of [0012] The present method may suitable employ any the estrogenic substances with substances that contain pharmaceutically acceptable substance with sufficient one or more carboxy (M+-OOC-) groups, wherein M+ progestogenic activity. The present invention encom- represents a hydrogen or (akali)metal cation. Hence, in passes the use of substances that exhibit progestogenic 5 a particularly preferred embodiment, the precursors are activity per se as well as precursors of such substances. derivatives of 17β-estradiol or a progestogen, wherein The invention also encompasses the use of pro- the hydrogen atom of at least one of the hydroxyl groups gestogen metabolites that exhibit progestogenic activi- has been substituted by -CO-R, wherein R is a hydro- ty. Examples of progestogens that may suitably be em- carbon radical comprising from 1-25 carbon atoms. ployed in accordance with the invention include dydro- 10 Preferably R is hydrogen, or an alkyl, alkenyl or aryl rad- gesterone, norethisterone, levonorgestrel, norgesti- ical comprising from 1-20 carbon atoms. mate, drospirenone, 3-beta-hydroxydesogestrel, 3-keto [0015] An important advantage of the present method desogestrel, 17-deacetyl norgestimate, 19-norproges- resides in the fact that it suppresses endometrial growth. terone, acetoxypregnenolone, allylestrenol, anage- Typically, in the present method, the continuous admin- stone, chlormadinone, cyproterone, demegestone, de- 15 istration of the combination of estrogen and pro- sogestrel, dienogest, dihydrodydrogesterone, dihydro- gestogen is effective in maintaining a substantially con- gesterone, dimethisterone, ethisterone, ethynodiol dia- stant thin endometrium with a thickness of less than 8 cetate, flurogestone acetate, gastrinon, gestodene, mm, preferably of less than 6 mm. gestrinone, hydroxymethylprogesterone, hydroxypro- [0016] The continuous administration of the combina- gesterone, lynestrenol, medrogestone, medroxypro- 20 tion of estrogen and progestogen is advantageously gesterone, megestrol, melengestrol, nomegestrol, continued for a period of at