HRP20020666A2 - Drospirenone for hormone replacement therapy - Google Patents

Description

Područje izuma Field of invention

Prezentirani izum odnosi se na farmaceutsku kompoziciju koja sadržava drospirenon i estrogen, i metodu hormonske nadomjesne terapije aplikacijom drospirenona i estrogena kod žena deficijentnih s estrogenom. The presented invention relates to a pharmaceutical composition containing drospirenone and estrogen, and a method of hormone replacement therapy with the application of drospirenone and estrogen in estrogen-deficient women.

Pozadina izuma Background of the invention

Uspon u životnom očekivanju i posljedično porast broja žena u peri- i post-menopauzi vodi do porasta javne i zdravstvene svijesti o razdoblju klimakterija prelaženja iz reprodukcijske faze žene. Menopauza, zadnja menstruacija, javlja se kod većine žena u globi između 45 i 55 godine. Brojni faktori, uključujući rasu, genetiku, ishranu, nadmorsku visinu, pušenje,, broj poroda, upotrebu hormonalne kontracepcije, dužine menstrualnog ciklusa i dobi početka puberteta su svojstva, koja pravilno ili nepravilno, utječu na dob kada će biti zadnja menstruacija. The rise in life expectancy and the consequent increase in the number of women in peri- and post-menopause leads to an increase in public and health awareness about the climacteric period, the transition from the reproductive phase of a woman. Menopause, the last period, occurs in most women between the ages of 45 and 55. Numerous factors, including race, genetics, diet, altitude, smoking, number of births, use of hormonal contraception, length of menstrual cycle and age of onset of puberty are properties that, properly or improperly, affect the age when the last menstruation will occur.

Tijekom te faze života, endokrina aktivnost žene proći će brojne promjene, koje rezultiraju nepovoljnim štetnim djelovanjem na brojna fizikalna i fiziološka svojstva žene. Hormonska nadomjesna terapija pomaže poboljšati kvalitetu života žene tijekom prirodnog procesa starenja olakšava simptome povezane uz to vrijeme promjena i redukciju vjerojatnosti ili polaku progresiju smetnji i bolesti povezanih s reduciranom hormonskom aktivnosti. During this stage of life, the endocrine activity of a woman will undergo numerous changes, which result in unfavorable harmful effects on numerous physical and physiological properties of a woman. Hormone replacement therapy helps improve a woman's quality of life during the natural aging process by easing the symptoms associated with this time of change and reducing the likelihood or slow progression of disorders and diseases associated with reduced hormonal activity.

Drospirenon je poznat iz DE 26 52 761 u kojem je obznanjena njegova upotreba kao diuretika. Drospirenone is known from DE 26 52 761, which discloses its use as a diuretic.

Gestagenu slična aktivnost i posljedična korist kao kontraceptivnog sredstva u nivou doze 0.5-50 mg je obznanjena u DE 30 22 337. Progestagen-like activity and consequent benefit as a contraceptive agent at the dose level of 0.5-50 mg is disclosed in DE 30 22 337.

Upotreba i uloga progesterona u suprotnim oblicima zamjenske hormonske terapije proučavala je znanstvena zajednica (Lobo R.A., 1992; Sobel N.B., 1994) kao što režim obuhvaća estrogena i progesterona (Corson S. L., 1993; Jones K.P:, 1992). The use and role of progesterone in opposite forms of hormone replacement therapy has been studied by the scientific community (Lobo R.A., 1992; Sobel N.B., 1994) such as the regimen comprising estrogen and progesterone (Corson S.L., 1993; Jones K.P:, 1992).

Upotreba pripravka za nadomjesnu terapiju i uloga progesterona u suprotnim oblicima hormonske nadomjesne terapije i za oralnu kontracepciju sadržava najmanje jedan progesteron i najmanje jedan estrogen gdje doza estrogena varira u skladu s periodičnosti kao što je gubitak krvi je suštinski izbjegnut obznanjeno u PCT/EP94/002997. The use of a composition for replacement therapy and the role of progesterone in opposite forms of hormone replacement therapy and for oral contraception contains at least one progesterone and at least one estrogen where the dose of estrogen varies according to the periodicity such as blood loss is essentially avoided disclosed in PCT/EP94/002997.

Sažetak izuma Summary of the invention

U prvom aspektu izum se odnosi na farmaceutsku kompoziciju koja sadržava kao prvo aktivno sredstvp, estrogen (ili prirodni ili njegov sintetički derivat) u dostatnoj količini za tretiranje bolesti/ smetnji i simptoma povezanih s endogenim deficitom nivoa estrogena u žena, i kao sekundarno aktivno sredstvo 6β, 7β; 15β;16β-dimetilen-3-okso~17α-preg-4-en-21,17-karbolakton (drospirenon) u dostatnoj količini za zaštitu endiometrija od štetnog utjecaja estrogena, zajedno s farmaceutski prihvatljivim pomoćnim sredstvom ili nosačem. In the first aspect, the invention relates to a pharmaceutical composition that contains, as the first active agent, estrogen (or natural or its synthetic derivative) in a sufficient quantity for the treatment of diseases/disorders and symptoms associated with endogenous estrogen deficiency in women, and as a secondary active agent 6β , 7β; 15β;16β-dimethylene-3-oxo~17α-preg-4-ene-21,17-carbolactone (drospirenone) in a sufficient amount to protect the endometrium from the harmful effects of estrogen, together with a pharmaceutically acceptable auxiliary agent or carrier.

Drugi aspekt, izuma se odnosi na farmaceutsku kompoziciju koja sadržava kao prvo aktivno sredstvo estradiol u količini koja odgovara dnevnoj dozi od 1 do 3 mg za tretiranje bolesti, smetnji i simptoma povezanih s endogenim deficitom nivoa estrogena u žena, i kao sekundarno aktivno sredstvo 6β,7β;15β;16β-dimetilen-3-okso-17α-preg-4-en-21,17-karbolakton (drospirenon) u količini koja odgovara dnevnoj dozi od 1 do 3.5 mg za zaštitu endometrija od štetnog djelovanja estrogena, zajedno s farmaceutski prihvatljivim pomoćnim sredstvom i nosačem. Another aspect of the invention relates to a pharmaceutical composition that contains as the first active agent estradiol in an amount corresponding to a daily dose of 1 to 3 mg for the treatment of diseases, disorders and symptoms associated with an endogenous deficit of estrogen levels in women, and as a secondary active agent 6β, 7β;15β;16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dose of 1 to 3.5 mg to protect the endometrium from the harmful effects of estrogen, together with pharmaceutical with an acceptable aid and carrier.

Sljedeći aspekt izuma odnosi se na upotrebu kombinacije estrogena i drospirenona za pripravu madikamenata u kojima je količina estrogena dostatna za tretiranja bolesti, smetnji i simptoma povezanih s deficijencijom endogenog nivoa estrogena a količina drospirenona je dostatna da zaštiti endometrij od štetnog djelovanja estrogena. The next aspect of the invention relates to the use of a combination of estrogen and drospirenone for the preparation of medicaments in which the amount of estrogen is sufficient to treat diseases, disorders and symptoms associated with the deficiency of endogenous estrogen levels, and the amount of drospirenone is sufficient to protect the endometrium from the harmful effects of estrogen.

U daljnjem aspektu/ izum se odnosi na postupak tretiranja bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena obuhvaća aplikaciju estrogena u dostatnoj količini za ublažavanje navedenih simptoma i drospirenon u dostatnoj količini da zaštiti endometrij od štetnog djelovanja estrogena. In a further aspect, the invention relates to the procedure for treating diseases, disorders and symptoms associated with a deficit of endogenous estrogen levels in women, including the application of estrogen in a sufficient amount to alleviate the above-mentioned symptoms and drospirenone in a sufficient amount to protect the endometrium from the harmful effects of estrogen.

Osim toga, izum se odnosi na postupak tretiranja i preveniranja bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena obuhvaća aplikaciju estradiola u količini koja odgovara dnevnoj dozi od 1 do 3 mg, kao l, 2, ili 3 mg, i drospirenon u odgovarajućoj dnevnoj dozi od 1 do 3,5, kao što je 1, 1.5., 2, 2.5, 3, ili 3.5 mg. In addition, the invention relates to the procedure for treating and preventing diseases, disorders and symptoms associated with a deficit of endogenous estrogen levels in women, including the application of estradiol in an amount corresponding to a daily dose of 1 to 3 mg, such as 1, 2, or 3 mg, and drospirenone in an appropriate daily dose of 1 to 3.5, such as 1, 1.5, 2, 2.5, 3, or 3.5 mg.

Detaljni prikaz izuma Detailed description of the invention

U prezentiranom kontekstu, pojam ciklus sam ili kada je povezan s pojmom menstrualni je namijenjen za značenje broja dana između menzesa kod žena. Može biti u granicama od 21-31 dana, uobičajeno 28 dana. In the presented context, the term cycle alone or when connected with the term menstrual is intended to mean the number of days between menses in women. It can be in the range of 21-31 days, usually 28 days.

U prezentiranom kontekstu, pojam menopauza podrazumjeva zadnju prirodnu (jajnicima induciranu) menstruaciju. To je jedinstven slučaj i rezultira disfunkcijom folikula ovarija koja ovisi o godinama. Menopauza rezultira padom produkcije seksualnih hormona estrogena i progesterona u jajnicima. Kada broj folikula padne ispod određenog praga (prag krvarenja), ovariji ne mogu dulje producirati zrele folikule i seksualne hormone. Mogućnost reproduktivne sposobnosti završava menopauzom. In the presented context, the term menopause means the last natural (ovarian-induced) menstruation. It is a unique case and results in age-dependent ovarian follicle dysfunction. Menopause results in a decline in the production of the sex hormones estrogen and progesterone in the ovaries. When the number of follicles falls below a certain threshold (bleeding threshold), the ovaries can no longer produce mature follicles and sex hormones. The possibility of reproductive ability ends with menopause.

Faza peri-menopauze počinje s početkom simptoma klimakterija kada ciklus postaje nepravilan i navršava godinu dana nakon menopauze. Kraj faze peri-menopauze može se identificirati nakon produženog razdoblja bez krvarenja. Post-menopauzalna faza je faza koja počinje menopauzom i nastavlja se do smrti. The peri-menopause phase begins with the onset of climacteric symptoms when the cycle becomes irregular and ends one year after menopause. The end of the peri-menopause phase can be identified after a prolonged period without bleeding. The post-menopausal phase is the phase that begins with menopause and continues until death.

Glavni cilj nadomjesne hormonske terapije je obnoviti nivo steroidnih seksualnih hormona u prirodnoj ili prijevremenoj pre-menopauzi, menopauzi i post-menopauzi žena ili uspostavljanja nivoa kod hipogonadnih žena. The main goal of hormone replacement therapy is to restore the level of steroid sex hormones in natural or premature pre-menopause, menopause and post-menopause women or to restore the level in hypogonadal women.

Monoterapija, također upućuje na nesmetanu terapiju, je tretiranje samo s estrogenima, Egzogeni estrogeni stimuliraju proliferaciju endometrija. U estrogenoj monoterapiji, odsutan je ometani učinak progesterona koji ometa proliferaciju. Faza deskvamacije, tijekom koje se gubi gornji sloj endometrija, ne javlja se a prolifercija endometrija javlja se u više iztegnutoj nego u fazi sve do uključivanja pre-menopauzne faze. Rezultira hiperplazijom, s rizikom pojave karcinoma endometrija. Monotherapy, also referring to uninterrupted therapy, is treatment with only estrogens. Exogenous estrogens stimulate the proliferation of the endometrium. In estrogen monotherapy, the interfering effect of progesterone that interferes with proliferation is absent. The desquamation phase, during which the upper layer of the endometrium is lost, does not occur, and endometrial proliferation occurs in a more extended phase than in the phase up to the inclusion of the pre-menopausal phase. It results in hyperplasia, with the risk of endometrial cancer.

Kombinirana terapija, također upućuje na suprotnu terapiju, tretman gdje je progestagen dodan za zaštitu endometrija od hiperplazije. Combination therapy also refers to the opposite therapy, a treatment where a progestagen is added to protect the endometrium from hyperplasia.

Upotreba prirodnog progesterona u kombiniranoj terapiji je-limitirana slabom bioraspoloživosti prirodnog progesterona, čak i u mikroniziranom obliku. Značajno je, da je utvrđeno da je znatno učinkovitija kombinirana terapija koja obuhvaća upotrebu drospirenona kao progesterona. Drospirenon (DRSP), 17α-spirolakton derivat, je sintetski progesteron koji ima iznenađujuće jednostavan fiziološki profil za progesteron i ima očito bolju bibraspoloživost. To je prvi sintetički progesteron koji ima progesteronu sličan farmakološki profil po tome da ima antiestrogeno, antiandrogeno, i antimineralkortikoidno djelovanje. The use of natural progesterone in combined therapy is limited by the low bioavailability of natural progesterone, even in micronized form. It is significant that it was determined that the combined therapy that includes the use of drospirenone as progesterone is significantly more effective. Drospirenone (DRSP), a 17α-spirolactone derivative, is a synthetic progesterone that has a surprisingly simple physiological profile for progesterone and has apparently better bioavailability. It is the first synthetic progesterone that has a pharmacological profile similar to progesterone in that it has antiestrogenic, antiandrogenic, and antimineralocorticoid effects.

Ostvarenje izuma farmaceutske kompozicije estrogena, ili prirodnog ili njegovog sintetičnog derivata, u dostatnoj količini za liječenje bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena, i kao sekundarno aktivno sredstvo, 6β,7β;15β;16β-dimetilen-3-okso-17α-preg-4-ene-21,17-karbolakton (drospirenon) u dostatnoj količini za zaštitu endometrija od štetnog učinka estrogena, zajedno s farmaceutski prihvatljivim pomoćnim sredstvom ili nosačem. The realization of the invention of a pharmaceutical composition of estrogen, or its natural or synthetic derivative, in sufficient quantity for the treatment of diseases, disorders and symptoms associated with the deficiency of the endogenous level of estrogen in women, and as a secondary active agent, 6β,7β;15β;16β-dimethylene-3- oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone) in an amount sufficient to protect the endometrium from the harmful effects of estrogen, together with a pharmaceutically acceptable adjuvant or carrier.

Posebno od same aktivne supstancije, razmatrano je da se ester ili protvar drospirenona može koristiti u prezentiranoj kompoziciji, npr. oksiiminopregnan karbolakton koji je predstavljen u WO 98/24801. Especially from the active substance itself, it has been considered that an ester or prodrug of drospirenone can be used in the presented composition, for example oxyiminopregnane carbolactone which is presented in WO 98/24801.

Nedostatni nivo estrogena može se javiti iz različitih razloga. Kompozicija može biti takva da je adekvatna za različite nivoe estrogena, bez obzira na uzrok. Slučajevi su anticipirani terapijom, ali ne limitiraju, prirodnu menopauzu, peri-menopauze, post-menopauzu, hipogonadizam, kastraciju ili primarni ovarijalni nedostatak. Insufficient estrogen levels can occur for various reasons. The composition can be such that it is adequate for different levels of estrogen, regardless of the cause. Cases are anticipated by therapy, but not limited to, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian deficiency.

Niski nivo estrogena, bez obzira na uzrok, vodi sveopćem padu kvalitete života žene. Simptomi, bolesti i smetnje u granicama od same nelagodnosti pa sve do prijetnje životu. Kompozicija ove terapije anticipira učinkoviti porasta svih fizioloških i psiholoških znakova deficijencije estrogena. A low level of estrogen, regardless of the cause, leads to a general decrease in the quality of life of a woman. Symptoms, diseases and disorders range from discomfort to life-threatening. The composition of this therapy anticipates the effective increase of all physiological and psychological signs of estrogen deficiency.

Prolazni simptomi, kao što su vazomotorni znakovi i psihološki simptomi su svakako ostvarenje na području terapije. Vasomotorni simptomi obuhvaćaju ali nisu limitirani samo na udare vrućine, napade znojenja kao što je noćno znojenje, i lupanje srca. Psihološki simptomi deficijencije estrogena obuhvaćaju, ali nisu limitirani na, besanicu, smetnje spavanja, slabu memoriju, gubitak pouzdanja, promjene raspoloženja, tjeskobu, gubitak libida, teškoće u koncentraciji, teškoće u donošenju odluka, smanjenje energije i mišljenja, iritabilnost, i napade plaća. Transient symptoms, such as vasomotor signs and psychological symptoms are certainly an achievement in the field of therapy. Vasomotor symptoms include but are not limited to hot flashes, sweating attacks such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency include, but are not limited to, insomnia, sleep disturbances, poor memory, loss of confidence, mood swings, anxiety, loss of libido, difficulty concentrating, difficulty making decisions, decreased energy and thinking, irritability, and seizures.

Tretiranje gore spomenutih simptoma može biti povezano s peri-menopauzalnom fazom ženinog života ili kasnije, ponekad duže nakon menopauze. To je anticipirano tako da je izum primjenjiv na te i druge prolazne simptome tijekom peri-menopauzalne faze, menopauze, ili post-menopauzalne faze. Međutim, gore spomenuti simptomi mogu se razviti kada je slučaj deficijencije hipogonadizam, kastracija ili primarni ovarijalni nedostatak. Treatment of the above-mentioned symptoms may be related to the peri-menopausal phase of a woman's life or later, sometimes longer after menopause. It is anticipated that the invention is applicable to these and other transient symptoms during the peri-menopausal phase, menopause, or post-menopausal phase. However, the above-mentioned symptoms may develop when the case of deficiency is hypogonadism, castration or primary ovarian deficiency.

U sljedećem ostvarenju izuma, terapija se koristi za tretiranje permanentnog učinka deficijencije estrogena. Permanentni učinak obuhvaća fizikalne promjene kao što je atrofija urogenitalnog trakta, atrofija prsa, kardiovaskularne bolesti, promjene u distribuciji kose, gustoći kose, promjene u kondiciji koje i osteoropoza. In another embodiment of the invention, the therapy is used to treat the permanent effect of estrogen deficiency. The permanent effect includes physical changes such as urogenital tract atrophy, chest atrophy, cardiovascular disease, changes in hair distribution, hair density, changes in fitness and osteoporosis.

Urogenitalna atrofija, kondicija udružena s njom kao vaginalna suhoća, porast vaginalnog pH i posljedično promjena flore, ili što dovodi čak do atrofije, kao što je pad vaskularizacije, fragmentacije elastičnih vlakana, fuzije kolagenih vlakana, ili smanjenja volumena stanica su simptomi koji su osobito relevantni za tu terapiju. Urogenital atrophy, conditions associated with it such as vaginal dryness, an increase in vaginal pH and consequently a change in flora, or even leading to atrophy, such as a decrease in vascularization, fragmentation of elastic fibers, fusion of collagen fibers, or a decrease in cell volume are symptoms that are particularly relevant for that therapy.

Osim toga, smatra se da je izum relevantan za druge urogenitalne promjene povezane s deficijencijom estrogena kao što je pad dužine i/ili diametra vagine, pada produkcije mukoze, promjene u populaciji stanica, pad produkcije glikogena, pad rasta laktobacila ili porast rasta streptokoka, stafilokoka, ili kaliformnih bacila. Druge pridružene promjene koje će biti prevenirane izumom su one koje mogu ponoviti vagina sumnjiva oštećenja ili infekcije, kao što su eksudativne smetnje, vaginitis, i dispareunija. Osim toga, infekcije urinarnog trakta i inkontinencija su drugi uobičajeni simptomi povezani s sniženim nivoem estrogena. In addition, the invention is considered to be relevant for other urogenital changes associated with estrogen deficiency, such as a decrease in the length and/or diameter of the vagina, a decrease in mucus production, changes in the cell population, a decrease in glycogen production, a decrease in the growth of lactobacilli or an increase in the growth of streptococci, staphylococci , or calliform bacilli. Other associated changes that will be prevented by the invention are those that can repeat the vagina suspected damage or infection, such as exudative disorders, vaginitis, and dyspareunia. In addition, urinary tract infections and incontinence are other common symptoms associated with low estrogen levels.

Drugo postignuće izuma uključuje prevenciju ili ublažavanje fizičkih promjena povezanih s deficijencijom estrogena, kao što su promjene kože, promjene distribucije kose, gustoće kose, atrofiju prsa, ili osteoporozu. Another achievement of the invention includes the prevention or mitigation of physical changes associated with estrogen deficiency, such as skin changes, changes in hair distribution, hair density, breast atrophy, or osteoporosis.

Prevencija i upravljanje osteoporozom, brojne zabilježene post-menopauzalne osteoporoze, su osobito interesantna ostvarenja. Osim toga, demineralizacija kosti, redukcija mase kosti i gustoće, smanjivanje i pucanje trabekula, i/ili posljedični porast fraktura ili deformacija kosti su čini se osobito relevantni. Profilaktički tretman osteoporoze je zanimljiva terapijska aplikacija izuma. The prevention and management of osteoporosis, numerous recorded post-menopausal osteoporosis, are particularly interesting achievements. In addition, bone demineralization, reduction of bone mass and density, reduction and rupture of trabeculae, and/or the consequent increase in fractures or bone deformation seem to be particularly relevant. Prophylactic treatment of osteoporosis is an interesting therapeutic application of the invention.

Osobito zanimljivo ostvarenje izuma obuhvaća upotrebu kompozicije za smanjivanje frekvencije, perzistencije, trajanja i/ili broja udara vrućine, napada znojenja, udaranja srca, smetnji spavanja, promjena raspoloženja, nervoze, tjeskobe, slabe memorije, gubitka povjerenja, gubitka libida, slabe koncentracije, smanjenja energije, razdražljivosti, atrofije urogenitalnog trakta, atrofije prsa, kardiovaskularnih bolesti, promjena u distribuciji kose, gustoći kose, promjena kondicije kože i osteoporoze, jako značajne udare vrućine, napade znojenja, lupanje srca, smetnje spavanja, gubitak povjerenja, nervoze, depresije, atrofiju urogenitalnog trakta, atrofiju prsa ili prevenciju ili upravljanje osteoporozom. A particularly interesting embodiment of the invention includes the use of a composition to reduce the frequency, persistence, duration and/or number of hot flashes, sweating attacks, palpitations, sleep disturbances, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, reduction energy, irritability, atrophy of the urogenital tract, chest atrophy, cardiovascular diseases, changes in hair distribution, hair density, changes in skin condition and osteoporosis, very significant heatstrokes, sweating attacks, palpitations, sleep disturbances, loss of confidence, nervousness, depression, atrophy urogenital tract, breast atrophy or prevention or management of osteoporosis.

Farmaceutska kompozicija za HRT pokazuje da obuhvaća estrogen. U preferiranom ostvarenju, estrogen je odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, etinil estradiol, estron, estriol, estriol sukcinat i konjugirane estrogene, uključujući konjugirane konjske estrogene kao što su estron sulfate, 17β-estradiol sulfat, I7α-estradiol sulfat, ekvilin sulfat, 17β-dihidroekvilin sulfat, 17α-dihidroekvilin sulfate, ekvilenin sulfat, 17β-dihidroekvilenin sulfat i 17α-dihidroekvilenin sulfat ili njihovu smjesu. Osobito zanimljivi estrogeni odabrani su iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, estron, i estron sulfat ili njihova smjesa, zabilježeni su estradiol, estradiol valerat, estradiol benzoat i estradiol sulfamati. Više preferirani su estradiol ili estradiol sulfamati, osobito estradiol. The pharmaceutical composition for HRT shows that it includes estrogen. In a preferred embodiment, the estrogen is selected from the group consisting of estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate, and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equilin sulfate, 17β-dihydroequilin sulfate, 17α-dihydroequilin sulfate, equilenin sulfate, 17β-dihydroequilin sulfate and 17α-dihydroequilin sulfate or their mixture. Particularly interesting estrogens are selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or their mixture, estradiol, estradiol valerate, estradiol benzoate, and estradiol sulfamates are recorded. More preferred are estradiol or estradiol sulfamates, especially estradiol.

Osobito relevantno mišljenje je da mikronizirani oblici estrogena, kao što je mikronizirani estradiol, mikronizirani estradiol sulfamat, mikronizirani estradiol valerat, mikronizirani estradiol benzoat, mikronizirani estron, ili mikronizirani estron sulfat ili njihova smjesa, zabilježen je mikronizirani estradiol, mikronizirani estradiol valerat, mikronizirani estradiol benzoat ili mikronizirani estradiol sulfamat. Više se preferira mikronizirani estradiol ili mikronizirani estradiol sulfamat, osobito mikronizirani estradiol. A particularly relevant opinion is that micronized forms of estrogen, such as micronized estradiol, micronized estradiol sulfamate, micronized estradiol valerate, micronized estradiol benzoate, micronized estrone, or micronized estrone sulfate or a mixture thereof, have been reported micronized estradiol, micronized estradiol valerate, micronized estradiol benzoate or micronized estradiol sulfamate. More preferred is micronized estradiol or micronized estradiol sulfamate, particularly micronized estradiol.

U određenim postignućima izuma, gdje kompozicija obuhvaća više od jednog estrogena, jedan ili više estrogena može biti u mikroniziranom obliku, tako 2 ili svi estrogeni. In certain embodiments of the invention, where the composition comprises more than one estrogen, one or more estrogens may be in micronized form, thus 2 or all estrogens.

Nadalje, zanimljivo ostvarenje izuma obuhvaća kompoziciju gdje je drospirenon (DRSP) u mikroniziranom obliku, tako da jedan ili oba estrogena i DRSP su u mikroniziranom obliku, preferira se da su oba estrogena i DRSP u mikroniziranom obliku. Furthermore, an interesting embodiment of the invention comprises a composition where drospirenone (DRSP) is in micronized form, so that one or both estrogens and DRSP are in micronized form, preferably both estrogens and DRSP are in micronized form.

Drospirenon, koji može biti pripravljen u suštini kao što je opisano u, tj. US 4,129,564 ili WO 98/06738, je slabo topljiva supstancija u vodi i vodenim puferima na različitim pH vrijednostima. Osim toga, drospirenon je rearanžiran u inaktivni izomer u kiselim uvjetima i hidroliziran u aklaknim uvjetima. Za osiguravanje dobre bioraspoloživosti supstancije, je zato prednostno osiguran u oblik tako da se promovira njihova raspadljivost. Drospirenone, which can be prepared essentially as described in, ie, US 4,129,564 or WO 98/06738, is a poorly soluble substance in water and aqueous buffers at various pH values. In addition, drospirenone is rearranged into an inactive isomer under acidic conditions and hydrolyzed under alkaline conditions. To ensure good bioavailability of the substance, it is therefore preferably provided in a form that promotes their degradability.

Utvrđeno je da kada je drospirenon osiguran u mikroniziranom obliku u farmaceutskim kompozicijama, javlja se in vitro brza raspadljivost aktivne supstancije iz kompozicije. Mikronizirana supstancija je kao što je testirana serija (cca. 200 mg) čestica, ovdje čestice drospirenona, imaju površinu veću od 10,000 cm2/g, i imaju slijedeću distribuciju veličine čestica drospirenona koja je mikroskopski determinirana: ne više od 2 Čestice serije (cea, 200 mg) dijametar ne veći od 30 μm, preferira se ≤ 20 čestica s dijametrom ≥ 10 μm i ≤ 30 μm. Pojam "brzo otpuštanje" je definiran kao otpuštanje od najmanje 70% iznad oko 30 minuta, osobito najmanje 80% iznad oko 20 minuta, drospirenona iz tablete koja sadržava 3 mg drospirenona u 900 ml vode na 37 °C određeno po USP XXIII Paddle Method upotrebom USP test aparata 2 za disoluciju na 50 rpm. It has been established that when drospirenone is provided in micronized form in pharmaceutical compositions, rapid disintegration of the active substance from the composition occurs in vitro. The micronized substance is as tested a series (approx. 200 mg) of particles, here particles of drospirenone, have a surface area greater than 10,000 cm2/g, and have the following size distribution of drospirenone particles that was determined microscopically: no more than 2 Particles of the series (cea, 200 mg) diameter not greater than 30 μm, preferably ≤ 20 particles with a diameter ≥ 10 μm and ≤ 30 μm. The term "immediate release" is defined as a release of at least 70% over about 30 minutes, especially at least 80% over about 20 minutes, of drospirenone from a tablet containing 3 mg of drospirenone in 900 ml of water at 37 °C as determined by the USP XXIII Paddle Method using USP test apparatus 2 for dissolution at 50 rpm.

Kao alternativa da se osigura drospirenon u mikroniziranom obliku, moguće je otopiti u odgovarajućem otapalu, npr. metanol ili etil acetat, i raspršiti ga po površini inertnog nosača čestica čemu slijedi inkorporacija čestica koje sadržavaju drospirenon na njezinu površinu u kompoziciji. As an alternative to provide drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, eg methanol or ethyl acetate, and spray it on the surface of an inert particle carrier followed by the incorporation of particles containing drospirenone on its surface in the composition.

Bez želje da se ograniči posebno bilo koja teorija, javlja se to da in vitro količina otpuštenog drospirenona je povezana na otpuštenu količinu in vivo rezultira brzom absorpcijom drospirenona in vivo nakon oralne aplikacije supstancije. To je jedna od prednosti jer izomerizacija supstancije u probavnom traktu i/ili hidroliza u crijevu u suštini je reducirana, dovodi do dobre bioraspoloživosti supstancije. Without wishing to be bound by any particular theory, it appears that the in vitro amount of drospirenone released is related to the in vivo amount released resulting in rapid absorption of drospirenone in vivo following oral administration of the substance. This is one of the advantages because isomerization of the substance in the digestive tract and/or hydrolysis in the intestine is essentially reduced, leading to good bioavailability of the substance.

U odnosu na estrogen koji može biti slabo topljiva supstancija, iako je uobičajeno manje osjetljiva na degradaciju od drospirenona u uvjetima koji prevladavaju u probavnom traktu, to je isto jedna prednost koja je osigurana mikroniziranim oblikom ili raspršenom otopinom, npr. u etanolu, na površinu inertnog nosača čestica. To ima dodatnu olakšavajuću prednost jer je homogenija distribucija estrogena s kompozicijom. Kada je estrogen osiguran u mikroniziranom obliku, preferira se da ima sljedeću distribuciju veličine čestica koja se mikroskopski određuje: 100% čestica ima dijametar od ≤ 15.0 μm, 99% čestica ima promjer od ≤ 12.5 μm, 95% čestica ima promjer od ≤ 10.0 μm, a 50% čestica ima promjer od ≤ 3.0 μm. Osim toga, nema čestica Većih od 20 μm, i ≤ 10 čestica imaju promjer od ≥ 15 μum i ≤ 20 μm. In relation to estrogen, which can be a poorly soluble substance, although it is usually less susceptible to degradation than drospirenone under the conditions prevailing in the digestive tract, this is also one advantage that is provided by the micronized form or sprayed solution, for example in ethanol, on the surface of an inert particle carriers. This has the added benefit of facilitating a more homogenous distribution of estrogen with the composition. When the estrogen is provided in micronized form, it preferably has the following particle size distribution as determined microscopically: 100% of the particles have a diameter of ≤ 15.0 μm, 99% of the particles have a diameter of ≤ 12.5 μm, 95% of the particles have a diameter of ≤ 10.0 μm , and 50% of the particles have a diameter of ≤ 3.0 μm. In addition, there are no particles larger than 20 μm, and ≤ 10 particles have a diameter of ≥ 15 μm and ≤ 20 μm.

Distribucija veličine čestica estradiol hemihidrata preferira se tako da 100% čestica i datoj seriji ima promjer manji od 15.0 μm, 99% ima promjer manji od 12.5 μm, 95% ima promjer manji od 10.0 μm, 50% ima promjer manji od 3.0 μm, ili 40% ima promjer manji od 1.1 μm. The particle size distribution of estradiol hemihydrate is preferred such that 100% of the particles in a given batch have a diameter of less than 15.0 μm, 99% have a diameter of less than 12.5 μm, 95% have a diameter of less than 10.0 μm, 50% have a diameter of less than 3.0 μm, or 40% have a diameter smaller than 1.1 μm.

Za dobivanje još većeg stupnja otpuštanja, preferira se uključivanje nosača ili pomoćnog sredstva, koji dovode do povećanja otpuštanja objih aktivnih supstancija. Primjeri takvih nosača i pomoćnih sredstava uključuju supstancije koje su lako topljive u vodi kao što su derivati celuloze, karboksimetil celuloza, hidroksipropil celuloza, hidroksipropil metil celuloza, gelled škrob, želatina ili polivinil pirolidon. Napose, anticipirano je mišljenje da polivinilpirolidon može pomoći boljem otpuštanju. To obtain an even higher degree of release, it is preferred to include a carrier or auxiliary agent, which lead to an increase in the release of both active substances. Examples of such carriers and auxiliaries include substances that are easily soluble in water such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelled starch, gelatin or polyvinyl pyrrolidone. In particular, it is anticipated that polyvinylpyrrolidone can help with better release.

Preferira se takva doza drospirenona u svakoj kompoziciji koja će zaštititi endometrij od štetnog djelovanja estrogena. DRSP, u dostatnoj dozi, može se koristiti kao oponent estrogenu za zaštitu endometrija od hiperplazije ili karcinoma. Such a dose of drospirenone in any composition that will protect the endometrium from the harmful effects of estrogen is preferred. DRSP, in a sufficient dose, can be used as an estrogen antagonist to protect the endometrium from hyperplasia or cancer.

U nekim slučajevima, međutim, doza DRSP može biti dostatna tako da stabilizira menstrualni ciklus i krvarenje. U takvim slučajevima, doze etrogena mogu biti niske ili nula. Produkcija adipoznog tkiva estroxgenom može biti takva da se ne zahtjevaju ili zahtjevaju male doze estrogena za stabiliziranje menstrualnog ciklusa i krvarenja. Osim toga, u određenom postignuću, gdje žene pate od smetnji koje nisu kompatibilne s upotrebom vanjskih izvora estrogena (kao što su apsolutne kontraindikacije za brojne bolesti jetre i trudnoću ili za relativne kontraindikacije karcinoma endometrija i entlometrioze, mamarni karcinom, tromboembolija vena, hipertenzija, dijabetes melitus, otoskleroza i melanom) u kompoziciji može biti ništa ili vrlo niski nivo estrogena. U takvom postignuću, doza DRSP može takva da se ublaže smetnje, bolesti ili simptomi. In some cases, however, the dose of DRSP may be sufficient to stabilize the menstrual cycle and bleeding. In such cases, estrogen doses may be low or zero. The production of adipose tissue by the estrogen gene can be such that no or small doses of estrogen are required to stabilize the menstrual cycle and bleeding. In addition, in a certain achievement, where women suffer from disorders that are not compatible with the use of external sources of estrogen (such as absolute contraindications for numerous liver diseases and pregnancy or for relative contraindications of endometrial cancer and entlomometriosis, breast cancer, venous thromboembolism, hypertension, diabetes mellitus, otosclerosis and melanoma) in the composition may be none or a very low level of estrogen. In such an achievement, the dosage of DRSP may be such that the disorders, diseases or symptoms are alleviated.

U preferiranom postignuću, doza DRSP korespondira s 15 do 70 mg po ciklusu, odnosno 20 do 60 mg po ciklusu, osobito 40 do 60 mg po ciklusu. Dužina ciklusa, određena kao supra može varirati od 21 do 31 dan. Gledano na drugi način, kompozicija može sadržavati količinu DRSP koja odgovara dnevnoj dozi u granicama od 0.25 do 10, kao što je oko 0.25 do 8, 0.25 do 6, 0.25 do 5, 0.5 do 4.5, l do 4, i 1.5 do 3.5 mg. In a preferred embodiment, the dose of DRSP corresponds to 15 to 70 mg per cycle, or 20 to 60 mg per cycle, especially 40 to 60 mg per cycle. The length of the cycle, determined as above, can vary from 21 to 31 days. Viewed another way, the composition may contain an amount of DRSP corresponding to a daily dose in the range of 0.25 to 10, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg. .

Doza estrogena može varirati od žene do žene, ovisno o fazi njezinog života (perimenopauza ili post-menopauza), endogenom nivou estrogena, brojnosti simptoma, smetnjama ili bolesti, smetnjama, bolesti ili ciljanim simptomima, upotrebi drugih medikamenata u druge svrhe, i drugih farmakokinetičkih varijabli. The dose of estrogen may vary from woman to woman, depending on the phase of her life (perimenopause or post-menopause), endogenous estrogen levels, number of symptoms, disorders or diseases, disorders, diseases or targeted symptoms, use of other medications for other purposes, and other pharmacokinetic variables.

U drugim postignućima, doza estrogena i/ili DRSP je dostatna za tretiranje udara vrućine, napada znojenja, lupanja srca, smetnji spavanja, promjena raspoloženja, nervoze, tjeskobe, lošeg pamćenja, gubitka samopouzdanja, gubitka libida, slabe koncentracije, gubitka energije, gubitka snage, razdražljivosti, atrofije urogenitalnog trakta, atrofije prsa, kardiovaskularnih bolesti, promjena u distribuciji kose, promjena u kondiciji kože ili za prevenciju ili upravljanje osteoporozom. In other achievements, the dose of estrogen and/or DRSP is sufficient to treat hot flashes, sweating attacks, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, poor concentration, loss of energy, loss of strength , irritability, atrophy of the urogenital tract, atrophy of the chest, cardiovascular diseases, changes in hair distribution, changes in skin condition or for the prevention or management of osteoporosis.

Doza estrogena i/ili DRSP može ovisiti o tretmanu, koji može biti zaštita endometrija od krvarenja, prevencija ili upravljanje osteoporozom, tretiranje simptoma menopauze, kao što je redukcija broja, frekvencija, težine udara vrućine, noćnog znojenja, lupanje srca na mahove, besanica i druge smetnje spavanja, promjena raspoloženja, nervoza, tjeskoba, slabe memorije, gubitka samopouzdanja, gubitka libida, slaba koncentracija, gubitka energije, gubitka snage i razdražljivost. The dose of estrogen and/or DRSP may depend on the treatment, which may be to protect the endometrium from bleeding, prevent or manage osteoporosis, treat menopausal symptoms, such as reducing the number, frequency, severity of hot flashes, night sweats, palpitations, insomnia and other sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, poor concentration, loss of energy, loss of strength and irritability.

U postignuću gdje je estrogen estradiol, količina estradiola odgovara dnevnoj dozi u granici od 0.1 do 5 mg, kao što je oko 0.2 do 4.5, 0.5 do 4, 1 do 3, i napose 1, 2, ili 3 mg. In an embodiment where the estrogen is estradiol, the amount of estradiol corresponds to a daily dose in the range of 0.1 to 5 mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, and especially 1, 2, or 3 mg.

S obzirom na doze derivata estradiola s većom aktivnosti, npr. estardiol valerat, usporedna doza može se kalkulirati podešavanjem gore navedenog doziranja u skladu s aktivnosti. With regard to doses of estradiol derivatives with higher activity, eg estardiol valerate, a comparative dose can be calculated by adjusting the above dosage according to activity.

U postignuću kad je žena u peri-menupauzi doza estrogena i/ili DRSP može ovisiti 6 danu ciklusa, odnosno, kada je ona u preovulacijskoj ili postovulcijskoj fazi ciklusa, i kakva je prednost unutar svake faze. U ostvarenju gdje je žena u post-menopauzi ili čak pre-menopauzi, doza estrogena i/ili DRSP može ovisiti o vremenu koje je prošlo od zadnje menstruacije. In achieving when a woman is in peri-menopause, the dose of estrogen and/or DRSP may depend on day 6 of the cycle, that is, when she is in the preovulatory or postovulatory phase of the cycle, and what is the advantage within each phase. In an embodiment where the woman is post-menopausal or even pre-menopausal, the dose of estrogen and/or DRSP may depend on the time since the last menstrual period.

U određenom ostvarenju izuma, medikament se aplicira u obliku brojnih odvojenih pakiranja i jedinica doza koje se pojedinačno mogu odstraniti smještenih u jedinicu pakiranja i namjenjene su za oralnu aplikaciju za razdoblje od najmanje 21 dan, već najmanje 28 dana, već najmanje 30 do 31 dan. U takvom ostvarenju, doza DRSP i/ili estrogena može biti jednaka unutar svake jedinice doze ili može varirati. Postignuću gdje je količina DRSP i/ili estrogena u jedinici doze varira u skladu s fazom ili danom perioda od najmanje 21 dan, već najmanje 28 dana tako da navedena jedinica doze će biti aplicirana, kao kompozicija, metoda tretmana a pripravak se naziva multi-fazni. In a certain embodiment of the invention, the medication is applied in the form of numerous separate packages and dose units that can be individually removed placed in the package unit and are intended for oral application for a period of at least 21 days, at least 28 days, at least 30 to 31 days. In such an embodiment, the dose of DRSP and/or estrogen may be the same within each dosage unit or may vary. The achievement where the amount of DRSP and/or estrogen in the dose unit varies according to the phase or day of the period of at least 21 days, but at least 28 days so that the specified dose unit will be applied, as a composition, treatment method and the preparation is called multi-phase .

Doza proporcionalno može varirati u skladu s njezinom upotrebom. Preferirano postignuće doze proporcionalno estrogen i drospirenon za pripravljanje medikamenta je takvo da su doze estrogena za tretiranje bolesti, smetnji i simptoma povezanih s deficijencijom nivoa estrogena i količina drospirenona dostatna za zaštitu endometrija od štetnog djelovanja estrogena. The dose may vary proportionally according to its use. The preferred achievement of the proportional dose of estrogen and drospirenone for the preparation of the medication is such that the doses of estrogen for treating diseases, disorders and symptoms associated with the deficiency of estrogen levels and the amount of drospirenone are sufficient to protect the endometrium from the harmful effects of estrogen.

U preferiranom postignuću, proporcionalnost doza je dostatna za tretiranje udara vrućine, napada znojenja, lupanja srca, smetnji spavanja, promjena raspoloženja, potištenosti, tjeskobe, slabog pamćenja, gubitka samopouzdanja, gubitka libida, slabe koncentracije, smanjenja energije, smanjenja snage, razdražljivosti, atrofije urogenitalnog trakta, atrofije prsa, kardiovaskularnih bolesti, promjena U distribuciji kose, debljini kose, promjene kondicije kože ili za prevenciju ili upravljanje osteoporozom. In a preferred embodiment, the dose proportionality is sufficient to treat hot flashes, sweating attacks, palpitations, sleep disturbances, mood swings, depression, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, decreased energy, decreased strength, irritability, atrophy urogenital tract, chest atrophy, cardiovascular disease, changes in hair distribution, hair thickness, changes in skin condition or for the prevention or management of osteoporosis.

Izum se odnosi na postupak tretiranja bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena koji obuhvaća aplikaciju estrogena u dostatnoj količini za ublažavanje navedenih simptoma i drospirenona u dostatnoj količini da se zaštiti endometrij od štetnog djelovanja estrogena. Preferira se, primjena metode kada je nedostatni nivo estrogena uzrokovan prirodnom menopauzom, peri-menopauzom, post-menopauzom, hipogonidizmom, kastracijom ili primarnim ovarijalnom nedostatkom. The invention relates to a procedure for treating diseases, disorders and symptoms associated with a deficit of endogenous estrogen levels in women, which includes the application of estrogen in a sufficient amount to relieve said symptoms and drospirenone in a sufficient amount to protect the endometrium from the harmful effects of estrogen. It is preferred to use the method when the insufficient level of estrogen is caused by natural menopause, peri-menopause, post-menopause, hypogonidism, castration or primary ovarian deficiency.

Bolesti, smetnje i simptomi za koje se primjenjuje metoda obuhvaćaju udare vrućine, napadaje znojenja, lupanje srca, smetnje spavanja, promjene raspoloženja, potištenost, tjeskobu, slabo pamćenje, gubitak samopouzdanja, gubitak libida, slabu koncentraciju, smanjenje energije, smanjenje snage, razdražljivost, atrofiju urogenitalnog trakta, atrofiju prsa, kardiovaskularne bolesti, promjene u distribuciji kose, debljini kose, promjene kondicije kože ili prevenciju ili upravljanje osteoporozom. Diseases, disorders and symptoms for which the method is applied include hot flashes, sweating, palpitations, sleep disturbances, mood swings, depression, anxiety, poor memory, loss of self-confidence, loss of libido, poor concentration, decreased energy, decreased strength, irritability, urogenital tract atrophy, chest atrophy, cardiovascular disease, changes in hair distribution, hair thickness, changes in skin condition or prevention or management of osteoporosis.

Primjenjeni postupak za aplikaciju estrogena, preferira estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, ethinil estradiol, estron, estriol, estriol sukcinat i konjugirane estrogene, uključujući konjugirane estrogene ekvida kao što je estron sulfat, 17β-estradiol sulfat, 17α-estradiol sulfat, ekvilin sulfat, 17β-dihidroekvilin sulfat, 17α-dihidroekvilin sulfat, ekvilenin sulfat, 17β-dihidroekvilenin sulfat i 17α-dihidroekvilenin sulfat ili njihova smjesa, većina estradiola, estradiol sulfamati, estradiol valerat, estradiol benzoat, estron, i estron sulfat ili njihova smjesa, osobito estradiol. The applied method for the application of estrogens, preferably estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate , equilin sulfate, 17β-dihydroequilin sulfate, 17α-dihydroequilin sulfate, equilenin sulfate, 17β-dihydroequilin sulfate and 17α-dihydroequilin sulfate or a mixture thereof, most estradiols, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or a mixture thereof , especially estradiol.

Osobito atraktivno postignuće izuma obuhvaća aplikaciju drospirenona (DRSP) i/ili estrogena u mikroniziranom obliku. Osim toga, osobito zanimljivo je kada je estrogen estradiol u mikroniziranom obliku. U takvom postignuću, jedna ili obje aktivne supstancije se apliciraju u mikroniziranom obliku. A particularly attractive achievement of the invention comprises the application of drospirenone (DRSP) and/or estrogen in micronized form. In addition, it is particularly interesting when the estrogen is estradiol in micronized form. In such an achievement, one or both active substances are applied in micronized form.

U određenim ostvarenjima, postupak obuhvaća aplikaciju doze DRSP koja odgovara 15 do 70 mg po ciklusu, kao što je 20 do 60 mg po ciklusu, osobito 40 do 60 mg po ciklusu. Postupak preferirano obuhvaća aplikaciju doze DRSP u količini DRSP koja odgovara dnevnoj dozi u granici od 0.25 do 10 mg, kao što je 0.25 do 8, 0.25 do 6, 0.25 do 5, o.5 do 4.5, 1 do 4, ili 1.5 do 3.5 mg. In certain embodiments, the method comprises administration of a dose of DRSP corresponding to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The method preferably comprises administering a dose of DRSP in an amount of DRSP corresponding to a daily dose in the range of 0.25 to 10 mg, such as 0.25 to 8, 0.25 to 6, 0.25 to 5, o.5 to 4.5, 1 to 4, or 1.5 to 3.5 mg.

Aplicirana količina estradiola može odgovarati dnevnoj dozi u granici od 0.1 do 5 mg, kao što je oko 0.2 do 4.5, 0.5 do 4, 1 do 3, napose 1, 2 ili 3 mg. The applied amount of estradiol can correspond to a daily dose in the range of 0.1 to 5 mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, especially 1, 2 or 3 mg.

Osobito postignuće koje se odnosi na farmaceutsku kompoziciju obuhvaća, kao prvo aktivno sredstvo, estradiol u količini koja odgovara dnevnoj dozi od 1 do 3 mg za tretiranje bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena i kao drugo aktivno sredstvo 6β,7β;15β;16-dimetilen-3-okso-17α-preg-4-ene-21,17-karbolakton (drospirenon) u količini koja odgovara dnevnoj dozi od 1 do 3.5 mg dostatne količine za zaštitu endometrija od štetnog djelovanja estrogena zajedno s farmaceutski prihvatljivim pomoćnom tvari i nosačem. A particular achievement related to the pharmaceutical composition includes, as the first active agent, estradiol in an amount corresponding to a daily dose of 1 to 3 mg for the treatment of diseases, disorders and symptoms associated with a deficit of the endogenous level of estrogen in women, and as the second active agent 6β,7β ;15β;16-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dose of 1 to 3.5 mg, a sufficient amount to protect the endometrium from the harmful effects of estrogen together with pharmaceutical acceptable excipient and carrier.

Određena preferirana kombinacija s obzirom na aktivne supstancije u kompoziciji, gdje je estradiol estroge obuhvaća 1 mg ,estradiola s 0.5 mg DRSP, 1 mg estradiola mg DRSP, l mg estradiola s 1.5 mg DRSP, 1 mg estradiola s 2 mg DRSP, 1 mg estradiola s 2.5 md DRSP, 1 mg estradiola s 3 mg DRSP, 2 mg estradiola s 1 mg DRSP i 2 mg estradiola s 4 mg DRSP. A certain preferred combination with regard to the active substances in the composition, where estradiol is estrogen includes 1 mg estradiol with 0.5 mg DRSP, 1 mg estradiol mg DRSP, 1 mg estradiol with 1.5 mg DRSP, 1 mg estradiol with 2 mg DRSP, 1 mg estradiol with 2.5 md DRSP, 1 mg estradiol with 3 mg DRSP, 2 mg estradiol with 1 mg DRSP and 2 mg estradiol with 4 mg DRSP.

U preferiranom postignuću, preferirano postignuće izuma odnosi se na farmaceutsku kompoziciju koja obuhvaća najprije aktivno sredstvo estradiol u količini koja odgovara dnevnoj dozi 1 do 3 mg, kao što je 1, 1.5, 2, 2.5, ili 3 mg estradiola, i kao drugo aktivno sredstvo 6β,7β;15β;16β-dimetilen-3-okso-17α-preg-4-ene-21,17-karbolakton (drospirenon) u količini koja odgovara dnevnoj dozi od 1 do 3.5 mg, kao što je 1, 1.5, 2, 2.5, 3, ili 3.5 mg DRSP, zajedno s farmaceutski prihvatljivom pomoćnom tvari ili nosačem. In a preferred embodiment, the preferred embodiment of the invention relates to a pharmaceutical composition comprising firstly the active agent estradiol in an amount corresponding to a daily dose of 1 to 3 mg, such as 1, 1.5, 2, 2.5, or 3 mg of estradiol, and as a second active agent 6β,7β;15β;16β-dimethylene-3-oxo-17α-preg-4-ene-21,17-carbolactone (drospirenone) in an amount corresponding to a daily dose of 1 to 3.5 mg, such as 1, 1.5, 2 , 2.5, 3, or 3.5 mg of DRSP, together with a pharmaceutically acceptable excipient or carrier.

U skladu, s preferiranim postignućem izuma koje se odnosi na postupak tretiranja i prevencije bolesti, smetnji i simptoma povezanih s deficitom endogenog nivoa estrogena u žena obuhvaća estradiol u količini koja odgovara dnevnoj dozi od 1 do 3 mg, kao što je 1, 2 ili 3 mg, i drospirenona u količini koja odgovara dnevnoj dozi od 1 do 3.5 mg, kao što je 1, 1.5, 2, 2.5, 3 ili 3.5 mg. In accordance with the preferred achievement of the invention, which relates to the method of treating and preventing diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, comprises estradiol in an amount corresponding to a daily dose of 1 to 3 mg, such as 1, 2 or 3 mg, and drospirenone in an amount corresponding to a daily dose of 1 to 3.5 mg, such as 1, 1.5, 2, 2.5, 3 or 3.5 mg.

Poznati deficit endogenog nivoa estrogena može biti udružen s, drugim uvjetima, prirodnom menopauzom, peri-menopauzom, post-menopauzom, hipogonadizmom, kastracijom ili primarnim nedostatkom jajnika, metoda tretiranja i prevencije udružena s bolestima, smetnjama i simptomima može postojati sve do smrti osobe. Tako se može reci da se kompozicija može aplicirati od dijagnoze do smrti, smetnji ili simptoma za cjelokupni život osobe. U određenom postignuću, postupak i kompozicija mogu se bazirati na ritmu menstrualnog ciklusa. Zato postignuće, postupak- može potpuno zanemariti prirodni ciklus. A known deficit of the endogenous level of estrogen can be associated with, among other conditions, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian deficiency, a method of treatment and prevention associated with diseases, disorders and symptoms may exist until the person's death. So it can be said that the composition can be applied from diagnosis to death, disorders or symptoms for the entire life of a person. In a particular embodiment, the process and composition can be based on the rhythm of the menstrual cycle. That's why the achievement, the procedure - can completely ignore the natural cycle.

Preferira se multi-fazni postupak. Postupak može obuhvaćati aplikaciju 10 do 12 dana dnevne jedinice doze koja sadržava estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg; osim toga aplikacija 10 do 12 dana dnevnih jedinica doze obuhvaća estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi od 0.25 do 6 mg; i povrh toga aplikaciju 4 do 8 dana dnevne jedinice doze koja obuhvaća estradiol u količini koja odgovara dnevnoj dozi u granici od 0.25 do 5 mg. A multi-phase process is preferred. The procedure may include the application for 10 to 12 days of a daily dose unit containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg; in addition, the application for 10 to 12 days of daily dose units includes estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose of 0.25 to 6 mg; and on top of that the application for 4 to 8 days of a daily dose unit that includes estradiol in an amount corresponding to a daily dose in the range of 0.25 to 5 mg.

Isto tako, multi-fazni postupak može obuhvaćati aplikaciju 10 do 12 dana dnevnih jedinica doze koje obuhvaćaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg, i osim toga aplikaciju 10 do 12 dana dnevne jedinice doze koje obuhvaćaju estradiol u količini koja odgovara dnevnoj jedinici doze u granici od 0.25 do 6 mg; i osim toga aplikaciju 4 do 8 dana dnevne jedinice doze koje sadržavaju placebo ili su prazne. Likewise, the multi-phase procedure may comprise the application for 10 to 12 days of daily dosage units comprising estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg, and in addition the application for 10 to 12 days of daily dosage units comprising estradiol in an amount which corresponds to a daily dose unit in the range of 0.25 to 6 mg; and in addition application for 4 to 8 days of daily dose units containing placebo or empty.

Režim postupka može obuhvaćati aplikaciju najmanje 21 dan dnevne jedinice doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg; i osim toga aplikaciju ne više od 7 dana dnevne jedinice doze koja sadržava placebo ili su prazne. Jednaki režim postupka može obuhvaćati aplikaciju najmanje 21 dana dnevne jedinice doze koje sadržavaju estradiol u količini koja odgovara dnevnoj jedinici doze u granici od 0.1 do 5 mg i drospirenona u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg; i još aplikaciju ne više od 7 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg. The procedure regimen may include the application of at least 21 days of daily dose units containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; and in addition, the application of no more than 7 days of daily dose units containing placebo or are empty. The same regimen of the procedure can include the application of at least 21 days of daily dose units containing estradiol in an amount corresponding to a daily dose unit in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; and another application for no more than 7 days of daily dose units containing estradiol in the amount corresponding to the daily dose in the range of 0.1 to 5 mg.

Alternativno, režim postupka može obuhvaćati barem 21 dan dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg; i ne više od 7 dana bez aplikacije dnevne jedinice doze. Alternatively, the procedure regimen may comprise at least 21 days of daily dose units containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; and no more than 7 days without applying a daily dose unit.

Alternativno ostvarenje postupka obuhvaća aplikaciju 21 do 28 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg. An alternative implementation of the procedure includes the application of 21 to 28 days of daily dose units containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg.

Režim može sadržavati kontinuiranu aplikaciju; tako da se kaže kroz 21 do 28 dana, dnevna doza estrogena se aplicira. Slično, dnevna doza drospirenona može se aplicirati, kao i jedan ili oba estrogena i DRSP jesu aplicirani kontinuirano. A regimen may include continuous application; so to say through 21 to 28 days, the daily dose of estrogen is applied. Similarly, a daily dose of drospirenone can be administered, as well as one or both estrogens and DRSP administered continuously.

U drugom postignuću, estrogen je apliciran kontinuirano a drospirenon je apliciran sekvencijalno. U tom ostvarenju, tijekom kontinuirane aplikacije estrogena, DKSP je apliciran u pravilnim intervalima, od 1 do 20 dana, kao što je od 3 do 15 dana, 5 do 14 dana, osobito 6 do 14 dana. U slijedećem zanimljivom ostvarenju režima postupka, doziranje estrogena je manje od 1 do 7 dana neposredno iza navedene uzastopne aplikacije drospirenona. In another achievement, estrogen was administered continuously and drospirenone was administered sequentially. In this embodiment, during the continuous application of estrogen, DKSP is applied at regular intervals, from 1 to 20 days, such as from 3 to 15 days, 5 to 14 days, especially 6 to 14 days. In the next interesting embodiment of the regimen of the procedure, the dosage of estrogen is less than 1 to 7 days immediately after the said consecutive application of drospirenone.

Osim toga, u postignuću izuma, postupak tretiranja i preveniranja bolesti, smetnji i simptoma povezanih s deficijencijom endogenog nivoa estrogena u žena obuhvaća kontinuiranu aplikaciju estrogena i prekide aplikacijom progestina. Specifičnim postupkom estrogen može biti apliciran kontinuirano 21 do 30 dana a drospirenon može se aplicirati u 3-dana-da-3-dana-ne ciklusu. Osobito atraktivno postignuće unutar te alternativne aplikacije drospirenona od 4 do 6 dana, 10 do 12, 16 do 18, 22 do 24, i 28 do 30, dok estrogen, kao što je estradiol aplicira kontinuirano. In addition, in the achievement of the invention, the procedure for treating and preventing diseases, disorders and symptoms associated with the deficiency of endogenous estrogen level in women includes continuous application of estrogen and interruptions with the application of progestin. With a specific procedure, estrogen can be applied continuously for 21 to 30 days, and drospirenone can be applied in a 3-day-on-3-day-off cycle. A particularly attractive achievement within that alternative application of drospirenone from 4 to 6 days, 10 to 12, 16 to 18, 22 to 24, and 28 to 30, while estrogen, such as estradiol is applied continuously.

Kompozicija jedinica doziranja može biti formulirana na bilo koji način uobičajen u farmaceutici. Osobito, kao što je indicirano gore, kompozicija može biti formulirana postupkom koji obuhvaća osiguravanje drospirenona i, ako je potrebno, estrogena kao što je estradiol u mikroniziranom obliku u navedenoj jedinici doziranja, ili u obliku raspršene otopine na čestice inertnog nosača u smjesi s jednim ili više farmaceutski prihvatljivom pomoćnom tvari koja pospješuje otpuštanje i estrogena tako da se ubrza otpuštanje drospirenona a preferira se estradiol u oralnoj aplikaciji. Primjeri odgovarajućeg pomoćnog sredstva uključuje punila, npr. šećere kao Što je laktoza, glukoza ili sukroza, šećerni alkoholi kao što je manitol, škrob kao što je kukuruzni ili krumpirov škrob ili modificirani škrob, lubrikanti kao što je talk ili magnezijev stearat i nosači kao što je polivinilpirolidon, derivati celuloze, karboksimetil celuloza, hidroksipropil celuloza, hidroksipropilmetil celuloza, metil celuloza/ ili želatina za izradu oralnih oblika za doziranje kao što su tablete, dražeje ili kapsule. Tablete uobičajeno mogu biti obložene s odgovarajućim sredstvom koje čini film, npr. hidroksipropilmetilceluloza. Prezentirane kompozicije mogu biti formulirane i u tekućem obliku , npr. kao otopina, suspenzija ili emulzija zajedno s uobičajenim otapalima ili pomoćnim sredstvima i na način koji je poznat od prije u farmaceutici. The composition of the dosage units may be formulated in any manner conventional in pharmaceuticals. In particular, as indicated above, the composition may be formulated by a process comprising providing drospirenone and, if necessary, an estrogen such as estradiol in micronized form in said dosage unit, or in the form of a dispersed solution on particles of an inert carrier in admixture with one or a more pharmaceutically acceptable excipient that promotes the release of estrogen so that the release of drospirenone is accelerated, and estradiol in oral administration is preferred. Examples of suitable excipients include fillers, eg sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, starches such as corn or potato starch or modified starches, lubricants such as talc or magnesium stearate, and carriers such as is polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose/ or gelatin for making oral dosage forms such as tablets, dragees or capsules. Tablets can usually be coated with a suitable film-forming agent, eg hydroxypropylmethylcellulose. The presented compositions can also be formulated in liquid form, for example as a solution, suspension or emulsion together with usual solvents or auxiliary agents and in a way that is already known in pharmaceuticals.

Osobito zanimljivi režim multi-faznog farmaceutskog pripravka obuhvaća sekvencijalnu aplikaciju i estrogena i drospirenona. Zanimljivo ostvarenje takvog režima će obuhvaćati tretiranje slobodnih intervala gdje nema apliciranja jedinica doziranja tako da obuhvaća alikaciju 20 do 24 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg, i drospirenon u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg za najmanje 10 do 12 dana od navedenih 20 do 24 dana, i bez aplikacije jedinica doze 4 do 8 dana. A particularly interesting regimen of a multi-phase pharmaceutical preparation involves the sequential application of both estrogen and drospirenone. An interesting realization of such a regimen will include the treatment of free intervals where no dosage units are applied, so that it includes the administration of 20 to 24 days of daily dosage units containing estradiol in an amount corresponding to the daily dose in the range of 0.1 to 5 mg, and drospirenone in an amount corresponding to the daily dose in the range of 0.25 to 6 mg for at least 10 to 12 days of the specified 20 to 24 days, and without application of dose units for 4 to 8 days.

Alternativno, za svaki interval bez aplikacije DRSP i estrogena, aplicira se placebo ili prazna. Takav režim hormonske nadomjesne terapije može učinkovito sadržavati postupak koji obuhvaća aplikaciju od 20 do 24 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granici od 0.1 do 5 mg, i dalje aplikaciju dorspirenona u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg za zadnjih 10 do 12 dana od navedenih 20 do 24 dana, i dalje aplikaciju 4 do 8 dana, dnevnih jedinica doze koje ne sadržavaju aktivnu supstanciju. Alternatively, for each interval without the application of DRSP and estrogen, a placebo or a blank is applied. Such a regimen of hormone replacement therapy can effectively contain a procedure comprising the application of 20 to 24 days of daily dosage units containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg, and further the application of dorspirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg for the last 10 to 12 days of the mentioned 20 to 24 days, and further application for 4 to 8 days, daily dose units that do not contain the active substance.

Alternativni režim obuhvaća aplikaciju 20 do 24 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi od 0.1 do 5 mg, i dalje aplikaciju drospirenona u količini koja odgovara dnevnoj dozi u granici od 0.25 do 6 mg za zadnjih 10 do 12 dana od navedenih 20 do 24 dana, čemu slijedi aplikacija 4 do 8 dana jedinica doze koja sadržava estradiol u količini manjoj od dnevne jedinice doze uzete za navedeni 20 do 24 dana aplikacije estradiola. An alternative regimen includes the application for 20 to 24 days of daily dosage units containing estradiol in an amount corresponding to a daily dose of 0.1 to 5 mg, and further application of drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg for the last 10 to 12 days from the specified 20 to 24 days, followed by the application for 4 to 8 days of a dose unit containing estradiol in an amount smaller than the daily dose unit taken for the specified 20 to 24 days of estradiol application.

U ostvarenju gdje je lijek u obliku određenog broja odvojenih pakiranja gdje je moguće pojedinačno odstraniti jedinice doze u jedinici pakiranja namjenjenih za oralnu aplikaciju u razdoblju od najmanje 21 dan, kao što je najmanje 28 dana i gdje je estradiol estrogen, preferira se najmanje 21 dnevna jedinica doze koja sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenon u količini u granici od oko 0.25 do 6 mg; i 7 ili manje dnevnih jedinica doze koje sadržavaju estradiol u količini od oko 0.1 do 5 mg. In an embodiment where the drug is in the form of a certain number of separate packages where it is possible to individually remove the dose units in the package unit intended for oral administration for a period of at least 21 days, such as at least 28 days and where estradiol is an estrogen, at least 21 daily units are preferred doses containing a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 to 6 mg; and 7 or less daily dosage units containing estradiol in an amount of about 0.1 to 5 mg.

Alternativno, lijek može biti u obliku brojnih odvojenih pakiranja i jedinica doze koje se mogu pojedinačno odstraniti a koje su smještene u jedinice pakiranja i namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 dana i najmanje 21 dnevna jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini u granicama od oko 0.25 do 6 mg i 7 ili manje dnevnih jedinica doze koje su prazne ili placebo. Alternatively, the drug can be in the form of a number of separate packages and dosage units that can be individually removed and which are placed in the packaging units and are intended for oral administration for a period of at least 28 days and at least 21 daily dosage units contain a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg and 7 or less daily dosage units that are blank or placebo.

Jednostavno slijedi da medikament može biti u obliku brojnih odvojenih pakiranja i može se pojedinačno odstraniti jedinica doze smještena u jedinicu pakiranja a namijenjena za oralnu aplikaciju u razdoblju najmanje 28 dana i najmanje 21 dnevna jedinica doze obuhvaća kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini od oko 0.25 do 6 mg. Može biti bez jedinica dociranja najmanje 7 ili manje dana režima. It simply follows that the medication can be in the form of numerous separate packages and the dose unit placed in the package unit and intended for oral administration for a period of at least 28 days and at least 21 daily dose units can be individually removed and includes a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in the amount of about 0.25 to 6 mg. Can be without dosing units for at least 7 or less days of regimen.

Strpljivo pokoravanje režimu brojnih ostvarenja može pomoći u smislu farmaceutskih pripravaka prilagođenih potrebama ili sklonostima pacijenta. Jedan takav pripravak može sadržavati određen broj odvojenih pakiranja i jedinice doze koje se pojedinačno mogu odstraniti a smještene su jedinicu pakiranja i namjenjene su za oralnu aplikaciju za razdoblje od najmanje 21 dan, kao što je najmanje 28 dana, a navedena jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenon u količini od oko 0.25 do 6 mg. Patient compliance with the regimen of numerous achievements can help in terms of pharmaceutical preparations adapted to the needs or preferences of the patient. One such preparation can contain a certain number of separate packages and dosage units that can be individually removed and are placed in a packaging unit and are intended for oral administration for a period of at least 21 days, such as at least 28 days, and said dosage unit contains a combination of estradiol in in the amount of about 0.1 to 5 mg and drospirenone in the amount of about 0.25 to 6 mg.

Osim toga, strpljivo pokoravanje može biti pomoć režimu koji sadržava multi-fazne farmaceutske pripravke. In addition, patient compliance can be helpful to a regimen containing multi-phase pharmaceutical preparations.

Svaki režim može jednostavno slijediti multi-fazni farmaceutski pripravak tako da jedan sadržava određeni broj odvojeno pakiranih i jedinica doze smještenih u jedinice pakiranja a koje se pojedinačno mogu odstraniti a namjenjene su za oralnu aplikaciju kroz 28 dana gdje navedene jedinice doze obuhvaćaju kombinaciju estradiola u količini u granici od oko 0.1 do 5 mg i drospirenona u količini u granici od oko 0.25 do 6 mg. U takvom pripravku, količina aktivne supstancije varira kroz 28-dnevno razdoblje. Each regimen can simply follow a multi-phase pharmaceutical preparation such that one contains a certain number of separately packaged and dose units placed in package units that can be individually removed and are intended for oral application for 28 days where said dose units include a combination of estradiol in an amount in in the range of about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 to 6 mg. In such a preparation, the amount of active substance varies over a 28-day period.

Jedno atraktivno ostvarenje odnosi se na multi-fazni farmaceutski pripravak koji sadržava određeni broj odvojeno pakiranih jedinica doze koje se pojedinačno mogu odstraniti smještenih u jedinice pakiranja, a namjenjene za oralnu aplikaciju za razdoblje od 21 do 30 uzastopnih dana gdje 10 do 15 navedenih jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenon u količini od oko 0.25 do 6 mg; i 10 do 15 navedenih dnevnih jedinica doze koje sadržavaju estradiol u količini u granicama od oko 0.1 do 5 mg. To ostvarenje osobito je prilagođeno za pripravak gdje se estrogen aplicira kontinuirano 21 do 30 dana a drospirenon u 3-dana-da-3-dana-ne ciklusu. Preferira se, unutar ostvarenja, da je pripravak dizajniran tako da je drospirenon apliciran od 4 do 6 dana, 10 do 12 dana, 16 do 18, 22 do 24 dana i 28 do 30 dana. One attractive embodiment refers to a multi-phase pharmaceutical preparation that contains a certain number of separately packaged dosage units that can be individually removed placed in the packaging units, and intended for oral application for a period of 21 to 30 consecutive days, where 10 to 15 said dosage units contain a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount of about 0.25 to 6 mg; and 10 to 15 of said daily dosage units containing estradiol in an amount ranging from about 0.1 to 5 mg. This embodiment is especially adapted for a preparation where estrogen is applied continuously for 21 to 30 days and drospirenone in a 3-day-on-3-day-off cycle. It is preferred, within the embodiment, that the preparation is designed so that drospirenone is applied from 4 to 6 days, 10 to 12 days, 16 to 18, 22 to 24 days and 28 to 30 days.

Osim toga, multi-fazni farmaceutski pripravak gdje je određeni broj dnevnih jedinica doze 21 do 28, ili višekratno 21 do 28, kao što je 2 do 24, kao što je 2 do 12, osobito 2 do 8, kao što je višekratno 2 do 6. In addition, a multi-phase pharmaceutical preparation where the specific number of daily dosage units is 21 to 28, or multiples of 21 to 28, such as 2 to 24, such as 2 to 12, especially 2 to 8, such as multiples of 2 to 6.

Slično,, izum se odnosi na postupak tretiranja bolesti, smetnji, i simptoma povezanih s deficijencijom estrogena, koji sadržava pripravak koji sadržava multi-fazni farmaceutski pripravak koji sadržava dnevne jedinice doze koje se apliciraju od l do 12, preferira se 2 do 8, kao što je 2, 3, 4, 5, 6, 7, i 8 višestruko po 28 dana. Similarly, the invention relates to a method of treating diseases, disorders, and symptoms associated with estrogen deficiency, comprising a composition comprising a multi-phase pharmaceutical composition comprising daily dosage units administered from 1 to 12, preferably 2 to 8, as which is 2, 3, 4, 5, 6, 7, and 8 multiples of 28 days.

Jedinica pakiranja sadržava gore opisane jedinice dnevne doze koje se mogu pripraviti na način analogan proizvodnji oralnih kontraceptiva ili režima nadomješćivanja hormona. To može biti naprimjer konvencionalno blister pakiranje ili bilo koji drugi oblik poznat u tu svrhu, naprimjer pakiranje sadržava određeni broj jedinica doze (u ovom slučaju najmanje 28, ili za određenu aplikaciju, višekratnik od 28) u zapečaćenom blisteru s ljepenkom, papirnom pločom, listićem ili plastičnim pokrovom i obuhvaćen odgovarajućim pokrovom. Svaki blister kontejner može odgovarajuće biti označen brojevima ili drugačije markiran. The package unit contains the daily dose units described above, which can be prepared in a manner analogous to the manufacture of oral contraceptives or hormone replacement regimens. It can be, for example, a conventional blister pack or any other form known for this purpose, for example a pack containing a certain number of dose units (in this case at least 28, or for a specific application, a multiple of 28) in a sealed blister with cardboard, a paper plate, a slip or plastic cover and covered with a suitable cover. Each blister container can be appropriately numbered or otherwise marked.

Isto tako je predviđeno da prezentirana kompozicija može biti u obliku parenteralne formulacije kao što je subkutani implantat ili transdermalna formulacija. Za izradu implantata, aktivno sredstvo može odgovarajuće biti formulirano zajedno s jednim ili više polimera tako da se postepeno erodira i razgrađuje kada se koristi, npr. polimeri silikona, etilen vinili acetat, polietilen ili polipropilen. It is also envisaged that the presented composition may be in the form of a parenteral formulation such as a subcutaneous implant or a transdermal formulation. For the manufacture of implants, the active agent may suitably be formulated together with one or more polymers so that it gradually erodes and degrades when used, eg silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.

Kada se odnosi na transdermalnu formulaciju, može se pripremiti u obliku jezgre ili membrana ili kao tekuće ili viskozne formulacije u ulju ili hidrogelu. Za transdermalne flastere, treba uključiti adheziv koji je kompatibilan s kožom, kao što je poliakrilat, silikonski adheziv ili polisobutilen, kao što je listić izrađen od, npr. polietilena, polipropilena, etilen vinilacetata, polivinilklorida, poliviniliden klorida ili poliestra, a zaštitna folija koja se odstranjuje izrađena je od, npr. poliestra ili papira obloženog silikonom ili fluorpolimerom. Za pripravljanje transdermalne otopine ili gela, može se koristiti voda ili organsko otapalo ili njihova smjesa. When referring to a transdermal formulation, it can be prepared in the form of a core or membrane or as a liquid or viscous formulation in oil or hydrogel. For transdermal patches, an adhesive that is compatible with the skin, such as polyacrylate, silicone adhesive or polyisobutylene, should be included, such as a sheet made of, for example, polyethylene, polypropylene, ethylene vinyl acetate, polyvinyl chloride, polyvinylidene chloride or polyester, and a protective film that is removed, it is made of, for example, polyester or paper coated with silicone or fluoropolymer. To prepare a transdermal solution or gel, water or an organic solvent or their mixture can be used.

Transdermalni gel može osim toga sadržavati jedno ili više odgovarajućih sredstava za geliranje ili sredstva za ugušćavanje kao što je silikon, tragakant, škrob ili derivate škroba, celulozu ili derivate celuloze ili poliakrilne kiseline ili njihove derivate. Transdermalna formulacija može isto sadržavati jednu ili više supstancija za povišenje absorbcije preko kože, kao što su soli žući ili njihovi derivati i/ili fosfolipidi. Odgovarajuće transdermalne formulacije mogu, naprimjer, biti izrađene na analogan način opisanom u WO 94/04157 za 3-ketodesogestrel. Alternativno, transdermalne formulacije mogu se pripremiti u skladu s postupkom prikazanim u, npr. BW Barry; "Deramtological Formulations, Percutaneous Absorpcion", Marcel Dekker Inc., New York-Basel, 1983, ili YW Chien; "Transdermal Controlled Systemic Medications", Marcel Dekker Inc.; New York-Basel; 1-987. The transdermal gel may additionally contain one or more suitable gelling agents or thickening agents such as silicone, tragacanth, starch or starch derivatives, cellulose or cellulose derivatives or polyacrylic acid or their derivatives. The transdermal formulation may also contain one or more substances to increase absorption through the skin, such as bile salts or their derivatives and/or phospholipids. Suitable transdermal formulations can, for example, be made in an analogous manner to that described in WO 94/04157 for 3-ketodesogestrel. Alternatively, transdermal formulations may be prepared according to the procedure described in, eg, BW Barry; "Dermatological Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York-Basel, 1983, or YW Chien; "Transdermal Controlled Systemic Medications", Marcel Dekker Inc.; New York-Basel; 1-987.

Prezentirani izum dalje je opisan u sljedećim primjerima koji nemaju svrhu ograničiti pregled izuma kao zahtjeva. The present invention is further described in the following examples which are not intended to limit the scope of the invention as claimed.

EKSPERIMENTALNO EXPERIMENTALLY

Primjer 1 Example 1

Priprema tableta koje sadržavaju drospirenon i estradiol može se provesti na slijedeći način The preparation of tablets containing drospirenone and estradiol can be carried out in the following way

Jezgra tablete je slijedećeg sastava The core of the tablet has the following composition

mikronizirani drospirenon 3.00 mg micronized drospirenone 3.00 mg

mikronizirani estradiol 1.00, 2.00, 3.00 mg micronized estradiol 1.00, 2.00, 3.00 mg

laktoza monohidrat 45.2, 46.2, 47.2 mg lactose monohydrate 45.2, 46.2, 47.2 mg

kukuruzni škrob 14.40 mg corn starch 14.40 mg

modificirani škrob 9.60 mg modified starch 9.60 mg

polivinilpirolidon 25,000 4.00 mg polyvinylpyrrolidone 25,000 4.00 mg

magnezijev stearat 0.80 mg magnesium stearate 0.80 mg

se priprema stavljanjem u fluidised bed granulator 31.68 kg kukuruznog škroba, 21.12 kg modificiranog škroba, 6.60 kg mikroniziranog drospirenona, 2.20, 4.40 ili 6,6 kg mikroniziranog estradiola (za 1 mg, 2 mg, i 3 mg doze) i 99.44, 101.64 ili 103.84 kg laktoze monohidrata (za 3 mg, 2 mg i 1 mg dozu) i aktivira se fluidised bed. Vodena otopina od 8.80 kg polivinilpirolidona 25,000 u 46.20 kg purificirane vode raspršuje se kontinuirano na fluidised bed dok se suši zagrijavanjem struje zraka fluidised bed. Na kraju procesa 1.76 kg magnezijevog stearata usiše se u granulator i miješa s granulama s podržavanjem fluidised bed. Dobivene granule se prešaju u jezgre tableta kompresijom koristeći rotacijsku prešu za tabletiranje. is prepared by placing in a fluidized bed granulator 31.68 kg of corn starch, 21.12 kg of modified starch, 6.60 kg of micronized drospirenone, 2.20, 4.40 or 6.6 kg of micronized estradiol (for 1 mg, 2 mg, and 3 mg doses) and 99.44, 101.64 or 103.84 kg of lactose monohydrate (for 3 mg, 2 mg and 1 mg dose) and the fluidized bed is activated. An aqueous solution of 8.80 kg of polyvinylpyrrolidone 25,000 in 46.20 kg of purified water is sprayed continuously onto the fluidized bed while it is dried by heating the fluidized bed with an air stream. At the end of the process, 1.76 kg of magnesium stearate is vacuumed into the granulator and mixed with the granules with the aid of a fluidised bed. The resulting granules are pressed into tablet cores by compression using a rotary tablet press.

Za tablete koje sadržavaju 1 mg estradiola, otopi se 2.22464 kg hidroksipropilmetilceluloze i 0.44528 makrogola 6000 u 14.64 kg purificirane vode. 0.44528 kg talka, 1.25906 kg titanijevog dioksida i 0.02575 kg pigmenta željeznog oksida suspendira se u 10.26 kg purificirane vode miješanjem i homogeniziranjem. Otopina i suspenzija se spoje i koriste za oblaganje jezgri tableta kontinuiranom aplikacijom suspenzije za oblaganje u stroju. Za tablete koje sadržavaju 2 ili 3 mg estradiola, specifična težina reagensa za pripravljanje obloga može se lagano izračunati. For tablets containing 1 mg of estradiol, dissolve 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol 6000 in 14.64 kg of purified water. 0.44528 kg of talc, 1.25906 kg of titanium dioxide and 0.02575 kg of iron oxide pigment are suspended in 10.26 kg of purified water by mixing and homogenizing. The solution and slurry are combined and used to coat the tablet core by continuous application of the coating slurry in the machine. For tablets containing 2 or 3 mg estradiol, the specific gravity of the coating reagent can be easily calculated.

Alternativna formulacija za obložene 1 mg tablete sadržava 2.22464 kg hidroksipropilmetilceluloze, 0.44528 kg makrogola 600, 0.44528 kg talka, 1.17326 titanijevog dioksida, 0.07634 pigmenta željeznog oksida, žutog, i 0.03520 kg pigmenta željeznog oksida, crvenog. Moguća formulacija za oblaganje 2 mg tableta sadržava 2.22464 kg hidroksipropilenceluloze, 0.44528 kg makrogola 600, 0.44528 kg talka, 1.19636 titanijevog dioksida i 0.08844 kg pigmenta željeznog oksida, crvenog. Moguća formulacija za oblaganje 3 mg tableta sadržava 2.22464 kg hidroksipropilmetilceluloze, 0.44528 makrogola 600, 0.44528 kg talka, 1.25906 titanijevog dioksida i 0.02574 kg pigmenta željeznog oksida, crvenog. An alternative formulation for coated 1 mg tablets contains 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.17326 of titanium dioxide, 0.07634 of iron oxide pigment, yellow, and 0.03520 kg of iron oxide pigment, red. A possible formulation for coating 2 mg tablets contains 2.22464 kg of hydroxypropylene cellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.19636 of titanium dioxide and 0.08844 kg of iron oxide pigment, red. A possible formulation for coating 3 mg tablets contains 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.25906 of titanium dioxide and 0.02574 kg of iron oxide pigment, red.

Primjer 2: Example 2:

Bioraspoloživost Bioavailability

Evaluacija bioraspoloživosti estradiola (E2) i drospirenona (DRSP), provedena je u otvorenoj randpmiziranoj na 2 načina kross over studiji s volonterima. E2/DRSP ankon tretiranja s 2 mg E2 + 2 mg DRSP, 2 mg E2 + 6 mg DRSP obloženim tabletama p.o.versus 2 mg E2 + 2 mg DRSP oralnom otopinom. The evaluation of the bioavailability of estradiol (E2) and drospirenone (DRSP) was carried out in an open randomized 2-way crossover study with volunteers. E2/DRSP ancon of treatment with 2 mg E2 + 2 mg DRSP, 2 mg E2 + 6 mg DRSP coated tablets p.o.versus 2 mg E2 + 2 mg DRSP oral solution.

Primjer 3: Example 3:

Ponovljena doza Repeat dose

Provedena je evaluacija farmakokinetike ponovljene doze (akumulacija) i potencijalna interakcija između estradiola i drospirenona. Taj otvorena-označena, randomizirana, inta-individualna cross-over studija s dva nivoa doza kombinirana s interventnom fazom ispiranja (4 tjedna), i multipla aplikacija preko 28 dana provedena je s kombinacijom 4 doze. Repeated dose pharmacokinetics (accumulation) and potential interaction between estradiol and drospirenone were evaluated. This open-label, randomized, intra-individual cross-over study with two dose levels combined with an intervention washout phase (4 weeks), and multiple application over 28 days was conducted with a combination of 4 doses.

Razdoblje promatranja od 4 tjedna provedeno je nakon zadnje doze. An observation period of 4 weeks was performed after the last dose.

Tretman A: 1 mg E2 + 1 mg DRSP, dnevno, p.o. Treatment A: 1 mg E2 + 1 mg DRSP, daily, p.o.

Tretman B: 1 mg E2 + 4 mg DRSP, dnevno, p.o. Treatment B: 1 mg E2 + 4 mg DRSP, daily, p.o.

Tretman C: 2 mg E2 + 1 mg DRSP, dnevno, p.o. Treatment C: 2 mg E2 + 1 mg DRSP, daily, p.o.

Tretman A: 2 mg E2 + 4 mg DRSP, dnevno, p.o. Treatment A: 2 mg E2 + 4 mg DRSP, daily, p.o.

Određivanjem Nisu zabilježene statistički značajne interakcije između dvije aktivne supstancije. Determination No statistically significant interactions between the two active substances were recorded.

Primjer 4: Example 4:

Zaštita endometrija Endometrial protection

Primarni cilj: Za evoluaciju učinkovitosti trinaest, 28 kontinuiranih dnevnih ciklusa kombinacije E2-DRSP komparirani su s kontinuiranom E2 analizom zaštite od hiperplazije žena u post-menopauzi. Primary objective: For the evolution of the efficacy of thirteen, 28 continuous daily cycles of the E2-DRSP combination were compared with continuous E2 analysis of protection against hyperplasia of post-menopausal women.

Sekundarni cilj: Za evaluaciju učinka na morfologiju endometrija, krvarenja, metaboličnih i hemostatskih laboratorijskih parametara. Well-being žena u post-menopauzi određen je s Women's Health Questionnaire (WHQ) i The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Učinak na frekvenciju i brojne udare vrućine, i na ublažavanje urogenitalnih simptoma. Nivo lijeka DRSP i E2. Detaljno su evaluirani metabolični parametri u podskupini. Secondary objective: To evaluate the effect on endometrial morphology, bleeding, metabolic and hemostatic laboratory parameters. Well-being of postmenopausal women was determined with the Women's Health Questionnaire (WHQ) and The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Effect on the frequency and number of hot flashes, and on the relief of urogenital symptoms. DRSP and E2 drug level. Metabolic parameters were evaluated in detail in the subgroup.

Pregled Review

Grupe doziranja: E2 1 mg; E2 1 mg + DRSP 0.5 mg; E2 1 mg + DRsp 1 mg; E2 1 mg + DRSP 2 mg; E2 1 mg + DRSP 3 mg. Dosage groups: E2 1 mg; E2 1 mg + DRSP 0.5 mg; E2 1 mg + DRsp 1 mg; E2 1 mg + DRSP 2 mg; E2 1 mg + DRSP 3 mg.

Ženama u post-menopauzi sa ili bez simptoma menopauze će biti propisan režim 1 do 5. Učinak na endometrij će biti evaluiran biopsijom kako bi se odredila pojava hiperplazije endometrija. Simptomi krvarenja će biti evaluirani iz osobnog dnevnika. Biti će evaluirani općenita sigurnost, i učinak na specifične biokemijske i hematološke parametre. Isto će biti učinjene post-menopauzalna kvaliteta kvalitete života i evaluacija zadovoljstva pacijenata. Postmenopausal women with or without menopausal symptoms will be prescribed regimens 1 through 5. The effect on the endometrium will be evaluated by biopsy to determine the occurrence of endometrial hyperplasia. Bleeding symptoms will be evaluated from the personal diary. General safety and effect on specific biochemical and hematological parameters will be evaluated. The same will be done post-menopausal quality of life and patient satisfaction evaluation.

Test dvosatne tolerancije na glukozu, i 15-minutna inzulinska tolerancija biti će provedeni na određenom mjestu. A two-hour glucose tolerance test and a 15-minute insulin tolerance test will be performed at a designated location.

Analiza podataka Data analysis

Biopsija endometrija pri Viziti 1 i Zadnjoj viziti. Informacije o krvarenju su zabilježene i dnevniku tijekom studije. Endometrial biopsy at Visit 1 and Last visit. Bleeding information was also recorded in a diary during the study.

Dvije analize koje će biti provedene za primarnu učinkovitost variraju: i) 2-strana komparacija tretmana i ii) 1-strana, unutar skupine intervala procjene učinka doze. The two analyzes to be performed for primary efficacy vary: i) 2-sided treatment comparison and ii) 1-sided, within-group dose-effect assessment interval.

Frekvencija u tabelama biti će generirana za vizitu kod koje će biti provedena biopsija. The frequency in the tables will be generated for the visit where the biopsy will be performed.

Te tabele će pokazati broj i postotak osoba za svaku kategoriju odgovora endometrija za svaku tretiranu skupinu (i s centrom u slučaju tretmanom-s-srednjom interakcijom). Biti će provedena komparacija za sve pojave hiperplazije između skupina i između tretiranih skupina. Ta analiza namijenjena je za tretiranje i testirati će nuli hipotezu bez razlike u odgovoru na tretman (nesmetan vs. sasvim različit estradiolu) kada se prilagođava centru. These tables will show the number and percentage of individuals for each category of endometrial response for each treatment group (and centered in the case of a treatment-by-mean interaction). A comparison will be made for all occurrences of hyperplasia between groups and between treated groups. This analysis is intended to treat and will test the null hypothesis of no difference in treatment response (unperturbed vs. quite different to estradiol) when adjusted for center.

Razdoblje procjene odgovora na dozu Dose response assessment period

Mogućnost πt će biti procijenjena za svaku dozu DRSP (t 0.0, 0.5, 1.0, 2.0, 3.0). Dodatno, gornja granica s jedne strane 95% pouzdanost intervala će biti izračunata odvojeno za svaki πt. To znači da će biti pouzdanost intervala ne-istodobna. The possibility πt will be estimated for each DRSP dose (t 0.0, 0.5, 1.0, 2.0, 3.0). Additionally, the upper limit of the one-sided 95% confidence interval will be calculated separately for each πt. This means that the reliability intervals will be non-simultaneous.

Primjer 5: Example 5:

Prevencija osteoroporoze Prevention of osteoporosis

Primarni cilj: Gustoća minerala u bedrenim kostima 104 tjedna nakon tretmana. Primary objective: Femoral bone mineral density 104 weeks after treatment.

Sekundarni cilj: gustoća minerala u bedrenim kostima (BMD) nakon 12, 28, 52 i 80 tjedana tretmana. BDM lumbalne kralježnice, midshaft radiusa, cijelog tijela. Učinak na parametre metabolizma kosti. Krvarenje. Općenito zaštita. Secondary objective: femur bone mineral density (BMD) after 12, 28, 52 and 80 weeks of treatment. BDM lumbar spine, midshaft radius, whole body. Effect on parameters of bone metabolism. Bleeding. General protection.

Studija je provedena kao dvostruko slijepi, placebo-kontrolirani pokus na 240 zdravih žena u post-menopauzi, randomiziranih, označenih kao jedna od 4 skupine po 60, nakon što su bile obavještene i dale pristanak. The study was conducted as a double-blind, placebo-controlled trial in 240 healthy post-menopausal women, randomized, assigned to one of 4 groups of 60, after informed consent.

Bile su sljedeće skupine: There were the following groups:

Img E2 + 1 mg DRSP Img E2 + 2 mg DRSP Img E2 + 3 mg t)RSP Img E2 + 1 mg DRSP Img E2 + 2 mg DRSP Img E2 + 3 mg t)RSP

Pregled Review

Četrdeset osteopeničhih pacijenata (BMD bedreni T-scor između -1 i -2.5) i 20 pacijenata bez-osteopenije bilo je uključeno u svaku skupinu. Svi tretmani primjenjivani su dnevno per os tijekom cijelog tretmana od 2 godina bez prekida. Osim toga, pacijenti su dobivali tablete kalcija (500 mg kalcija dnevno) Mjerenje gustoće minerala u bedrenoj kosti mjereno je na lijevoj strani koristeći dual-energy x-ray absorptiometry at screening, nulto, i nakon 12, 28, 52, 80, i 104 tjedna tretmana. Remodelirani biokemijski markeri kosti mjereni su u intervalima. Specifična alkalna fosfataza kosti u serumu, serumski N-mid osteokalcin, kalcij/kreatinin u urinu (drugo jutarnje pražnjenje), i urinarni CrossLaps®/kreatinin(drugo jutarnje pražnjenje) je dodatno evaluirano. Forty osteopenic patients (BMD femoral T-scor between -1 and -2.5) and 20 non-osteopenic patients were included in each group. All treatments were applied daily per person during the entire treatment of 2 years without interruption. In addition, patients received calcium tablets (500 mg calcium per day). Femoral bone mineral density was measured on the left side using dual-energy x-ray absorptiometry at screening, zero, and after 12, 28, 52, 80, and 104 week of treatment. Remodeled biochemical bone markers were measured at intervals. Serum bone specific alkaline phosphatase, serum N-mid osteocalcin, urinary calcium/creatinine (second morning discharge), and urinary CrossLaps®/creatinine (second morning discharge) were additionally evaluated.

Primjer 6: Example 6:

Simptomi menopauze Menopause symptoms

Cilj: Pokazati da je terapijska učinkovitost E2-DRSP na simptome menopauze bolja u odnosu na placebo Objective: To show that the therapeutic efficacy of E2-DRSP on menopausal symptoms is better compared to placebo

Primarni cilj: Udari vrućine Primary Target: Heatstroke

Sekundarni ciljevi: Epizode znojenja, problemi spavanja, depresivno raspoloženje, nervoza, urogenitalni simptomi (vagin-alna suhoća, pollakisurija, nokturia), krvarenje. Općenito zaštita. Secondary objectives: Sweating episodes, sleep problems, depressed mood, nervousness, urogenital symptoms (vaginal dryness, pollakiuria, nocturia), bleeding. General protection.

Pregled Review

Dvostruko slijepi, placebo kontrolirani pokus na zdravim ženama u post-menopauzi, randomizirane u jednu od 4 označene skupine A double-blind, placebo-controlled trial in healthy post-menopausal women, randomized to one of 4 indicated groups

1 mg E2 + 1 mg DRSP 1 mg E2 + 1 mg DRSP

1 mg E2 + 2 mg DRSP 1 mg E2 + 2 mg DRSP

1 mg E2 + 3 mg DRS£ 1 mg E2 + 3 mg DRS£

placebo placebo

Pregled: Review:

Glavni kriterij uključivanja: minimum 5 μmjerenih do jakih udara vrućine po danu zadnjih 7 dana u 2-tjednom razdoblju prije tretmana. Main inclusion criteria: a minimum of 5 μmeasured to severe hot flushes per day for the last 7 days in the 2-week period before treatment.

Trajanje tretmana bilo je 16 tjedana ( 4 28-dnevna ciklusa). The duration of the treatment was 16 weeks (4 28-day cycles).

Udari vrućine su određeni pomoću bilježenja frekvencije jakosti (srednji, umjeren ili jaki) i usporedbom između verum skupine i placeba. Kod pacijenata je bilježena pojava i jakost udara vrućine u dnevnik. Osim toga, istraživač je pitao svakog pacijenta pri svakoj viziti o drugim tipičnim simptomima za menopauzu (pojavi znojenja, problemima spavanja, depresivnom raspoloženju, nervozi, urogenitalnim simptomima). Intenzitet simptoma označavan je kao srednji, umjeren ili jaki. Hot flashes were determined by recording the frequency of severity (moderate, moderate or severe) and comparing the verum group with placebo. In patients, the occurrence and severity of hot flashes were recorded in the diary. In addition, the researcher asked each patient at each visit about other typical menopausal symptoms (sweating, sleep problems, depressed mood, nervousness, urogenital symptoms). The intensity of symptoms was marked as medium, moderate or severe.

Ukoliko pacijentica ima intaktan uterus, učestalost krvarenja bilježi se svaki dan tijekom studije u dnevnik. Pacijentica će dnevno1 unositi u dnevnik u skladu s intenzitetom krvarenja koji je dolje naveden. If the patient has an intact uterus, the frequency of bleeding is recorded in the diary every day during the study. The patient will enter daily1 in the diary according to the intensity of the bleeding listed below.

[image] [image]

Za urogenitalne simptome, koriste se sljedeći parametri i kategorije: For urogenital symptoms, the following parameters and categories are used:

[image] [image]

Analiza podataka Data analysis

Za parametre učinkovitosti, provedena je analiza i za analizu valjanih-slučajeva (VCA) i analizu intencije tretiranja (ITT). Primarna ciljana varijabla je individualno relativno promjenjena (C) u broju udara vrućine. C je definiran ka (T-B)/B, gdje T i B su individualna vrijednost. T je srednja vrijednost broja udara vrućine na tjedan, računat promatranjem t jekom 3 do 16 tjedana faze tretiranja. B je srednji broj udara vrućine po tjednu, izračunat prema promatranju 2 tjedna u fazi prije tretiranja. For efficacy parameters, analysis was performed for both valid-case analysis (VCA) and intention-to-treat analysis (ITT). The primary target variable was the individual relative change (C) in the number of hot flushes. C is defined as (T-B)/B, where T and B are individual values. T is the mean value of the number of hot flushes per week, calculated by observing t during the 3 to 16 week treatment phase. B is the mean number of hot flushes per week, calculated from the 2-week observation in the pre-treatment phase.

Primjer 7: Example 7:

Profil lipida Lipid profile

Cilj: Primarni cilj ove studije je usporena dva E2/DRSP tretmana i Premique®/Premelle® u odnosu na profil lipida. Profil lipida općenito je prihvaćen za glavni predstavnik krajnje točke za procjenu kardiovaskularnog rizika. Objective: The primary objective of this study is the retardation of two E2/DRSP treatments and Premique®/Premelle® in relation to the lipid profile. The lipid profile is generally accepted as the main endpoint representative for cardiovascular risk assessment.

Primarni cilj: Lipidi uključuju HDL kolesterol, LDL kolesterol Primary target: Lipids include HDL cholesterol, LDL cholesterol

Sekundarni cilj: Lipidi uključuju ukupni kolesterol, trigliceride, HDL2 kolesterol, HDL3 kolesterol, VLVL kolesterol, apolipoproteine (A-1, A-2, B, E), Lp (a); Secondary objective: Lipids include total cholesterol, triglycerides, HDL2 cholesterol, HDL3 cholesterol, VLVL cholesterol, apolipoproteins (A-1, A-2, B, E), Lp (a);

Simptomi menopauze; krvarenje, Zaštita endometrija; Općenito zaštita Menopause symptoms; bleeding, Endometrial protection; General protection

Nacrt studije: Studija je provedena kao open-label, multicentrična, komparativna studija na 300 žena u post-menopauzi randomiziranih u jednu od 3 označene skupine po 100 nakon što su detaljno informirane i dale pristanak. Study design: The study was conducted as an open-label, multicenter, comparative study of 300 post-menopausal women randomized into one of 3 marked groups of 100 each after they were thoroughly informed and gave their consent.

Skupine: Groups:

1 mg E2 + 2 mg DRSP 1 mg E2 + 2 mg DRSP

1 mg E2 + 3 mg DRSP 1 mg E2 + 3 mg DRSP

Premique®/Premelle®: 0.625 mg konjugiranog estrogena + 5 mg MPA Premique®/Premelle®: 0.625 mg conjugated estrogen + 5 mg MPA

Svi tretmani su primjenjeni dnevno oralno tijekom cijelog razdoblja tretiranja od 2 godine bez prekida. Mjerenje profila lipida provedeno je skriningom nakon 12, 28, 52 i 104 tjedna kao i šest tjedana nakon tretmana. All treatments were applied daily orally during the entire treatment period of 2 years without interruption. Lipid profile measurement was carried out by screening after 12, 28, 52 and 104 weeks as well as six weeks after treatment.

Claims (74)

1. Farmaceutska kompozicija naznačena time, da sadržava i) estrogen u dostatnoj količini za tretiranje bolesti, smetnji ili simptoma povezanih s deficijencijom endogenog nivoa estrogena u žena; ii) drospirenon u mikroniziranom obliku u dostatnoj količini za zaštitu endometrija od štetnog učinka estrogena, iii) zajedno s farmaceutski prihvatljivim pomoćnim sredstvom i nosačem.1. Pharmaceutical composition characterized in that it contains i) estrogen in sufficient quantity to treat diseases, disorders or symptoms associated with the deficiency of endogenous estrogen levels in women; ii) drospirenone in micronized form in sufficient quantity to protect the endometrium from the harmful effects of estrogen, iii) together with a pharmaceutically acceptable excipient and carrier. 2. Kompozicija u skladu sa Zahtjevom 1, naznačena time, da je estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, etinil estradiol, estron, estriol, estriol sukcinat i konjugirane estrogene, uključujući konjugirane konjske estrogene kao što je estron sulfat, 17β-estradiol sulfat, 17α-estradiol sulfat, ekvinil sulfat, 17β-dihidroekvinil sulfat, 17α-dihidroekvinil sulfat, ekvilenin sulfat, 17β-dihidroekvilenin sulfat i 17α-dihidroekvilenin sulfat ili njihovu smjesu.2. The composition according to Claim 1, characterized in that the estrogen is selected from the group consisting of estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as is estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equinyl sulfate, 17β-dihydroequinyl sulfate, 17α-dihydroequinyl sulfate, equilene sulfate, 17β-dihydroequilenine sulfate and 17α-dihydroequilenine sulfate or their mixture. 3. Kompozicija u skladu sa Zahtjevom 2, naznačena time, da je estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, estron, i estron sulfat ili njihovu smjesu.3. Composition according to Claim 2, characterized in that the estrogen is selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or a mixture thereof. 4. Kompozicija u skladu sa Zahtjevom 3, naznačena time, da je estrogen estradiol.4. Composition according to Claim 3, characterized in that the estrogen is estradiol. 5. Kompozicija u skladu sa Zahtjevima 2 ili 3, naznačena time, da je najmanje jedan estrogen u mikroniziranom obliku.5. Composition according to Claims 2 or 3, characterized in that at least one estrogen is in micronized form. 6. Kompozicija u skladu sa Zahtjevom 1, naznačena time, da doza DRSP odgovara dozi od 15 do 70 mg po ciklusu, kao što je 20 do 60 mg po ciklusu, osobito 40 do 60 mg po ciklusu.6. Composition according to Claim 1, characterized in that the dose of DRSP corresponds to a dose of 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, especially 40 to 60 mg per cycle. 7. Kompozicija u skladu sa Zahtjevom 1, naznačena time, da količina drospirenona odgovara dnevnoj dozi u granicama od 0.25 do 10 mg, kao što je oko 0.25 do 8, 0.25 do 6, 0.25 do 5, 0.5 do 4.5, 1 do 4, i 1.5 do 3.5 mg.7. Composition according to Claim 1, characterized in that the amount of drospirenone corresponds to a daily dose in the range of 0.25 to 10 mg, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg. 8. Kompozicija u skladu sa Zahtjevom 4, naznačena time, da količina estradiola odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, kao što je oko 0.2 do 4.5, 0.5 do 4, 1 do 3, i osobito 1, 2, ili 3 mg.8. Composition according to Claim 4, characterized in that the amount of estradiol corresponds to a daily dose in the range of 0.1 to 5 mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, and especially 1, 2, or 3 mg. 9. Farmaceutska kompozicija u skladu s bilo kojim od Zahtjeva 1 do 8, naznačena time, da je u obliku tableta, kapsula ili pilula.9. A pharmaceutical composition according to any one of Claims 1 to 8, characterized in that it is in the form of tablets, capsules or pills. 10. Upotreba kombinacije estrogena i drospirenona za pripravljanje medikamenta, naznačena time, da je količina estrogena dostatna za tretiranje bolesti, smetnji i simptoma povezanih s deficijencijom endogenog nivoa estrogena žena a količina drospirenona je dostatna za zaštitu endometrija od štetnog djelovanja estrogena.10. The use of a combination of estrogen and drospirenone for the preparation of medication, indicated by the fact that the amount of estrogen is sufficient to treat diseases, disorders and symptoms associated with the deficiency of the endogenous level of estrogen in women, and the amount of drospirenone is sufficient to protect the endometrium from the harmful effects of estrogen. 11. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je deficijentni nivo estrogena uzrokovan prirodnom menopauzom, peri-menopauzom, post-menopauzom, hipogonadizmom, kastracijom ili prirodnim nedostatkom ovarija.11. Use according to Claim 10, characterized in that the deficient estrogen level is caused by natural menopause, peri-menopause, post-menopause, hypogonadism, castration or natural lack of ovaries. 12. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je količina estrogena dostatna za tretiranje udara vrućine, napada znojenja, lupanja srca, smetnji spavanja, promjena raspoloženja, nervoze, tjeskobe, loše memorije, gubitka samopouzdanja, gubitka libida, slabe koncentracije, smanjenja energije, smanjenja snage, razdražljivosti, urogenitalne atrofije, atrofije prsa, kardiovaskularnih bolesti, promjena u distribuciji kose, debljini kose, promjena u kondiciji koze ili preventivi ili upravljanju osteoporozom.12. Use according to Claim 10, characterized in that the amount of estrogen is sufficient to treat hot flashes, sweating attacks, heart palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, poor concentration, decrease in energy, decrease in strength, irritability, urogenital atrophy, chest atrophy, cardiovascular disease, change in hair distribution, hair thickness, change in skin condition or prevention or management of osteoporosis. 13. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je količina estrogena dostatna za tretiranje udara vrućine, napada znojenja, lupanja srca, smetnji spavanja, promjena raspoloženja, nervoze, tjeskobe, urogenitalne atrofije, atrofije prsa, ili preventivu ili upravljanje osteoporozom.13. Use according to Claim 10, wherein the amount of estrogen is sufficient to treat hot flushes, sweating attacks, palpitations, sleep disturbances, mood swings, nervousness, anxiety, urogenital atrophy, chest atrophy, or the prevention or management of osteoporosis. 14. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je estrogen odabran iz skupine koja sadržava estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, etinil estradiol, estron, estriol, estriol sukcinat i konjugirane estrogene, uključujući konjugirane konjske estrogene kao što je estron sulfat, 17β-estradiol sulfat, 17α-estradiol sulfat, ekvinil sulfat, 17β-dihidroekvinil sulfat, 17α-dihidroekvinil sulfat, ekvilenin sulfat, 17β-dihidroekvilenin sulfat i 17α-dihidroekvilenin sulfat ili njihovu smjesu.14. Use according to Claim 10, characterized in that the estrogen is selected from the group containing estrogen selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equinyl sulfate, 17β-dihydroequinyl sulfate, 17α-dihydroequinyl sulfate, equilene sulfate, 17β-dihydroequilenine sulfate, and 17α-dihydroequilenine sulfate or a mixture thereof. 15. Upotreba u skladu sa Zahtjevom 14, naznačena time, da je estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, estron, i estron sulfat ili njihovu smjesu.15. Use according to Claim 14, characterized in that the estrogen is selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or a mixture thereof. 16. Upotreba u skladu sa Zahtjevom 15, naznačena time, da je estrogen estradiol.16. Use according to Claim 15, characterized in that the estrogen is estradiol. 17. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je drospirenon (DRSP) u mikroniziranom obliku.17. Use according to Claim 10, characterized in that the drospirenone (DRSP) is in micronized form. 18. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je estrogen u mikroniziranom obliku,18. Use according to Claim 10, characterized in that the estrogen is in micronized form, 19. Upotreba u skladu sa Zahtjevom 16, naznačena time, da je estradiol u mikroniziranom obliku.19. Use according to Claim 16, characterized in that the estradiol is in micronized form. 20. Upotreba u skladu sa Zahtjevom 10, naznačena time, da doza drospirenona odgovara dozi od 15 do 7-0 mg po ciklusu, kao što je 20 do 60 mg po ciklusu, osobito 40 do 60 mg po ciklusu.20. Use according to Claim 10, characterized in that the dose of drospirenone corresponds to a dose of 15 to 7-0 mg per cycle, such as 20 to 60 mg per cycle, especially 40 to 60 mg per cycle. 21. Upotreba u skladu sa Zahtjevom 10, naznačena time, da količina drospirenona odgovara dnevnoj dozi u granicama od 0.25 do 10 mg, tako od oko 0.25 do 8, 0.25 do 6, 0.25 do 5, 0.5 do 4.5, 1 do 4, i 1.5 do 3.5 mg.21. Use according to Claim 10, characterized in that the amount of drospirenone corresponds to a daily dose in the range of 0.25 to 10 mg, thus from about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg. 22. Upotreba u skladu sa Zahtjevom 16, naznačena time, da količina estradiola odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, tako da je oko 0.2 do 4.5, 0.5 do 4, 1do 3, i ososbito 1, 2, ili 3 mg.22. Use according to Claim 16, characterized in that the amount of estradiol corresponds to a daily dose in the range of 0.1 to 5 mg, so that it is about 0.2 to 4.5, 0.5 to 4, 1 to 3, and especially 1, 2, or 3 mg . 23. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je lijek u obliku određenog broja odvojenih pakiranja, a jedinice doze koje se mogu pojedinačno odstraniti su u jedinici pakiranja, a namijenjene su za oralnu aplikaciju u razdoblju od najmanje 28 dana; gdje najmanje 21 dnevna jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini u granici od oko 0.25 do 6 mg; i 7 ili manje dnevnih jedinica doze koje sadržavaju estradiol u količini od oko 0.1 do 5 mg.23. Use according to Claim 10, indicated by the fact that the drug is in the form of a certain number of separate packages, and the dose units that can be individually removed are in the package unit, and are intended for oral application for a period of at least 28 days; where at least 21 daily dosage units contain a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 to 6 mg; and 7 or less daily dosage units containing estradiol in an amount of about 0.1 to 5 mg. 24. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je lijek u obliku određenog broja odvojenih pakiranja, a jedinice doze koje se rogu pojedinačno odstraniti su u jedinici pakiranja, a namijenjene su za oralnu aplikaciju u razdoblju od najmanje 28 dana; gdje najmanje 21 dnevna jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini u granici od oko r. 25 do 6 mg; i 7 ili manje dnevnih jedinica doze koje su prazne ili placebo.24. Use in accordance with Claim 10, characterized by the fact that the drug is in the form of a certain number of separate packages, and the dose units that are individually removed are in the package unit, and are intended for oral application for a period of at least 28 days; where at least 21 daily dosage units contain a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount in the range of about r. 25 to 6 mg; and 7 or fewer daily dose units that are blank or placebo. 25. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je lijek u obliku određenog broja odvojenih pakiranja, a jedinice doze koje se mogu pojedinačno odstraniti su u jedinici pakiranja, a namijenjene su za oralnu aplikaciju u razdoblju od najmanje 28 dana; gdje najmanje 10 dnevnih jedinica doze sadržava estradiol u količini od oko 0.1 do 5 mg; i najmanje 10 dnevnih jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini u granicama od oko 0.25 do 6 mg, i 8 ili manje dnevnih jedinica doze koje su prazne ili placebo.25. Use according to Claim 10, indicated by the fact that the drug is in the form of a certain number of separate packages, and the dose units that can be individually removed are in the package unit, and are intended for oral application for a period of at least 28 days; where at least 10 daily dosage units contain estradiol in an amount of about 0.1 to 5 mg; and at least 10 daily dosage units contain a combination of estradiol in the amount of about 0.1 to 5 mg and drospirenone in the amount of about 0.25 to 6 mg, and 8 or fewer daily dose units that are blank or placebo. 26. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je lijek u obliku određenog broja odvojenih pakiranja, a jedinice doze koje se mogu pojedinačno odstraniti su u jedinici pakiranja, a namijenjene su za oralnu aplikaciju u razdoblju od najmanje 28 dana; gdje najmanje 10 dnevnih jedinica doze sadržava estradiol u količini od oko 0.1 do 5 mg; i najmanje 10 dnevnih jedinica doze sadržava estradiol u količini od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg; i 8 ili manje dnevnih jedinica doze sadržava estradiol u količini od oko 0.1 do 5 mg.26. Use according to Claim 10, indicated by the fact that the drug is in the form of a certain number of separate packages, and the dose units that can be individually removed are in the package unit, and are intended for oral application for a period of at least 28 days; where at least 10 daily dosage units contain estradiol in an amount of about 0.1 to 5 mg; and at least 10 daily dosage units contain estradiol in the amount of about 0.1 to 5 mg and drospirenone in the amount of about 0.25 to 6 mg; and 8 or less daily dosage units contain estradiol in an amount of about 0.1 to 5 mg. 27. Upotreba u skladu sa Zahtjevom 10, naznačena time, da je lijek u obliku određenog broja odvojenih pakiranja, a jedinice doze koje se mogu pojedinačno odstraniti su u jedinici pakiranja, a namijenjene su za oralnu aplikaciju u razdoblju od najmanje 28 dana; gdje najmanje 28 dnevnih jedinica doze sadržava kombinaciju estradiola u količini od oko 0.1 do 5 mg i drospirenona u količini od oko 0.25 do 6 mg.27. Use according to Claim 10, indicated by the fact that the drug is in the form of a certain number of separate packages, and the dose units that can be individually removed are in the package unit, and are intended for oral application for a period of at least 28 days; where at least 28 daily dosage units contain a combination of estradiol in an amount of about 0.1 to 5 mg and drospirenone in an amount of about 0.25 to 6 mg. 28. Upotreba u skladu s bilo kojim od Zahtjeva 10 do 22, naznačena time, da je lijek u obliku tableta, kapsula ili dražeja.28. Use according to any one of Claims 10 to 22, characterized in that the drug is in the form of tablets, capsules or dragees. 29. Metoda koja se koristi za tretiranje i preveniranje bolesti, smetnji i simptoma povezanih s deficijencijom endogenog nivoa estrogena u žena naznačena time, da sadržava aplikaciju estrogena u dostatnoj količini za olakšanje navedenih bolesti, smetnji i simptoma i drospirenon u dostatnoj količini za zaštitu endometrija od štetnog djelovanja estrogena.29. The method used for the treatment and prevention of diseases, disorders and symptoms associated with the deficiency of endogenous estrogen levels in women, characterized by the fact that it contains the application of estrogen in a sufficient amount to relieve the said diseases, disorders and symptoms and drospirenone in a sufficient amount to protect the endometrium from harmful effects of estrogen. 30. Metoda u skladu sa Zahtjevom 29, naznačena time, da je deficijencija nivoa estrogena uzrokovana prirodnom menopauzom, peri-menopauzom, post-menopauzom hipogonadizmom, kastracijom ili primarnim nedostatkom ovarija.30. The method according to Claim 29, characterized in that the estrogen level deficiency is caused by natural menopause, peri-menopause, post-menopause hypogonadism, castration or primary ovarian deficiency. 31. Metoda u skladu sa Zahtjevom 29, naznačena time, da su bolesti, smetnje i simptomi odabrani iz skupine koja obuhvaća i uključuje udare vrućine, napade znojenja, lupanje srca, smetnje spavanja, promjene raspoloženja, nervozu, tjeskobu, slabo pamćenje, gubitak samopouzdanja, gubitak libida, slabu koncentraciju, smanjenje energije, gubitak snage, razdražljivost, urogenitalnu atrofiju, attofiju prsa, kardiovaskularne bolesti, promjene u distribuciju kose, gustoći kose, promjene u kondiciji kože ili za prevenciju ili upravljane osteoporozom.31. The method according to Claim 29, characterized in that the diseases, disorders and symptoms are selected from the group consisting of hot flushes, sweating attacks, heart palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of confidence , loss of libido, poor concentration, decrease in energy, loss of strength, irritability, urogenital atrophy, chest atrophy, cardiovascular disease, changes in hair distribution, hair density, changes in skin condition or for the prevention or management of osteoporosis. 32. Metoda u skladu sa Zahtjevom 31, naznačena time, da su bolesti, smetnje i simptomi odabrani iz skupine koja obuhvaća i uključuje udare vrućine, napade znojenja, lupanje srca, smetnje spavanja, promjene raspoloženja, nervozu, tjeskobu, urogenitalnu atrofiju, atrofiju prsa, ili za prevenciju ili upravljane osteoporozom.32. The method according to Claim 31, characterized in that the diseases, disorders and symptoms are selected from the group consisting of hot flushes, sweating attacks, heart palpitations, sleep disturbances, mood swings, nervousness, anxiety, urogenital atrophy, chest atrophy , or for the prevention or management of osteoporosis. 33. Metoda u skladu, sa Zahtjevom 29, naznačena time, da je estrogen odabran i skupine koja sadržava estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, etinil estardiol, estron, estriol, estripl sukcinat i konjugirane estrogene, uključujući konjugirane konjske estrogene kao što je estron sulfat, 17β-estradiol sulfat, 17α-estradiol sulfat, ekvinil sulfat, 17β-dihidroekvinil sulfat, 17α-dihidroekvinil sulfat, ekvilenin sulfat, 17β-dihidroekvilenin sulfat i 17α-dihidroekvilenin sulfat ili njihovu smjesu.33. The method in accordance with Claim 29, characterized in that the estrogen is selected from the group containing estrogen selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, ethinyl estardiol, estrone, estriol, estriple succinate and conjugated estrogens , including conjugated equine estrogens such as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol sulfate, equinyl sulfate, 17β-dihydroequinyl sulfate, 17α-dihydroequinyl sulfate, equilene sulfate, 17β-dihydroequilenine sulfate, and 17α-dihydroequilenine sulfate or a mixture thereof. 34. Metoda u skladu sa Zahtjevom 33, naznačena time, da je estrogen odabran iz skupine koja sadržava estradiol, estradiol sulfamat, estradiol valerat, estradiol benzoat, estron, i estron sulfat ili njihovu smjesu.34. The method according to Claim 33, characterized in that the estrogen is selected from the group containing estradiol, estradiol sulfamate, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or a mixture thereof. 35. Metoda u skladu sa Zahtjevom 34, naznačena time, da je estrogen estradiol.35. The method according to Claim 34, characterized in that the estrogen is estradiol. 36. Metoda u skladu sa Zahtjevom 29, naznačena time, da je drospirenon (DRSP) u mikroniziranom obliku.36. The method according to Claim 29, characterized in that the drospirenone (DRSP) is in micronized form. 37. Metoda u skladu sa Zahtjevom 29, naznačena time, da je estrogen u mikroniziranom obliku.37. The method according to Claim 29, characterized in that the estrogen is in micronized form. 38. Metoda u skladu sa Zahtjevom 35, naznačena time, da je estradiol u mikroniziranom obliku.38. The method according to Claim 35, characterized in that the estradiol is in micronized form. 39. Metoda u skladu sa Zahtjevom 29, naznačena time, da doza drospirenona odgovara dozi od 15 do 70 mg po ciklusu, kao što je 20 do 60 mg po ciklusu, osobito 40 do 60 mg po ciklusu.39. The method according to Claim 29, characterized in that the dose of drospirenone corresponds to a dose of 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, especially 40 to 60 mg per cycle. 40. Metoda u skladu sa Zahtjevom 29, naznačena time, da količina drospirenona odgovara dnevnoj dozi u granicama o 0.25 do 10 mg, tako od oko 0.25 do 8, 0.25 do 6, 0.25 do 5, 0.5 do 4.5, 1 do 4, i 1.5 do 3.5 mg.40. The method according to Claim 29, characterized in that the amount of drospirenone corresponds to a daily dose within the limits of 0.25 to 10 mg, so from about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg. 41. Metoda u skladu sa Zahtjevom 35, naznačena time, da količina estradiola odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, tako da je oko 0.2 do 4.5, 0.5 do 4, 1 do 3, i osobito 1, 2, ili 3 mg.41. The method according to claim 35, characterized in that the amount of estradiol corresponds to a daily dose in the range of 0.1 to 5 mg, so that it is about 0.2 to 4.5, 0.5 to 4, 1 to 3, and especially 1, 2, or 3 mg. 42. Metoda u skladu sa Zahtjevom 29, naznačena time, da sadržava - prvo razdoblje tretmana od 10 do 12 dana dnevne jedinice doze koja sadržava estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg; i - slijedi aplikacija dnevnih jedinica doze kroz 10 do 12 dana koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg; - slijedi aplikacija dnevnih jedinica doze kroz 4 do 8 dana koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 5 mg.42. The method according to Claim 29, characterized in that it contains - the first treatment period of 10 to 12 days of a daily dose unit containing estradiol in an amount corresponding to the daily dose in the range of 0.1 to 5 mg; and - followed by the application of daily dose units for 10 to 12 days containing estradiol in the amount corresponding to the daily dose in the range of 0.1 to 5 mg and drospirenone in the amount corresponding to the daily dose in the range of 0.25 to 6 mg; - followed by the application of daily dose units for 4 to 8 days, which contain estradiol in an amount that corresponds to the daily dose in the range of 0.25 to 5 mg. 43. Metoda u skladu sa Zahtjevom 29, naznačena time, da sadržava - prvo razdoblje aplikacije dnevnih jedinica doze kroz 10 do 12 dana koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg; i slijedi aplikacija dnevnih jedinica doze kroz 10 do 12 dana koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg i drospirenon li količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg; i - slijedi aplikacija dnevnih jedinica doze kroz 4 do 8 dana koje su prazne ili placebo.43. The method according to Claim 29, characterized in that it contains - the first period of application of daily dose units for 10 to 12 days containing estradiol in the amount corresponding to the daily dose within the limits of 0.1 to 5 mg; followed by the application of daily dose units for 10 to 12 days containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; and - followed by the application of daily dose units for 4 to 8 days that are empty or placebo. 44. Metoda u skladu sa Zahtjevom 29, naznačena time, da sadržava - prvo razdoblje aplikacije dnevnih jedinica doze, kroz najmanje 21 dan, koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg; - slijedi aplikacija dnevnih jedinica ne više od 7 dana koje su prazne ili placebo.44. The method according to Claim 29, characterized in that it contains - the first period of application of daily dose units, for at least 21 days, containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; - followed by the application of daily units for no more than 7 days that are empty or placebo. 45. Metoda u skladu sa Zahtjevom 29, naznačena time, da sadržava - prvo razdoblje aplikacije dnevnih jedinica doze kroz najmanje 21 dan koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg; - slijedi aplikacija dnevnih jedinica doze ne više od 7 dana koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg.45. The method according to Claim 29, characterized in that it contains - the first period of application of daily dose units for at least 21 days containing estradiol in an amount corresponding to a daily dose in the range of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose in the range of 0.25 to 6 mg; - followed by the application of daily dose units for no more than 7 days containing estradiol in the amount corresponding to the daily dose in the range of 0.1 to 5 mg. 46. Metoda u skladu sa Zahtjevom 29, naznačena time, da sadržava aplikaciju kroz 21 do 28 dana dnevnih jedinica doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg i drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg;46. The method according to Claim 29, characterized by the fact that it contains the application over 21 to 28 days of daily dose units containing estradiol in an amount corresponding to a daily dose within the limits of 0.1 to 5 mg and drospirenone in an amount corresponding to a daily dose within the limits of 0.25 to 6 mg; 47. Metoda, u skladu s bilo kojim od Zahtjeva 29 do 41, naznačena time, da se estrogen aplicira kontinuirano.47. The method according to any one of Claims 29 to 41, characterized in that the estrogen is administered continuously. 48. Metoda u skladu s bilo kojim od Zahtjeva 29 do 41, naznačena time, da se estrogen i drospirenon apliciraju kontinuirano.48. The method according to any one of Claims 29 to 41, characterized in that estrogen and drospirenone are administered continuously. 49. Metoda u skladu s bilo kojim od Zahtjeva 29 do 41, naznačena time, da se estrogen aplicira kontinuirano a drospirenon se aplicira sekvencijalno.49. The method according to any one of Claims 29 to 41, characterized in that the estrogen is administered continuously and the drospirenone is administered sequentially. 50. Metoda u skladu sa Zahtjevom 49, naznačena time, da je doziranje estrogena smanjeno na l do 7 dana odmah iza navedene sekvencijalne aplikacije drospirenona.50. The method according to Claim 49, characterized in that the dosage of estrogen is reduced to 1 to 7 days immediately after the said sequential application of drospirenone. 51. Metoda u skladu sa Zahtjevom 29, naznačena time, da se estrogen aplicira kontinuirano a drospirenon aplicira u prekidima.51. The method according to Claim 29, characterized in that estrogen is applied continuously and drospirenone is applied intermittently. 52. Metoda u skladu sa Zahtjevom 51, naznačena time, da se estrogen aplicira kontinuirano kroz 21 do 30 dana, a drospirenon se aplicira u 3-dana-da-3-dana-ne ciklusima.52. The method according to Claim 51, characterized in that estrogen is applied continuously for 21 to 30 days, and drospirenone is applied in 3-day-on-3-day-off cycles. 53. Metoda u skladu sa Zahtjevom 52, naznačena time, da se drospirenon aplicira od 4 do 6 dana, 10 do 12 dana, 16 do 18 dana, 22 do 24 dana, i 28 do 30 dana.53. The method according to Claim 52, characterized in that drospirenone is applied from 4 to 6 days, 10 to 12 days, 16 to 18 days, 22 to 24 days, and 28 to 30 days. 54. Metoda u skladu sa Zahtjevima 29 do 41, naznačena time, da se estrogen i drospirenon svaki pojedinačno sekvencijalno aplicira s intervalima bez tretmana.54. The method according to Claims 29 to 41, characterized in that estrogen and drospirenone are each individually sequentially applied with intervals without treatment. 55. Metoda u skladu sa Zahtjevom 29, naznačena time, da se - prvo aplicira u razdoblju od 20 do 24 dana dnevne jedinice doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, a drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg kroz najmanje 10 do 12 dana od navedenih 20 do 24 dana, - slijedi razdoblje aplikacije 4 do 8 dana dnevnih jedinica doze koje ne sadržavaju aktivne supstancije.55. The method in accordance with Claim 29, characterized in that - first apply in a period of 20 to 24 days daily dose units containing estradiol in an amount corresponding to a daily dose within the limits of 0.1 to 5 mg, and drospirenone in an amount corresponding to a daily dose within the limits of 0.25 to 6 mg for at least 10 to 12 days from the specified 20 to 24 days, - followed by an application period of 4 to 8 days of daily dose units that do not contain active substances. 56. Metoda u skladu sa Zahtjevom 29, naznačena time, da se - prvo razdoblje aplikacije 20 do 24 dana apliciranja dnevne jedinice doze koja sadržava estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, i drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg kroz najmanje 10 do 12 dana od navedenih 20 do 24 ,dana, - slijedi aplikacija 4 do 8 dana dnevnih jedinica doze koje sadržavaju estradiol u količini manjoj od dnevne jedinice doze uzete za navedenu 20 do 24 dnevnu aplikaciju estradiola.56. Method in accordance with Claim 29, characterized in that - the first period of application 20 to 24 days of applying a daily dose unit containing estradiol in an amount corresponding to a daily dose within the limits of 0.1 to 5 mg, and drospirenone in an amount corresponding to a daily dose within the limits of 0.25 to 6 mg for at least 10 to 12 days from the mentioned 20 to 24 days, - followed by the application of 4 to 8 days of daily dose units containing estradiol in an amount smaller than the daily dose unit taken for the stated 20 to 24 daily application of estradiol. 57. Metoda u skladu sa Zahtjevom 29, naznačena time, da se aplicira 20 do 24 dana dnevne jedinice doze koje sadržavaju estradiol u količini koja odgovara dnevnoj dozi u granicama od 0.1 do 5 mg, a drospirenon u količini koja odgovara dnevnoj dozi u granicama od 0.25 do 6 mg kroz najmanje 10 do 12 dana od navedenih 20 do 24 dana, i ne aplicira se dnevne jedinice doze kroz 4 do 8 dana.57. The method in accordance with Claim 29, characterized in that 20 to 24 days of daily dose units containing estradiol in an amount corresponding to a daily dose within the limits of 0.1 to 5 mg, and drospirenone in an amount corresponding to a daily dose within the limits of 0.25 to 6 mg for at least 10 to 12 days of the specified 20 to 24 days, and no daily dose units are applied for 4 to 8 days. 58. Metoda u skladu sa Zahtjevima 29 do 57, naznačena time, da estrogen i/ili drospirenon se apliciraju u oralnoj formulaciji, iz flastera, iz implatata ili njihovom kombinacijom.58. The method according to Claims 29 to 57, characterized in that estrogen and/or drospirenone are applied in an oral formulation, from a patch, from an implant or a combination thereof. 59. Metoda U skladu sa Zahtjevom 58, naznačena time, da estrogen i/ili drospirenon jesu aplicirani u oralnoj formulaciji.59. Method According to Claim 58, characterized in that estrogen and/or drospirenone are administered in an oral formulation. 60. Metoda u skladu sa Zahtjevima 42 do 57, naznačena time, da se dnevne jedinice doze apliciraju kroz 1 do 12, preferira se 2 do 8, kao 2, 3, 4, 5, 6, 7 i 8 puta po 28 dana.60. The method according to Claims 42 to 57, characterized in that the daily dosage units are administered over 1 to 12, preferably 2 to 8, such as 2, 3, 4, 5, 6, 7 and 8 times per 28 days. 61. Metoda u skladu sa Zahtjevima 29 do 57, 59 i 60 naznačena time, da se estrogen i/ili drospirenon apliciraju kao tablete, kapsule- ili pilule.61. The method according to Claims 29 to 57, 59 and 60, characterized in that estrogen and/or drospirenone are administered as tablets, capsules or pills. 62. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 21 dana naznačen time, da navedena dnevna jedinica doze sadržava kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg, navedeni drospirenon je u mikroniziranom obliku.62. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit and are intended for oral application for a period of at least 21 days, indicated by the fact that the stated daily dose unit contains a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg, said drospirenone being in micronized form. 63. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 dana naznačen time, da navedena dnevna jedinica doze sadržava kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg, navedeni drospirenon je u mikroniziranom obliku.63. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit and are intended for oral application for a period of at least 28 days, indicated by the fact that the said daily dose unit contains a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg, said drospirenone being in micronized form. 64. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja, a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 dana, naznačen time, da najmanje 21 dnevna jedinica doze sadržava kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg i ne više od 7 navedenih jedinica doze je placebo ili prazna, navedeni drospirenon je u mikroniziranom obliku.64. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit, and are intended for oral application for a period of at least 28 days, indicated that at least 21 daily dose units contains a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg and no more than 7 stated dose units is a placebo or empty, said drospirenone is in micronized form. 65. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 dana, naznačen time, da najmanje 21 dnevna jedinica doze sadržava kombinaciju estradiola u količini U granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg; i ne više od 7 navedenih jedinica doze sadržava estradiol u količini u granicama od oko 0.1 do 5 mg, navedeni drospirenon je u mikroniziranom obliku.65. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit and are intended for oral application for a period of at least 28 days, indicated that at least 21 daily dose units contain a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and no more than 7 stated dosage units contain estradiol in an amount ranging from about 0.1 to 5 mg, said drospirenone is in micronized form. 66. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja, a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 uzastopnih dana, naznačen time, da najmanje 10 navedenih dnevnih jedinica doze sadržava kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg, i najmanje 10 navedenih dnevnih jedinica doze sadržava kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg; i ne više od 8 navedenih jedinica doze je placebo ili prazna, navedeni drospirenon je u mikroniziranom obliku.66. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit, and are intended for oral application for a period of at least 28 consecutive days, indicated that at least 10 of the stated daily the dose unit contains a combination of estradiol in an amount ranging from about 0.1 to 5 mg, i at least 10 stated daily dosage units contain a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and not more than 8 of the stated dosage units is placebo or blank, the stated drospirenone is in micronized form. 67. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja, a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 28 uzastopnih dana, naznačen time, da najmanje 10 dnevnih jedinica doze sadržava estradiol u količini u granicama od oko 0.1 do 5 mg; i najmanje 10 dnevnih jedinica doze koje sadržavaju kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg; i ne više od 8 navedenih jedinica doze sadržava estradiol u količini u granicama od oko 0.1 do 5 mg, navedeni drospirenon je u mikroniziranom obliku.67. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit, and are intended for oral application for a period of at least 28 consecutive days, indicated that at least 10 daily units doses contain estradiol in an amount ranging from about 0.1 to 5 mg; and at least 10 daily dosage units containing a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and no more than 8 stated dosage units contain estradiol in an amount ranging from about 0.1 to 5 mg, said drospirenone is in micronized form. 68. Multi-fazni farmaceutski pripravak sadržava određeni broj odvojenih pakiranja, a dnevne jedinice doze koje se mogu pojedinačno odstraniti smještene su u jedinicu pakiranja, a namjenjene su za oralnu aplikaciju za razdoblje od najmanje 21 dg 30 uzastopnih dana, naznačen time, da najmanje 10 do 15 dnevnih jedinica doze koje sadržavaju kombinaciju estradiola u količini u granicama od oko 0.1 do 5 mg i drospirenon u količini u granicama od oko 0.25 do 6 mg; i 10 do 15 navedenih jedinica doze sadržava estradiol u količini u granicama od oko 0,1 do 5 mg, navedeni drospirenon je u mikroniziranom obliku.68. The multi-phase pharmaceutical preparation contains a certain number of separate packages, and the daily dose units that can be individually removed are placed in the package unit, and are intended for oral application for a period of at least 21 days and 30 consecutive days, indicated that at least 10 up to 15 daily dosage units containing a combination of estradiol in an amount ranging from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and 10 to 15 of the mentioned dose units contain estradiol in an amount ranging from about 0.1 to 5 mg, the mentioned drospirenone is in micronized form. 69. Multi-fazni farmaceutski pripravak u skladu s bilo kojim od Zahtjeva 62 do 68, naznačen time, da je broj dnevnih jedinica doza najmanje 21 ili višekratno 21 kao što je 2 do 12, osobito 2 do 8, kao što je 2 do 6.69. Multi-phase pharmaceutical preparation according to any one of Claims 62 to 68, characterized in that the number of daily dosage units is at least 21 or a multiple of 21 such as 2 to 12, especially 2 to 8, such as 2 to 6 . 70. Multi-fazni farmaceutski pripravak u skladu s bilo kojim od Zahtjeva 62 do 68, naznačen time, da je broj dnevnih jedinica doza najmanje 28 ili višekratno 28 kao što je 2 do 12, osobita 2 do 8, kao što je 2 do 6.70. Multi-phase pharmaceutical preparation according to any one of Claims 62 to 68, characterized in that the number of daily dosage units is at least 28 or a multiple of 28 such as 2 to 12, especially 2 to 8, such as 2 to 6 . 71. Multi-fazni farmaceutski pripravak u skladu s bilo kojim od Zahtjeva 62 do 68, naznačen time, da navedene jedinice doze sadržavaju estradiol u mikroniziranom obliku ili obliku raspršene otopine na čestice inertnog nosača.71. Multi-phase pharmaceutical preparation according to any one of Claims 62 to 68, characterized in that said dosage units contain estradiol in micronized form or in the form of a dispersed solution on particles of an inert carrier. 72. Multi-fazni farmaceutski pripravak u skladu s bilo kojim od Zahtjeva 62 do 71, naznačen time, da jedinice doze su odabrane iz skupine koja sadržava tablete, kapsule i pilule.72. A multi-phase pharmaceutical composition according to any one of Claims 62 to 71, characterized in that the dosage units are selected from the group consisting of tablets, capsules and pills. 73. Upotreba estrogena naznačena time, da je u dostatnoj količini za tretiranje simptoma menopauze ili post-menopauze i prevenciju osteoporoze žena u menopauzi ili post-menopauzi i drospirenona u dostatnoj količini za zaštitu endometrija od štetnog djelovanja estrogena za proizvodnju lijeka.73. The use of estrogen indicated by the fact that it is in sufficient quantity to treat symptoms of menopause or post-menopause and to prevent osteoporosis in women in menopause or post-menopause and drospirenone in sufficient quantity to protect the endometrium from the harmful effects of estrogen for the production of medicine. 74. Upotreba estrogena naznačena time, da je u dostatnoj količini za tretiranje simptoma menopauze ili post-menopauze i prevenciju osteoporoze žena u menopauzi ili post-menopauzi i drospirenona u dostatnoj količini za zaštitu endometrija od štetnog djelovanja estrogena za proizvodnju lijeka za hormonsku nadomjesnu terapiju.74. The use of estrogen indicated by the fact that it is in sufficient quantity to treat menopause or post-menopause symptoms and prevent osteoporosis in women in menopause or post-menopause and drospirenone in sufficient quantity to protect the endometrium from the harmful effects of estrogen for the production of a drug for hormone replacement therapy.