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Home , Algestone, Algestone acetophenide, Anagestone, Demegestone, Dydrogesterone, Gestrinone

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 . 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 and daily units containing an estrogen in an continuously for at least 3 months, wherein amount equivalent to 2.2-5 mg 17β- 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 levels may have a a progestogen. positive impact on the occurrence of premenstrual syn- 15 drome and the risk of . 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- , 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 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 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 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, , , norgesti- ical comprising from 1-20 carbon atoms. mate, , 3-beta-hydroxydesogestrel, 3-keto [0015] An important advantage of the present method , 17-deacetyl , 19-norproges- resides in the fact that it suppresses endometrial growth. terone, acetoxypregnenolone, , anage- Typically, in the present method, the continuous admin- stone, , , , de- 15 istration of the combination of estrogen and pro- sogestrel, , dihydrodydrogesterone, dihydro- gestogen is effective in maintaining a substantially con- gesterone, , , ethynodiol dia- stant thin with a thickness of less than 8 cetate, flurogestone acetate, gastrinon, , mm, preferably of less than 6 mm. , hydroxymethylprogesterone, hydroxypro- [0016] The continuous administration of the combina- gesterone, , , medroxypro- 20 tion of estrogen and progestogen is advantageously gesterone, , , , continued for a period of at least 4 months, more pref- norethindrone (=norethisterone), norethynodrel, norg- erably for a period of at least 6 months. Most preferably, estrel, , normethisterone, , the present method employs continuous combined ad- , (17alpha)-17-hydroxy-11-methylene- ministration of the two for at least 9 months. 19-norpregna-4,15-diene-20-yn-3-one, , tri- 25 [0017] The term "continuous" as used in here, means megestone, acetophenide, nestorone, that the combination of estrogen and progestogen is ad- , 17-hydroxyprogesterone esters, ministered at relatively regular intervals, with no (thera- 19-nor-17hydroxyprogesterone, 17alpha-ethinyl-testo- peutically) significant interruptions. Naturally, minor in- sterone, 17alpha-ethinyl-19-nor-, d- terruptions may occur that do not affect the overall ef- 17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon- 30 fectiveness of the present method, and indeed such ab- 4-en-3-one oxime, precursors of these progestogens errations are encompassed by the present invention. In and combinations thereof. Preferably, the progestogen a preferred embodiment, and more arithmetically, the is selected from the group consisting of dydrogesterone, administration regimen is deemed to be continuous if dihydrodydrogesterone, norethisterone, levonorgestrel, the longest interval between 2 subsequent administra- desogestrel, norgestimate, drospirenone, cyproterone, 35 tions is not more than 3.5 times as long as the average gestodene, , progesterone, precursors of interval. Even more preferably said longest interval is these progestogens and combinations thereof. Even not more than 2.5 times, most preferably not more than more preferably, the progestogen is selected from the 1.5 times as long as the average interval. group consisting of dydrogesteron, dihydrodydrogester- [0018] The present method requires continuous ad- one, norethisterone, precursors of these progestogens 40 ministration of the combination of estrogen and pro- and combinations thereof. Most preferably, the pro- gestogen for a period of at least 3 months. In order to gestogen is dydrogesterone, dihydrodydrogesterone or minimise the risk of so called breakthrough bleeding, it a precursor thereof. can be advantageous to periodically interrupt the con- [0013] The present method may suitably employ a tinuous administration for a period of 4-12 days, prefer- precursor of 17β-estradiol or a precursor of the pro- 45 ably for a period of 5-9 days. These interruptions will gestogen. Such precursors are capable of liberating cause a predictable withdrawal bleeding, following 17β-estradiol or a progestogen when used in the which continuous administration of the combination of present method, e.g. as a result of metabolic conver- estrogen and progestogen can be resumed with a re- sion. Examples of suitable precursors of 17β-estradiol duced risk of breakthrough bleeding. Preferably, such and progestogens include such substances wherein the 50 an interruption occurs after 3-12 months of continuous hydrogen atom of at least one of the hydroxyl groups administration, more preferably after 3-8 months and has been substituted by an acyl radical of a hydrocarbon most preferably after 3-6 months of continuous admin- carboxylic, sulfonic acid or sulfamic acid of 1-25 carbon istration. In a particularly preferred embodiment, the atoms; tetrahydrofuranyl; tetrahydropyranal; or a present method employs a protocol with at least 2 inter- straight or branched chain glycosidic residue containing 55 ruptions following periods of continuous combined ad- 1-20 glycosidic units per residue. ministration. [0014] Typical examples of precursors which can suit- [0019] As explained before, it is a critical element of ably be used in accordance with the invention are esters the present invention to administer a relatively high dose

3 5 EP 1 462 107 A1 6 of estrogen. In a particularly preferred embodiment the [0026] The used in the present method is estrogen is administered in an amount equivalent to a preferably selected from the group consisting of dehy- daily oral dosage of at least 2.4 mg 17β-estradiol, more droepiandrosterone (DHEA); DHEA-sulphate; testo- preferably of at least 2.5 mg and most preferably of at sterone; testosterone esters such as testosterone least 2.6 mg 17β-estradiol. Preferably, the estrogen is 5 undecanoate , , testosterone administered in a dosage that does not exceed an phenylpropionate, testosterone isohexanoate, testo- amount equivalent to a daily oral dosage of 4.5 mg 17β- sterone enantate, testosterone bucanate, testosterone estradiol, more preferably it does not exceed an amount decanoate, ; ; gestrinone; equivalent to a daily oral dosage of 4 mg 17β-estradiol ; mesterolon; ; androsten- and most preferably, it does not exceed an amount 10 edione; ; androstanediol; meteno- equivalent to a daily oral dosage of 3.5 mg 17β-estradiol. lon; ; ; methandrosten- [0020] In another preferred embodiment of the olol; 7α-methyl-19-nortestosterone (MENT); precursors present method the progestogen is administered in an capable of liberating these when used in the amount equivalent to a daily oral dosage of 8-30 mg dy- present method and mixtures thereof. Most preferably drogesterone, more preferably in an amount equivalent 15 the androgen is selected from the group consisting of to a daily oral dosage of 10-20 mg dydrogesterone. The DHEA, danazol, gestrinone, testosterone esters, an- equivalent daily oral dosages for the progestogen nore- drostenedione, precursors capable of liberating these thisterone acetate may be calculated by dividing the rec- androgens when used in the present method and mix- ommended dosages for dydrogesterone by 10. Similar- tures thereof. Preferably the testosterone esters em- ly, equivalent dosages for other progestogens may be 20 ployed in the present method comprise an acyl group obtained by using conversion factors that are known in which comprises at least 6, more preferably from 8-20 the art or that may be established by methods well and preferably 9-13 carbon atoms. Most preferably the known to the person skilled in the art. androgens used in the present method are DHEA and/ [0021] The amount of estrogen administered in ac- or . These androgens offer cordance with the present method is preferably effective 25 the advantage that they can effectively be used in oral to achieve a 17β-estradiol serum concentration of at dosage units. least 30 pg/ml, more preferably of at least 50 pg/ml. [0027] It is noted that, for instance, DHEA, testoster- [0022] The present method is particularly suitable for one undecanoate and are precursors treating humans, primates, bovines, porcines, equines, of testosterone and that said precursors per se exhibit canines or felines. Most advantageously the present 30 virtually no affinity for androgen receptors in the female method is employed in the treatment of humans. body. The effectiveness of the androgens within the [0023] It was found that the present method is partic- method of the invention is determined by their function- ularly advantageous in non-smoking females. Although ally active form, which may well be different from the the inventors do not wish to be bound by theory it is be- form in which they are administered. lieved that smoking interferes with E2-metabolisation in 35 [0028] In a preferred embodiment the androgen is a way that reduces the of E2, e.g. by in- provided in an amount equivalent to a daily oral dosage creasing 2- of E2. Thus, the present meth- of 5 to 250 mg DHEA, which is equivalent to a daily oral od is preferably employed to prevent conception in a dosage of 1 to 50 mg testosterone undecanoate. More non-smoking human female. preferably the androgen is provided in an amount which [0024] It was surprisingly found that the anti-prolifer- 40 is equivalent to a daily oral dosage of 10-120 mg DHEA. ative effect of the present combination of estrogen and Most preferably the androgen is administered in an progestogen on the endometrium may be enhanced fur- amount which is equivalent to a daily oral dosage of ther by co-administration of an androgen. In addition, 20-60 mg DHEA. the continuous co-administration of an androgen in the [0029] Another aspect of the invention relates to a kit present contraceptive regimen offers the advantage of 45 comprising a plurality of oral dosage units, said plurality even less vaginal breakthrough spotting and bleeding. of daily hormone units containing an estrogen in an Consequently, in another preferred embodiment of the amount equivalent to 2.2-5 mg 17β-estradiol and a pro- invention, the present method comprises co-administra- gestogen in an amount equivalent to 5-50 mg dydroges- tion of an androgen. terone, wherein the estrogen is selected from the group [0025] Preferably, in the present method, androgen is 50 consisting of 17β-estradiol, precursors of 17β-estradiol co-administered in an amount effective to maintain the and combinations thereof. Because the present kit is in- serum androgen concentration of the female mammal tended for use in a continuous combined contraceptive at a level equivalent to between 0.5 and 5.0, preferably method, said kit preferably does not contain dosage between 0.7 and 4.0 and most preferably between 1.0 units that do not contain a combination of estrogen and and 3.0 nanomoles testosterone per litre. Here the tes- 55 progestogen. Even more preferably, the kit does not tosterone concentrations relate to the total testosterone contain any dosage units that do not contain the combi- present in the serum, i.e. including both free testoster- nation of estrogen and the progestogen in the indicated one and bound testosterone. amounts.

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[0030] Typically, the present kit contains at least 40 out pauses for 4 months. Similar results are obtained as dosage units, preferably at least 60, more preferably at described in Example 1. least 100 dosage units. These dosage units may be held in a container, or alternatively they may be held in a strip Example 3 from which they may be removed individually by the us- 5 er. [0036] The study described in Example 2 is repeated [0031] The invention is further illustrated by means of with the exception that after the period of 4 months of the following examples. continuous combined administration, the participants receive placebo's during 7 subsequent days, resulting EXAMPLES 10 in withdrawal bleeding in all subjects. Immediately fol- lowing these 7 days, the participants again receive the Example 1 combination of E2 and dydrogesterone uninterruptedly for another 4 months. Following this period of 4 months [0032] A clinical study was conducted in 30 young the women yet again receive placebo's during 7 subse- healthy female volunteers (15 smokers and 15 non- 15 quent days. Also this time, withdrawal bleeding is ob- smokers) who were using a combined monophasic oral served in all participants during the placebo period. contraceptive with at least 30 microgram ethinyl estra- [0037] In parallel, another group of 30 women, which diol at the moment of enrolment. women were selected on the basis of the same criteria [0033] Immediately following 19-25 days of taking this mentioned in Example 1, receives the combination of monophasic oral contraceptive, without observing a tab- 20 E2 and dydrogesterone continuously, i.e. without inter- let-free period, treatment with the study medication was ruptions, during a period of 8 months and 14 days. commenced. The study medication comprised of con- [0038] It was found that the incidence of bleeding and tinuously administering 3 mg 17beta-estradiol (E2) com- spotting in the latter group was significantly higher than bined with 1.5 mg without paus- in the group that alternately received the combination of es for 3 months. Follicular development and endometrial 25 E2 and dydrogesterone for 4 months followed by an ad- thickness were measured by ultrasonography once eve- ministration-free interval of 7 days. ry 3 or 4 days depending on follicle growth. Vaginal spot- ting and bleeding was scored daily by the participants in a diary. In addition, endocrine measurements (E2 and Claims progesterone) were performed in a subgroup of the par- 30 ticipants (4 individuals who exhibited follicular growth, 5 1. Use of an estrogen in the manufacture of a pharma- randomly selected non-smokers and 5 randomly select- ceutical preparation for use in a method of contra- ed smokers). Specific contraceptive side-effects, mood ception in a female mammal of childbearing capa- changes and volunteer appreciation were also evaluat- bility, said method comprising orally administering ed. 35 to the female a combination of estrogen and pro- [0034] No ovulations were observed in any of the par- gestogen continuously for at least 3 months, where- ticipants. In 4 of the 30 participants (2 smokers and 2 in the estrogen is selected from the group consisting non-smokers) persistent follicles of 25-30 mm were of 17β-estradiol, precursors of 17β-estradiol and seen. In these women, no increase in the progesterone combinations thereof, said estrogen being adminis- levels was observed. No dominant follicles were seen 40 tered in an amount equivalent to a daily oral dosage in the other 26 women (median diameter 5 mm). En- of 2.2-5 mg 17β-estradiol and said progestogen be- dometrial thickness did not change during treatment ing administered in an amount equivalent to a daily (median 4.5 mm before and 4.0 mm after treatment). oral dose of 5-50 mg dydrogesterone. After an initial adaptation period spotting was found to occur infrequently in 3 out of 15 non-smokers. In smok- 45 2. Use according to claim 1, wherein the progestogen ers however bleeding and spotting occurred in 3 out of is selected from the group consisting of dydroges- 15 women and spotting only in another 5 women. In terone, norethisterone, levonorgestrel, norgesti- some women breast tension, and oc- mate, drospirenone, 3-beta-hydroxydesogestrel, curred during treatment. No mood changes were regis- 3-keto desogestrel, 17-deacetyl norgestimate, tered. Of the 30 participating women, 12 would use this 50 19-norprogesterone, acetoxypregnenolone, al- contraceptive when available and 12 would consider its lylestrenol, , chlormadinone, cyproter- use. one, demegestone, desogestrel, dienogest, dihy- drodydrogesterone, dihydrogesterone, dimethister- Example 2 one, ethisterone, ethynodiol diacetate, flurogestone 55 acetate, gastrinon, gestodene, gestrinone, hy- [0035] Example 1 is repeated with the exception that droxymethylprogesterone, hydroxyprogesterone, the participants continuously receive 3 mg 17beta-es- lynestrenol, medrogestone, , tradiol (E2) combined with 15 mg dydrogesterone with- megestrol, melengestrol, nomegestrol, norethin-

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drone (=norethisterone), norethynodrel, , gen in an amount equivalent to 2.2-5 mg 17β-estra- norgestrienone, normethisterone, progesterone, diol and a progestogen in an amount equivalent to quingestanol, (17alpha)-17-hydroxy-11-methyl- 5-50 mg dydrogesterone, wherein the estrogen is ene-19-norpregna-4,15-diene-20-yn-3-one, tibolo- selected from the group consisting of 17β-estradiol, ne, trimegestone, , nestor- 5 precursors of 17β-estradiol and combinations one, promegestone, 17-hydroxyprogesterone es- thereof. ters, 19-nor-17hydroxyprogesterone, 17alpha-ethi- nyl-testosterone, 17alpha-ethinyl-19-nor-testoster- 12. A kit according to claim 11, wherein the kit does not one, d-17beta-acetoxy-13beta-ethyl-17alpha-ethi- contain dosage units that do not contain the estro- nyl-gon-4-en-3-one oxime, precursors of these pro- 10 gen and the progestogen in the indicated amounts. gestogens and combinations thereof. 13. A kit according to claim 11 or 12, wherein the kit 3. Use according to claim 2, wherein the progestogen contains at least 40 dosage units, preferably at least is selected from the group consisting of dydroges- 100 dosage units. terone, dihydrodydrogesterone, norethisterone, 15 levonorgestrel, desogestrel, norgestimate, dros- pirenone, cyproterone, gestodene, trimegestone, progesterone, precursors of these progestogens and combinations thereof. 20 4. Use according to claim 3, wherein the progestogen is dydrogesterone, dihydrodydrogesterone or a pre- cursor thereof.

5. Use according to any one of the preceding claims, 25 wherein the precursor of 17β-estradiol is an ester of 17β-estradiol.

6. Use according to any one of claims 2-4, wherein the precursor of the progestogen is an ester of said pro- 30 gestogen.

7. Use according to any one of the preceding claims, wherein the continuous administration of the com- bination of estrogen and progestogen is effective in 35 maintaining a substantially constant endometrial thickness of less than 8 mm, preferably of less than 6 mm.

8. Use according to any one of the preceding claims, 40 wherein the estrogen is administered in an amount equivalent to a daily oral dosage of 2.4-4 mg 17β- estradiol, preferably to a daily oral dosage of 2.5-3.5 mg 17β-estradiol. 45 9. Use according to any one of the preceding claims, wherein the progestogen is administered in an amount equivalent to a daily oral dosage of 8-30 mg dydrogesterone, preferably to a daily oral dosage of 10-20 mg dydrogesterone. 50

10. Use according to any one of the preceding claims, wherein the estrogen is administered in an amount effective to achieve a 17β-estradiol serum concen- tration of at least 30 pg/ml. 55

11. A kit comprising a plurality of oral dosage units, said plurality of daily hormone units containing an estro-

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