(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . _ . . 3 May 2012 (03.05.2012) WO 2012/055840 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/00 (2006.01) A61P 5/30 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/565 (2006.01) A61P 5/34 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/57 (2006.01) A61P 15/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 33/30 (2006.01) A61P 15/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/EP201 1/068596 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, 25 October 201 1 (25.10.201 1) RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (25) Filing Language: English ZM, ZW. (26) Publication Langi English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/407,570 28 October 2010 (28.10.2010) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, (71) Applicant (for all designated States except US): BAYER RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, PHARMA AKTIENGESELLSCHAFT [DE/DE]; DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, Muller Strasse 178, 13353 Berlin (DE). LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, (72) Inventors; and GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/ Applicants (for US only): LEZZAIQ, Samer [LB/US]; 501 9th Street #5 15, Hoboken, New Jersey Published: 07030 (US). SCHNEEWEIS, Axel [DE/DE]; Schreiner- — with international search report (Art. 21(3)) str. 27, 10247 Berlin (DE). PATCHED, Vladimir [DE/DE]; Illtisweg 16, 07749 Jena (DE). (74) Common Representative: BAYER PHARMA AK¬ TIENGESELLSCHAFT; Patents & Licensing, Muller Strasse 178, 13353 Berlin (DE).

(54) Title: COMPOSITION AND PREPARATION FOR TREATMENT OF DYSMENORRHEA AND MENSTRUAL PAIN AND USE OF A HORMONAL AGENT AND A ZINC SALT FOR TREATMENT OF MENSTRUAL DISORDERS

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© (57) Abstract: The inventions refers to a pharmaceutical composition and a preparation (regime) containing a hormone and a bio - compatible zinc salt, as well as the use of a zinc salt and a contraceptive active hormone for the treatment of menstrual disorders, Q in particular to alleviate dysmenorrhea. Composition a d preparation for treatment of dysmenorrhea and menstrual pain and use of a hormonal agent and a zinc salt for treatment of menstrual disorders

Field of the invention

[0001] The present invention is related to a composition and a preparation (regime) for the treatment of dysmenorrhea (or dysmenorrhoea) and menstrual pain, otherwise known as menstrual cramping. A preparation comprising a progestin or an agent having a progestogenic activity and a sufficient amount of zinc to alleviate menstrual disorders, especially dysmenorrhea and menstrual pain. The invention refers furthermore to the use of a progestin and a biocompatible zinc salt for the preparation of a medicament for treatment of menstrual disorders.

Background of the invention

[0002] Dysmenorrhea (Greek for painful menstruation) is one of the most common gynecological complaints in young women who visit clinicians (Dawood, 2006 4 ; Jamieson and Steege, 1996( ) .

[0003] Dysmenorrhea is a medical condition characterized by severe uterine pain during menstruation. While many individuals experience minor pain during menstruation, dysmenorrhea is diagnosed when the pain is so severe as to limit normal activities, or require medication. Most women begin having dysmenorrhea during adolescence, usually within four to five years of the first menstrual period. Painful periods become less common as women age. Dysmenorrhea may coexist with excessively heavy blood loss, known as menorrhagia or heavy menstrual bleeding (HMB). For clinical purposes, dysmenorrhea is divided into two broad categories, primary and secondary (congestive) dysmenorrhea (Dawood, 1985 ( ) .

[0004] Primary dysmenorrhea is defined as menstrual pain not associated with macroscopic pelvic pathology. It occurs in the first few years after menarche (Koltz in Lemek et a/., 1992 ) and affects up to 50% of post-pubescent females (Dawood, 1988(¾) . The peak incidence of primary dysmenorrhea occurs in late adolescence and the early 20s (Fraser, 992 18 ) . [0005] In an epidemiological study of an adolescent population (aged 12-17 y, n=2700), Klein and Litt (1981) ( reported a prevalence of dysmenorrhea of 59.7%. Of patients reporting pain, 12% described it as severe; 37%, as moderate; and 49%, as mild. Dysmenorrhea caused 14% of patients to miss school frequently. Although black adolescents reported no increased incidence of dysmenorrhea, they were absent from school more frequently (23.6%) than whites (12.3%), even after adjusting for socioeconomical status.

[0006] Similar figures have been reported by Proctor and Farquhar (2006( after

Weissman et a!., 2004 ) , reporting that absenteeism from work and school as a result of dysmenorrhea is common (13% to 51% women have been absent at least once and 5% to 14% are often absent owing to the severity of symptoms).

[0007] Davis et al. (2005) 2 stress that morbidity, due to dysmenorrhea, represents a substantial public health burden. Based on estimates from the U.S. Census (2000), approximately 2 million adolescents, or 15% of the total females aged 13-19 years, experience severe dysmenorrhea (Davis et al., 2003 after Census 2000 data for the United States). Ylikorkal and Dawood (1978) estimated that dysmenorrhea is the single greatest cause of lost working hours and school absence in adolescent girls.

[0008] Primary dysmenorrhea has been associated with alterations in prostaglandin synthesis and metabolism. Investigations of women with primary dysmenorrhea reveal elevated levels of prostaglandin F2a in the endometrium.

[0009] Prostaglandins are modified forms of unsaturated fatty acids and function as mediators of a variety of physiological responses such as inflammation, vascular dilation, platelet aggregation and muscle contraction by regulating the tone of smooth muscles. The levels of prostaglandins formed in the lining of the uterus increase as menstruation approaches, with the highest levels at the onset of the menstrual period. An excessive amount of prostaglandins increases uterine contractions causing cramps and pain, also resulting from vasoconstriction, decreased blood perfusion and hypoxia. Generalized effects of prostaglandin excess may account for the headaches, dizziness, hot and cold flashes, diarrhea and nausea that can accompany painful periods.

[0010] The role of prostaglandins (PGs) in the pathogenesis of primary dysmenorrhea has been explained by several observations. Prostaglandins, especially prostaglandin

F2 (PGF2a) are considered essential factors in the pathogenesis of dysmenorrhea, excess menstrual bleeding and associated pelvic pain (Rosenwaks , Seegar-Jones 2 (2003) in Wright et al. . Accordingly, suppression of prostaglandin production or diminution of the uterus liability to their action represent efficient therapeutic approaches to dysmenorrhea and heavy menstrual bleeding (Lethaby et al. (2007) (2¾ .

[0011] Prostaglandin synthesis and metabolism in the uterus is controlled by

2 2 progesterone (Rebsamen et a/.,2004)< ; Young M and Funder J (2003)< ; Zhang Z et al. (2002) 2 . Deficient progesterone secretion (e.g. as a result of anovulation or corpus luteum insufficiency in adolescents), and the resulting increase in prostaglandin production, causally contribute to painful menstruation and increased menstrual blood loss. Although progestin treatment (e.g. in the form of oral contraceptives) is a proven therapeutic option, abrupt treatment cessation (e.g. hormone-free pause of oral contraceptive administration) can rapidly evoke increased prostaglandin production and sensitivity in the uterus and recurrence of painful pelvic sensation and increased blood loss.

[001 2] The clinical symptoms of primary dysmenorrhea are similar to those induced by the administration of prostaglandins (PGF-2ct and PGE2) for the induction of labour. The increased production of prostaglandins by the endometrium during the luteal and menstrual phases of ovulatory cycles is consistent with the occurrence of primary dysmenorrhea mainly in ovulatory cycles. The concentrations of prostaglandins in the endometrium and menstrual fluid of dysmenorrheic women are significantly higher than in controls [Dawood (2006) after Pickles (1957) and Pickles et al. (1963)]<1 >and certain prostaglandin inhibitors are useful in the treatment of dysmenorrhea. The change in prostaglandin production can explain the major symptoms of primary dysmenorrhea, including the increased uterine contractility, uterine ischemia and the lowering of the pain threshold to chemical and physical stimuli in the pelvic nerve terminals. Since ovulation is a prerequisite for primary dysmenorrhea, ovarian steroid hormones are likely to be involved in regulating the intrauterine production of prostaglandins at menstruation. It has been suggested that high circulating estrogen levels in the luteal phase may cause the excessive prostaglandin production. Prostaglandin action on the uterus has been determined to be dependent on progesterone levels, with high levels of progesterone rendering the uterus resistant to prostaglandin stimulation. When progesterone falls prior to menses, excess prostaglandins cause dysmenorrhea. However, it has been observed that only 70-90 % of dysmenorrheic women experience pain relief after treatment with prostaglandin synthetase inhibitors. This suggests that other factors in addition to prostaglandins might be responsible for the hyperstimulation of uterine contractions. Recent experimental data indicate that leucotrienes, platelet activating factor and vasopressin might be alternative pathogenetic causes of dysmenorrhea.

[0013] Secondary dysmenorrhea is defined as menstrual pain resulting from anatomic and/or macroscopic pelvic pathology (Dawood, 1990 ( ; Klotz in Lemeke et a!., 1992 )) . This condition is most often observed in women aged 30-45 years. Approximately 40% of adult females have menstrual pain, and 10% are incapacitated for 1-3 days each month.

[0014] There is a number of treatments available for women with dysmenorrhea, which are described in the following sections.

[0015] Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain associated with primary dysmenorrhea (Dawood 1988 (2)) . They have a direct analgesic effect through inhibition of prostaglandin synthesis and also have other properties that act against inflammatory factors that may be responsible for heavy menstrual bleeding. NSAIDs may be most effective when therapy is started before the onset of menstrual pain and flow or as soon as the symptoms begin, and then are taken on a regular schedule for two to three days. Unfortunately, the pain of primary dysmenorrhea is generally of such intensity that more potent analgesics are often required.

[0016] Common side effects of NSAIDs used intermittently include nausea, vomiting, and diarrhea, and may include effects on the nervous system such as headache, drowsiness, and dryness of the mouth. Caution should be exercised in using these medications in patients with existing cardiovascular or renal issues or with difficulty handling intravascular volume, as they may worsen or lead to the onset of hypertension. Long-term use of any NSAID can cause increasing adverse effects, for example increase the risk for gastrointestinal bleeding and ulcers, and the overuse of NSAIDs for menstrual disorders may contribute to iron deficiency anaemia due to Gl blood loss.

[0017] Also birth control pills are know to be effective in treating women with dysmenorrhea. Combined oral contraceptive pills comprising estrogen and progestin attenuate myometrial activity by lowering endometrial prostaglandin production and by thinning the lining of the uterus, where prostaglandins are formed, thereby decreasing the uterine contractions and menstrual bleeding that contribute to pain and cramping. Continuous OCs have the potential for helping women with either heavy bleeding, painful periods, or both. Combined oral contraceptives and NSAIDs are often considered first-line therapy for women with primary or secondary dysmenorrhea. Estrogen and progestin may each cause different side effects, especially during the first two to three months of treatment, but this usually declines with time. When using a progestin-only contraceptive, caution must be given to prevent estrogen deficiencies and loss of bone mineral density; also unscheduled bleeding episodes are a frequent untoward effect of progestin-only contraceptives.

[0018] Progestin and especially levonorgestrel (LNG) releasing intrauterine systems

(IUS) are shown to be very beneficial for menstrual disorders. The hormones in these types of devices help control the growth of the lining of the uterus so less prostaglandin is made resulting in fewer contractions, less blood flow, and less pain. Hormones may stop the growth of fibroids and endometriosis. Some studies suggest that the LNG-IUS is more effective than oral contraceptives for controlling heavy menstrual bleeding. Since progestin released by an intrauterine system mainly affects the uterus and cervix and serum levels of levonorgestrel are usually very low, the device causes far fewer side effects than the progestin pills do.

[0019] Zinc at sufficient doses has been shown to prevent essentially menstrual

1 171 cramping (Kelly 1983< ; Prasad 2000< ) .

[0020] The dose effect of zinc on menstrual pain has been investigated by Goei

(1982) (12) in a clinical study. He could show, that patients consuming 3 1 mg zinc per day, premenstrual tension (PMT) symptoms did not occur, while in patients consuming 15 mg of zinc PMT symptoms did occur.

[0021] Dependencies of menstrual pain against dose and date of administration has been evaluated by Eby (2007 ( ) by taking data and observations from case histories.

[0022] The case studies, in Eby (2007 ) , on Zn effect on dysmenorrhea, mention various doses and regimens, e.g. 15 mg Zn every 2-3 waking hours; 30 mg 1x3 per day 1-4 days before expected menses start; 60 mg b.i.d 3-4 days before the expected menses start. It is worthwhile mentioning that the exhibited effect of zinc was when it was administer 1-2 days before commencement of menstrual bleeding.

[0023] Eby (2007) concludes that best results are obtained when zinc administration take place 1-4 days prior the menses and with doses of 3 1 mg per day. As the United States Institute of Medicine, Food and Nutrition Board recommended a daily allowance (RDA) for zinc of 9 mg( 4 per day for women (see also figure 1/4). Eby (2007) concludes that this dose is too low to optimize women's health and prevent menstrual cramps.

[0024] There are various hypotheses discussed on the effect of zinc. Zinc may interfere with different pathways of prostaglandin synthesis and/or metabolism.

[0025] Another hypothesis is that zinc might improve micro-vessel circulation in the uterus, as is seen with angina pectoris (Eby, 2006) ( . Since strong uterine contractions temporarily reduce or stop the blood supply to the uterus, thus depriving the uterus of oxygen resulting in contractions and pain, improvement in micro-vessel circulation by zinc treatment may be sufficient to prevent cramping and pain. Ischemia followed by reperfusion, results in the release of active oxygen species which can cause tissue damage and pain.

[0026] In the human uterus reactive oxygen species including superoxide radicals are generated in the endometrium and they are increased in the late secretory phase endometrium, just before menstruation. These radicals are known to stimulate human endometrial stromal cells to produce prostaglandins (PGF2a), which are involved in endometrial breakdown.

[0027] Copper-zinc dismutase enzyme (super oxide dismutase) in the uterus controls prostaglandin production by inactivating and preventing accumulation of these oxygen radicals (see for example Sugino (2000) ( ) . These radicals, stimulate human endometrial stromal cells (ESC) to produce Prostaglandins (F2a), which are involved in endometrial breakdown Zinc treatment enhances the levels of this enzyme, which in turn could result in relieving cramping and pain. Zinc is an effective anti-inflammatory and antioxidant agent, and it can readily down-regulate inflammatory cytokines. Zinc also protects plasma cell membranes preventing damage to cells by a wide variety of cytotoxic agents in a dose dependent manner extending far above physiologic concentrations. Zinc may regulate cyclooxygenase-2 (COX-2), an enzyme involved in pain and inflammation, and implicated in certain cancers, and COX-2 can be lowered by zinc treatment.

[0028] Finally, zinc has been shown to interfere with the efficacy of transcription factors with essential role in the propagation of signals associated with inflammation and reactive oxygen species (Uzzo et al., 2006) (2¾ . Object of the invention

[0029] The problem to be solved by the present invention is to provide a pharmaceutical composition for preventing or alleviating dysmenorrhea and menstrual pain, which is effective with timely-administered, reduced zinc doses. A second problem to be solved, is to provide a pharmaceutical preparation which ensures a timely intake of the zinc salt, preferably 1-4 days prior the menses.

[0030] According to the invention the first object is solved by making available a pharmaceutical composition comprising a hormonal agent, in particular an estrogen and/or one or more progestin and a biocompatible zinc salt and pharmaceutically acceptable excipients and carriers.

[0031] The second aspect of the invention (timely intake of zink salt) is met by providing a pharmaceutical preparation/regime, which is, e.g. predetermined by a blister package with a fixed sequence of dosage units containing a an oral contraceptive active hormone and/or a biocompatible zinc salt and optionally placebo pills. In the context of this invention the term "placebo pill" means hormone free tablet. However, such hormone free tablets can contain other ingredients such as vitamins, nutritional supplements and/or Metafolin respectively folic acid.

Summary of the invention

[0032] The invention is based on the realization, which is surprising in relation to the state of the art, that treatment and prevention of menstrual disorders with a combination of a biocompatible zinc salt and pharmaceutical composition comprising progestin and/or estrogen allows for a dose reduction regarding the effective amount of zinc. Detailed description of the inve tio

[0033] The present invention makes available a pharmaceutical composition for treatment (prevention or alleviation) of dysmenorrhea and menstrual pain, which is effective with reduced zinc doses.

[0034] This object was achieved by a pharmaceutical composition comprising an hormonal agent and a biocompatible zinc salt in a pharmaceutical acceptable carrier.

[0035] In principle all biocompatible zinc salts are suitable with regard to the present invention, preferred is zinc- acetate, zinc-bis(hydrogen-DL-aspartate), -orotate, -gluconate, -sulphate or -cetrate.

[0036] Reduced zinc doses in the context of the present invention means daily doses which are below 3 1 mg/day. The lower limit with regard to the zinc dose is 5 mg/day.

[0037] In principle higher doses of zinc, e.g. up to 50 mg/day, are feasible. However, considering the Recommended Daily Allowance (RAD) for zinc, such high zinc doses should be considered only for short-term use, e.g. if the zinc is administered exclusively in the hormone-free interval.

[0038] In general the zinc dose should be in the range of 5-40 mg, preferably in the range of 10-40 mg. In a particular preferred embodiment of the invention the zinc dose is in the range of 15-30 mg.

[0039] If zinc is administered concomitantly over the complete cycle, a lower dose in the early phase and an increased dose in the late phase of the cycle (preferably 4-5 days prior the menses) is advantageous.

[0040] In a preferred embodiment of the invention the zinc salt is administered either during the hormone free phase or in combination with progestin alone, or with estrogen plus progestin.

[0041] For clarity, it is remarked that the quantity of zinc given in this specification refers to the zinc ions, as zinc salts are ionic compounds consisting, for example, of two moles of a monovalent radical for each mole of zinc. Therefore, the total amount of salt present in the composition has to be calculated against the respective negative ion selected. In those cases where crystal water is present in the zinc salt (e.g. ZnSO x

7 H2O), the crystal water has also to be considered.

[0042] As a hormonal agent present in the pharmaceutical composition, all known active hormones that exhibit a contraceptive efficacy at therapeutic doses (contraception as a side effect) are suitable in principle. Preferred in the context of this invention are estrogen/progestin combinations but also "Progestin only" pills.

[0043] If the hormonal agent is administered orally, hormones which are bioavailable after oral administration are used.

[0044] Preferred estrogens are estradiol valerate, ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated equine estrogens.

[0045] Preferred progestins and their active forms are selected from the group of levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta- hydroxydesogestrel, 3-ketodesogestrel (= etonogestrel), 17-deacetylnorgestimate, 19- norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol (= lynoestrenol), mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (= norethisterone), norethynodrel, norgestrel (including d- norgestrel and dl-norgestrel), norgestrienone, norm ethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-1 1-methylene-19-norpregna-4,15-dien-20-yn-3- one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17- hydroxyprogesterone esters, 19-nor-1 7hydroxyprogesterone, 17alpha- ethynyltestosterone, 17alpha-ethynyl-1 9-nortestosterone, d- 17beta-acetoxy- 13beta- ethyl-17alpha-ethynylgon-4-en-3-one oxime and or 6β,7β;15β,16p-dimethylene-3-oxo- 17-pregna-4,9(1 1)-diene-21 ,17p-carbolactone or tanaproget.

[0046] A preferred composition according to the present invention contains an estrogen/progestin hormonal combination containing Drospirenone and Ethinyl Estradiol.

[0047] In a preferred embodiment of the present invention 2-4 mg Drospirenone (DRSP) and 20-30 g Ethinyl Estradiol (EE) are contained. [0048] The present invention furthermore provides a pharmaceutical preparation / regime, e.g. predetermined by a blister package with a fixed sequence of dosage units containing the hormone and/or a biocompatible zinc salt and optionally placebo pills.

[0049] With regard to the present invention all known contraceptive regimes (with a hormone free interval) are suitable in principle. Most combined pills come in the form of a calendar pack containing 2 1 pills. One pill is taken daily for 2 1 days, followed by a tablet-free break (usually 7 days) during which bleeding occurs. Instead of the tablet- free break, it is possible to take inactive pills (placebos). This makes it easier to remember to continue to take tablets regularly (one pill every day without exception). However, there are other intake regimens available. In addition to the a.m. 2 1 plus 7 regime also a 24 plus 4 day regime is very common.

[0050] Also, regimens with a different hormone dose fall under the scope of the present invention. Such regimens with a varying hormone dose are, for example, known from the product Qlaira®/ ATAZ A ™, where initially on days 1 and 2 only 3 mg estradiol valerate (E2V) are administered followed by, 2 mg E2V and 2 mg Dienogest

(DNG) on days 3-7, followed by 3 mg DNG 2 mg E2V on days 8-24 respectively 1 mg

E2V on days 25 and 26. A 2 day hormone free interval completes the 28 cycle pack.

[0051] Zinc can be added in various regimens, for example:

1) Concomitant, that means an additional daily dose of zinc to the estrogen and/or progestin hormonal combination.

2) Intermittent: Addition of a daily dose of zinc during a certain part of the regimen.

3) Stepwise: addition of varying doses of zinc during various parts of the estrogen/progestin combination.

[0052] An overview of about potential treatment regimes is given in Figure 2/4 (for a 2 1 plus 7 regime) and in Figure 3/4 for a 24 plus 4 day regime.

[0053] Basically a x-phase system with m separately packed single dosage units containing only a hormonal agent, followed by n dosage units containing a hormonal agent plus a zinc salt, followed by o dosage units containing the zinc salt only followed by p placebo units is possible. In a 21+7 regime m can be 0 to 2 1 and p can be 0-7 under the proviso that m+n+o+p is 28, n is 2 1 minus m and o is 7 minus p. Depending on the meaning of m or p, x can be 2 , 3 or 4 . (If m and p are zero x is 2 , if m or p are zero x is 3 if m and p are unequal 0 , x is 4).

[0054] In an preferred embodiment of the invention n is 2 1 and p is 7 or n is 2 1 and o is

7 .

[0055] Particular preferred is a 2-phase regime, where m is 2 1 and o is 7 or a 3-phase system where m plus n are 2 1 and o is 7 .

[0056] With regard to an 24 plus 4 regime (Figure 3/4) m can be 0 to 24 and p can be

0-4 under the proviso that m+n+o+p is 28, n is 24 minus m and o is 4 minus p. Depending on the meaning of m or p, x can be 2,3 or 4 . (If m and p are zero x is 2 , if m or p are zero x is 3 if m and p are unequal 0 , x is 4).

[0057] In an preferred embodiment of the invention n is 24 and p is 4 or n is 24 and o is 4 .

[0058] Particular preferred is a 2-phase regime, where m is 24 and o is 4 or a 3-phase system where m plus n are 24 and o is 4 .

[0059] Instead of an placebo pills also "tablet free" days are possible.

[0060] In Figure 2/4 and 3/4 the preferred regimens are highlighted in light grey and the particular preferred regimens are highlighted in dark grey.

[0061] In all dosage units the amount of the hormonal agent and zinc is variable, e.g. in the market product QIaira /NATAZ IA™ the progestin hormone dose (dienogest) is in the initial phase 2 mg (day 4 to 7) followed by 3 mg (16 days). The same is true with regard to the zinc dose. If, e.g. the zinc salt is concomitantly administered with the hormone, a lower zinc dose is possible compared to the scenario where zinc is given in a separate dosage unit instead of a placebo pill in the hormone free interval.

[0062] Preferably the zinc is administered 3 to 5 days prior the menses only. In this case the preferred administered dose is 20-30 mg. If it is concomitantly administered with the hormone(s), then the dose could be lower and is preferably between 10-20 mg per single dosage unit.

[0063] In a preferred embodiment of the invention the pharmaceutical preparation (regimen) contains 5-30 mg zinc and as a zinc salt zinc acetate, -gluconate, -sulphate zinc-bis(hydrogen-DL-aspartate), zinc-orotate or -cetrate. [0064] As a hormonal agent the preparation contains progestin or a progestin derivative, cyproterone acetate, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone, norethisterone, norethisterone acetate, norgestimate, drospirenone, dienogest, gestodene, 19-nor- 17-hydroxy progesterone esters, 17a- ethinyltestosterone and derivatives thereof, 17a-ethinyl-1 9-nor-testosterone and derivatives thereof, ethynodiol diacetate, megestrol, dydrogesterone, norethynodrel, chlormadinone acetate, allylestrenol, tibolone, medrogestone, norgestrienone, ethisterone, dl-norgestrel or 6p,7P;15p,16p-dimethylene-3-oxo-17-pregna-4,9(1 1)- diene-21 ,17p-carbolactone .

[0065] In a particular preferred embodiment of the invention the preparation contains a combination of Drospirenone and an Estrogen and as zinc salt zinc acetate or zinc gluconate.

[0066] In is furthermore preferred that the preparation contains Levonorgestrel and an Estrogen and zinc acetate or zinc gluconate.

[0067] As estrogen in the preparation estradiol, estradiol ester, estradiol valerate, estradiol hemihydrate or ethinyl estradiol is preferred.

[0068] In particular preferred is ethinylestradiol, mestranol, quinestranol, estradiol, estradiol valerate, estrone, estrane, estriol, estetrol and conjugated equine estrogens and/or a progestin.

[0069] The tablets used in the preparation can be prepared by the known methods. A zinc and hormone-containing tablet can be prepared analogue to the hormone- containing pills, such as by fluidized bed granulation or by direct tableting. Here, the usual pharmaceutical excipients are used. Finally the tablet can then be coated or painted with a film former.

[0070] Another aspect of the invention refers to the use of the a.m. compositions or pharmaceutical preparations for the treatment of dysmenorrhea and/or menstrual pain. EXPERIMENTAL PART

[0071] The invention is described below in greater detail in the following, non-limiting examples.

[0072] As prostaglandin F2a is the principal factor accounting for the contractile activity of the myometrium and, thus, is causally contributing to cramps and pelvic pain during menstruation (i.e. a situation which is invariably associated with precipitous decrease of endogenous progesterone concentrations). The examples 1 and 2 underline the capacity of zinc to exert therapeutic effects in such conditions by decreasing the concentrations of PGF2a in the affected organ, as well as the responsiveness of the myometrium to this endogenous mediator of smooth muscle contractions.

Demonstration of disease-relevant effects of zinc treatment in experimental animals

[0073] Female Wistar rats (180-185g b.w., 2.5 month old) were housed at circadian day / night cycle with at libitum chock food and water access. Under general anesthesia with Calypsol (Calypsol, Gedeon Richter, 10 mg/kg, i.p.) and aseptic conditions the rats were ovariectomized through bilateral dorsal approach. Each animal was injected postoperatively with a single dose of Gentamycin (Gentamycin,

Sopharma, 8 mg/kg, i. m.) which was followed by a 14 day recuperation and randomization to three treatment groups: "continuous progestin", "progestin withdrawal" and "progestin withdrawal plus Zn".

[0074] The rats were injected with Estradiol [50 pg/rat, subcutaneous (s.c.)] on 3 consecutive days. On the day following the last Estradiol treatment, matrix-driven delivery systems releasing Levonorgestrel per day (Innovative Research of America, Sarasota) were implanted subcutaneously under light anesthesia (Calypsol) and skin analgesia (Lidocaine ointment 5 % , Actavis) to all animals. The implants were removed after 7 days (group "continuous progestin") or 4 days (groups "progestin withdrawal" and "progestin withdrawal plus Zn").

[0075] Zinc gluconate (Merck, Darmstadt) was administered daily to the animals of the group "progestin withdrawal plus Zn" upon Levonorgestrel pellet removal for 4 consecutive days. The daily dose of 30 mg/rat was formulated as aqueous solution and administered by oral gavage in a volume of 0.5 ml. The remaining groups received daily an equal volume of the solvent (distilled water).

[0076] The animals were sacrificed by excess CO2 exposure and exsanguination. The uterus was removed and submersed in chilled medium. Portions of the uterine horn (20 mm in situ length) were excised for in vitro examination of the contractile activity. The remaining tissue was frozen in liquid nitrogen for biochemical investigations.

Example 1 Zinc treatment suppresses prostaglandin-induced uterine contractions

[0077] The isolated horn preparation was placed horizontally between two ring platinum electrodes (4 mm diameter) located at a distance of 10 mm and 26 mm from the outlet of a 1 ml plastic double-jacketed tissue chamber (37° C) and superfused at a constant flow rate of 1 ml/min by means of a peristaltic pump (Miniplus 2 , Gilson 312) with a medium of the following composition (mM): NaCI 136.9, KCI 2.7, CaCI 2 1.8,

gSO 0.6, NaHCO 3 11.9, KH2PO4 0.5, Glucose 11.5, supplemented with albumin 25 mg/l and EDTA 10 mg/l gassed with 5% CO2 in O2 (pH 7.3-7.5). One end of the preparation was tied to a Grass FT 03C force-displacement transducer connected by tensometric bridge (Microtechna) to a Lineacorder (TZ 4620) for registration of isometric changes in tension. The preparation was stretched (0.5-0.8 rrsN) until reached approximately the in situ length and allowed to equilibrate for 60 min. Myotropic electrical stimulation with 5 s trains of rectangular pulses of 50 V , 10 Hz, 6 ms, was delivered at 180 s by MFS-1 stimulator to evoke myogenic contractions. Prostaglandin F2a (Prostin, Pfizer, PGF2a) was applied with the medium for 20 min at a concentration of 50 nM.

[0078] The mean amplitude of contractions over 10 min episodes before and during prostaglandin application and their frequency were estimated. For each animal the ratio of post- to pre-prostaglandin values was calculated. Statistical evaluations were performed by one-way analysis of variance, followed by the two-tailed t-test, where appropriate.

[0079] The basal amplitude of myogenic contractions was similar in all groups, whereas PGF2a produced a clear stimulatory effect in all preparations (Figure 4/4). The figure shows the amplitude of the myogenic contractions of the uterine horn in different treatment groups. Low-amplitude spontaneous (independent of electric stimulation) contractions were recorded in some preparations: 4 of the group "continuous progestin" (mean frequency 5.75 ± 0.85 in 10 min), 5 of the group "progestin withdrawal" (mean frequency 4.5 ± 0.866) and only 2 preparations of the group "progestin withdrawal + Zn" (mean frequency 4.5 ± 0.5). PGF2a produced a very strong increase in the spontaneous contractile activity of the group "progestin withdrawal" (response ratio 131 ± 109), while its effect was modest in preparations originating from animals of the treatment groups "continuous progestin" (response ratio 4.0 ± 0.8) or "progestin withdrawal + Zn" (response ratio 3.3 ± 1.0).

[0080] The data presented in this example indicate that systemic treatment with zinc gluconate following precipitous progestin withdrawal significantly diminishes the contractile responsiveness of the uterus to prostaglandin F2a challenge.

The amplitude increased 6-fold in the group "Continuous progestin" and 4.5-fold in the group "Progestin withdrawal". Stimulation of myogenic contractions by PGF2a application was significantly attenuated in the preparations isolated from the animals treated with zinc following progestin withdrawal (2.5-fold increase).

[0081] In summary the data show, that systemic zinc administration in rats suppresses the liability of the uterus to prostaglandin-induced contractions and decreases uterine prostaglandin levels.

[0082] Similarly, the frequency of myogenic contractions was significantly lower in uterus preparations deriving from the group "Progestin withdrawal + Zn" (see table 1). Example 2 Zinc treatment reduces uterine content of PGF2a

[0083] Uterine tissue samples were homogenized in 3 ml cold 0.15 M KCI-10 mM potassium phosphate buffer, pH 7,4 in Potter-Elvehjem glass homogenizers with Teflon pestle. After sonication (4 x 30 s), the tissue preparations were centrifuged at 400 g for 20 min. The obtained supernatants were stored at -28 °C for biochemical analysis. A portion of the supernatant was mixed with 10 pg/ml indomethacin (Sigma, Deisenhofen), acidified to pH = 3.5 with 2N HCI and prostaglandins were extracted twice with 2ml ethyl acetate. After centrifugation at 1000 rpm the organic phase was separated and evaporated under nitrogen stream. The residue was dissolved in 250 µ Ι assay buffer. Prostaglandin F2a was determined by enzyme immunoassay kit (Assay Designs, In., Cat. No. 900-069, Lot No. 042409 13); photometric measurements were made with GENios Plus Multi-Detection Reader, Tecan Inc. The calibration curve covered the range between 3 and 50000 pg/ml; the assay sensitivity was 6.7 pg/ml. The data are expressed in ng/100 mg tissue.

[0084] The results of this experiment document that systemic treatment with zinc gluconate significantly reduces the concentration of prostaglandin 2Fa in the uterus of rats subjected to precipitous progestin withdrawal, but also as compared to animals receiving continuous progestin treatment.

[0085] Suitable treatment regimes (pharmaceutical preparations) are described in the examples 3 to 5 .

[0086] In principle all fertility control (FC) regimes described in the literature are applicable to the present invention. The most common regimes are regimes with a 28 days cycle, which are known as a 24/4 regimen (24 days active pill oral contraceptive, followed by 4 days of hormone-free interval or placebo pills) or as 21/7 regime (21 days active pill oral contraceptive, followed by 7 days hormone-free interval or placebo pills).

[0087] Thus in the context of the present invention a large number of variations shown in Figure 2/4 and 3/4 are possible in principle. In this connection they can be differentiated as follows

i- concomitant: Addition of 10-30 mg of zinc to the active hormone tablets,

ii- an intermittent: Addition of 10-30 mg of zinc to tablets 25-28 and a

iii- stepwise addition of e.g. x mg of zinc to the active tablets in the midcycle (days 13-18), followed by an enhanced zinc dose of y mg to tablets 19-24, followed by a further enhanced zinc dose of z mg as stand-alone in the hormone-free pills (day 25-28), (whereby, x < y < z , e.g. x = 10-15 mg zinc per day and y = 20-25 mg and z = 25-30 mg zinc per day)

Example 3 [0088] 24 tablets comprising 3mg Drospirenone (DRSP) and 20-30 g Ethinyl Estradiol (EE) followed by four tablets each containing up to 30 mg zinc. The possible variations include:

(For ease, days 25, 26, 27 and 28 and labelled as A , B, C and D, respectively) a) Tablets on days 25, 26, 27 and 28 all have the same zinc dose

Therefore, zinc dose is A = B = C = D = X mg (up to 30 mg)

- tablets 1-24: 3mg DRSP + 20-30 g EE - tablets 25-28: Xmg zinc

b) Tablet on day 25 has the highest zinc dose, tablet on day 26 has less zinc than day 25, tablet on day 27 has less zinc than day 26, and tablet 28 has less zinc than day 27.

Therefore, zinc dose is A > B > C > D tablets 1-24: 3mg DRSP + 20-30 EE tablet 25: A mg Zinc (up to 30 mg) tablet 26: B mg Zinc tablet 27: C mg Zinc tablet 28: D mg Zinc

c) Tablets on days 25 and 26 have equally the highest zinc dose, tablets on days 27 and 28 have equally less zinc.

Therefore, zinc dose is (A = B) > (C = D)

- tablets 1-24: 3mg DRSP + 20-30 g EE - tablet 25: A mg Zinc (up to 30 mg) - tablet 26: B mg Zinc - tablet 27: C mg Zinc - tablet 28: D mg Zinc

Example 4

[0089] 12 tablets comprising 3mg Drospirenone and 20-30 µg Ethinyl Estradiol, followed by six tablets (day 13-18) each containing a dose 10 mg of zinc with 3mg Drospirenone and 20-30 g Ethinyl Estradiol, followed by six tablets each containing a dose 20 mg of zinc with 3mg Drospirenone and 20-30pg Ethinyl Estradiol (day 19-24), followed by four tablets (days 25-28) containing 20-30 mg of zinc.

Example 5

[0090] With a multi-phase regimen as shown in table 3 :

- tablets 1-2: 3 mg Estradiol Valerate (E2V) + Xmg Zinc

- tablets 3-24: varying E2V + Dienogest (DNG) doses

- tablets 25-26: 1 mg Estradiol Valerate (E2V) + Xmg Zinc - tablets 27-28: Ymg Zinc where X < Y and Y is up to 30 mg Table 3

Example 6 Preparation of a tablet from a hormone-containing granules with the addition of an external phase consisting of a zinc salt and additives

[0091] With fluidized bed granulation granules consisting of ethinyl estradiol [as β- Cyclodextrin (CD complex)] and drospirenone are prepared. For this purpose the hormones and other fillers, binders and disintegrants are granulated in a fluidized bed granulator with a binder solution consisting of water and a binder. After completion of the granulation, the granules are mixed with zinc-D- gluconate and other fillers, disintegrants and lubricants. The mixture is then compressed into tablets and subsequently coated. For this purpose a film coating consisting of a film former, a plasticizer with the addition of color pigments is used.

The respective amounts and the used excipients (film formers, plasticizers and color pigments) can be taken from Table 4 .

Example 7 Preparation of a zinc containing hormones tablet by means of fluidized bed granulation

[0092] With fluidized bed granulation granules consisting of Ethinylestradiol (as β- CD complex), drospirenone and a zinc salt are produced. For this purpose, the hormones, the zinc salt, other fillers, binders, and disintegrants are granulated in a fluidized bed granulator with a binder solution consisting of water and a binder. After completion of the granulation disintegrant and lubricant are added as external phase to the granules. The mixture is then compressed into tablets and subsequently coated. For this purpose a film coating, consisting of a film former, a plasticizer with the addition of color pigments is used.

The particular amounts, the selected zinc salt and the used excipients (film formers, plasticizers and color pigments) can be taken from Table 5 .

Table 5 Example 8 Preparation of a tablet from a direct tabletting mixture of hormones, zinc and other additives

[0093] A direct mixture consisting of Ethinylestradiol (as β-CD complex), drospirenone and zinc-orotate is produced. For this purpose, the hormones and the zinc salt with other fillers and dry binders are mixed. Then, disintegrant and lubricant are added as external phase to the mixture. The mixture is then compressed into tablets and subsequently coated. For this purpose, a film coating comprising a film former, a plasticizer and color pigments is used.

The particular amounts, and the used excipients (film formers, plasticizers and color pigments) can be taken from Table 6 .

References

(1) Dawood, M.Y. (1985). Dysmenorrhea. Journal of Reproductive Medicene 30(3): 154-167.

(2) Dawood, M.Y. (1988). Nonsteroidal Anti-inflammatory Drugs and Changing Attitudes Toward Dysmenorrhea. American Journal of Medicine 84(5A):23-29.

(3) Dawood, M.Y. (1990). Dysmenorrhea. Clinical Obstetrics and Gynecology 33(1):168-178.

(4) Dawood, M.Y. (2006). Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstetncs and Gynecology 108(2):428-441 .

(5) Jamieson, D.J. and Steege, J.F. (1996). The Prevalence of Dysmenorrhea,

Dyspareunia, Pelvic Pain, and Irritable Bowel Syndrome in Primary Care Practices. Obstetrics and Gynecology 87(1): 55-8.

(6) Klein, J.R. and Litt, I.F. (1981). Epidemiology of Adolescent Dysmenorrhea. Pediatrics 68(5):661-4.

(7) Koltz MM: Dysmenorrhea, endometriosis and pelvic pain. In: Lemeke DP, Pattison J, Marshall LA, Cowley DS, eds. Primary Care of Women. Norwalk Conn: Appleton & Lange; 1992: 420-32.

(8) Proctor, M . and Farquhar, C. (2006). Diagnosis and Management of Dysmenorrhoea. BMJ 332:1 134-1 138.

(9) Weissman, A.M.; Hartz, A.J..; Hansen, M.D.; Johnson, S.R. (2004). The natural History of Primary Dysmenorrhoea: A Longitudinal Study. BJOG 111:345-352.

(10) Yiikorkala, O. and Dawood, M.Y. New Concepts in Dysmenorrhea. Am J Obstet Gynecol 130:833-47.

( 1 1) Kelly et al., Biol. Reprod. 1983, 28, 883-889

(12) G . S. Goei et al. (J Appl Nutr. 1982; 34: 1-8)

(13) G Eby et al., Med Hypotheses. 2007, 69, 297-301 (14) Institute of Medicine, Food and Nutrition Board (2001). Recommended Dietary Allowances for Zinc for Infants over 7 months, Children, and Adults. Retrieved on August 9 , 2010 from http://ods.od.nih .gov/factsheets/cc/zinc.html#rda

(15) G . Eby et al., Med. Hypotheses 2006, 66, 169-172

(16) Sugino et al., Mol. Hum. Reprod. 2000, 6 , 19-26

(17) Prasad et al., Ann. Intern. Med. 2000, 133, 245-252

(18) Fraser, I.S. (1992). Prostaglandins, Prostaglandin Inhibitors and their Roles in Gynaecological Disorders. Baillieres Clin Obstet Gynaecol 6(4): 829-57.

(19) a) Pickles VR. A plain muscle stimulant in the menstruum. Nature 1957;180:1 198-9.

b) Eglinton G , Rahael RA, Smith GN, Hall WJ, Pickles VR. Isolation and identification of two smooth muscle stimulants from menstrual fluid. Nature 1963:200:960.

(20) Davis et al. 2005, Oral Contraceptives for Dysmenorrhea in Adolescent Girls: A Randomized Trial. OBS & GYN 106(1):97-104

(21) Rosenwaks Z , Seegar-Jones G "Menstrual pain: its origin and pathogenesis". J Reprod Med 25 (4 Suppl): 207-12; Wright, Jason and Solange Wyatt. The Washington Manual Obstetrics and Gynecology Survival Guide. Lippincott Williams and Wilkins, 2003

(22) Uzzo RG, Crispen PL, Golovine K , Makhov P, Horwitz EM, Kolenko V M (2006) Diverse effects of zinc on NF-kB and AP-1 transcription factors: implications for prostate cancer progression. Carcinogenesis 27: 1980-1990

(23) Lethaby A , Augood C, Duckitt K , Farquhar C (2007) "Nonsteroidal anti¬ inflammatory drugs for heavy menstrual bleeding". Cochrane Database Syst Rev (4): CD000400

(24) (Rebsamen et a/.,2004) Endocrinology 145: 3135-3142;

(25) Young M and Funder J (2003) Endocrinology 144: 3848-3851;

(26) Zhang MZ et al. (2002) Am J Physiol 383: F509-F516). What we claim is:

1. Pharmaceutical composition comprising an hormonal agent, a biocompatible zinc salt and pharmaceutical acceptable excipients.

2 . Pharmaceutical composition, wherein the hormonal agent and the biocompatible zinc salt are present in different dosage units.

3 . Pharmaceutical composition according to claim 1 or 2 , wherein the daily amount of zinc is 5-40mg.

4 . Pharmaceutical composition according to claim 2 , wherein the zinc salt containing dosage unit contains 5-40 mg of zinc.

5 . Pharmaceutical composition according to any of the preceding claims, wherein the amount of zinc is between 10 and 40 mg per dosage unit.

6 . Pharmaceutical composition according to any of the preceding claims, wherein the amount of zinc is between 15 and 30 mg per dosage unit.

7 . Pharmaceutical composition according to any of the preceding, wherein the hormonal agent contains an estrogen/progestin hormonal combination.

8 . Pharmaceutical composition according to claim 1-6, wherein the hormonal agent is a progestin.

9 . Pharmaceutical composition according to claim 8 , wherein the estrogen is selected from the group of estradiol valerate, ethinylestradiol, mestranol, quinestranol, estradiol, estrone, estrane, estriol, estetrol and conjugated equine estrogens.

10. Pharmaceutical composition according to any of the preceding claims, wherein the progestin is selected from the group of levonorgestrel, norgestimate, norethisterone, dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3- ketodesogestrel (= etonogestrel), 17-deacetylnorgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, amgestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, fluorogestone acetate, gastrinone, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol (= lynoestrenol), mecirogestone, medroxyprogesterone, megestrol, melengestrol, nomegestrol, norethindrone (= norethisterone), norethynodrel, norgestrel (including d-norgestrel and dl-norgestrel), norgestrienone, normethisterone, progesterone, quingestanol, (17alpha)-17-hydroxy-1 -methylene- 19-norpregna- 4,1 5-dien-20-yn-3-one, tibolone, trimegestone, algestone-acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor- 17hydroxyprogesterone, 17alpha-ethynyltestosterone, 17alpha-ethynyl-19- nortestosterone, d-1 7beta-acetoxy-1 3beta-ethyl-1 7alpha-ethynylgon-4-en-3-one oxime, 6p,7p;15p,16p-dimethylene-3-oxo-17-pregna-4,9(1 1)-diene-21 ,17p- carbolactone ortanaproget .

11. Pharmaceutical composition according to anyone of the preceding claims, wherein the estrogen/progestin hormonal combination is a combination of Drospirenone and Ethinyl Estradiol.

12. Pharmaceutical composition according to claim 10 containing 2-4 mg Drospirenone (DRSP) and 20-30 Ethinyl Estradiol (EE).

13. Pharmaceutical composition according to anyone of the claims 1-12 wherein the biocompatible zinc salt is zinc- acetate, zinc-bis(hydrogen-DL-aspartate), -orotate, -gluconate, -sulphate or -cetrate.

14. Pharmaceutical composition according to anyone of the claim 1-13, wherein zinc is present in an amount of 15-30 mg.

15. A x-phase preparation with separately packaged single dosage units containing an oral contraceptive active hormone as hormonal agent and a zinc salt, wherein the zinc salt and the hormonal agent are present in the same or in different dosage units.

16. A x-phase preparation with separately packaged single dosage units according to claim 15, wherein at least one dosage unit contains an oral contraceptive active hormone and the zinc salt.

17. A x-phase preparation according to claim 15 or 16, containing (a) m pills containing an oral contraceptive active hormone, (b) n pills containing an oral contraceptive active hormone and a biocompatible zinc salt, (c) o pills containing a zinc salt followed by (d) p placebo pills wherein

X is 2 , 3 or 4 , = 1 up to 2 1 n = 2 1 minus m o = 0 up to 7 and p=7 minus o under the proviso that n+m+o+p is 28 and that n+o > 0 .

18. A x-phase preparation according to claim 17, wherein x = 3 p = 0 m+n = 2 1 with m and n ≠ 0

19. A x-phase preparation according to claim 17, wherein

X = 2 n and p = 0

20. A x-phase preparation according to claim 17, wherein x = 2 n = 2 1 and

0 = 7

2 1. A x-phase preparation according to claim 17 , wherein x = 2 n = 2 1 and = 7

22. A x-phase preparation according to claim 15 or 16, containing (a) m pills containing an oral contraceptive active hormone, (b) n pills with an oral contraceptive active hormone and a biocompatible zinc salt, (c) o pills containing a zinc salt followed by (d) p placebo pills wherein x is 2 , 3 or 4 , m = 0 up to 24 n = 24 minus m o = 0 up to 4 and p = 4 minus o under the proviso that n+m+o+p is 28 and that n+o > 0 .

23. A x-phase preparation according to claim 22, wherein x = 3 p = 0 m+n = 24 with m and n ≠ 0

24. A x-phase preparation according to claim 22, wherein X = 2 n and p = 0

25. A x-phase preparation according to claim 22, wherein x = 2 n = 24 and 0 = 4

26. A x-phase preparation according to claim 22, wherein x = 2 n = 24 and p = 4

27. A preparation according to anyone of the claims 15-26, wherein the zinc salt is zinc acetate, zinc-bis(hydrogen-DL-aspartate), -orotate, -gluconate, -sulphate or -cetrate.

28. A preparation according to any of the claims 15-26, wherein the zinc containing dosage unit contains 15-30 mg zinc.

29. A preparation according to any of the claims 15-28, wherein zinc and estrogen are not present in the same dosage unit of the preparation.

30. A preparation according to any of the claims 15-29, wherein the oral contraceptive active hormone is progestin or its derivatives, cyproterone acetate, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone, norethisterone, norethisterone acetate, norgestimate, drospirenone, dienogest, gestodene, 19-nor- 17-hydroxy progesterone esters, 17a-ethinyltestosterone and derivatives thereof, 17a-ethinyl-19-nor-testosterone and derivatives thereof, ethynodiol diacetate, megestrol, dydrogesterone, norethynodrel, chlormadinone acetate, allylestrenol, tibolone, medrogestone, norgestrienone, ethisterone, di- norgestrel or 6β,7β; 5β,16β-dimethylene-3-oxo-1 7-pregna-4,9(1 1)-diene-21 ,17β- carbolactone .

3 1. A preparation according to any of the claims 15-30, wherein the oral contraceptive active hormone is a combination of Drospirenone and an Estrogen.

32. A preparation according to any of the claims 15-31 , wherein the oral contraceptive active hormone is a combination of Levonorgestrel and an Estrogen and wherein the zinc salt is zinc acetate or zinc gluconate.

33. A preparation according to claim 3 1 or 32, wherein the estrogen is selected from the group of estradiol, estradiol ester, estradiol valerate, estradiol hemihydrate or ethinyl estradiol.

34. Use of a biocompatible zinc salt and an estrogen selected from the group of ethinylestradiol, mestranol, quinestranol, estradiol, estradiol valerate, estrone, estrane, estriol, estetrol and conjugated equine estrogens and/or a progestin, for treatment of menstrual disorders.

35. Use according to claim 34 for the treatment of dysmenorrhea and/or menstrual pain.

International application No PCT/EP2011/068596

A . CLASSIFICATION O F SUBJECT MATTER INV. A61K31/00 A61K31/565 A61K31/57 A61K33/30 A61P5/30 A61P5/34 A61P15/0Q A61P15/18 ADD. According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practical, search terms used)

EPO-Internal BIOSIS, EMBASE, WPI Data

C . DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO 2005/091872 A2 (BRI ERRE BARBARA T [US] ) 1 ,2,8, 1 6 October 2 5 (2005-10-06) exampl e 6

EBY ET AL: "Zinc treatment prevents 1-35 dysmenorrhea" , MEDICAL HYPOTHESES, EDEN PRESS, PENRITH, US, vol . 69, no. 2 , 1 January 2007 (2007-01-01) , pages 297-301, XP022096172 , ISSN : 0306-9877, D0I : 10. 1016/J .MEHY.2006. 12.O09 page 298 - page 299 1-35

/ -

Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but "A" document defining the general state of the art which is not cited to understand the principle or theory underlying the considered to be of particular relevance invention "E" earlier document but published on or after the international "X" document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to "L" document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another " document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the "O" document referring to a n oral disclosure, use, exhibition or document is combined with one or more other such docu¬ other means ments, such combination being obvious to a person skilled in the art. "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

13 December 2011 23/12/2011

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Loher, Flori an International application No PCT/EP2011/068596

C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

SUNAR FUSUN ET AL: "The Effect of Low 1-35 Dose Zinc Supplementation t o Serum Estrogen and Progesterone Level s i n Post-menopausal Women" , BIOLOGICAL TRACE ELEMENT RESEARCH , HUMANA PRESS, CLI FTON, NJ , US, vol . 126, no. Suppl . 1, 1 December 2008 (2008-12-01) , pages S11-S14, XP009154730, ISSN : 0163-4984, D0I : 10. 1007/S12011-008-8211-Y page S12

NABRINK M ET AL: "Modern oral 1-35 contraceptives and dysmenorrhea" , CONTRACEPTION , GER0N-X, INC. , LOS ALTOS, CA, US, vol . 42, no. 3 , 1 September 199Q (1990-09-01) , pages 275-283, XP023167453 , ISSN : 0010-7824, D0I : 10. 1016/0010-7824(90)90015-N [retri eved on 1990-09-01] the whole document

W0 03/094956 Al (NOVO NORDISK AS [DK] ) 1 , 13 20 November 2003 (2003-11-20) c l aims 1 , 16; examples 1-7 International application No Information on patent family members PCT/EP2011/068596

Patent document Publication Patent family Publication cited in search report date member(s) date

W0 2005091872 A2 06-10-2005 CA 2554860 Al 06- 10--2005 GB 2426928 A 13- 12--2006 O 2005091872 A2 06- 10--2005

W0 03094956 Al 20-11-2003 AT 496064 T 15- 02--2011 AU 2003236201 Al 11- 11--2003 EP 1506230 Al 16- 02--2005 ES 2360182 T3 01- 06--2011 P 2006511441 A 06-.0 .-2006 US 2004006000 Al 08- 01--2004 US 2005261168 Al 24- 11--2005 O 03094956 Al 20- 11--2003