SA01210754B1 - Pharmaceutical combination of DROSPIRENONE and estrogen for hormone replacement therapy - Google Patents

Abstract

A pharmaceutical composition comprising as a first active ingredient an estrogen, such as estradiol or estradiol valerate, in sufficient amounts to treat disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active ingredient 6 beta , 7 beta ; 15 beta ; 16 beta -dimethylene-3-oxo-17 alpha -preg-4-ene-21, 17-carbolactone (drospirenone, DRSP) in sufficient amounts to protect the endometrium from the adverse effects of estrogen is useful for, amongst others, treating peri-menopausal, menopausal and post-menopausal women. This composition may be used for hormone replacement therapy and may be administered as a multi-phased pharmaceutical preparation. This combination therapy may comprise continuous, sequential or interrupted administration, or combinations thereof, of DRSP and estrogen, each optionally in micronized form.

Description

Pharmaceutical union of drospirenone(s si jr sd) cestrogen and estrogen 8170860 for hormone replacement therapy Full description BACKGROUND BACKGROUND The present invention relates to a pharmaceutical formulation comprising drospirenone and cestrogen and to methods of hormone replacement therapy by administering estrogen sy drospirenone to women who She suffers from -estrogen deficiency The increase in life expectancy and, consequently, the increase in the number of women in pre- and post-menopause led to an increase in public and medical awareness regarding the menopause period and its transformation in the reproductive phase in women. Last menstruation; between the age of £0 years 5 00 years in most women. AS is affected by factors including sex or race »heredity, nutrition, height, smoking, number of births, use of contraceptive hormones, length of the menstrual cycle and age The onset of puberty combined - in a right or wrong way - with the age at which the last menstrual period occurs.During these stages of life, the activity of the endocrine glands in the female undergoes a series of changes, and the result is that the physical and psychological condition of many women is adversely affected.The treatment aims Hormone replacement aims to improve women's quality of life during the natural aging process by relieving symptoms associated with this transition time and by reducing the likelihood or slowing the progression of disorders and diseases associated with reduced hormonal activity. Drospirenone is known from Patent No. 2652761 DE which discloses its use as a diuretic. The gestagen-like activity of drospirenone and thus its usefulness as a Ble pregnancy agent at levels de ja of 1.59 mg to 00 mg are disclosed in Patent No. 3022337 DE Y. A study of the use and role of progestogens in reversible forms of Omen replacement therapy by the practical group (1994) (Lobo R.A, 1992; Sobel N.B., as if they were regimens including (Corson S.L., 1993; Jones K.P., 1992) progestogens estrogens yay v The use of a replacement therapy and oral contraceptive preparation comprising at a dose of 0.7-7 mg/day) at least one drospirenone (as progestagen at least one) is detected ps 1-7 mg in a dose of at least one estradiol (as estrogens periodically so that blood loss is effectively avoided in the patent application estrogen changes dus The preparation is always available in oral form. (WO 95 07081) © PCT/EP94/02997 —+,0 of a dose of drospirenone as cgestagen Use WO 9827929 prescribed in mg/day for the treatment of disorders; ?-1 de ja in Jie estradiol mg/day; in combination with “©65008; concentration; reduced Coan RED such as sleep disturbances; mood changes; nervousness. anxiety; Loss of union may be used in the treatment of testosterone energy; Rapid irritation due to elevated levels of 0 Symptoms mentioned in the perimenopausal period. 0 In a micronized form drospirenone previously unpublished combination of WO 0115701 describes 00001 micron (micron) particulate matter (with a surface area greater than = micronized = (micronized in vitro vs. dissolving at least 79,760 g of the drospirenone component and rapidly dissolving [au min. in vitro dissolution test]) active Ye from a solid dose form over a period to inhibit ovulation In females, ethinyl estradiol 5 d is described as “carboxylic particles in:

Bauer KH, Fromming KH and Fiihrer C (Pharmazeutische Technologle; 4. Aufl;

Thieme, Stuttgart/New York; 1993). The invention relates in a first appearance to a pharmaceutical composition in oral dosage form comprising Y. “ethinyl estradiol by assaying” Jol natural or synthetic derivative 4 (as active agent 4) estrogen estrogen in quantities sufficient to treat diseases, disorders and symptoms associated with deficiency levels of 16B-dimethylene-3-oxo-17a-preg-4-ene- 158 78 «6p in women; and on Lid intrauterinely as a second active agent in sufficient amounts to protect the lining membrane (drospirenone) 21,17-carbolactone together with carriers or acceptable excipients uterine estrogens from the adverse effects of the ve to yo mentioned in an amount corresponding to a daily dose of pharmaceutical grade drospitenone and said drospirenone is in a carbonated form; Or drospirenone is mg and is 0 cross-linked

¢ A form having a surface area greater than 00001 sq/g or said drospirenone is in such a rapid solubility form that at least 0/71 of said drospirenone dissolves within yo min when the composition is subjected to the 00 dissolution test mL of water at 71 “” percolator using USP XXIII Paddle Method 11 operating at agitation rate of 0 © rpm. ° The Al aspect of the invention relates to the use of a combination of drospirenone 5 estrogen in the preparation of a drug for the treatment of diseases; disorders and symptoms associated with menopause; perimenopause; post menopause; functional hypogonadism; Castration or primary ovarian insufficiency in females “where the amount of estrogen is sufficient to treat diseases”; Disorders and symptoms associated with low levels of isd as estrogen and select diseases; The aforementioned disorders and symptoms are from group 0 of heat waves; sweat spells; palpitations » sleep disturbances; mood changes; nervousness; (BEN) memory impairment; loss of confidence; loss of erotica; poor concentration; decreased energy and activity; irritability; atrophy of the genitourinary system; atrophy of the breast; cardiovascular disease; changes in hair distribution, hair density, 0 changes in alls of the skin, osteoporosis An amount of drospirenone is sufficient to protect the inner cavity from harmful effects of estrogenand said drospirenone 00001 said in a form having a greater surface area than drospirenone in a carbonated form; or ve

Ive stated in a rapid solubility form such that it dissolves at least drospirenone g or is [am 00 min] when the formulation is subjected to the solubility test in Vo stated drospirenone from agent at USP XXIII Paddle Stir Rate Method 11 mL of water at “1?”C using 0 rpm. Ye The invention further relates to a pharmaceutical preparation consisting of a number of separate packaged and transportable single daily dose units placed in a package unit and intended for enteral administration for a period of at least 71 days; so that the said daily dose units shall comprise a combination of estradiol in an amount of 1.1 to © mg and said drospirenone shall be in a carbonated form; or said drospirenone is in a form having a surface area greater than [Tas 00001 g] or said drospirenone Ye mentioned in JSG has such a rapid solubility that at least 770 of said drospirenone dissolves in Ye min at The formula undergoes a solubility test in 000 yay

°

mL of water at 17*returns using an operating USP XXIII Paddle Method 11 at a stirring rate of 0 rpm.

Furthermore it; The invention relates to a method for the treatment and prevention of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women comprising the administration of estradiol in quantities

0 corresponds to daily doses of 1 (mg to ©mg) such as 1 mg or ? mg or © mg and give

drospirenone in quantities corresponding to daily doses of 1 (mg to 7.5 mg) such as 1 mg or 1.0 mg or ? mg or Yo mg or 7 mg or 7.5 mg. Detailed description of the invention

In this context, the term “7016 cycle” is meant by itself or when associated with the term “menstrual.”

menstrual 0 is the number of days between menstruation and the next in women. It can range from YY day to VV day

Typically, TA is a day.

In this context, the term “menopause” is understood as the last normal menstrual cycle (ovarian-induced) and is considered an individual case and as a result of age-dependent dysfunction of the ovarian follicles. Menopause results from a lack of ovarian production of the sex hormones progesterone and estrogen.

ve the number of follicles drops below a certain onset (onset of bleeding); The ovaries can no longer produce

Mature follicles and sex hormones. The possibility of being able to produce again ends in despair.

The premenopausal phase begins with the onset of menopausal symptoms when the menstrual cycle becomes irregular and ends after a year of menopause. The end of perimenopause marks after a prolonged period of time without bleeding. Menopause is the phase that begins at menopause and continues until death.

steroid, and one of the main goals of hormone replacement therapy is to restore the levels of Y. sex hormones in women before menopause in a natural way or before, during and after term, or to achieve these levels in females with weak reproductive systems.

Monotherapy - which refers to treatment without opposition - is treatment with estrogens

Just. Exogenous estrogens stimulate the proliferation of the lining of the uterus. And in monoprocessing with

estrogen vo absent the anti-progesterone effect that eliminates reproduction. No phase occurs

crusting during which the upper layers of the lining membrane of the uterus peel off or peel off; Yay membrane proliferation occurs

The lining of the uterus to a greater extent than it is in the phases until it contains the premenopausal phase. The result is hyperplasia, which is a risk factor for endometrial cancer. Combined therapy - which also refers to counter-treatment - is a treatment in which 0p is added to protect the lining of the uterus from hyperplasia ° and the use of natural progesterone in combination therapy is limited by the lack of bioavailability of natural progesterone even in the form of mechanized. Clearly, it has been found that the combined treatment including the use of the progestagen Jie drospirenone is significantly Yad. The “(DRSP) drospirenone derivative”]17-a-spirolactone is a synthetic progestagen with a physiological profile strikingly similar to progesterone but with 0 significantly better bioavailability. It is considered the first synthetic progestagen to have a pharmacological profile similar to progesterone in that it is an anti-testosterone, anti-androgenic, and has anti-mineralocorticoid activity. The invention embodies a pharmaceutical composition comprising cestrogen or a natural derivative thereof or (Clima) in quantities sufficient to treat diseases; disorders and symptoms associated with decreased levels of endogenous estrogen ae in women; and as an agent cS Jad 68;78 158; (drospirenone) 163-dimethylene-3-oxo-170-preg-4-ene-21,17-carbolactone in amounts sufficient to protect the lining of the uterus from the harmful effects of estrogen together with a pharmaceutically acceptable carrier or excipient. For the active substances themselves, it is envisaged that the ester or the prodrug drospirenone could be used in the composition Glad eg oxyiminopregnane carbolactone as disclosed in WO 98/24801 Decreased estrogen levels can occur for a variety of reasons. The formulation can be such that it is sufficient to compensate for the deficient ©0708 levels regardless of the cause. The expected causes by treatment are, but are not limited to, natural menopause; premenopause; postmenopause; vo dysfunctional gonads, castration or primary ovarian insufficiency, low levels of estrogen, regardless of cause; to a general decrease in the joy of life in women. Symptoms, disorders and diseases range from the uncomfortable to the rude

0 only indicates that it is life threatening. The combination of this treatment is expected to effectively relieve all physiological and psychological pathological signs resulting from estrogen deficiency. Temporary symptoms Jie vasomotor signs and psychological symptoms are embodied in the field of treatment. Vasomotor signs include; But not exclusively; on heat waves; 0 bouts of sweating Jie night sweats and palpitations. Psychological symptoms of estrogen deficiency include, but are not limited to, insomnia and other disturbances, especially coil; memory impairment; lost confidence; mood changes; anxiety; loss of estrus Difficulty concentrating. difficulties in making decisions decreased energy and activity; excitability and crying spells. The treatment of the aforementioned symptoms may be related to the premenopausal phase for the age of the women or 0 - to the postmenopause; Sometimes for a long time. It is expected that the invention will be applicable to these and other temporary symptoms during perimenopause, menopause or postmenopause. Furthermore; The aforementioned symptoms can be alleviated if the cause of the estrogen ali is gonadal dysfunction, castration, or primary ovarian insufficiency. and in the AT embodiment of the invention; Treatment is used to treat permanent effects estrogen aiid ae Permanent effects include normal changes such as atrophy of the urinary and reproductive systems; breast atrophy; cardiovascular diseases; changes in hair distribution; hair density; Changes in skin condition and osteoporosis. atrophy of the urinary and reproductive systems and related conditions such as vaginal dryness, increased pH of the vagina and consequent changes in germination; or conditions in which Jie hypotrophy, fragmentation of elastic fibers, or fusion of collagen fibers lead to a decrease in cell volume; These are symptoms thought to be associated with that treatment. in addition to; It is believed that the invention is related to other changes of the urinary and reproductive systems associated with Jie estrogen deficiency, namely decrease in the length and/or diameter of the vagina; decrease in mucus production changes in LIAN number decrease in glycogen production decrease in growth of lactobacilli increase in ve growth of streptococci or [p51801710008; or coli. Other related changes which, however, may be prevented by the invention are those which can render the vagina vulnerable to wounding or injury such as secretory flow, vaginitis and dyspareunia. Furthermore; the a

A urinary tract infections and enuresis are other general symptoms associated with low A estrogen levels. Other embodiments of the invention contain the prevention or mitigation of normal changes associated with the deficiency of A, changes in the skin, changes in hair distribution or hair density, or mammary atrophy. Jie estrogen or osteoporosis. 0 phrase (bY! The prevention and treatment of osteoporosis, especially the most osteoporosis after an embodiment of the invention is of particular importance. Moreover, the removal of mineral salts from the bone in Bone mass and density, thinning and cutting of the trabeculae and/or consequent increase in patil bone fractures or bone deformities are believed to be particularly relevant.The prophylactic treatment of osteoporosis is an important therapeutic application of the present invention. A particularly important embodiment of the present invention includes the use of the composition in order to reduce the frequency, persistence, and/or severity of heat waves; mood changes, nervousness, ca gill, decreased energy, decreased activity and irritability, and atrophy of the urinary and reproductive systems; breast atrophy, cardiovascular disease; changes in hair distribution; hair density and changes in skin condition ve cas and osteoporosis; Most notably, heat waves; sweating spells; palpitations » disturbances mood changes; nervousness; anxiety; atrophy of the urinary and reproductive systems; atrophy of the breast or for the prevention or treatment of osteoporosis. eli ul estrogen disclosed here on HRT and includes the pharmacological method for supination. and in preferred models; 6500880 is selected from the set of estradiol v. “estrone” estradiol benzoate estradiol valerate cestradiol sulfamates “conjugated equine estradiol like conjugated estrogens containing estrogens s estriol succinate “estriol cequilin sulfate “17a-estradiol sulfate “17 (3-estradiol sulfate “estrone sulfate cequilenin sulfate” 17a- dihydroequilin ~~ sulfate «173-dihydroequilin ~~ sulfate or a mixture thereof. 1 Ta-dihydroequilenin sulfate 5 173-dihydroequilenin sulfate M estradiol »estradiol is selected from the group of 5 or a mixture ‎ estrone sulfates «estrone estradiol benzoate» estradiol valerate «sulfamates

Yay q -estradiol sulfamates s estradiol benzoate “estradiol valerate” estradiol in particular (agi estradiol in particular estradiol sulfamates or estradiol and the most preferred in this are carcinized”; estradiol Jie is particularly suitable; estrogens It is believed to be carbonated forms of carcinated: estradiol benzoate, estradiol valerate, estradiol sulfamates (Sas), estradiol, or a mixture of them, especially estradiol sulfate and estradiol valerate. carbonated estradiol sulfamates or “carbonated estradiol benzoate.” 0 drospirenone Furthermore, an important embodiment of the invention includes a composition wherein one or both of the DRSPs are estrogen in a carboxylic form; so that one of the (DRSP) is in a carbonated form. In WO 9806738 US Patent No. 417498704 or in sel pe water and in aqueous pH buffers at different pH values. Furthermore, it is inactive under acidic conditions and its isomer is hydrolyzed to drospirenone that rearranges with water under alkaline conditions. To ensure a good bioavailability of the compound; Thus, it is provided in a distinctive form that dissolves quickly.

Y. It has been found that when drospirenone Lis in a carboxytic form in a pharmaceutical formulation; Rapid dissolution of the active compound of the formulation occurs in the test tube. The carbonized material shall be such that the test group is (701 mg) of particulate matter; Here are particles 070501760006; have a surface area greater than 00001 cm/g; It has the following particle size distribution of drospirenone as determined under a microscope; There are no more than two particles in the given group (calibre 0000 mg) of larger diameter

Troe vo µm preferably < Yo particle with diameter > 10 µm and To < µm. The term “rapid dissolution 78010 is defined as a dissolution of at least 7976 in Ve min, specifically at least 0 in Yo min of drospirenone from a tablet preparation containing

And

1 milliliter of water at 1?”C is determined by 000 in drospirenone at ? mg cycle in #50 number? at USP using the USP XXIII Paddle Method Precision Dissolve Inspection Device. Alternatively, to provide 88050780008 in mechanized form; be able to be dissolved in a suitable solvent; And it is spread on the surface of the particles of the carrier, acetate or m-methanol, for example, on their surfaces in the inert drospirenone formula. This is followed by the fusion of the particles containing and without belief in limiting it to any special theory; It turns out that the rate of dissolution in the test tube of that rapid absorption for ming is related to the rate of dissolution in the organism drospirenone for OY, and this is the advantage of ail in the organism in administering the compound via the special isomeric drospirenone by the compound in the gastric media and/or hydrolysis in the intestine is actually reduced to 0 and this leads to a high bioavailability of the compound. which can also be a poorly soluble substance; However it is less estrogen and with respect to under circulating conditions in the gastrointestinal tract; Drospirenone is characterized by a rapid dissolution of ethanol by providing it in a carbonized form or by converting it into a spray of drospirenone Lad liquid and spraying it on the surface of the particles of the inert carrier. It has the added advantage of facilitating ve estrogen profile in all parts of the formula. And when estrogen provides a more homogeneous distribution of mechanization; Preferably, the particle size distribution should be as determined under a microscope: es Spe < 11 particles with a diameter of 1) + + VY,0 μm > a particle with a diameter of 4 μm; f < 01 of the particles have a diameter of 5 of the particles have a diameter of < ? 0 000 > 0 10 µm particles and < Tr plus there is no particle larger than 510 µm in diameter and < half aqueous such that estradiol or estradiol It is preferable that the particle size distribution be from: Yo μm V0 of the particles from the given group have a diameter less than 0 ies Sue VY,0 z 4 have a diameter less than rough

1 01 μm of Ji has a diameter of 5 with a diameter of less than ? micrometer or 0 μm. 1.1 with a diameter of less than 1.1 and to obtain a more rapid dissolution rate it is preferable to include carriers or excipients which improve the solubility of the two active substances. The majority of these carrier materials and excipients contain oe hydroxypropyl “carboxymethyl cellulose” cellulose, Jia derivatives that are easily soluble in water, or gelatin, hydroxypropyl methyl cellulose “cellulose.” Polyvinylpyrrolidone, especially Polyvinylpyrrolidone is expected to be useful in improving solubility. In each formulation so that it protects the endometrium drospirenone preferably dose 01 in sufficient doses - as an anti-DRSP and uterine estrogen can be used from harmful effects of To protect the endometrium from hyperplasia or cancer. Sufficient estrogen to act on DRSP and in some cases; On the other hand; Low dose estrogen can be in these cases; Jie doses may stabilize the menstrual cycle and bleeding pattern. In so that estrogen or non-existent. In these cases; It can be the production of adipose tissue. Very 1 to stabilize the menstrual cycle ALE or requires a dose of estrogen Requires no dose of bleeding form. Furthermore; and in certain models; Where the woman suffers from other disorders, for example, the use of liquids (J) estrogen is not compatible with the use of an external source of absolute in the case of serious liver diseases and pregnancy or for relative contraindications in the case of endometrial cancer and endometrial tumor; breast cancer; venous thromboembolism; hypertension; yl or estrogen and diabetes mellitus; And otosclerosis and melanoma) have very small amounts of DRSP within the formula so that the disorder or disease is mitigated. DRSP None. In these forms it can be a dose or a serving. mg per menstrual cycle; such as 11 from 10 mg to DRSP and in preferred embodiments; A dose of 1 mg per cycle corresponds to 1 mg per menstrual cycle; Especially from 50 mg to 1 mg to Ye .ve day. Other than that.; TY monthly. And the length of the menstrual cycle can change as mentioned above from 1? to a

YY

mg to YO corresponding to a daily dose of DRSP The formulation may include an amount of approximately: Jie mg; 0 mg A Yo to 1 mg 1.59 of to © mg 0.79 ° to 8.0 mg 15 to ; 1 mg of vio to 0.9 mg of Jd) from one woman to another, depending on her stage of life, estrogen, and the dose of endogenous can change the degree of severity of the symptom(s) or estrogen (menopausal or postmenopausal); 0 cs levels at disease or disorder; Targeted disease or disorder » Women's use of drugs and other pharmacokinetic variables. Sufficient to treat heat waves, DRSP seizures and/or estrogen, and in other embodiments, the dose of sweating, palpitations, sleep disturbances, mood changes, nervousness, tension, memory impairment and loss Self-confidence, loss of libido, poor concentration, decreased energy, decreased activity, irritability (vulnerability to excitability), atrophy of the urinary and reproductive systems, breast atrophy, cardiovascular disease, changes in hair distribution and hair density, changes in skin condition, or prevention or management of osteoporosis. Jie pattern of treatment being endometrial prophylaxis DRSP and/or estrogen dose dependent (Sas) decrease in number and frequency of Jie bleeding; for prevention or management of osteoporosis; for menopausal symptoms; heat and perspiration Nocturnal palpitations, mood swings, insomnia, other sleep disturbances, mood changes, nervousness, anxiety, memory impairment, loss of self-confidence, loss of libido, weakness in concentration, decreased energy, decreased activity, and irritability. and in embodiments where it is 1.5 mg to 4.8 mg; and from about 17 Jie mg to © mg; 1/10 for a daily dose of mg or ? mg or ? mg. 1 mg to ? mg and especially 1? mg; It is 0 YO estradiol valerate, for example, “SST is as effective as estradiol and in relation to doses of its derivatives. Comparative doses can be calculated by adjusting the previously mentioned doses according to relative effectiveness. yay

VY

DRSP and/or estrogen and in models where the woman is premenopausal the dose may depend on the day within the menstrual cycle; meaning; The fact that the woman is in the phase before or after ovulation, the menstrual cycle; and how to progress through each phase. In embodiments where the woman is postmenopausal or even premenopausal, the dose of DRSP and/or premenopausal estrogen depends on the time starting from the last menstrual period. In certain embodiments of the invention, the drug is administered in the form of a number of dose units. Packed separately and transportable individually placed in a packaging unit and intended for oral administration for a period of one day. In these models, 71 days; and such as at least 90 YA or at least YA Jie day; YY at least equal within each dose unit or estrogen and/or DRSP can be dosed from in the dose unit according The estrogen phase and/or DRSP are changing. In these models where the amount of YA per day changes; and such as at least 71 or the day within the menstrual cycle that extends at least > 0 given as the stated dose unit; These formulations, methods of treatment, and preparations are expressed in polyphasic phases. The dosage ratios may change according to their use. In preferred models, the dose ratios for the treatment of diseases are estrogen to prepare the drug so that the doses of drospirenone s estrogen of endogenous origin and the amount of estrogen and the disorders and symptoms associated with a deficiency of 1 levels of estrogen are sufficient to protect the endometrium from harmful effects For drospirenone, and in preferred models, the dosage ratios are sufficient to treat heat waves, sweating attacks, palpitations, sleep disorders, mood and nervous changes, tension, poor memory, loss of self-confidence according to eroticism, poor concentration, decreased energy, decreased activity, irritability (susceptibility to excitation) and atrophy. Urinary and reproductive systems, breast atrophy, cardiovascular disease, changes in hair distribution ©, hair density, changes in skin condition, prevention or management of osteoporosis. In women, it includes giving Lidl internal estrogen estrogen in sufficient quantities to protect the endometrium from the harmful effects of the aforementioned drospirenone, for which the method is used, is estrogen. Normal menopause, premenopause, postmenopause, functional hypogonadism, castration, or primary ovarian insufficiency. yay y¢ Diseases, disorders, and symptoms for which the method is used include heat waves, sweating spells, palpitations, sleep disturbances, mood changes, and nervousness tension, poor memory, loss of self-confidence, loss of arousal, poor concentration, decreased energy, decreased activity, irritability, atrophy of the urinary and reproductive systems, breast atrophy, cardiovascular disease, changes in hair distribution and hair density, changes in skin condition, prevention or management 1 osteoporosis. In particular; It is expected that the method will be used to treat heat waves, sweating attacks, palpitations, sleep disorders, mood and nervous changes, tension, atrophy of the urinary and reproductive systems, breast atrophy, and prevention and management of osteoporosis. succinate “estriol” estrone “ethinyl estradiol” estradiol benzoate “valerate 0 17B-estradiol “estrone sulfate Jie Conjugated equine estrogens containing estrogens 170- “17B-dihydroequilin sulfate “equilin sulfate”]17a-estradiol sulfate “sulfate 17a- 5 17B-dihydroequilenin sulfate «equilenin sulfate «dihydroequilin sulfate cestradiol sulfamates» estradiol pH and 1270L 06 or a mixture of them. most preferred sulfate or a mixture thereof; Specifically estrone sulfate 5 estrone estradiol benzoate “estradiol valerate” more estradiol t/r (DRSP) drospirenone A particularly effective embodiment of the invention comprises the administration of an estrogen in a carbonated form. Furthermore and of particular importance where estrogen is these forms; One or both of the Jie's active components are given in electrified form. In estradiol esterified form. Ye mg per 71 to 15 mg of DRSP and in certain embodiments the method includes administration of a dose of 0 mg to 00 mg per menstrual cycle; Especially from 10 mg to 10 menstrual cycles; An example of a DRSP corresponds to an amount of DRSP in mg per menstrual cycle. Preferably, the method includes giving about: die mg; 01 mg to 1.78 mg for a daily dose ranging from 4 to 175 mg of Ye 1 to 176 mg of 75 to © mg and yo to £0 mg 1.5 to - mg 1 to m mg. V,0 from Jie mg to © mg; mg; from 19 mg to 4.5 mg; of 1.7 about 0 mg or 7 mg or mg. As the first active agent, estradiol and a relevant form relate to a pharmaceutical composition comprising mg to ? mg for the treatment of diseases, disorders and symptoms 1 in amounts corresponding to a daily dose of 168- and over 68; 78; 158;cell in La wall endogenous estrogen associated with decreased levels of factor II (drospirenone) dimethylene-3-oxo-17a-preg-4-ene-21, 17-carbolactone 0 mg to 7, 8 mg in amounts sufficient to protect the endometrium from 1 in quantities corresponding to a daily dose of Pharmaceutical Acceptable AE gous in combination with a carrier or estrogen Adverse effects of estrogen Certain combinations are preferred with respect to the active ingredients in the formulation Whereas 1 mg of DRSP (18 mg with estradiol) 1 mg of estradiol containing 1 mg (DRSP) is 1 mg of #1 with estradiol 1 mg of DRSP with 1 mg of estradiol 1 mg of DRSP with 7.5 mg of estradiol 1 mg of 1 mg with DRSP estradiol and DRSP mg of 1 mg of estradiol with ? mg of [45a(a; ? mg of estradiol)

DRSP with 4 mg estradiol estradiol and in preferred form; A preferred embodiment of the invention relates to a pharmaceutical composition comprising or ? mg 7.9 Ye 0 mg to ? mg; 1 as active agent in amounts corresponding to a daily dose of 0 16B-dimethylene-3-oxo0-17a-preg-4-ene-21, 17- 158 70 '6B 5' estradiol from 3.5 mg to 1 as a second active agent in amounts corresponding to a daily dose of (drospirenone) carbolactone together with a carrier or excipient (DRSP) or 7.0 mg of © (Y.0 7 1.8 0 Jie Therefore, a preferred embodiment of the invention relates to a method of treatment and prophylaxis of endogenous Yo diseases and disorders in women comprising the administration of estrogen and symptoms associated with deficiency levels of 1 mg or 1 mg or 1 mg to ?mg; as 1 in amounts corresponding to daily doses of estradiol

mg; drospirenone s in amounts corresponding to daily doses of 1 mg to V0 mg as 1 fer YoYo 8 mg. This given decrease in levels of endogenous estrogens could be associated, among other conditions, with natural menopause; perimenopause; post menopause; functional hypogonadism; castration or o primary ovarian insufficiency; A method of treatment and prevention associated with diseases, disorders and symptoms can continue until the woman's death. meaning; The formulation may be given depending on the diagnosis of the disease, disorder, or symptoms for the entire life of the individual. In certain embodiments, the method and formula may be based on the regularity of the menstrual cycle. in other models; The method can completely ignore the normal menstrual cycle.

01 It is preferable that the method be multiphase. The method may include administration of a daily dose unit for 10 to VY days and this dose includes estradiol in amounts corresponding to daily doses ranging from 11 mg to ¥ 1 mg; give Ladd a daily dose unit for 10 to 11 days containing estradiol in amounts corresponding to daily doses ranging from 1.1 mg to ¾ mg; drospirenone in amounts corresponding to a daily dose of 178 mg to 71 mg; And give too

Ne unit daily dose for whom? days to A days containing estradiol in amounts corresponding to daily doses ranging from 176 mg to © mg.

Similarly the polyphasic method may include administration of a daily dose unit from 10 days to 11 days comprising estradiol in amounts corresponding to daily doses ranging from 11 mg to ½ mg; And also give a daily dose unit for 10 days to VY day containing estradiol in caplets

Ole ja in quantities corresponding to drospirenone s mg to © 11 mg corresponding to daily doses ranging from 8 0 mg to + mg; Also give a daily dose unit for the duration of; Days to 1.75 days ranging from days that include sterile medication given to calm the patient (satisfying therapy) or devoid of active ingredients.

The method regimen may include administration of a daily dose unit for at least 71 days, including:

contains estradiol in amounts corresponding to daily doses ranging from 1.1 mg to drospirenone s ©

ve in amounts corresponding to daily doses ranging from YO + mg to 1 mg; And also give a unit dose

daily for no more than days that include a satisfactory or devoid of active ingredients. And it could

A regimen similar to the method includes administration of a daily dose unit for at least 71 days comprising the inoculum

VY drospirenone 5 mg to © 6.1 mg in amounts corresponding to daily doses ranging from estradiol mg to + mg; And also give a unit dose of YO + in amounts corresponding to daily doses ranging from in amounts corresponding to daily doses ranging from daily estradiol for a period not exceeding days including mg to © 1 ° and by the Aly method it can include The method consists in administering a unit daily dose for at least TY day comprising estradiol in amounts corresponding to daily doses ranging from 11 mg to drospirenone in amounts corresponding to doses deg from 1.76 mg to 1 cane and a unit dose is not given for a period not exceeding “days”. An alternative version of the method includes administration of a daily unit dose for a period of 1 ?day to YA day 0 comprising estradiol in amounts corresponding to daily doses ranging from 11 mg to drospirenone in amounts corresponding to daily doses ranging from 1.79 mg to 1 mg. The regimen may include continuous administration; meaning that it is on Jae from 71 days to YA days; A daily dose of estrogen is similarly given; Drospirenone can be administered continuously and thus one or both of the estrogen and DRSP Vo are given continuously and in another embodiment the estrogen is given continuously and drospirenone is given sequentially. In this form, over the course of continuous administration of cestroge, DRSP is given at regular intervals; for a period of one day to Te day; Jie for how long? days to 15 days; From © days to Ve days; In particular from 1 day to VE day. In another important model of a system of method; The dose of estrogen is lower in the 1- to 2-day period immediately following sequential administration of drospirenone. Furthermore; In one embodiment of the invention; The use of element Yo for the treatment and prevention of diseases, disorders and symptoms associated with a lack of endogenous estrogen level in women includes continuous administration of estrogen and intermittent administration of progestin, especially 00 can be given continuously for a period of TY days to 71 day 5 drospirenone can be given for ? days, then Yo block it for © days, periodically. The preferred dala form within this alternative drospirenone can be given on days from; to 8, from 01 to OF, from 11 to VA, from TY to YE, from YA to Fe, while estradiol Jie estrogen can be given continuously. And

Ya

The composition of the unit dose may be formulated in any manner traditional in the art of pharmacy. especially; As previously described (Se) the formulation shall be formulated in such a way as to provide drospirenone plus - as desired estradiol Jie estrogen carbonated form in said unit dose form; or spray from a solution onto particles of an inert carrier by mixing with a single excipient Or more, 1 pharmaceutically acceptable, which improves the solubility of estrogen 5 drospirenone, in order to improve the rapid solubility of drospirenone, preferably estradiol given orally.The appropriate excipients A Td contain dalle substances, for example, sugar Glucose dactose ie or “sucrose” and sugar alcohols cmannitol Jie Starch Lis (Jae corn, potato or modified starch; lubricants such as Stale magnesium stearate and binders such as polyvinylpyrrolidone “cellulose” derivatives hydroxypropylmethyl hydroxypropyl cellulose «carboxymethyl cellulose 0 amethyl cellulose »cellulose or gelatin to make oral dosage forms Jie tablets, pills or capsules The tablets can be coated in a conventional way with a suitable agent that forms a thin film around the tablet, for example -hydroxypropylmethyleellulose Lad The present formulation can be formulated as a liquid; eg as solutions, suspensions or vo emulsions; together with conventional diluents or excipients in a manner substantially known in the art of pharmacy. An important and specific system concept for a polyphasic pharmaceutical includes the sequential administration of both estrogen and 0705011©008. An effective model for such a regimen would include a treatment-free period in which no unit dose is administered such as that containing a daily unit dose of Te to YE days and comprising estradiol in amounts corresponding to daily doses of CY Y- .mg to © 5 mg drospirenone in amounts corresponding to daily doses of 0.75 mg to 1 mg for at least 01 to 11 days of the period mentioned by Yo day to YE day; No dose units are given for how long? days to 4 days. in an alternative way Any period in which neither DRSP nor estrogen is administered is considered satisfactory or devoid of active ingredients. The HRT regimen may include method 0 of administration as a daily dose unit for a period of YO day to YE day comprising estradiol in amounts corresponding to daily doses ranging from 1.1 mg to ∼ mg; Also give drospirenone in amounts corresponding to daily doses ranging from YO mg to + mg in the last 10 to VY days of the mentioned period and

from Yo yum to YE yum; And also give a unit daily dose for a period of? Days to + Days does not include any active ingredient. The hay regimen comprises the administration of a daily dose unit of 51 to 1 YE per day comprising estradiol in amounts corresponding to daily doses ranging from 1.1 mg to ¥ mg; also administer drospirenone in amounts corresponding to daily doses ranging from TO mg to > mg in the last 01 to 11 days of the said period of 01 days to YE days; This is followed by giving for a duration; days to 8 days A daily dose unit containing estradiol in quantities less than a daily dose unit taken in the stated period from Ve day to YE day in which 68080101 is administered. And in embodiments where the drug is in the form of a number of packaged dose units Separate and removable

0 single placed in a packing unit and intended for oral administration for at least TY day; Such as YA at least a day and where the estrogen is estradiol Preferably daily dose units taken for at least 71 days comprising a combination of estradiol in an amount of about 1.1 mg to © 5 mg drospirenone in an amount ranging from about Yo mg to 6 mg; Units of daily dose taken for 7 days or less include estradiol in an amount of about 11 mg to 4 mg.

b By the Aly method the drug may be in the form of a number of single transportable dose units and in separate packages placed in packing units and intended for oral administration for at least YA day and daily dose units taken for 71 days on BY ) includes a combination of estradiol in an amount of about 1.1 mg to © mg drospirenone sy in an amount of about 176 mg to + mg and daily dose units taken for 17 days or less (dads) Satisfying or substance-free treatment

x. effective.

It is easy to trace the drug which can be in the form of a number of dose units that can be transported individually and separately wrapped and placed in a packaging unit and intended for oral administration for at least TA days and daily dose units taken at least 71 sad days It comprises a combination of estradiol in an amount of about 1.1 mg to 5 mg and drospirenone in an amount ranging from about YO 7 mg to 7 mg. There may not be any dose units in the last 7 days or less of the regimen. Yiay

Ye. Patient compliance can be aided in the many models of the system by means of a pharmaceutical preparation made to suit patients' needs or habits. One of these preparations may consist of a number of individually packaged transportable daily dose units (DUs) sealed separately on at least YA day; Such as 71 placed in a packaging unit and intended for oral administration for a period of time in an amount ranging from estradiol where the said daily dose units comprise a combination of JV on 1 0 in an amount ranging from about 0.75 mg to drospirenone s mg to ~11 mg of about mg. In addition, patient compliance can be aided by a regimen that includes a polyphasic pharmaceutical.

0 Each regimen can easily be constrained by a multiphasic pharmaceutical preparation such as consisting of the number of individual transportable daily dose units separately packaged in a packing unit and intended for oral administration for YA days where said daily dose units comprise a combination of estradiol in amounts ranging from about (+) mg to about © mg drospirenone s in amounts ranging from about 1.79 mg to about + mg. In this preparation, the amount of the rectifier changes

01 -_ Effective during the twenty-eight day period.

A preferred embodiment relates to a polyphasic pharmaceutical formulation consisting of a number of individually wrapped daily transportable dose units placed in a packing bang and intended for oral administration for 0 to 71 days in a row where Ae all albumin units The aforementioned, which is taken for a period of 10 to ve days, includes a combination of estradiol in an amount ranging from about 0.1

0 mg to about © 5 mg drospirenone in amounts ranging from about 1.75 mg to about 1 mg; The mentioned daily dose units which are taken for a period of 10 to 15 days include estradiol in an amount ranging from about 1.1 mg to about © mg. This form is particularly suitable for preparations where estrogen is given continuously for a period of 1? day to 50 days and drospirenone is given for a period of ? days and ban it for? days periodically. It is preferable within this form to be done

Yo designed the preparation so that drospirenone is given on days from; to 7 from 01 to OY from 1 to OA from ?? to YE and from 4? to .01

yay

Moreover, in a multiphasic Vana formulation where the number of daily dose units is 1 or (YA) or a multiple of 1? or YA joint Jie from ? to YE as from Y To 101 and in particular from ? to 8; Jie multiple ? to 1 joint. Similarly, the invention relates to a method for treating diseases, disorders and symptoms associated with the deficiency of Jad estrogen 0 on a multiphasic pharmaceutical preparation comprising daily dose units which aad from 1 to 1 day, preferably from ? to A days, such as To 4 FY 1 and call a common multiple of YA day.An encapsulated unit containing daily dose units can be prepared which Described above in a manner similar to that in which HRTs or oral contraceptives are made 0. This may for example be a traditional blister pack or any other form known for this purpose; for example a pack of a number suitable dose units (in this case at least YA or for special purposes; a common YA multiplier) in a sealed blister pack with a cardboard, paperboard, foil or plastic backing inside a suitable cap. Another for each blister container in the traditional way. Vo also envisions that the current formulation could be in the form of a non-gut prescription, Jie, a subcutaneous or transdermal instillation. For the work of implantation, the active agents can be formulated in an appropriate manner along with one or more polymers, which gradually erode or degrade when used on “ethylene vinylacetate” silicone polymers “Jill duu polypropylene i polyethylene 7” and in the case of recipes given Through the skin; It can be prepared in the form of an interfacial tissue or membrane or as a fluid or viscous recipe in oil or hydrogels. For transdermal patches; An adhesive that is a WIA de such as silicone “polyacrylate adhesive” or “polyisobutylene” must be included along with a foil made of - for example — “ethylene vinylacetate “polypropylene” polyethylene “polyvinylidene chloride” polyvinylchloride or Polyester and foil for transferable toilet paper made of, for example, polyester or paper coated with silicone or fluoropolymer. Gels, water, organic solvents or a mixture of them can be used to prepare the foam.

YY

Solutions for transdermal preparations. In addition, gels administered transdermal silicone gum may contain one or more suitable gel-converting agents or thickeners such as, polyacrylic acids, cellulose, or cellulose derivatives “Lis starch” or derivatives. ctragacanth derivatives. Recipes that are administered through the skin in an appropriate manner may also contain one substance, bile salts or its derivatives and/or Jie fat, or more, which improve the absorption process through the skin. 0 db recipes can be prepared in a way, 3. Ketodesogestrel For WO 94/04157 described in transdermal according to the method disclosed for example in:

BW Barry, Dermatological Formulations, Percutaneous Absorption, Marcel

Dekker Inc., New York — Basel, 1983, or YW Chien, “Transdermal Controlled 3.”

Systemic Medications:, Marcel Dekker Inc., New York — Basel, 1987. The present invention is also described in the following examples: Experimental examples Example 1: In the following way: estradiol 5 drospirenone A procedure for preparing tablets containing Sa vo (Sa vo) tablet cores are prepared from the following composition mg £V,Y 5.7 mg 16, Y Lactose monohydrate corn starch 4 mg mg; Polyvinylpyrrolidone 0500 mg mg Magnesium stearate “YAY starch kg” 0.348 kg “corn starch” by filling a granulator with a layer coated with carbonized estradiol; dana) converted into kg VY AE or 01014 mg, respectively) and 545,454 or Tg mg and 7 mg 1 mc (for a dose of ? mg, ? mg, and 1 mg, respectively); The layer, lactose monohydrate, is activated from 7.7 kg of 160000 polyvinylpyrrolidone kg of aqueous AA, and then an aqueous solution of VO is continuously sprayed on the aqueous layer while drying is carried out by heating the special air stream, ie water. into magnesium stearate in the fluidized bed.At the end of the process 1,716 kg of yay is suctioned out.

YY

Granulation tool and mixed with the particles by maintaining the fluid layer. The resulting granule is pressed into tablet cores by a compression process using a rotary tablet press. 0.77114 kg of estradiol 1 mg and for tablets containing 14.17 kg of water are dissolved in 000 macrogol and 4/4207 kg hydroxypropylmethyleellulose adhesive and 0785 kg purified dioxide. 44,814 kg is suspended, 1,1894035 kg is suspended as a kg of purified water, with stirring until it becomes homogeneous. 0111 is placed in ferric oxide pigment solution and suspension together and used to coat the tablet cores by continuously placing the coating suspension in a coating apparatus. For tablets containing ¥ mg or ¥ mg 68080101”; The specific weights of the reagents for the preparation of the dye can easily be calculated. 1 kg and an alternative formulation for tablet coating includes vs talc kg 44874 3200 macrogol kg 46774 chydroxylpropylmethylcellulose « jal ferric oxide pigment kg +, + VATE titanium dioxide kg of 7 mg Y red. Possible formulations for coating tablets include ferric oxide pigment pigment 7570 kg and macrogol 446774 kg of hydroxypropylmethylcellulose containing 4 37.7741 kg of ferric oxide +, AAEE and dtitanium dioxide of 0,1 ATT. In kg Ala 014 Tew Vo kg of YYY ETE A possible formulation for coating © mg tablets includes . eal (pigment kg 14874 300 macrogol kg of +, £E0YA 5 hydroxypropylmethyleellulose red. ferric oxide pigment kg +, YoV¢ 5 titanium dioxide from 1,1894031 tale Example: Relative Bioavailability In a comprehensive study (DRSP) drospirenone 5 (E2) esradiol evaluating relative bioavailability for 9 after treatment with either ?mg 1:2 [DRSP], a two-way randomized, open-label trial using volunteers. vs. ?P.O Coated lozenges DRSP 1 mg of E2 + 1 mg of ¥ (DRSP mg of Y + E2 from an oral adaptogen. DRSP? mg of E2 + mg from Example?: a repeat dose of estradiol The pharmacokinetics of a repeated dose (accumulation) and the potential interaction between Yo and this comprehensive study was conducted among individuals in a randomized, open manner, drospirenone, in combinations between two dose levels with a washout phase (?; weeks) ) nested; as well as making applications and

Multiple over TA day combinations of ; doses. After the last dose, the observation period was carried out for ; weeks. Treatment A: 1 mg 1 + E2 mg (DRSP daily P.O.) Treatment B: 1 mg 122 + 4 mg (DRSP daily P.O.) Treatment C: ? 12 mg + 1 mg DRSP daily P.O. Treatment D: ?mg E2 + 4 mg (DRSP daily P.O.) Evaluation: No statistically significant interaction was observed between the two active injectors. Example: endometrial prophylaxis MAJOR OBJECTIVES: To evaluate the efficacy of YA ag To day courses for combinations of 1:2-21517 Continuous 0 compared with Continuous B2 analyzes for the prevention of hyperplasia in postmenopausal women Secondary Objectives: To assess the effect of endometrial formation; bleeding patterns; and determinants Metabolic and hemorrhagic laboratory Well-being of postmenopausal women as assessed by the Women's Health Questionnaire (WHQ) and the Medical Outcomes Study 36-item Short - Form Health Survey (SF — 36). Frequency and Severity of Heat Waves Reduction of Urogenital Symptoms Drug Levels in Relative to E23 DRSP Detailed Evaluation of Subgroup Metabolic Determinants Conclusion Dosing Combinations: 1 152 mg; 1 E2 mg + DRSP 0,+ mg 1 E2 mg + 1 DRSP 1 E2 mg + DRSP 1 mg; 1 E2 mg + 101150 VV mg. 1 Postmenopausal women who first show symptoms of menopause will follow one system of © systems. Effects on the endometrium will be evaluated by a live sample to determine the occurrence of endometrial hyperplasia. Symptoms and bleeding patterns will be assessed from the patient's diary. Overall safety and effects on biochemical and hematological parameters will be evaluated. An evaluation of postmenopausal well-being and the patient's satisfaction will also be done. pay Yo Conduct glucose tolerance tests for two hours and insulin tolerance tests for one minute at designated locations. Data analysis: yay

Yo An endometrial sample is taken at the first visit and at the last visit; The data of the bleeding form are recorded in a diary and this is done daily throughout the entire study period. Two analyzes of the main efficacy variable will be done: (a) a two-sided comparison of treatment. (b) a one-sided comparison within the estimation period for a dose-effect group. Frequency schedules are established for the visits at which endometrial samples are taken. These tables will show the number and percentage of subjects under investigation in each category in relation to the endometrial response for each treatment group (and by center in the case of central reaction therapy). A general group comparison will be made regarding the incidence or effect of hyperplasia between treatment groups. The analysis will be prepared for treatment and the null hypothesis will be examined for the absence of a difference in response for 0 oppositional versus non-opposing) when adjusting for the center. estradiol) for treatment Estimating the dose response period: In addition (0 YY # 0; 1) DRSP will estimate the probability ,7 for each dose of The maximum one-sided 7495 confidence interval for each ,7 will be calculated separately. This means that the confidence intervals will be asynchronous Example #: prevention of osteoporosis weeks of treatment. Vf Primary objective: hip bone mineral density after YA OY of the hip after BMD Secondary objectives: mineral density In bone of the lumbar spine; of the middle column of the radius; for the whole body. Effects BMD a week of treatment. On determinants of bone metabolism; bleeding model; general safety. Two healthy postmenopausal women are randomly allocated into one of four groups of YE, after giving their consent. The groups will be as follows:

DRSP 1 mg + E2 1 mg ve

DRSP 1 mg + E2 1 mg

DRSP 122 mg + 1 vaccinum

Conclusion: 40 patients with osteopenia (BMD hip 1 — score between — 1 and — 2.5) and 51 patients without osteopenia should be placed in each group. All treatments are done daily, orally, during the entire treatment period of two years, without interruptions in treatment. In addition, patients will be provided with calcium tablets (+ © mg of calcium per day). The mineral density of the left hip bone will be measured using a dual-power X-ray absorptiometry when blocked; Baseline and after YA OY CVV Ved weeks of treatment. Biochemical markers of bone reconstruction will be measured at intervals. Ve and GUA are evaluated in addition to a serum alkaline phosphatase enzyme; Serum -N Medium for Osteoarthritis; creatine [calcium urine (second morning emptying); creatine /CrossLaps® poly (second morning dump). Example +: Menopausal symptoms: 1c Objective: To demonstrate that drug efficacy with respect to Lad 172-1851 for menopausal symptoms is better as a satisfying drug. Main target: heat waves. Secondary targets: sweating spells; sleep problems; psychological frustrations; nervousness; Genitourinary symptoms (vaginal dryness; (Jp) nocturia); bleeding patterns.” Public Safety. 1 mg E2 + 1 mg DRSP 1 mg E2 + ¥ mg DRSP 1 vo 122 mg + ¥ mg DRSP Satisfying Medicine Extract: YR4ay

Lal

Main involved measure: at least moderate to severe heat waves for at least 1 to 1 day of the 2-week period preceding treatment.

The VU treatment period will be 1 week (cycles of YA X days).

Heatwaves will be evaluated by Chad, frequency (frequency) and severity (spectrum).

moderate and acute) and comparing this between the active treatment groups and the satisfying treatment group.

The patient will record the occurrence of heat waves and their degree of severity in album cards. In addition, the therapist will ask the patient at each visit about other typical menopausal symptoms (sweating spells; cp gill problems; depression; nervousness; urinary and reproductive symptoms). Symptoms will be graded as mild, moderate or severe.

1 In patients with a healthy uterus, the occurrence of bleeding will be recorded every day during the study in daily cards. The patient will enter each day's data into the journal card according to the following definitions of bleeding intensity:

The code number has a definition of zero, there is no _- - no vaginal bleeding 1 Spotting less than normal menstruation according to the patient's experience Y mild Less than related to normal menstruation according to the patient's experience with no need for protection Normal Je Normal menstruation according to the patient's experience For the patient's experience, heavier than normal menstruation in relation to the patient's experience, and the following determinants and categories will be used for genitourinary symptoms: Determinant Categories Vaginal dryness yes / no / not applicable Increased frequency of urination 1 no / yes for ©0 enuresis no / yes (aad) Means wetting at least twice during two or more nights within the preceding week) Data Analysis:

For determinants of efficacy; A validity state analysis (VCA) and intention-to-treat analysis (TT) are performed and the main target variable is the individual relative change (©) in the number of heat waves. (©) is defined as Wil (1-13)/3[ where 1 and 13 are individual means, and T is the average number of heat waves per week, calculated by observation during weeks © through 16 of the treatment phase.

Ahhhh

Ya

It is the average number of heat waves per week; Calculated by observation during B and the two weeks preceding treatment. Lipid profile 1: Example [Premelle®s 22 [DRSP] Objective: The main objective of this study is to compare two types of treatment in relation to lipid profile. The shape of the lipid is generally accepted as an alternative endpoint for cardiovascular risk assessment Premique® 0.

LDL chlosterols HDL chlosterols Primary targets: lipid model containing driglycerides “IS cholesterol contains pad” Secondary targets: sample apolipoproteins “VLDL cholesterol” HDL3 cholesterol <HDL2 cholesterol Menopausal symptoms; bleeding model; Endometrial Integrity; General Safety. Lp(a)” (EB A-2 0) The study was conducted as a multicentre, open comparative study of 7060 postmenopausal women randomly enrolled in one of three groups of one hundred with their consent. DRSP: 1 mg + 122 mg 1 Vo

DRSP mg ¥ + E2 mg 1

MPA 5008605 mg conjugate + © 170 mg +, Premique® [Premelie®] Use of all oral therapies daily during the entire course of treatment, which we estimate Jug Kemph YA OY 2 years without treatment-free periods. Lipid profile measurements are made at blocking and weeks after treatment. 1 week of treatment combined with Vets 0 and

Claims (1)

Y-elements in oral dosage form The Bickert-1 pharmaceutical composition comprises: Y tethinyl esradiol by esterification of estrogen (1 0 mg; 1 0 to YO in an identical amount for a daily dose of drospirenone (b) ¢ (c) a pharmaceutically acceptable excipient or carrier; ° G. [lam 00001 stated in a form having a greater surface area than drospirenone where > in an oral dosage form Pharmaceutical composition 7-1 comprises: Y ethinyl esradiol except estrogen (1) v mg; and 01 to 1786 in an amount corresponding to a daily dose of drospirenone (b) 1 (c) pharmaceutically acceptable excipient or carrier in a rapidly soluble form such that at least 7970 of drospirenone dissolves where is > 00 min when the formulation undergoes the solubility test at Te listed within drospirenone No Agent at USP XXIII Paddle Method II rate ?#C using 17 mL water at A rpm 0 Stir 4 in oral dosage form The pharmaceutical composition 7-Pharmaceutical Composition 1 comprises: Y tethinyl esradiol excluding estrogen (1) r mg; and 01 YO administered in an amount corresponding to a daily dose of drospirenone (b) 1 (c) a clinically acceptable excipient or carrier. 5 drospirenone of a solution of drospirenone spray dus or 7;1 ;- The composition according to protection element 1 Ala Als sale Clap le v from the estrogen group, where the combination is chosen from to 1 according to any of the protection elements © 1 “estradiol benzoate estradiol valerate “estradiol sulfamates” estradiol Consisting of Y conjugates and a mixture of them. estrogens s estriol succinate “estriol” estrone v YRAY Ye conjugate from the group constituting estrogen the composition according to claim 0 where - + 01 “equilin sulfate “<17a-estradiol sulfate “17f3-estradiol sulfate estrone sulfate from Y 17]8- <equilenin sulfate “17a” is selected -dihydroequilin sulfate «17B-dihydroequilin sulfate 1 -17a-dihydroequilenin sulfate s dihydroequilenin sulfate $ from the group formed estrogen according to the claim © where composition -# 01 and mixtures of estradiol benzoate and valerate estradiol sulfamates are selected “estradiol from ¥ of them. Y .estradiol is estrogen where V is the combination according to claimant #1 in estrogen where A is to 1 of any of the claimants Wh composition 4-1 denatured form. in sufficient quantities drospirenone to; Where 1 is the combination according to any of the protective elements 0 - 1 is estrogen to protect the inner lining of the uterus from the harmful effects of Y dose drospirenone to 10; Where the amount of 1 formulation corresponds to any of the claims 11-1 mg to 8.0 mg. 16 daily ranging from ¥ in adequate amounts estrogen where OY) to 1 formulation according of any of the protective elements YY internal estrogen for the treatment of diseases, disorders and symptoms associated with deficiency levels in women. Lisa) v in sufficient quantities estrogen wherein OY is to 1 the combination according to any of the protective elements SY To treat the diseases, disorders, and symptoms associated with menopause; perimenopause; post y menopause; functional hypogonadism; castration or primary ovarian insufficiency; Diseases choose; 1 the aforementioned disorders and symptoms from the group consisting of heat waves; sweaty spells; 1 loss of AEN; memory impairment; Loss of palpitations (BIE), sleep disturbances, mood changes, nervousness, eroticism, poor concentration, decreased energy and activity, irritability, atrophy of the urinary system: genitalia, breast atrophy, cardiovascular disease, changes in hair distribution, density Hair; v changes in skin condition and osteoporosis. A daily dose of estradiol where the amount of VY corresponds to 1 of the formulation according to any of the claims - 1 06 mg to © 1.1 mg. range from about yay -1#1 formulation under any of Claims 1 to VE wherein the daily oral dose form 0 is in tablet form”; capsule or pill. ) = a pharmaceutical preparation consisting of a number of individually packaged daily transportable dose units (Y) placed in a packing unit and intended for oral administration r for a period of at least 71 days; Whereas the daily dose units mentioned include a combination of estradiol in an amount of about 11 mg to 5 mg drospirenone in an amount of about 8 mg to 7 mg and in a form having a surface area greater than 00001 cm'/g . VY) a pharmaceutical preparation consisting of a number of single daily dose units ALE for transfusion with separate packaging placed in a packing unit and intended for oral administration v for a period of at least TY day; Where daily dose units comprise a combination of estradiol ¢ in an amount of about 1.1 mg to drospirenone s in an amount of about YO mg to 7 mg and in a fast soluble form so that it dissolves on Least 1 7970 of said drospirenone in 1 minute when unit de all is subjected to a solubility test of 7 in 0 milliliters of water at 71 ?*C using USP XXIII Paddle Method IT working at rate A Stirring 0 0 rpm. -118 01 A pharmaceutical preparation consisting of a number of individually packaged transportable daily dose units placed in a packing unit and prepared for oral administration for a period of at least TY day; Whereas the daily dose units mentioned include a combination of estradiol in an amount of about 1 mg to 5 mg drospirenone in an amount of about YO mg to 1 mg; And it is in a enabled form. -1 00 Wh preparation for any of the OAT claims wherein said Y administration is by mouth for YA day: -71 The preparation according to any of the VAT claims and is intended for oral administration mouth for a period of 74 days; in which at least the VY daily dose units comprise estradiol in an amount from v about 1 mg to drospirenone s in an amount from about yo mg to 1 ¢ mg.” and not more than 1 dose unit containing estradiol in a bogus or inactive dose 2 in an amount ranging from about 11 mg to © mg. yay YY YA It is intended for oral administration for the OAV period of the preparation according to any of the claims - “71 1 estradiol daily dose units mentioned at least on 01 consecutive days” where the mentioned daily dose units include at least 01 to © mg; Comprising 10 in amounts of drospirenone s mg to © 1.1 mg in amounts of about estradiol in a combination of daily dose units A mg to + mg; and not more than 175 in amounts ranging from about s mentioned to include a bogus or inactive dose. 1 YA and is intended for oral administration for the OAT period The preparation according to any of the claims 01-77 in an amount ranging from estradiol at least daily on de ja 01 units for a consecutive day; Wherein estradiol daily dose units comprise at least a combination of 10 to © mg; Comprising 1,1 between 3 in an amount ranging from about drospirenone 5 mg to © 1,1 mg in an amount ranging from about the said daily dose units A includes A mg; and not more than 1 mg to YO to 1 mg © in an amount ranging from estradiol Gob ??- the preparation according to any of Claims 18-19; Where the aforementioned administration is about 01 units of the daily dose mentioned Ve to 01 consecutive days, which includes 700 YY to mouth for a period of Y in an amount ranging from 5 drospirenone to 1.1 mg © in an amount ranging from estradiol to a combination of said daily dose unit Ve to 01 to 75 to a mg; and more than 1 to © 11 mg. in an amount ranging from estradiol ° in estradiol units, where the amount of YY T preparation varies according to any of the protective elements YE 0 - the dose mentioned according to the day of the mentioned period in which not less than 1? Day. Y in units of estradiol, where the amount of YY of the preparation is in accordance with any of the protective elements -Ye 0 The mentioned dose is the same in each unit as the dose in the packaging unit. 1 in drospirenone where the amount is (Yo) Prepared under any Claim Y1 —1 Dose units stated are the same for each unit dose contained in the packing unit. Y of drospirenone solution prepared under any Claim 17-77; spray -717 on inactive carrier particles. drospirenonc 7 mentioned in estradiol where YY prepared according to any of the claims “YA” is a carbonated form or sprayed from a solution onto particles of an inert carrier. 114Y vy The number of units of Cun FATTY 5 is 18-15 of any of the claims lide Preparation Y4 — 1 combined. YY or multiple of YY Daily dose is less than Y preparation according to claim 79; Where is the number of daily dose units? to ©0 1 co. YY or a multiple of 1 Y where the number of daily dose units YAY prepared under any of the claims is ¥Y 1 co. YA or a multiple of YA is Y where is the number of daily dose units is ? To FY 7?- the preparation according to CCP 1. YA or a multiple of VY 7 + where the number of daily dose units is ? To (FY 7?- preparation according to common claim 1. YA or multiple v wherein the dosage form is by 3-17 preparation according to any of the claims TE Oral is a tablet; capsule Or tablet ¥ For preparation of a drug for oral administration drospirenone 5 estrogen Use of a combination of 1 —Ye and for the treatment of diseases; disorders and symptoms associated with normal menopause; premenopause; postY menopause; hypogonadism; castration or primary ovarian insufficiency in women, where v diseases, disorders and symptoms are selected from the group that contains heat waves; 1 memory impairment; (BBY) sweating intentions; palpitations; ° lack of confidence, loss of libido, poor concentration, decreased energy, decreased vigor and irritability, atrophy of the urinary and reproductive systems, breast atrophy, cardiovascular disease, changes in hair distribution and hair density, changes in skin condition, osteoporosis; where the amount of A estrogen is sufficient to protect the lining of the uterus from the harmful effects of drospirenone 5 cm'/g. ?- Use a combination of 1 and to treat diseases; disorders and symptoms associated with menopause; perimenopause; after ¥ menopause; functional hypogonadism; castration or primary ovarian insufficiency in women; Where 1 diseases are selected; Disorders and symptoms from the group that include heat waves; memory impairment; mood changes; nervousness;° y14y Ye 1 lost confidence; al lost focus; decrease in energy diminished activity” and irritability; v atrophy of the urinary and reproductive systems; breast atrophy; cardiovascular disease; changes in hair distribution A hair density changes in skin condition; and osteoporosis” where the amount of drospirnone is sufficient 9 to protect the endometrium from harmful estroger UF and where the drospirenone is in a form having a rapid solubility 1 such that at least 7976 of said drospirenone dissolves within Ye min at The drug was subjected to a dissolution test in 900 mL water at 1 ?*C using USP XXII Paddle Method II VY agent at a stirring rate of 0 © rpm. 1 71?- the use of a combination of drospirenone 5 estrogen to prepare a drug for oral administration and for the treatment of “disorders and symptoms associated with menopause”; perimenopause; post 3 menopause; functional hypogonadism; castration or primary ovarian insufficiency in women; Where diseases »disorders and symptoms are selected from the group that contains heat waves; o sweating intentions; (EAN) sleep disturbances; mood changes; nervousness; (BIE) memory impairment; 1 loss of confidence; loss of libido; poor concentration; decreased energy; diminished activity; irritability; v and atrophy of the urinary system (Juli y atrophy) breast; cardiovascular disease; changes in A hair distribution; hair density and changes in skin condition and osteoporosis” wherein the amount of drospirenone 9 is sufficient to protect the lining of the uterus from harmful effects — the two drospirenone 01 estrogens mentioned which are in enabled form. 8*- Use according to claim To or daa (FN) Sprinkle drospirenone from drospirenone solution 7 onto the lanes of an inert carrier. -ve use pursuant to any of claims 785 to (YA) where estrogen is in the form of denatured Y. 400- Use according to claim (FE) where the said carbonic estrogen is as 2100 00% of particles having a diameter < 10 µm. 1)€— Use under the claim of where the said carbonic estrogen is as 0 758 percent of particles having a diameter < 01 µm. 0 7;- Use is auxiliary according to any of the claims Ye to 141; dus is estrogen in an amount of Y sufficient to treat (al gal) disorders and symptoms selected from the set of waveforms Y18Y Yo GUI nerve atrophy; estrogen Use pursuant to claim 47 where 49 -1 is Fever; estradiol benzoate “estradiol valerate” estradiol sulfamates “estradiol” consisting of conjugated Y. estrogen s estriol succinate “estriol “estrone” ethinyl estradiol 1 conjugate from estrogen where the use is off according to the protection element —fo 1 “17a-estradiol sulfate “17f3-estradiol sulfate estrone sulfate [Group Y] 70-dihydroequilin sulfate < 17f3-dihydroequilin sulfate celso sulfate v .17a-dihydroequilenin sulfate 5 178-dihydroequilenin sulfate «equilenin sulfate ¢ From the group consisting of estrogen, where (ff) the use is chosen according to protection element 7 and mixtures of estradiol benzoate 020101 and valerate estradiol sulfamates “estradiol ¥ 1” and so on. Estradiol is an estrogen of an element protection 81 where il Usage -4977 01 Dosage drospirenone 8;- Use under any of the claims ©497-7; where the quantity of 01 corresponds to 8,; 019 mg daily ranging from 7 daily doses ranging from estradiol where corresponds to the amount of EY 4;- use under claim 001 to © 1 mg. Y of any of the claims £9270 (where The oral dosage form in Use Wb -#1 is 00 capsules or tablets. pa Form Y Use according to Claims 70-89 (where the drug is in the form of a number of -#1 units Individual transportable dose in separate packaging placed in a packaging unit and prepared for administration 1 day TA day; preferably at least for 1 Y Y period Orally for at least 1 period Same in each estrogen unit 7 ?©- Use according to Clause 0 where the dose of 01 is the dose in the packaging unit. Y rude —oY 01 Use according to Claim ©1 or Cus (OF) The dose of drospirenone is the same in Y per dose unit contained in the packing unit. 1#- Use according to any of the claims (00) where transferable dose units 0 individual in combination form as specified in any of claims 1 to No —eo 001 use Wh for claim cot where drug is in the form of a number of claim units Ae ja A single, separate-encapsulated [Jul] Y cap placed in a encapsulation unit as specified in any of the FET r protection captive elements yay