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Home , Algestone, Algestone acetophenide, Anagestone, Demegestone, Melengestrol acetate, Norethisterone enanthate

US 20080234240A1 (19) (12) Patent Application Publication (10) Pub. No.: US 2008/0234240 A1 Disterberg et al. (43) Pub. Date: Sep. 25, 2008

(54) EXTENDED USE COMBINATION (30) Foreign Application Priority Data COMPRISINGESTROGENS AND PROGESTINS Nov. 26, 2003 (EP)...... O3O904.056 Publication Classification (75) Inventors: Bernd Disterberg, Báenkleu (DE); Jan Endrikat, Kirkland (CA); Rolf (51) Int. Cl. Schurmann, Teltow (DE) A6II 3/56 (2006.01) A6II 3L/S65 (2006.01) A6II 3/566 (2006.01) Correspondence Address: A6II 3/567 (2006.01) MILLEN, WHITE, ZELANO & BRANGAN, A6II 3/569 (2006.01) P.C. A 6LX 3/57 (2006.01) 22OO CLARENDON BLVD. A6IP 5/00 (2006.01) SUTE 14OO (52) U.S. Cl...... S14/17O ARLINGTON, VA 22201 (US) (57) ABSTRACT (73) Assignee: SCHERING AG, Berlin (DE) A pharmaceutical preparation to obtain a continuous hor (21) Appl. No.: 10/584,045 monal treatment over a desired period of time longer than 21-28 days comprising a first composition containing at least (22) PCT Filed: Nov. 20, 2004 one and/or at least one progestin in a predetermined amount to be administered in the first 21-28 days and a second (86). PCT No.: PCT/EPO4/13545 composition which contains at least one estrogen and/or at least one progestin in a predetermined amount higher than the S371(c)(1), amount of the first composition and comprises a mono or (2), (4) Date: Oct. 9, 2007 multiphase sequence of pharmaceutical dosages. US 2008/0234240 A1 Sep. 25, 2008

EXTENDED USE COMBINATION COMPRISING biphasic or polyphasic preparations are obtained. A typical AND PROGESTINS pattern for this group of contraceptives comprises an estrogen and progestin administration in which a relatively dominant TECHNICAL FIELD estrogenic formulation is given at the beginning of the treat ment cycle with an increasing progestogenic activity towards 0001. The present invention refers to an extended use of a the end. This administration pattern seems to achieve a better pharmaceutical preparation comprising estrogens and endometrial stability limiting breakthrough bleeding or spot progestins where a progressive increase of the estrogens and/ ting due to poor epithelialisation of the . Con or progestins dosage after the typical 28 day time period traceptive reliability is mainly provided by the progestincom achieves a continues stimulation of the endometriums. This ponent administered during the treatment. Therefore at least leads to the desired endometrial stability and to a bleeding the minimum progestin dosage to effectively inhibit ovula free extended regimen. tion should be provided with a daily dosage. On the other 0002 More particularly the present invention refers to a hand the estrogen increases the inhibitory effects of pharmaceutical preparation to obtain a continuous hormonal progestin and ensures cycle stability. treatment overa desired period oftime longer than 21-28 days comprising a first composition containing at least one estro 0010 Typical regimen for hormonal contraceptive treat gen and/or at least one progestinina predetermined amount to ments resemble the natural course of the cycle with an admin be administered in the first 21-28 days and a second compo istration-free interval of about 7 days whereby withdrawal sition containing at least one estrogen and/or at least one bleeding simulates the natural menses. Thus, as mentioned progestin in a predetermined amount higher than the amount above, 21 day intervals of administration alternate of the first composition and which comprises a mono or with 7 days during which no are administered. multiphase sequence of pharmaceutical dosages. 0011 Since the psychological and physical ability in 0003. Furthermore the present invention refers to a women during the premenstrual phase is subject to limita method of inhibiting ovulation in a mammal, in particular a tions, in several circumstances a delay of the menses is our human, comprising administering to said mammal a first days often required. Typical cases are for example sportcom composition containing a certain amount of an estrogen alone petitions, particular medical exams or certain travel situa or in combination with a progestin for 21-28 days followed by tions. a further administration of a second composition containing 0012. A delay of menstruation in women treated with an an estrogen and a progestin to obtain a continuous hormonal hormonal preparation like those previously mentioned is eas treatment over a period of time longer than 21-28 days. The ily affordable as reported in the literature (“Kontrazeption mit second composition contains an amount of estrogen and Hormonen: ein Leitfaden für die Praxis, Hans-Dieter Taub progestin which is higher than the amount of the first com ert and Herbert Kuhl, 2" edition 1995, Georg Thieme Verlag, position. The second composition further comprises mono or pp. 199-201). multiphase sequences of pharmaceutical dosages. 0013 By monophasic preparation for example it is pos 0004 The use of a pharmaceutical preparation for the sible to achieve said delay simply starting on the 22" day of manufacture of an agent for inhibiting ovulation in a mam treatment a new kit of contraception pills and maintain the mal, in particular a human, for inducing long term amenor treatment for the desired period of time up to 2-3 days before rhoeaand for diminishing symptoms related to hormonal the desired withdrawal bleeding. Only the dose of the last withdrawal is also an aim of the present invention. phase should be applied for a delay of the menstruation when 0005 The present invention further refers to a pharmaceu polyphasic hormonal preparations are used. tical package to be used in a pharmaceutical treatment with an 0014. In general with the methods previously mentioned a extended regimen. withdrawal bleeding delay of at least 7 days can be easily obtained. BACKGROUND OF THE INVENTION 0015 The hormonal treatment can be directed not only to 0006 Pharmaceutical contraceptive preparations contain prevent but also to avoid all derived symptoms ing a large number of hormonal components were developed related to hormonal withdrawal like for example premen with regard to their suitability in very different administration strual symptoms, , endometriosis, menstrual schemes. migraine and . 0007. A classification divides the common contraceptive 0016. In these cases a longer inhibition of the ovulation preparations on the market in two general groups. The first obtained through the would allow to one refers to contraceptives containing a constant amount of overcome problems related to hormonal changes revealing to estrogen and progestin prepared for example in the form of 21 be well accepted and particularly effective over a three month tablets with the combination of active agents and 7 tablets period (84 days). with no active agent. The amount of active agent is the same in each tablet. They are known as monophasic preparation. 0017 Such a treatment longer then 21-28 is also known as extended use regimen. WO03/049744 describes female oral 0008 Undesired effects related to these kind of pills contraceptives that prevent pregnancy and treat premenstrual depend to Some extent on the balance between the estrogen syndrome (PMS) including premenstrual dysphoric disorder and the progestin. (PMDD). Said document further describes a method of pre 0009. The second group of contraceptives comprises venting pregnancy and treating PMS including PMDD, by preparations in which the levels of estrogen or progestin vary avoiding complete withdrawal of estrogen at the end of the over the time. According to the number of hormonal levels treatment period, or between treatment periods, by adminis US 2008/0234240 A1 Sep. 25, 2008 tering oral contraceptives in an extended regimen without a mal, in particular a human and for diminishing symptoms break. According to the above document premenstrual symp related to hormonal withdrawal is also a goal of the present toms are rare when menstruation is infrequent, for this reason invention. users of oral contraceptives would have lower rates of pre menstrual symptoms, when exposed to peaks and troughs of 0025 A further aim of the present invention is to provide endogenous with a protective effect against a method of inhibiting ovulation in a mammal, in particular a PMDD. human, comprising administering to said mammal a first composition containing at least one estrogen and/or at least 0018 WO03/049744 further describes a method of pre one progestin in a predetermined amount for 21-28 days venting pregnancy, which involves administering one or two comprising a further administration of a second composition combination regimens of oral contraceptive. The hormonal containing at least one estrogen and at least one progestin in treatment is applied for 110 consecutive days. a predetermined amount performed to obtain a continuous 0019. The main drawbacks of the method reported in hormonal treatment over a desired period of time longer than WO03/049744 concern the variation of the hormonal levels 21-28 days. The second composition contains at least one during the extended treatment. Increasing and decreasing of estrogen and/or at least one progestin in a predetermined estrogen and progestin dosages determine instability of the amount which is higher than the amount of the first compo endometrium with an increasing of side effects like break sition and comprises a mono or multiphase sequence of phar through bleeding. maceutical dosages. 0020. An altered standard 21-day/7-day oral contraceptive 0026 Said method can be further advantageously used in regimen with the use of a monophasic pill with 30 to 35ug of hormonal withdraw related syndrome for diminishing pre and different type of progestins to delay menstrual symptoms, dysmenorrhea, endometriosis, men menses and reduce hormone withdrawal symptoms is also strual migraine. The continues use of an oral contraceptive known in the art (PJ Sulak et al., Am J ObstetGynecol, 2002: according to the above method have also a favourable effect 186: 1142-1149). Also in this case one of the main side effects on acne since acne typically reoccurs during the pill free relates to a high incidence of breakthrough bleeding, which is period. a common cause for discontinuation of the regimen. 0027. The present invention further refers to pharmaceu 0021 WO99/09993 describes an oral contraception regi tical package for an extended regimen treatment longer than men which comprises sequentially administering two or more 21-28 days comprising a first composition containing at least progestational agents exhibiting different effects on the one estrogen and/or at least one progestin in a predetermined human endometrium in combination with an estrogen. Par amount to be administered in the first 21-28 days and a second ticularly an extended use of an oral contraception regimen is composition containing at least one estrogen and/or at least reported which comprises the sequential administration of one progestin in a predetermined amount higher than the two or more progestational agents in combination with an amount of the first composition to be administered in the estrogen. Once again the extended regimen is based on the following of the treatment and comprising a mono or mul modulation of the progestational agent with a waving pattern tiphase sequence of pharmaceutical dosages. while the estrogen dose remains constant. 0028. The concept of a prolonged hormonal treatment to 0022 Extended use regimens would be clearly desirable inhibit ovulation, for example over a three month time period both to inhibit ovulation and to offer freedom from menstrual and with a constant stepwise increase of the hormonal dosage flow and premenstrual symptoms for extended periods of originated from the observation that during pregnancy bleed time. Such extended use regimens would also have a favour ing abnormalities are seldom observed. Furthermore, during able therapeutic use in premenstrual-type symptoms, dys gestation the hormonal levels of estrogen and progestin menorrhea, menstrual migraine. The continues use of an oral gradually increase with the time. contraceptive can also have a favourable effect on acne since acne typically reoccurs during the pill free period. Such a 0029. According to the present invention, a progressive method particularly for the intended long bleeding free period increase of the estrogen and/or progestin dosage allows a should not present the incidence of bleeding abnormalities continuos and stepwise increasing stimulation of the Such as spotting or breakthrough bleeding while exhibiting a endometrium, which leads to the desired stability of the favourable effect on endomentrial morphology. endometrium and bleeding free extended regimen. DESCRIPTION OF THE INVENTION 0030 The pharmaceutical preparation to obtain a continu 0023 The present invention aims to set aside the draw ous hormonal treatment over a desired period of time longer backs related to the known art and particularly aims to pro than 21-28 days comprises, according to the present inven vide a pharmaceutical preparation to obtain a continuous tion, a first composition containing at least one estrogen and/ hormonal treatment over a desired period of time longer than or at least one progestin in a predetermined amount to be 21-28 days comprising a first composition containing at least administered in the first 21-28 days. To said first composition one estrogen and/or at least one progestin in a predetermined follows a second composition comprising at least one estro amount to be administered in the first 21-28 days and a second gen and/or at least one progestin in a predetermined amount composition comprising at least one estrogen and/or at least higher than the amount of the first composition and also one progestin in a predetermined amount higher than the comprising a mono or multiphase sequence of pharmaceuti amount of the first composition and also comprising a mono cal dosages. or multiphase sequence of pharmaceutical dosages. 0031 More in detail, in the second composition of the 0024. The use of a pharmaceutical preparation for the pharmaceutical preparation only the amount of estrogen or manufacture of an agent for inhibiting ovulation in a mam only the amount of progestin or both the amount of estrogen US 2008/0234240 A1 Sep. 25, 2008 and progestin are higher than the respective amount com hydroxyprogesterone hexanoate, hydroxyprogesterone prised in the first composition. caproate, hydroxyprogesterone enanthate, , acetate, acetate, norethindrone 0032. The estrogen used in the first and/or in the second acetate, acetate, , composition can be at least one synthetic estrogen, at least acetate, (17alpha)-17-hydroxy-11-methylene one biogenic estrogen or mixtures thereof. 19-norpregna-4,15-diene-20-yn-3-one, , 0033 According to the invention said synthetic estrogen acetophenide, nestorone, , 17-hydroxyproges can be selected from the group consisting of ethinylestradiol. terone esters, 19-nor-17 hydroxyprogesterone esters, , quinestranol, precursors capable of liberating Such 17alpha-ethinyl-. an estrogen when used in the present pharmaceutical prepa 0038 Preferably the progestin is selected from the group ration and mixtures thereof. Most preferably the synthetic consisting of , , , dro estrogen is ethinylestradiol or a precursor capable of liberat spirenone, and precursors thereof. ing ethinylestradiol. The daily hormone units for use during the whole extended treatment preferably contain the synthetic 0039 The daily hormone units for use during the whole estrogen in an amount equivalent to 0.005-0.050 mg of ethi extended treatment preferably contain the at least one proges nylestradiol, most preferably in an amount equivalent to tin in an amount of 0.03-0.25 mg of levonorgestrel and/or 0.005-0.030 mg of ethinylestradiol. 0.5-5 mg of dienogest and/or 0.03-0.15 mg of gestodene, and/or 0.5-5 mg of or equivalent dosages of 0034. The biogenic estrogen is preferably selected from other progestins. the group consisting of , , estran, , , conjugated equine estrogens, precursors capable of 0040 Best results are obtained with the pharmaceutical liberating Such an estrogen when used in the present pharma preparation according to the invention when the estrogen is ceutical preparation and mixtures thereof. Most preferably ethinylestradiol and/or estradiolora precursor thereof and the the biogenic estrogen is estradiol or a precursor capable of progestin is selected from the group consisting of levonorg liberating estradiol, the term estradiol encompassing 17beta estrel, dienogest, gestodene, drospirenone, and their precur estradiol. Most preferably the biogenic estrogen is estradiol SOS. or a precursor thereof. 0041. Thus in a preferred embodiment the pharmaceutical 0035. The daily oral hormone units for use during the preparation to obtain a continuous hormonal treatment over a whole extended treatment preferably contain the biogenic desired period of time longer than 21-28 days comprises, estrogen in an amount equivalent to 0.1-5 mg of estradiol. according to the present invention, a first composition con most preferably in an amount equivalent to 0.1-3.0 mg of taining ethinylestradiol and/or estradiolor precursors thereof in a therapeutically effective amount to inhibit ovulation and/ estradiol. or a progestin preferably selected from the group consisting 0036) The progestin contained in the pharmaceutical of levonorgestrel, dienogest, gestodene, drospirenone, and preparation according to the invention is preferably selected their precursors in a predetermined therapeutically effective from the group consisting of levonorgestrel, , amount to be administered in the first 21-28 days. To said first norethisterone, , drospirenone, 3-beta-hy composition follows a second composition comprising at droxydesogestrel, 3-keto (=), least one estrogen and/or at least one progestin both selected 17-deacetyl norgestimate, 19-norprogesterone, acetoxypreg from the group estrogen and progestin previously mentioned nenolone, , , acetate, in a predetermined therapeutically effective amount higher acetate, , desogestrel, dienogest, than the amount of the first composition. dihydrogesterone, , , ethynodiol diacetate, fluorogestone acetate, gastrinon, gestodene, 0042. According to a particularly favourable embodiment , hydroxymethylprogesterone, hydroxyprogester of the present invention the second composition comprises a one, (=lynoestrenol), , medroX mono or multiphase sequence of pharmaceutical dosages so yprogesterone acetate, megestrol, melengestrol, nomege that the estrogen and progestin hormonal concentration can strol, norethindrone (=norethisterone), norethynodrel, be gradually increased over the time. (includes d-norgestrel and dl norgestrel), norg 0043. The hormonal dosages of estrogen and progestin estrienone, normethisterone, progesterone, quingestanol, previously reported refer particularly to oral formulations. (17alpha)-17-hydroxy-11-methylene-19-norpregna-4,15-di The formulation of an estrogen and progestin for the prepa ene-20-yn-3-one, tibolone, , nestor ration of a combined preparation according to the invention is one, promegestone, 17-hydroxyprogesterone esters, 19-nor effected in a manner completely analogous to that already 17hydroxyprogesterone, 17alpha-ethinyl-testosterone, known for conventional oral contraceptives having a 21-day 17alpha-ethinyl-19-nor-testosterone, d-17beta-acetoxy administration period of active ingredients, such as, for 13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oXime, example, Femovan(R), Meliane(R) and Mirelle R (ethinylestra hydroxytriendione ((21S)-21-hydroxy-21-methyl-14, diol/gestodene), or Miranova R and Microgynon R. (ethi 17ethano-19-nor-pregna-4.9, 15-triene-3,20-dione), 5-2-hy nylestradiol/levonorgestrel), or Yasmin(R) and YazR (ethi droxy-3-1-(2-fluoro-5-trifluoromethylphenyl)-cyclopro nylestradiol/drospirenone) or Valette(R) (ethinylestradiol/ pyl-2-trifluoromethyl-propionylamino-phthalide and dienogest). precursors of these compounds. 0044) The formulation of the exclusively progestin-con 0037 Specific examples of progestin precursor which taining unit doses can also be carried out in a completely may be employed in accordance with the present invention analogous manner to that known for progestin-containing comprise: anagestone acetate, gestodene acetate, hydroxym agents designed for oral administration that are already avail ethylprogesterone acetate, hydroxyprogesterone acetate, able, for example MicrolutR) with 0.03 mg LN. US 2008/0234240 A1 Sep. 25, 2008

0045. The unit doses of the first composition of the phar the first composition and comprises a mono or multiphase maceutical preparation according to the invention may also sequence of pharmaceutical dosages. be in the form of a plaster (transdermal application), an 0054 The method according to this invention can be fur implant, a or another depot formulation and thus ther advantageously used for diminishing symptoms related administered continuously. to hormonal withdrawal Such as premenstrual symptoms, 0046) The hormone units according to the invention may dysmenorrhea, endometriosis and menstrual migraine. The be also administered parenterally for example in an daily continues use of an oral contraceptive can also have a favour amount of 0.01-0.10 mg estradiol or equivalents of other able effect on acne since acne typically reoccurs during the biogenic estrogens, Sublingually, transdermally, intravagi pill free period. nally, intranasally or buccally. The daily hormonal units can 0055. The method according to the present invention with Suitably be administered orally, transdermally or intravagi a stepwise increase of the hormonal intake exhibits an opti nally. mum combination of contraceptive reliability, cycle control 0047 For such administration which avoids a first pass and minimum side-effects along the whole extended regimen. effect lower hormone units are administered, for example 0056. According to a particular form of embodiment of the lower dosages of biogenic estrogens equivalent to 0.005 method according to this invention the user of this particular 0.030 mg of ethinylestradiol can be used. extended regimen starts the intake of the lowest dose on the first day of menstruation. Said lowest dose corresponds to the 0.048. A particularly favourable form of embodiment of said first composition. The individual takes this first dose this invention refers to a preparation for transdermal admin uninterruptedly until experiencing early signs of spotting istration for example in the form of a plaster comprising said (e.g., brown vaginal discharge) normally for at least 28 days. first or second composition suitable formulated therein, for On this day of first signs of spotting the user Switches to intake example dissolved in a convenient percentage in a non-flow of the next higher dosage form corresponding to said second able, physiologically acceptable gel that is microdispersed in composition or according to a particular embodiment of this a cross-linked silicone elastomer. invention to one of the multiphase sequences of said second 0049. In order to determine equivalently effective amounts composition. of ethinyloestradiol and estradiol on the one hand and of 0057 The user follows this stepwise increasing intake different progestins, such as levonorgestrel, dienogest, schedule until spotting during intake of the highest dosed gestodene and drospirenone, on the other hand, reference is tablets occurs. At this point the intake period comes to an end made to the data given in EP-A-0253 607. Further details for and a 7-day free interval will allow withdrawal bleeding. determining dosage equivalents of different progestogenic After this week the treatment period would start again. active ingredients may be found, for example, in “Probleme der Dosisfindung: Sexualhormone” (Problems of dosage 0058. A pharmaceutical package for an extended regimen determination: sexual hormones); F. Neumann et al. in “Arz treatment longer than 21-28 days is also part of the present neimittelforschung' ( Research) 27, 2a, 296-318 (1977) invention and comprises: and in Aktuelle Entwicklungen in der Hormonalen Kon 0059 a first composition containing at least one estro traZeption” (Current developments in hormonal contracep gen and/or at least one progestin in a predetermined tion), H. Kuhl in “Gynakologe 25: 231-240 (1992). amount to be administered in the first 21-28 days 0050. According to the present invention the pharmaceu 0060 a second composition containing at least one tical preparation can comprise pharmaceutical dosages for estrogen and/or at least one progestin in a predetermined the administration over a total time of 56, 84, 112 or 140, 168 amount higher than the amount of the first composition days. The preferred administration regimen cover a total time to be administered in the following of the treatment and of 84 and 112 days. comprising a mono or multiphase sequence of pharma 0051 Between the administration of two sequential phar ceutical dosages. maceutical preparations, a free hormonal administration 0061 A particularly favourable form of embodiment of period of 1-7 days can be provided. Said period can be accord the invention comprises as a form of packing for the pharma ingly to a particular form of embodiment of the invention of ceutical preparation ablister; other forms of packing known 4-7 days. for that purpose are, however, also possible. 0.052 The present invention further relates to a method of inhibiting ovulation in a mammal, in particular a human, DESCRIPTION OF SOME FORM OF comprising administering to said mammal said first compo EMBODIMENT sition containing at least one estrogen and/or at least one 0062). Other features and advantages of the invention will progestin in a predetermined amount for 21-28 days and a become apparent from the following description of some further administration of said second composition containing favourable form of embodiment, provided purely as a non at least one estrogen and at least one progestin in a predeter restricting examples: mined amount performed to obtain a continuous hormonal treatment over a desired period of time longer than 21-28 Example 1 days. 0063. The following clinical study is performed to exam 0053 Said second composition as previously described ine the efficacy of the Suggested step-up dose regimens for the contains at least one estrogen and/or at least one progestin in extended use of hormonal contraception. The study is a predetermined amount which is higher than the amount of designed to test the hypothesis that a phasic regimen with US 2008/0234240 A1 Sep. 25, 2008 increasing dosages, for example of estrogens and progestins, results in bleeding free intervals of 84 days while maintaining the contraceptive protection. Preparation A 0.020 mg EE plus 0.080 mg LNG for 28 days 0064. In the present study two different phasic regimens 0.030 mg EE plus 0.100 mg LNG for 28 days 0.030 mg EE plus 0.125 mg LNG for 28 days with a conventional 21 day regimen based on the number of 0.030 mg EE plus 0.150 mg LNG for 28 days bleeding days during an observation period of 84 days are Preparation B 0.030 mg EE plus 0.080 mg LNG for 28 days considered. 0.030 mg EE plus 0.100 mg LNG for 28 days 0.030 mg EE plus 0.125 mg LNG for 28 days 0065. The number and type of adverse events are com 0.030 mg EE plus 0.150 mg LNG for 228 days pared and the number of are registered as well. Preparation C (ref.) 0.030 mg EE plus 0.100 mg LNG for 21 days plus 7 days placebo 0066. A three arms, multicenter, randomised, open study 0.020 mg EE plus 0.100 mg LNG for 21 days plus is designed with a study population with young fertile women 7 days placebo 0.020 mg EE plus 0.100 mg LNG for 21 days plus of 18-35 having regular menstrual cycles. Exclusion criteria 7 days placebo comprised contraindications for hormonal contraceptives. 0.020 mg EE plus 0.100 mg LNG for 21 days plus 0067 Test treatments (EE=ethinylestradiol, DRSP=dro 7 days placebo spirenone) Example 4 Preparation A 0.015 mg EE plus 2.0 mg DRSP for 28 days 0072 A further clinical study is performed according to 0.020 mg EE plus 2.5 mg DRSP for 28 days the protocol of example 1 but with the following test treat 0.030 mg EE plus 3.0 mg DRSP for 28 days ment (EE=ethinylestradiol, DNG=dienogest): Preparation B 0.020 mg EE plus 2.0 mg DRSP for 28 days 0.020 mg EE plus 2.5 mg DRSP for 28 days 0.020 mg EE plus 3.0 mg DRSP for 28 days Preparation C (reference) 0.020 mg EE plus 3.0 mg DRSP for 21 days plus 7 days placebo Preparation A 0.010 mg EE plus 1.50 mg DNG for 28 days 0.020 mg EE plus 3.0 mg DRSP for 21 days 0.015 mg EE plus 2.00 mg DNG for 28 days plus 7 days placebo 0.020 mg EE plus 2.50 mg DNG for 28 days 0.020 mg EE plus 3.0 mg DRSP for 21 days 0.030 mg EE plus 2.50 mg DNG for 28 days plus 7 days placebo Preparation B 0.010 mg EE plus 2.00 mg DNG for 28 days 0.015 mg EE plus 2.00 mg DNG for 28 days 0.020 mg EE plus 2.00 mg DNG for 28 days 0.030 mg EE plus 2.00 mg DNG for 28 days 0068 The primary efficacy variable is the number of Preparation C (ref.) 0.030 mg EE plus 2.00 mg DNG for 21 days plus bleeding days (slight and heavy bleeding) during the whole 7 days placebo 0.030 mg EE plus 2.00 mg DNG for 21 days plus observation period of 84 days. 7 days placebo 0.030 mg EE plus 2.00 mg DNG for 21 days plus 0069. The secondary efficacy variable is the number of 7 days placebo adverse events and pregnancies. The number of Subjects is 0.030 mg EE plus 2.00 mg DNG for 21 days plus determined biometrically with roughly about 200 subjects per 7 days placebo test group. Example 2 0073. The results deriving from the previous example are 0070 An other clinical study is performed according to compared to those of the reference preparations with the the protocol of example 1 but with the following test treat following remarks: ment (EE=ethinylestradiol, GSD=gestodene): 0074 Lower rate of intermenstrual bleeding, shorter period of bleeding and lower bleeding intensity; 0075 Lower rate of hormone withdrawal related symp Preparation A 0.015 mg EE plus 0.060 mg GSD for 28 days toms; 0.020 mg EE plus 0.075 mg GSD for 14 days 0.030 mg EE plus 0.075 mg GSD for 14 days 0076) Improved women wellbeing. 0.030 mg EE plus 0.100 mg GSD for 14 days Preparation B 0.030 mg EE plus 0.060 mg GSD for 28 days 0077. The invention is described above with reference to 0.030 mg EE plus 0.075 mg GSD for 28 days preferred forms of embodiment. It is nevertheless clear that 0.030 mg EE plus 0.100 mg GSD for 28 days the invention is susceptible to numerous variations within the Preparation C (ref.) 0.015 mg EE plus 0.060 mg GSD for 24 days plus 4 days placebo framework of technical equivalents. 0.015 mg EE plus 0.060 mg GSD for 24 days plus 4 days placebo 1. A pharmaceutical preparation to obtain a continuous 0.015 mg EE plus 0.060 mg GSD for 24 days plus 4 hormonal treatment over a desired period of time longer than days placebo 21-28 days comprising a first composition containing at least one estrogen and/or at least one progestin in a predetermined amount to be administered in the first 21-28 days and a second Example 3 composition characterised in that it contains at least one estrogen and/or at least one progestin in a predetermined 0071 An other clinical study is performed according to amount higher than the amount of the first composition and the protocol of example 1 but with the following test treat comprises a mono or multiphase sequence of pharmaceutical ment (EE=ethinylestradiol, LNG=levonorgestrel): dosages. US 2008/0234240 A1 Sep. 25, 2008

2. A pharmaceutical preparation according to claim 1 char droxy-3-1-(2-fluoro-5-trifluoromethylphenyl)-cyclopro acterised in that it comprises pharmaceutical dosages for the pyl)-2-trifluoromethyl-propionylamino-phthalide and administration over a total time of 56, 84, 112, 140, or 168 precursors thereof. days. 12. A pharmaceutical preparation according to claim 1 3. A pharmaceutical preparation according to claim 1 char characterised in that the at least one progestin is preferably acterised in that the second composition comprises a one selected from the group consisting of levonorgestrel, phase sequence of pharmaceutical dosages. dienogest, gestodene, drospirenone, and precursors thereof. 4. A pharmaceutical preparation according to claim 1 char 13. A pharmaceutical preparation according to claim 1 acterised in that the second composition comprises a two characterised in that the daily hormone units of at least a phase sequence of pharmaceutical dosages. progestin for use during the whole extended treatment pref erably contain the progestin in an amount of 0.03-0.25 mg of 5. A pharmaceutical preparation according to claim 3 char levonorgestrel and/or 0.5-5 mg of dienogest and/or 0.03-0.15 acterised in that the pharmaceutical dosage of at least one mg of gestodene, and/or 0.5-5 mg of drospirenone or equiva estrogen of the second composition is higher than the amount lent dosages of other progestins. contained in the first composition. 14. A pharmaceutical preparation according to claim 1 6. A pharmaceutical preparation according to claim 3 char characterised in that the hormone units are administered acterised in that the pharmaceutical dosage of at least one orally, parenterally, Sublingually, transdermally, intravagi progestin of the second composition is higher than the nally, intranasally or buccally. amount contained in the first composition. 15. A pharmaceutical preparation according to claim 1 7. A pharmaceutical preparation according to claim 4 char characterised in that the hormone units are for oral adminis acterised in that the pharmaceutical dosage of at least one tration. estrogen and/or at least one progestin of the second compo 16. A pharmaceutical preparation according to claim 1 sition are higher than the amount contained in the first com characterised in that the hormone units are daily units. position. 17. Use of a pharmaceutical preparation according to claim 8. A pharmaceutical preparation according to claim 1 char 1 for the manufacture of an agent for inhibiting ovulation in a acterised in that the at least one estrogen is selected from the mammal, in particular a human. group consisting of following synthetic estrogens: ethi 18. Use of a pharmaceutical preparation according to claim nylestradiol, mestranol, quinestranol, or a precursors capable 17 characterised in that the administration of said preparation of liberating Such an synthetic estrogen and/or from the group extends over a time of 56, 84, 112, 140 or 168 days. of the following biogenic estrogens: estradiol, estrone, estran, 19. Use of a pharmaceutical preparation according to claim estriol, estetrol, conjugated equine estrogens, precursors 17 for the manufacture of an agent for diminishing symptoms capable of liberating Such a biogenic estrogen. related to hormonal withdrawal Such as premenstrual symp 9. A pharmaceutical preparation according to claim 8 char toms, dysmenorrhea, endometriosis, menstrual migraine. acterised in that the at least one estrogen is ethinylestradiol 20. Use of a pharmaceutical preparation according to claim and/or estradiol. 17 for the manufacture of an agent for diminishing symptoms 10. A pharmaceutical preparation according to claim 1 related to acne characterised in that the daily hormone units of estrogen 21. A pharmaceutical package for an extended regimen preferably contain ethinylestradiol in an amount of 0.005-50 treatment longer than 21-28 days comprising: mg, most preferably in an amount of 0.005-0.030 mg and/or a first composition containing at least one estrogen and/or the estradiol in an amount of to 0.1-5.0 mg. at least one progestin in a predetermined amount to be 11. A pharmaceutical preparation according to claim 1 administered in the first 21-28 days characterised in that the at least one progestin is selected from a second composition containing at least one estrogen and/ the group consisting of levonorgestrel, norgestimate, nore or at least one progestin in a predetermined amount thisterone, dydrogesterone, drospirenone, 3-beta-hydroxy higher than the amount of the first composition to be desogestrel, 3-keto desogestrel (=etonogestrel), 17-deacetyl administered in the following of the treatment and com norgestimate, 19-norprogesterone, acetoxypregnenolone, prising a mono or multiphase sequence of pharmaceuti allylestrenol, anagestone, , cyproter cal dosages. one acetate, demegestone, desogestrel, dienogest, dihy 22. Pharmaceutical package according to claim 21 charac drogesterone, dimethisterone, ethisterone, ethynodiol diac terised in that said first composition and said second compo etate, fluorogestone acetate, gastrinon, gestodene, gestrinone, sition correspond to the first and the second composition as hydroxymethylprogesterone, hydroxyprogesterone, defined in the pharmaceutical preparation according to claim lynestrenol (=lynoestrenol), medrogestone, medroxyproges 1 to 16. terone acetate, megestrol, melengestrol, nomegestrol, nore 23. Pharmaceutical package according to claim 21 charac thindrone (=norethisterone), norethynodrel, norgestrel terised in that the first and/or the second composition are (includes d-norgestrel and dl norgestrel), , administered in daily doses. normethisterone, progesterone, quingestanol, (17alpha)-17 24. Pharmaceutical package according to claim 21 charac hydroxy-11-methylene-19-norpregna-4,15-diene-20-yn-3- terised in that the first and/or the second composition are one, tibolone, algestone acetophenide, nestorone, promege arranged for separate sequential administration like for Stone, 17-hydroxyprogesterone esters, 19-nor example in separate blisters. 17hydroxyprogesterone, 17alpha-ethinyl-testosterone, 25. Pharmaceutical package according to claim 21 charac 17alpha-ethinyl-19-nor-testosterone, d-17beta-acetoxy terised in that the administration of the first and second com 13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oXime, position extends over a time of 56, 84, 112, 140 or 168 days. hydroxytriendione ((21S)-21-hydroxy-21-methyl-14, 17ethano-19-nor-pregna-4.9, 15-triene-3,20-dione), 5-2-hy c c c c c