UA81388C2 - Pharmaceutical composition comprising estrogen and drospirenone 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 , 7 , 15 , 16 -dimethylene-3-oxo-17 -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

Description of the invention

The present invention relates to a pharmaceutical composition including drospirenone and estrogen, and to methods of 2 hormone replacement therapy by administering drospirenone and estrogen to women with estrogen deficiency.

The expected increase in life expectancy and the associated increase in the number of peri- and postmenopausal women has led to increased public and medical awareness of the climacteric period of life, which is in the phase of transition from the reproductive period. Menopause, the last menstruation, occurs between the ages of 45 and 55 in most women. Many factors, including race, heredity, diet, height, smoking, 70 live births, use of hormonal contraception, menstrual cycle length, and age at onset of puberty, contribute, either favorably or unfavorably, to the age at last menstrual period.

During these phases of life, a woman's endocrine activity undergoes a number of changes, as a result of which the physical and psychological well-being of many women is adversely affected. Hormone replacement therapy 19 is aimed at improving the quality of life of women during this natural aging process, at alleviating the symptoms associated with this time of transition and at reducing the likelihood or slowing the progression of disorders and diseases associated with reduced hormonal activity,

Drospirenone is known from OE 26 52 761, which describes its use as a diuretic.

The progestagen-like activity of drospirenone and, as a result, its suitability as a contraceptive agent at the dose level of 0.5-5 Ωg is described in OE 30 22 337.

The use and role of progestogens in other forms of hormone replacement therapy was studied by the scientific community (Obro K.A., 1992; Bore! M.V., 1994); this also applies to regimes that include estrogens and progestogens (Soggop 5.I.., 1993; dopez K.R., 19921).

The use of the drug for replacement therapy and for oral contraception, which includes at least one of 29 progestogens and at least one estrogen, in which the dose of estrogen changes with such frequency that blood loss (3) is practically not observed, described in PCT/ЕРО4А/02997.

A first aspect of the present invention relates to a pharmaceutical composition comprising as a first active agent estrogen (or a natural or synthetic derivative thereof) in amounts sufficient to treat diseases, disorders and symptoms associated with a deficiency in endogenous estrogen levels in women, and as a second so 30 active agent - bV, 7D; 158; 16-dimethyl-3-oxo-17o-preg-4-ene-21,17-carbolactone (drospirenone) in amounts sufficient to protect the endometrium from the adverse effects of estrogen, together with pharmaceutically acceptable excipients or carriers. at

In the second aspect, the present invention relates to a pharmaceutical composition that includes estradiol as the first active agent in amounts corresponding to a daily dose of 1 to 1 mg for the treatment of diseases, disorders and

Of the symptoms associated with the deficiency of the level of endogenous estrogen in women, and as the second active agent -br, 7p; 15 years; so 16-dimethyl-3-oxo-17o-preg-4-en-21,17-carbolactone (drospirenone) in amounts corresponding to a daily dose of 1 to 3.5 mg to protect the endometrium from the adverse effects of estrogen, together with a pharmaceutically acceptable filler or carrier. "

Another aspect of the present invention relates to the use of a combination of estrogen and drospirenone for C 79 the manufacture of a medicinal product, in which the amount of estrogen is sufficient for the treatment of diseases, disorders and c symptoms associated with a deficiency in the level of endogenous estrogen in women, and the amount of drospirenone is sufficient for: » protection of the endometrium from the adverse effects of estrogen.

In yet another aspect, the present invention relates to a method of treating diseases, disorders and symptoms associated with a deficiency in endogenous estrogen levels in women, which comprises administering estrogen in amounts sufficient to alleviate said symptoms and drospirenone in amounts sufficient to protect the endometrium from the adverse effects of estrogen. - In addition, the present invention relates to a method of treatment and prevention of diseases, disorders and symptoms associated with a deficiency in the level of endogenous estrogen in women, which includes the introduction of estrogen in oz 50 amounts, corresponding to daily doses from 1 to Zmg, such as 1, 2 or Zmg, and drospirenone in amounts corresponding to daily doses from 1 to 3.5 mg, such as 1, 1.5, 2, 2.5, C or 3.5 mg.

In this context, the term "cycle" by itself or when it is associated with the term "menstrual" refers to the number of days between periods in a woman. It can vary from 21 to 31 days, usually 28 days.

In this context, the term "menopause" means the last natural (ovarian-induced) menstruation. It is a one-time event and the result of age-related dysfunction of ovarian follicles. Menopause is the result of a decrease in the production of the sex hormones estrogen and progesterone by the ovaries. When the quantity

GF) follicles falls below a certain threshold (bleeding threshold), the ovaries can no longer produce mature follicles and sex hormones. The ability to reproduce ends with menopause. o The perimenopause phase begins with the onset of climacteric symptoms, when the cycle becomes irregular and ends a year after menopause. The end of the perimenopause phase can be determined after a long period of time without bleeding. Postmenopause is a phase that begins with menopause and continues until death.

The main goal of hormone replacement therapy is to restore the levels of sex steroid hormones in women who are in natural or premature premenopause, menopause and postmenopause, or to establish the indicated levels in women with reduced hormonal activity of the gonads.

Monotherapy, also called single therapy, is estrogen-only treatment. Exogenous b5 estrogens stimulate endometrial proliferation. In estrogen therapy, the opposite effect of progesterone, which stops proliferation, is absent. The desquamation phase, during which the surface layers of the endometrium are shed, is not observed, and endometrial proliferation occurs to a greater extent than during the phases up to and including the premenopausal phase. The result is hyperplasia, a risk factor for endometrial cancer.

Combination therapy, also called dual therapy, is a treatment in which a progestogen is added to protect the endometrium from hyperplasia.

The use of natural progesterone in combination therapy is limited by the low bioavailability of natural progesterone, even in micronized form. An important fact has been established that combined therapy, including the use of drospirenone as a progestogen, is remarkably effective. Drospirenone (OK5P), a derivative of 17-o-spironolactone, is a synthetic progestogen that has a surprisingly similar physiological profile to progesterone and much higher bioavailability. It is the first synthetic progestogen, which has a pharmacological profile similar to progesterone in that it is an anti-estrogen, anti-androgen and has an anti-mineralocorticoid effect.

The present invention covers a pharmaceutical composition comprising estrogen or its natural or synthetic derivative, in amounts sufficient to treat diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, and as a second active agent - 6 DV, 7p ; 15 years; 16-dimethyl-3-oxo-17 y5-preg-4-ene-21,17-carbolactone (drospirenone) in amounts sufficient to protect the endometrium from the adverse effects of estrogen, together with pharmaceutically acceptable excipients or carriers.

In addition to the active substances themselves, it is possible to consider the possibility of using a complex ester or prodrug of drospirenone in this composition, for example, carbolactone oxyiminopregnane, as described in UUO 98/24801.

Estrogen deficiency can occur for many reasons. The composition may be such as to adequately combat a deficiency in estrogen levels, regardless of its cause. Conditions intended to be treated with this therapy include, but are not limited to, natural premenopause, perimenopause, postmenopause, hypogonadism, castration, or primary ovarian insufficiency.

Low estrogen levels, regardless of their cause, lead to a decrease in the quality of life of women in all senses. at

Symptoms, diseases and disorders range from simple inconveniences to life-threatening conditions.

The proposed treatment composition is approximately effective in alleviating all physiological and psychological symptoms of estrogen deficiency. co

Transient symptoms, such as vasomotor symptoms and psychological symptoms, are, of course, included in the scope of treatment. Vasomotor signs include, but are not limited to, hot flashes, excessive sweating such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency include, without limitation, insomnia and other disorders Go! sleep, poor memory, loss of self-confidence, mood swings, anxiety, loss of libido, difficulty concentrating, difficulty making decisions, decreased energy and motivation, irritability and tearfulness. -

Treatment of the symptoms mentioned above can be related to the perimenopause phase in a woman's life or after it, sometimes much later than menopause. It is expected that the present invention will have application for these and other fleeting symptoms during the perimenopause, menopause or postmenopause phase. In addition, the symptoms mentioned above can be alleviated if the cause of estrogen deficiency is hypogonadism, castration or primary ovarian failure. "

In another variant of the implementation of this invention, this therapy is used to treat the permanent effects of estrogen deficiency. Permanent effects include physical changes such as urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair pattern, hair thickness, skin changes, and osteoporosis.

Urogenital atrophy, conditions associated with it, such as vaginal dryness, increased pH of vaginal secretions | further changes in the flora, or phenomena that lead to the indicated atrophy, such as a decrease in the number of blood vessels

Go | vessels, fragmentation of elastic fibers, fusion of collagen fibers or reduction of cell volume, are symptoms that, as it appears, are particularly suitable for treatment with the help of the indicated therapy. In addition, this invention, as presented, is particularly suitable for the treatment of other urogenital changes associated with estrogen deficiency, such as a decrease in the length and/or diameter of the vagina, a decrease in the production of mucus, changes in the cell population, a decrease in the production of glycogen, a decrease in the growth of lactic acid bacteria or increased growth of streptococci, staphylococci or coliform bacteria. Other related changes believed to be preventable by the present invention are those that may make the vagina susceptible to injury or infection, such as exudative discharge, vaginitis, and dyspareunia. In addition, urinary tract infections and urinary incontinence are common symptoms associated with low estrogen levels.

Other embodiments of the present invention include preventing or alleviating physical changes associated with

F) with a deficiency of estrogens, such as skin changes, changes in hair growth, hair thickness, atrophy of the mammary glands or osteoporosis.

Prevention and treatment of osteoporosis, especially osteoporosis associated with postmenopause, is a particularly interesting variant of the implementation of this invention. In addition, bone demineralization, decreased bone mass and density, thinning and tearing of trabeculae, and/or a subsequent increase in the frequency of bone fractures or bone deformities appear to be particularly suitable for treatment according to the present invention.

Prophylactic treatment of osteoporosis is an interesting therapeutic application of this invention.

A particularly interesting variant of the implementation of this invention includes the use of a composition to reduce the frequency, persistence, duration and/or severity of hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, decreased energy and motivation, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair growth, hair thickness, changes in skin condition and osteoporosis, especially hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness , anxiety, urogenital atrophy, breast atrophy, or for the prevention or treatment of osteoporosis.

The pharmaceutical composition for HRT described herein includes estrogen. In a preferred embodiment of the present invention, the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinylestradiol, estrone, estriol, estriol succinate, and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17 p- estradiol sulfate, 70 T/o-estradiol sulfate, equiline sulfate, 17p-dihydroequiline sulfate, 17o-dihydroequiline sulfate, equilenin sulfate, 17p-dihydroequilenine sulfate and 17o-dihydroequilenine sulfate, or their mixtures. Particularly interesting estrogens are selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone and estrone sulfate or mixtures thereof, especially estradiol, estradiol valerate, estradiol benzoate and estradiol sulfamates. Most preferred are estradiol or estradiol sulfamates, 75 especially estradiol.

Micronized forms of estrogens such as micronized estradiol, micronized estradiol sulfamates, micronized estradiol valerate, micronized estradiol benzoate, micronized oestrone or micronized estrone sulfate or mixtures thereof are believed to be particularly suitable for this invention, especially micronized estradiol, micronized estradiol valerate, micronized estradiol benzoate or micronized estradiol sulfamates. Most preferred is micronized estradiol or micronized estradiol sulfamates, especially micronized estradiol.

In some embodiments of the present invention, in which the composition includes more than one estrogen, one or more estrogens can be in micronized form, for example, 2 or all estrogens.

In addition, an interesting variant of the implementation of this invention includes a composition in which drospirenone (OKR) is in micronized form, for example, one or more estrogens and OKR are in micronized form, preferably, both estrogen and OKR are in micronized form. at

Drospirenone, which can be obtained practically as described, for example, in 05 4 129 564 or UMO 98/06738, is a substance moderately soluble in water and aqueous buffers with different pH values. In addition, drospirenone in acidic conditions turns into an inactive isomer, and is hydrolyzed in alkaline conditions. In order to guarantee good bioavailability of the compound, it is therefore desirable to produce it in a form that facilitates its rapid dissolution. co

It was established that when drospirenone is present in the pharmaceutical composition in micronized form, "With is observed a rapid dissolution of the active compound from the composition ip migo. The micronized substance is such that the test batch (approximately 200 mg) of particles, here - drospirenone particles, has a surface area of more than 10,000 cm 2 /g, and - has the following particle size distribution for drospirenone, according to the results of microscopy: no more than 295 particles. with in this series (approximately 20Ω) with a diameter of more than ZOμm, and, mainly, "2095 particles with a diameter" of 10μm and "

ZOmkm. The term "rapid dissolution" is defined as the dissolution of at least 7095 within approximately 30 minutes, in particular, at least 8095 within approximately 20 minutes, of drospirenone from a tablet preparation "containing Zmg of drospirenone in 90O0ml of water at 372C, as determined by the method of the United States Pharmacopeia (OR) XXI! Happy

The method using apparatus 2 for the dissolution test (OR) at 50 rpm. - c As an alternative to obtaining drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, for example, methanol or ethyl acetate, and spray it on the surface of the particles of an inert carrier, and then incorporate the particles containing drospirenone on their surface into the composition.

Without intending to be bound by any particular theory, it is believed that the ip migo dissolution rate of drospirenone is related to the ip mimo dissolution rate, resulting in rapid absorption of drospirenone ip so mimo after oral administration of the compound. This is an advantage, since the isomerization of the compound in the stomach contents and/or hydrolysis in the intestine are significantly reduced, which leads to a high bioavailability of the compound. for As for estrogen, which can also be a substance moderately soluble in water, although usually so 20 is less susceptible to decomposition than drospirenone, under the conditions prevailing in the gastrointestinal tract, it is also advantageous to provide it in micronized form or sprayed from a solution , for example, in ethanol, on the surface (Che) of particles of an inert carrier. This creates an additional advantage in the form of facilitating a more homogeneous distribution of estrogen in the composition. In the case when estrogen is present in micronized form, it preferably has the following size distribution, according to the results of microscopy: 10095 particles have a diameter of 15.0 µm, 9995 particles have a diameter of 12.5 µm, 9595 particles have a diameter of 10.00 µm and 5095 particles have a diameter of "

Z, Ohm. In addition, there are no particles with a diameter greater than 20 μm, and 10 particles have a diameter of "15 μm" by 20 μm. The particle size distribution for estradiol and estradiol hemihydrate is preferably such that 10,095 particles in this series have a diameter of less than 15.0 µm, 9,995 have a diameter of less than 12.5 µm, 9,595 have a diameter of less than 60,10 µm, 5,095 have a diameter of less than 3, Ohm or 4095 have a diameter of less than 1.1 µm.

To obtain a higher dissolution rate, it is preferable to include carriers or fillers that contribute to the dissolution of both active substances.

Examples of said carriers and fillers include substances that are readily soluble in water, such as cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it is anticipated that polyvinylpyrrolidone may be particularly useful in facilitating dissolution.

The dose of drospirenone in each composition is preferably that which protects the endometrium from the adverse effects of estrogen. OK5R in sufficient doses can be used as an opponent of estrogen to protect the endometrium from hyperplasia or cancer.

In some cases, however, the dose of OK5R may be sufficient to stabilize the menstrual cycle and the nature of bleeding. In these cases, estrogen doses may be low or absent. The production of estrogens by adipose tissue can be such that very low doses of estrogen are needed to stabilize the menstrual cycle and the pattern of bleeding, or none at all. Moreover, in certain variants of the implementation of this invention, when a woman suffers from other disorders incompatible with the use of an exogenous source of 7/o estrogens (as in cases of absolute contraindications in connection with severe liver diseases and pregnancy, or relative contraindications in connection with endometrial cancer and endometriosis, breast cancer, venous thrombosis, hypertension, diabetes, otosclerosis and melanoma), the composition may contain very small amounts of estrogen, or it may be absent at all. In the specified variants of the implementation of this invention, the dose

The OC5R may be such as to alleviate a disorder, disease or symptom.

In preferred embodiments of the present invention, the dose of OK5R corresponds to 15-7Omg per cycle, for example, from to bOmg per cycle, especially from 40 to bOmg per cycle. The length of the cycle, as mentioned above, can vary from 21 to 31 days. Accordingly, the composition may include an amount of OK5R corresponding to a daily dose in the range of 0.25 to 10, for example, approximately 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, vidido 4 and from 1.5 to 3.5 mg. 20 The dose of estrogen may be different for different women, depending on the phase of her life (perimenopause or postmenopause), the endogenous level of estrogens, the severity of the symptom(s), the disorder or disease, the disorder, disease or symptom being treated, the woman's use of other drugs with other purposes and other pharmacokinetic variables.

In other embodiments of the present invention, the dose of estrogen and/or OK5R is sufficient to treat hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating , decreased energy, decreased drive, (8) irritability, urogenital atrophy, mammary gland atrophy, cardiovascular disease, changes in hair growth, hair thickness, skin conditions, or for the prevention or treatment of osteoporosis.

The dose of estrogen and/or OK5R may depend on the treatment, whether the treatment is for the protection of the endometrium, such as the pattern of bleeding, for the prevention or treatment of osteoporosis, for the treatment of menopausal symptoms, such as reducing the number, frequency and severity of hot flashes, night sweats, palpitations , associated with mood swings, insomnia and other sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, decreased energy, decreased drive, and irritability. h-

In such embodiments of the present invention, in which the estrogen is estradiol, the amount of estradiol corresponds to a daily dose in the range of from 0.01 to 5 mg, for example, from about 0.2 to 4.5, from 0.5 to 4, from 1 to With, in particular, 1, 2 or Zmg.

For doses of estradiol derivatives with higher activity, such as estradiol valerate, a comparable dose can be calculated by bringing the above doses into line with the relative activity. In such embodiments of the present invention, when a woman is in perimenopause, the dose of estrogen and/or OK5R may depend on the day of the cycle, that is, whether she is in the preovulatory or postovulatory phase of the cycle, and how long each phase continues. In such embodiments of the present invention, when a woman is postmenopausal or even premenopausal, the dose of estrogen and/or OCRI may depend on the time since the last menstrual period. In certain embodiments of the present invention, the medicinal product is administered in the form of a series of individually packaged and dosed units, which are removed from the package separately, placed in the package unit and intended for - oral administration for a period of time of at least 21 days, such as at least 28 days, such as with at least 30 or 31 days. In these embodiments of the present invention, the dose of estrogen and/or OCD may be the same in each dosage unit or may vary. In such embodiments of the present (or) invention, in which the amount of OK5P and/or estrogen in the dosage unit varies depending on the phase or day (over a period of time of at least 21 days, such as at least 28 days, during which said dosage unit is to be administered , the specified compositions, methods of treatment and drugs are called multiphase.

The ratio of doses may vary according to its application. In preferred embodiments of the present invention, the ratio of doses of estrogen and drospirenone for the manufacture of a medicinal product is such that the doses of estrogen should treat diseases, disorders and symptoms associated with a deficiency in the level of endogenous

GF) of estrogen, and the amount of drospirenone is sufficient to protect the endometrium from the adverse effects of estrogen.

Ф In preferred embodiments of this invention, the dosage ratio is sufficient to treat hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, decreased energy, reduction of stimulation, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair growth, hair thickness, changes in skin condition, or for the prevention or treatment of osteoporosis.

The present invention relates to a method of treating diseases, disorders and symptoms associated with a deficiency in endogenous estrogen levels in women, comprising the administration of estrogen in amounts sufficient to alleviate said symptoms and drospirenone in amounts sufficient to protect the endometrium from the adverse effects of estrogen . Preferably, the estrogen deficiency in which this method is used is the result of natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary ovarian failure.

Diseases, disorders and symptoms for which this method is used include hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, decreased energy, decreased stimulation, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair growth, hair thickness, changes in skin condition, or use for the prevention or treatment of osteoporosis. Specifically, this method is expected to be used for hot flashes, sweating, palpitations, sleep disturbances, 7/0 mood swings, nervousness, anxiety, urogenital atrophy, mammary gland atrophy, or for the prevention or treatment of osteoporosis.

This method refers to the introduction of estrogen, mainly estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens, such as estrone sulfate, 17 p-estradiol sulfate, 75 M /o-estradiol sulfate, equiline sulfate, 17p-dihydroequiline sulfate, 17o-dihydroequiline sulfate, equilenin sulfate, 17p-dihydroequilenine sulfate and 17o-dihydroequilenine sulfate, or their mixtures, most preferably, estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone "II estrone sulfate or their mixtures, especially estradiol.

A particularly attractive variant of the implementation of this invention includes the introduction of drospirenone (OKZR) and/or estrogen in micronized form. In addition, the variant in which estrogen is estradiol in micronized form is of particular interest. In these embodiments, one or both active ingredients are administered in micronized form.

In certain embodiments of the present invention, the specified method includes administration of a dose of OK5R corresponding to 15-70 mg per cycle, for example, from 20 to bOmg per cycle, especially from 40 to bOmg per cycle. The indicated method of urine preferably includes the administration of a dose of OK5R, in which the amount of OK5R corresponds to a daily dose in the range from 0.25 to 10 mg, for example, approximately from 0.25 to 8, from 0.25 to 6, from 0.25 to 5, from 0.5 to 4.5, from 1 to 4 or from i) 1.5 to 3.5 mg.

The amount of estradiol administered may correspond to a daily dose in the range from 0.1 to Bmg, for example, approximately from 0.2 to 4.5, from 0.5 to 4, from 1 to 3, in particular, 1, 2 or Zmg. co

A particularly suitable variant of the implementation of this invention refers to a pharmaceutical composition that includes as the first active agent estradiol in amounts corresponding to a daily dose of 1 to Zmg, for the treatment of diseases, disorders and symptoms associated with a deficiency in the level of endogenous estrogens in women, and like the second Go! active agent - br, 78; 15 years; 16D-dimethyl-3-oxo-17 d-preg-4-ene-21,17-carbolactone (drospirenone) in amounts corresponding to a daily dose of 1 to 3.5 mg, sufficient to protect the endometrium from the adverse effects of estrogen, together with a pharmaceutically acceptable filler or carrier. at

Certain preferred combinations of the active ingredients in a composition in which the estrogen is estradiol include 1 mg estradiol with 0.5 mg OK5R, 1 mg estradiol with img OK5R, 1 mg estradiol with 1.5 mg OK5R, 1 mg estradiol with 2 mg OK5R, 1 mg of estradiol with 2.5 mg OK5R, 1 mg of estradiol with Zmg OK5R, 2 mg of estradiol with img OKR and 2 mg of estradiol with 4Amg OK5R. "

In a preferred embodiment, a preferred embodiment of the present invention relates to a pharmaceutical 8s composition, which includes as the first active agent estradiol in amounts corresponding to a daily dose of 1 to 10 mg, such as 1, 1.5, 2, 2.5 or 1 mg estradiol, and as a second active agent b d, 78; 15 years; is" 16p-dimethylene-3-oxo-17x-preg-4-ene-21,17-carbolactone (drospirenone) in amounts corresponding to a daily dose of 1 to 3.5 mg, such as 1, 1,5, 2, 2.5, 3 or 3.5 mg OK5R, together with a pharmaceutically acceptable filler or carrier. (ee) Accordingly, a preferred embodiment of the present invention relates to a method of treatment and prevention of diseases, disorders and symptoms associated with a deficiency in the level of endogenous estrogen in women, which includes the administration of estradiol in amounts corresponding to daily doses from 1 to Zmg, such such as 1, 2 or Zmg, and (6) drospirenone in amounts corresponding to daily doses of 1 to 3.5 mg, such as 1.1.5, 2, 2.5, C or C3.5 mg. so 20 Taking into account the fact that the deficiency of the level of endogenous estrogens can be associated, among other reasons, with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary 12; ovarian failure, the method of treatment and prevention of related diseases, disorders and symptoms may continue until the death of the individual. In other words, the composition can be administered from the time of diagnosis of the disease, disorder or symptoms and throughout the life of the individual. In certain embodiments of the present invention, the method and composition may be based on the rhythm of the menstrual cycle. In other embodiments, the method may completely ignore the natural cycle.

IF) This method is mostly multiphase. The method may include the administration for 10-12 days of daily standard doses that include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg, and the subsequent administration for 10-12 days of daily standard doses that include estradiol in amounts, 60 corresponding to daily doses in the interval from 0.1 to Bmg, and drospirenone, in amounts corresponding to daily doses in the interval from 0.25 to Bmg; and further administration for 4-8 days of daily standard doses, including estradiol in amounts corresponding to daily doses in the range from 0.25 to 5 mgHg.

Similarly, the multiphasic method may include the administration for 10-12 days of daily standard doses that include estradiol in amounts corresponding to daily doses in the range from 0.1 to bmg; and further administration for 10-12 days of daily standard doses, which include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses in the range from 0.25 to bmg; and subsequent administration for 4-8 days of daily standard doses that do not contain the active start, pacifier, or placebo.

The mode of the method can include the introduction for at least 21 days of daily standard doses that

Include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses in the range from 0.25 to bmg; and subsequent administration for no more than 7 days of daily standard doses including placebo or pacifier. A similar mode of the method may include the administration for at least 21 days of daily standard doses that include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses in the 70 range from 0.25 to bmg; and further administration for no more than 7 days of daily standard doses, including estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg.

Alternatively, the mode of the method may include the administration for at least 21 days of daily standard doses that include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses in the range from 0.25 to bmg; and further lack of administration of doses within u75B No more than 7 days.

An alternative embodiment of the method includes the introduction during 21-28 days of daily standard doses, which include estradiol in amounts corresponding to daily doses in the range from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses in the range from 0.25 to bmg.

The mode may include continuous input; in other words, for 21-28 days, a daily dose of 200 mg of estrogen is administered. Similarly, drospirenone can be administered continuously, such that one or both of them, estrogen and OK5R, are administered continuously.

In another embodiment, estrogen is administered continuously and drospirenone is administered sequentially. In a similar embodiment, against the background of continuous estrogen administration, OCRIs are administered at regular intervals of 1-20 days, such as 3-15 days, 5-14 days, especially 6-14 days. In another interesting variant with the implementation of the regime of this method, the dose of estrogen is lower for 1-7 days, immediately following the indicated sequential administration of drospirenone. at)

In addition, in one embodiment of the present invention, the method of treatment and prevention of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women includes continuous administration of estrogen and intermittent administration of progestin. Specifically, in the method, estrogen can be administered continuously for 21-30 days, and drospirenone - in the form of a cycle "From days of intake - From days of omission." A particularly attractive variant of implementation within the specified alternative is the introduction of drospirenone from 4 to 6, from 10 to 12, from 16 to 18, from 22 to 24 and from 28 to 30 days, while estradiol is administered continuously. with

The composition of the standard dosage unit can be made by any conventional method accepted in pharmacy. In particular, as indicated above, the composition can be made by a method that includes the inclusion in the indicated dosage form of drospirenone, and, if desired, an estrogen such as estradiol, in micronized form with or sprayed from a solution onto particles of an inert carrier, in a mixture with one or more pharmaceutically acceptable excipients, to facilitate the dissolution of drospirenone and estrogen, to promote rapid dissolution of drospirenone and, preferably, estradiol, after oral administration. Examples of suitable excipients include excipients such as sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, starches such as corn or potato starch or modified starch, lubricating agents such as talc or magnesium stearate, and binding agents, such as polyvinylpyrrolidone, a cellulose derivative, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose or gelatin, for the manufacture of dosage forms for oral administration such as tablets, pills or capsules. It is convenient to coat the tablets with a suitable film-forming agent, for example, Hydroxypropyl methylcellulose. This composition may also be prepared in liquid form, for example, in the form of solutions or emulsions, together with conventional diluents or fillers, in a manner known regularly in the pharmaceutical industry. A particularly interesting mode of application of a multiphase pharmaceutical composition includes the sequential administration of both estrogen and drospirenone. An attractive variant of such a regimen would include a treatment-free interval in which the dosage unit is not administered, for example, which involves the administration for 20-24 days (o) of daily standard doses that include estradiol in amounts corresponding to daily doses in the interval of 0.1 so up to 5 mg, and drospirenone, in amounts corresponding to daily doses in the range from 0.25 to bmg during the last 10-12 days of the specified 20-24 days, and no administration of any doses during 4-8 days.

Alternatively, during any interval when neither OK5R nor estrogen is administered, a placebo or pacifier is administered. Such a regimen of hormone replacement therapy may effectively include a method comprising the administration for 20-24 days of daily standard doses comprising estradiol in amounts corresponding to

HF) daily doses in the range from 0.1 to 5 mg, and further administration of drospirenone in amounts corresponding to the daily

F doses in the interval from 0.25 to bmg, during the last 10-12 days of the indicated 20-24 days, and subsequent administration for 4-8 days of daily doses that do not include the active ingredient. The alternative regimen includes the introduction for 20-24 days of daily standard doses that include estradiol in amounts corresponding to daily doses in the interval from 0.1 to Bbmg, and the subsequent administration of drospirenone in amounts corresponding to daily doses in the interval from 0.25 to bmg , during the last 10-12 days of the indicated 20-24 days, and further administration during 4-8 days of daily standard doses, including estradiol in amounts less than the daily dose, which was administered during the 20-24 days of estradiol administration. 65 In such embodiments of the present invention, when the drug is in the form of a series of individually packaged and dosed units, removed from the package separately, placed in the package unit and intended for oral administration for a period of time of at least 21 days, in which the estrogen is estradiol, preferably , at least 21 daily dosage units contain a combination of estradiol in an amount of about 0.1 to BbBmg and drospirenone in an amount in the range of about 0.25 to bmg; and 7 or less daily dosage units include estradiol in an amount of about 0.1 to 5 mg.

Alternatively, the medicament may be in the form of a series of individually packaged and individually unpackaged dosage units, placed in the packaging unit and intended for oral administration over 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 bmg and drospirenone in an amount in the range of about 0.25 to /0 bmg 17 or less daily, not containing the active start, dosage units (pacifiers) or placebo.

From this it is easy to conclude that the medicinal product can be in the form of a number of individually packaged and dosage units, removed from the packaging separately, placed in the packaging unit and intended for oral administration for a period of time 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 Bbmg and drospirenone in an amount in the range of about 0.25 to bmg. For the last 7 days or less, there may be no dosage units at all.

Patient adherence to regimens and treatment regimens in many regimen implementations can be achieved by manufacturing a pharmaceutical preparation that meets the needs or habits of patients. One such preparation may consist of a number of individually packaged and dosed units, individually removed from the packaging, placed in the packaging unit and intended for oral administration over a period of time of at least 21 days, such as at least 28 days, in which the indicated daily standard doses include a combination of estradiol in an amount in the range of about 0.1 to 5 Bmg, and drospirenone in an amount in the range of about 0.25 to 5 mg.

In addition, a regimen that includes a multiphasic pharmaceutical preparation can help the patient adhere to the regimen and treatment regimen in many variants of the regimen. high school

Each regimen can easily be followed by a multiphase pharmaceutical preparation, such as a preparation consisting of a number of individually packaged and dosed units, individually removed from the package, placed in a package unit and intended for oral administration over a 28-day time period in which the specified daily standard doses include a combination of estradiol in an amount in the range of about 0.1 to 5 mgH, and drospirenone in an amount in the range of about 0.25 to bmg. In a similar preparation, the amount of the active ingredient changes over a 28-day period.

An attractive embodiment of the present invention relates to a multiphasic pharmaceutical formulation consisting of a number of individually packaged and dosed units, which are individually removed from the package, placed in the package unit and intended for oral administration for a period of time from 21 to 30 consecutive days, in which from 10 to 15 indicated daily dosage units comprise a combination of estradiol in an amount in the range of about 0.1 to 5 mg, and drospirenone in an amount in the range of about 0.25 to so bmg;, and from 10 to 15 indicated daily dosage units include estradiol in an amount in the range of about 0.1 to bmg. This variant of the implementation of this invention is especially suitable for preparations in which estrogen is administered continuously for 21-30 days, and drospirenone is administered in the form of a cycle "From day of reception - From day of omission". Preferably, within the scope of this variant of the implementation of this invention, the drug is made in this way, " 40. THAT drospirenone is administered from 4 to 6, from 10 to 12, from 16 to 18, from 22 to 24 and from 28 to 30 days. with c In addition, a multiphase pharmaceutical preparation in which the number of daily dosage units is 21 or 28, or a plurality of 21 or 28, such as from 2 to 24, such as from 2 to 12, especially from 2 to 8, such as: from" the set from 2 to 6.

Similarly, the present invention relates to a method of treating diseases, disorders and symptoms associated with estrogen deficiency, comprising a multiphasic pharmaceutical preparation comprising daily standard doses administered over a period of from 1 to 12, preferably from 2 to 8, for example, 2, 3, 4, 5,6, 7 and 8 multiples of 28 days. - A unit package containing the daily standard doses described above can be manufactured in a manner similar to that used for the manufacture of oral contraceptives or hormone replacement regimens. It can be, for example, a conventional blister package or any other form known for this purpose, for example, a package including an appropriate number of dosage units (in this case, at least 28, or for a specific application, a plurality of 28 ) in a hermetically sealed blister pack with a cardboard, paper, foil or plastic base and covered with an appropriate coating. It is convenient if each blister container can be numbered or marked in some other way.

It is also proposed that this composition may be in the form of a composition for parenteral administration, such as a subcutaneous implant or a composition for transdermal administration. For the manufacture of implants, it is convenient (F) to combine active agents together with one or more polymers that are gradually washed out or decomposed

F in the process of using, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.

As for compositions for transdermal administration, they can be made in the form of matrices or membranes in liquid or viscous compositions in oil or hydrogels. Transdermal patches should include an adhesive that is compatible with the skin, such as polyacrylate, silicone adhesive, or polyisobutylene, and a foil made of, for example, polyethylene, polypropylene, ethylene vinyl acetate, polyvinyl chloride, polyvinylidene chloride, or polyester, and a removable protective foil, made, for example, of polyester or paper coated with silicone or fluoropolymer. Water or organic solvents or their mixtures can be used for the production of transdermal solutions or gels. Transdermal gels may, in addition, contain one or more suitable gelling agents or thickeners, such as silicone, tragacanth, starch or starch derivatives, cellulose or a cellulose derivative, or polyacrylic acids or derivatives thereof. Transdermal compositions may conveniently contain one or more substances that enhance absorption through the skin, such as bile acids or their derivatives and/or phospholipids.

Appropriate transdermal compositions can, for example, be produced by a method similar to that described in UUO 94/04157 for Z-ketodesogestrel. Alternatively, transdermal compositions can be made in accordance with the method described, for example, in V.MU. Vagu, "YUOeptayoiIodisa! Rogtiayopz, Regscapeoiz

Arzogriyop", Magse! YuOekKeg Ips., Mem MogKK - Vaze!i, 1983, or M.MuU. SNiep, "Ttapzdegta! SopygoPed BZuvietis

Meaisayopvg", Magse! OekKkKeg Ips., Mem HogKk - Vazei, 1987. 70 The present invention is further described in the following examples, which in no way are intended to limit the claimed scope of this invention.

EXPERIMENTAL PART

Example 1

Tablets containing drospirenone and estradiol can be made in this way

The core part of tablets of the following composition: micronized drospirenone 3,bOmg micronized estradiol 1.00, 2.00, 3,OOmg lactose monohydrate 45.2, Ab, 2, AT 2mg corn starch 14.40mg modified starch 9.6Omg polyvinylpyrrolidone 25,000 4, OOmg magnesium stearate Oh, inOmg! c re is made by loading into a fluidized bed granulator 31.68 kg of corn starch, 21.12 kg of modified starch, 6.b0 mg of micronized drospirenone, 2.20, 4.40 or 6.bkg of micronized Ho) estradiol (for a dose of mg, 2 mg and Zmg, respectively) and 99.44, 101.64 or 103.84 kg of lactose monohydrate (for a dose of

Zmg, 2mg and img, respectively) and activating the current layer. An aqueous solution of 8.80 kg of polyvinylpyrrolidone 25,000 in 46.20 kg of purified water is continuously sprayed onto the fluidized bed, simultaneously drying it with a current of 20 °C of heated air. By the end of the process, 1.7 bkg of magnesium stearate is sucked into the granulator and mixed with the granules while maintaining a fluidized bed. The obtained granulate is pressed to obtain the core parts (he) of tablets on a rotary press for the manufacture of tablets.

For tablets containing 1 mg of estradiol, 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 kg of macrogol Bk 6000 are dissolved in 14.67 kg of purified water. 0.44528 kg of talc, 1.25906 bkg of titanium dioxide and 0.02575 kg of iron oxide pigment are suspended in 10.2 bkg of purified water with stirring and homogenized. The solution and suspension are combined and used to coat the core parts of the tablets by continuous application of the coating suspension in a coating apparatus. For tablets containing 2 or 100 mg of estradiol, it is easy to calculate the specific weights of the coating reagents.

An alternative composition for coating 1 mg tablets includes 2.22464 kg of hydroxypropyl methylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.1732 bkg of titanium dioxide, 0.07634 kg of iron oxide pigment, C yellow, and 0.03520 kg of iron oxide pigments, red . A possible composition for coating 2 mg tablets includes c 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.19636 kg of titanium dioxide and : c» 0.08844 kg of iron oxide pigment, red. A possible composition for coating Zmg tablets includes 2.22464 kg of hydroxypropyl methyl cellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.25906 kg of titanium dioxide and 0.02574 kg of red iron oxide pigment. and and and

Example 2: Relative bioavailability of so ! x vi ! . ! ! no! the price of relative bioavailability of estradiol (E2) and drospirenone (OKR) was carried out in a randomized - two-way cross-over study with the participation of volunteers. E2/OK5R after treatment or 2mg of E2 plus 2mg

OKR, or 2 mg E2 and bmg OK5R tablets in a shell p/o were compared with an oral solution containing 2 mg o E2 - 2 mg Oko y (o e | Example 3: Repeated dose

Pharmacokinetics of repeated doses (accumulation) and potential interaction between estradiol and sodrospirenone were evaluated. This open-label, randomized, intra-individual cross-over study of two-dose combinations with a treatment-free phase (4 weeks) interspersed with multiple administrations over 28 days 5 was conducted using 4 dose combinations. A 4-week observation period was conducted after the last dose.

GF) Treatment A: mg E2 i- mg OK5R, daily, p/o.

Treatment B: mg E2 i- 4 mg OK5R, daily, p/o. o Treatment C: 2 mg E2 i- 1 mg OK5R, daily, p/o. in Treatment 0: 2 mg E2 - 4 mg OK5R, daily, p/o.

Evaluation: No statistically significant interaction was observed between the two active ingredients.

Example 4: Protection of the endometrium

Main objective: To evaluate the effectiveness of thirteen 28-day cycles of continuous use of E2-OK5R in comparison with continuous use of E2 by analyzing the protection against hyperplasia in postmenopausal women. c5 Secondary tasks: Assess the impact on endometrial morphology, the nature of bleeding, metabolic and hemostatic laboratory parameters. The well-being of postmenopausal women as assessed using MUotep's Neay questionnaires

Opevziioppaiige (M/NO) and Tne Meadisa! Ocisotez Ziszczau 36-KMet Zpop-Bogt Neay Zygmeu (ZE-36). Effect on frequency and severity of hot flashes and relief of urogenital symptoms. OK5R and E2 levels. Detailed assessment of metabolic parameters by subgroups.

Brief overview:

Dosage groups: E2 1mg; E2 mg - OK5BR O.5 mg; E2 mg - OKR mg; E2 Tmg - OK5R 2mg; E2 mg - OK5R Zmg.

Postmenopausal women with or without menopausal symptoms are assigned to receive regimens 1 through 5. Endometrial effects are assessed by biopsy to determine the frequency of endometrial hyperplasia.

Symptoms and the nature of bleeding are assessed according to the diary entries of the participants. Evaluate general safety and 7/0 Impact on specific biochemical and hematological parameters. The patient's assessment of the quality of life in postmenopause and the assessment of the patient's satisfaction with the quality of life are also carried out.

Two-hour glucose tolerance tests and 15-minute insulin tolerance tests were performed at some stations.

Data analysis

Endometrial biopsy at visit 1 and last visit. Information on the nature of bleeding is noted in diaries throughout the study.

Two analyzes of the primary efficacy variable are performed: 1) two-way comparison of treatment regimens and 2) one-way, within the group interval, evaluation of the dose effect.

Frequency tables are obtained during visits when endometrial biopsy is performed. The specified tables show

Number and percentage of patients for each category of endometrial reaction for each treatment group (by center, in case of interaction of centers). A general and intergroup comparison of the frequency of hyperplasia among the treatment groups is performed. This analysis is an "intention-to-treat" analysis and tests the null hypothesis of no difference in response to treatment (treatment with estradiol alone versus combined treatment) when centered. with

Estimation of dose-response intervals

The probability x is estimated for each OCD dose (Her 0.0, 0.5, 1.0, 2.0, 3.0). In addition, the upper limit of a one-sided 9595 confidence interval is calculated for each l, separately (o). This means that the confidence intervals do not match.

Example 5: Prevention of osteoporosis p

Main objective: Femoral bone mineral density after 104 weeks of treatment.

Secondary objectives: Bone mineral density (BMD) of the hip after 12, 28, 52 and 80 weeks of treatment. VMO of the lumbar spine, the middle part of the radius, the whole body. Effect on the parameters of bone metabolism. The nature of bleeding. General safety.

The study is performed as a double-blind placebo-controlled trial with the participation of 240 healthy postmenopausal women, who will be randomly assigned to 4 groups of 60 people after obtaining their consent based on complete information about the study.

The groups are as follows: 1 mg E2 i- mg OK5oR 1 mg EE? "2 mg ОР " 1 mg Е2 и- Zmi ОК5Р -о s Brief review: и In each group, forty osteopenic patients (T-score of WMO femur between -1 and -2.5) and 20 "" non-osteopenic patients were administered. All types of treatment are carried out daily during the entire treatment period of 2 years, without breaks. In addition, patients are provided with calcium tablets (500 mg of calcium daily).

Measurement of the mineral density of the thigh is carried out on the left side using an absorptiometer

Go! with double energy X-rays, at screening, determination of initial values and after 12, 28, 52, 80 and 104 weeks of treatment. Biochemical markers of bone remodeling are measured at intervals. Additionally, bone-specific alkaline phosphatase in blood serum, serum osteocalcin M, urinary calcium/creatine (second morning urination) and urine StozziarzF/creatine (second morning urination) are evaluated.

Example 6: Menopausal Symptoms with Objective: To demonstrate that the therapeutic efficacy of E2-OK5BR with regard to menopausal symptoms with is superior to placebo.

Main task: Tides

Secondary problems: Sweating episodes, sleep problems, depressed mood, urogenital symptoms (vaginal dryness, pollakiuria, nocturia), the nature of bleeding. General safety

Brief review (F; Double-blind, placebo-controlled trial involving healthy postmenopausal women, who will be randomly assigned to one of 4 groups 1mg E2 i- mg OK5oR in mg E2 i 2mg OKR 1mg E2 i- Zmi OK5R placebo

Brief overview:

Main inclusion criterion: A minimum of 5 moderate to severe hot flushes per day for at least 7 to 65 days during the 2-week period preceding treatment.

The duration of treatment is 16 weeks (4 28-day cycles).

Hot flushes are assessed by recording frequency and severity (mild, moderate, severe) and comparing data between treatment and placebo groups. The patient notes the frequency and severity of hot flashes and keeps a diary. In addition, the researcher at each visit asks the patient about other typical symptoms of menopause (episodes of sweating, sleep problems, depressed mood, nervousness, urogenital symptoms). The intensity of symptoms is rated as mild, moderate, or severe.

If the patient has an intact uterus, the presence of bleeding is noted in the diaries every day throughout the study. The patient records in a diary every day according to the definitions of bleeding intensity presented below.

(with the application of calcareous soil 0001 every day) 5

The following parameters and categories are used for urogenital symptoms: urination with research) (8)

Data analysis

For efficacy parameters, the method of validity analysis (MOA) and "intent to treat" analysis (ITT) are performed. The main target variable is the individual relative change (C) in the number of tides. (C) co is defined as (T-B)/B, where T and B are individual average values. T represents the mean number of hot flushes per week calculated from observations during weeks 3 to 16 during the treatment phase. (B) co means the average number of hot flushes per week calculated from observations during the 2 weeks of the pre-treatment phase.

Example 7: Lipid profile h-

Purpose: The main purpose of this study is to compare two treatment regimens E2/OK5R and co

Rhegaiidoev/RgeteiPetya in what concerns the lipid profile. Lipid profile is commonly accepted as a surrogate endpoint for cardiovascular risk assessment.

The main task: Lipid composition, including HDL cholesterol, LDL cholesterol

Secondary tasks: Lipid composition, including total cholesterol, triglycerides, HDL cholesterol 2, « 70 HDL cholesterol 3Z, LDL cholesterol, apolipoproteins (A-1, A-2, B, E), Yr(a); symptoms of menopause; nature of Z7Z bleeding; endometrial safety; general safety. c Experimental design: The research is carried out as an open, multicenter, comparative study with the participation of 300 postmenopausal women, randomly divided into 3 groups of 100 people, after obtaining their consent based on full information about the study.

Groups: so 1mg E2 i 2mg OKR 1mg E2 i- Zmi OK5R -y Rgetidsef/Rgetegetv: 0.625mg of conjugated estrogens i- 5mMg MRA with All types of treatment are carried out daily, orally, during the entire treatment period of 2 years without breaks. Lipid profile measurements are performed at screening and after 12, 28, 52, and (se) 104 weeks of treatment, as well as six weeks after treatment. iii")

Claims (157)

The formula of the invention is different 1. A pharmaceutical composition in an oral dosage form intended for the treatment and prevention (FI of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, which includes an estrogen with the exception of ethinyl estradiol; and drospirenone in an amount corresponding to a daily dose in in the range of 0.25 to 10 mg, and in a pharmaceutically acceptable excipient or carrier, wherein the drospirenone is present in a form having a surface area of greater than 10,000 cm/g. 2. The composition according to claim 1, in which drospirenone is sprayed from its solution onto particles of an inert carrier. C. The composition according to claim 1 or 2, in which the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate, 65 conjugated estrogens and mixtures thereof. 4. The composition according to item C, in which conjugated estrogens are selected from the group that includes estrone sulfate, 17B-estradiol sulfate, 17A-estradiol sulfate, equiline sulfate, 17B-dihydroequiline sulfate, 17A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequilenine sulfate, and 17A-dihydroequilenine sulfate. 5. The composition according to item C, in which the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate and their mixtures. 6. The composition according to claim 5, in which the estrogen is estradiol. 7. The composition according to any one of claims 1-6, in which the estrogen is in a micronized form. 8. The composition according to any one of claims 1-6, in which drospirenone is present in amounts sufficient to protect the endometrium from the adverse effects of estrogen. 70 9. The composition according to any one of claims 1-8, in which the amount of drospirenone corresponds to a daily dose in the range of about 0.5 to 4.5 mg. 10. The composition of any one of claims 1-9, wherein the estrogen is present in amounts sufficient to treat diseases, disorders and symptoms associated with deficient levels of endogenous estrogen in women. 11. The composition according to any one of claims 1-10, in which estrogen is present in amounts sufficient to treat /5 diseases, disorders and symptoms associated with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary ovarian failure in women, where the diseases, disorders and symptoms are selected from the group consisting of hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue , reduction of drive, irritability, urogenital atrophy, atrophy of mammary glands, tibial vascular disease, changes in hair growth, hair thickness, changes in skin condition and osteoporosis. 12. The composition according to any one of claims 1-11, in which the amount of estradiol corresponds to a daily dose in the range from 0.1 to 5 mg. 13. The composition according to any one of claims 1-12, wherein the oral dosage form is a tablet, capsule or pill. with 14. A pharmaceutical composition in an oral dosage form for the treatment and prevention of diseases, disorders and symptoms associated with deficient levels of endogenous estrogen in women, which includes (8) estrogen with the exception of ethinyl estradiol; drospirenone in an amount that corresponds to a daily dose in the range from 0.25 to 10 mg, and a pharmaceutically acceptable filler or carrier, so that drospirenone is present in a fast-dissolving form, which is characterized by the fact that at least 70 95 drospirenone dissolves within 30 minutes. when conducting a test for dissolution of the composition in 900 ml of water at 37 rpm and a stirring speed of 50 rpm. according to the method of the US Pharmacopoeia (O5P) XXII!! Radaie s Meiinoa I. 15. The composition according to claim 14, in which drospirenone is sprayed from its solution onto particles of an inert carrier. h- 16. The composition according to claim 14 or 15, in which the estrogen is selected from the group consisting of estradiol, co-estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate, conjugated estrogens and their mixtures. 17. The composition according to claim 16, in which the conjugated estrogens are selected from the group consisting of estrone sulfate, 17B-estradiol sulfate, 17A-estradiol sulfate, equilin sulfate, 17B-dihydroequiline sulfate, "7A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequilenin sulfate and 17A-dihydroequilenine sulfate. - about the village 18. The composition according to claim 16, in which the estrogen is selected from the group consisting of estradiol, and estradiol sulfamates, estradiol valerate, estradiol benzoate, and their mixtures. "" 19. The composition according to claim 18, in which the estrogen is estradiol. 20. The composition according to any one of claims 14-19, in which the estrogen is in micronized form. 21. The composition according to any one of claims 14-19, in which drospirenone is present in amounts sufficient for Go! protection of the endometrium from the adverse effects of estrogen. 22. The composition according to any one of claims 14-21, in which the amount of drospirenone corresponds to a daily dose in the range of about 0.5 to 4.5 mg. co 23. The composition according to any one of claims 14-22, in which the estrogen is present in amounts sufficient to treat diseases, disorders and symptoms associated with deficient levels of endogenous estrogen in women. (oh) 24. The composition according to any one of claims 14-23, in which estrogen is present in amounts sufficient to treat diseases, disorders and symptoms associated with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary ovarian insufficiency in women, where the diseases, disorders and symptoms are selected from the group consisting of hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue, reduction of desire, irritability, urogenital atrophy, (F) atrophy of mammary glands, cardiovascular disease, changes in hair growth, hair thickness, changes in skin condition, etc. osteoporosis. 25. The composition according to any one of claims 14-24, in which the amount of estradiol corresponds to a daily dose in the range of up to 5 mg in vivo. 26. The composition according to any one of claims 14-25, wherein the oral dosage form is a tablet, capsule or pill. 27. A pharmaceutical composition in an oral dosage form, intended for the treatment and prevention of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, which includes 65 estrogen with the exception of ethinyl estradiol; micronized drospirenone in an amount corresponding to a daily dose in the range from 0.25 to 10 mg; and a pharmaceutically acceptable excipient or carrier. 28. The composition according to claim 27, in which the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate, conjugated estrogens and mixtures thereof. 29. The composition according to claim 28, in which the conjugated estrogens are selected from the group consisting of estrone sulfate, 17B-estradiol sulfate, 17A-estradiol sulfate, equiline sulfate, 17B-dihydroequiline sulfate, 17A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequilenine sulfate, and 17A-dihydroequilenin sulfate. ZO. The composition according to claim 28, in which the estrogen is selected from the group consisting of estradiol, /o estradiol sulfamates, estradiol valerate, estradiol benzoate and mixtures thereof. 31. The composition according to claim 3, in which the estrogen is estradiol. 32. The composition according to any one of claims 27-31, in which the estrogen is in micronized form. 33. The composition according to any one of claims 27-31, in which drospirenone is present in amounts sufficient to protect the endometrium from the adverse effects of estrogen. 34. The composition according to any one of claims 27-33, in which the amount of drospirenone corresponds to a daily dose in the range of about 0.5 to 4.5 mg. 35. The composition of any one of claims 27-34, wherein the estrogen is present in amounts sufficient to treat diseases, disorders and symptoms associated with deficient levels of endogenous estrogen in women. 36. The composition according to any one of claims 27-35, in which the estrogen is present in amounts sufficient to treat diseases, disorders and symptoms associated with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary ovarian insufficiency in women, where the diseases, disorders and symptoms are selected from the group consisting of hot flashes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue, reduction of desire, irritability, urogenital atrophy, with atrophy of mammary glands, cardiovascular disease, changes in hair growth, hair thickness, changes in skin condition and osteoporosis. at 37. The composition according to any of claims 27-36, in which the amount of estradiol corresponds to a daily dose in the range from 0.1 to 5 mg. 38. The composition according to any one of claims 27-37, wherein the oral dosage form is a tablet, capsule or soso pill. 39. A pharmaceutical kit intended for the treatment and prevention of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, which consists of a number of individually packaged daily dosage units that are individually removed from the package, placed in the package unit and intended for oral administration over a period of time of at least 21 days, in which the same daily dosage units are indicated, include a combination of estradiol in an amount in the range of about 0.1 to 5 mg, and sodrospirenone in an amount in the range of about 0.25 to 6 mg , and drospirenone is present in a form that has a surface area of more than 10,000 cm?/g. 40. The kit of claim 39 for oral administration over a period of 28 days. 41. The kit of claim 39 for oral administration over a period of time of 28 days, "in which at least 21 dosage units comprise a combination of estradiol in an amount in the range of about 0.25 to 6 mg; and no more than 7 dosage units include a pacifier, placebo, or estradiol in an amount ranging from about 0.1 to 5 mg. "" 42. The kit of claim 39 for oral administration over a period of time of 28 consecutive days, wherein at least 10 daily dosage units comprise estradiol in an amount in the range of about 0.1 to 5 M Go! at least 10 daily dosage units include a combination of estradiol in an amount 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, and no more than 8 dosage units include a placebo or dummy. with 43. The kit according to claim 39 for oral administration for a period of time that is 28 consecutive days, in which at least 10 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg; "o at least 10 daily dosage units comprise a combination of estradiol in an amount 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, and no more than 8 daily dosage units comprise estradiol in an amount in the range about 0.1 to 5 MG. 44. The kit of claim 39 for oral administration over a period of time of 21-30 consecutive days, (F; wherein 10 to 15 daily dosage units comprise a combination of estradiol in an amount 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; and 10 to 15 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg. 45. The kit of any of claims 39-44, wherein the estradiol content of the dosage units varies from day to day over a time period of at least 21 days. 46. The kit according to any one of claims 39-44, in which the content of estradiol in the dosage units is the same in each dosage unit in the package unit. 47. The kit according to any one of claims 39-46, in which the content of drospirenone in dosage units is the same in every 65 dosage units in the package unit. 48. The kit according to any one of claims 39-47, in which drospirenone is sprayed from its solution onto particles of an inert carrier. 49. The kit according to any one of claims 39-48, in which the estradiol is in micronized form or sprayed from a solution onto particles of an inert carrier. 50. A set according to any of claims 39 and 43-49, in which the number of daily dosage units is at least 21 or a multiple of 21. 51. The kit according to claim 50, in which the number of daily dosage units is a multiple of 21, such as from 2 to 12. 52. A kit according to any of claims 39-49, in which the number of daily dosage units is 28 or a multiple of 28. 53. The kit according to claim 52, in which the number of daily dosage units is a multiple of 28, something from 2 to 12. 70 54. The kit according to claim 53, in which the number of daily dosage units is a multiple of 28, such as from 2 to 6. 55. The kit according to any one of claims 39-54, in which the oral dosage form is a tablet, capsule or pill. 56. A pharmaceutical kit intended for the treatment and prevention of diseases, disorders and symptoms associated with a deficiency of endogenous estrogen levels in women, consisting of a number of individually packaged /5 daily dosage units that are individually removed from the package, placed in the package unit and intended for oral administration over a period of time of at least 21 days, in which said daily dosage units include a combination of estradiol in an amount in the range of about 0.1 to 5 mg, and drospirenone in an amount in the range of about 0.25 to b mg, and drospirenone is present in a fast-dissolving form, which is characterized by the fact that at least 70 95 drospirenone dissolves within 30 minutes. when conducting a test on the dissolution of a dosage unit in 900 ml of water at З/С and at a stirring speed of 50 rpm. according to the United States Pharmacopoeia (USP) XXIII Radae Meijos method 1. 57. The kit of claim 56 for oral administration over a period of 28 days. 58. The kit of claim 56 for oral administration over a period of 28 days, wherein at least 21 dosage units comprise a combination of estradiol in an amount in the range of about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 up to 6 mg, and no more than 7 dosage units include a pacifier, placebo or estradiol in an amount in the range of i) about 0.1 to 5 mg. 59. The kit of claim 56 for oral administration over a period of 28 consecutive days, wherein at least 10 daily dosage units comprise estradiol in an amount in the range of about 0.1 to 5 s MG, at least 10 daily dosage units comprise 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 dosage units include a placebo or dummy. 60. The kit according to claim 56 for oral administration during a period of time that is 28 consecutive days, in which h- at least 10 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 so MG; at least 10 daily dosage units include 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 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg. from the village 61. The kit according to claim 56 for oral administration for a period of time that is 21-30 consecutive days, and in which from 10 to 15 daily dosage units include a combination of estradiol in an amount in the interval and? about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 to 6 mg; and 10 to 15 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg. Go! 62. The kit of any one of claims 56-61, wherein the estradiol content of the dosage units varies from day to day over a time period of at least 21 days. - 63. The kit according to any one of claims 56-61, in which the content of estradiol in the dosage units is the same in each dosage unit in the package unit. 64. The kit according to any one of claims 56-63, in which the content of drospirenone in dosage units is the same in each (o) dosage unit in the package unit. at 65. The kit according to any one of claims 56-64, in which drospirenone is sprayed from its solution onto particles of an inert carrier. 66. The kit according to any one of claims 56-65, in which the estradiol is in micronized form or sprayed from a solution onto particles of an inert carrier. 67. A set according to any of claims 56 and 60-66, in which the number of daily dosage units is (F) at least 21 or a multiple of 21. t 68. The kit according to claim 67, in which the number of daily dosage units is a multiple of 21, such as from 2 to 12. 69. A set according to any of claims 56-66, in which the number of daily dosage units is 28 or a multiple of 28. 70. The set according to claim 69, in which the number of daily dosage units is a multiple of 28, such as from 2 to 12. 71. The set according to claim 70, in which the number of daily dosage units is a multiple of 28, such as from 2 to 6. 72. The kit of any one of claims 56-71, wherein the oral dosage form is a tablet, capsule or pill. 73. A pharmaceutical kit intended for the treatment and prevention of diseases, disorders and b5 symptoms associated with a deficiency of endogenous estrogen levels in women, which consists of a number of individually packaged daily dosage units that are individually removed from the package, placed in the package unit and prescribed for oral administration over a period of time of at least 21 days, wherein said daily dosage units include a combination of estradiol in an amount ranging from about 0.1 to 5 mg, and micronized drospirenone in an amount ranging from about 0.25 to 6 mg. 74. The kit of claim 73 for oral administration over a period of 28 days. 75. The kit of claim 73 for oral administration over a period of time of 28 days, wherein at least 21 dosage units comprise a combination of estradiol in an amount in the range of about 0.1 to 5 mg and drospirenone in an amount in the range of about 0.25 up to 6 mg; and no more than 7 dosage units include a pacifier, placebo, or estradiol in an amount in the range 70 of about 0.1 to 5 mg. 76. The kit according to claim 73 for oral administration for a period of time that is 28 consecutive days, in which at least 10 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 MG; at least 10 daily dosage units include a combination of estradiol in an amount 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, and no more than 8 dosage units include a placebo or dummy. 77. The kit according to claim 73 for oral administration for a period of time that is 28 consecutive days, in which at least 10 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 MG; at least 10 daily dosage units include 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 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg. 78. The kit of claim 73 for oral administration over a period of 21-30 consecutive days, wherein 10 to 15 daily dosage units comprise a combination of estradiol in an amount 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, and (o) another 10 to 15 daily dosage units include estradiol in an amount in the range of about 0.1 to 5 mg. 79. The kit of any one of claims 73-78, wherein the estradiol content of the dosage units varies from day to day over a time period of at least 21 days. 80. The kit according to any one of claims 73-78, in which the content of estradiol in the dosage units is the same in each dosage unit in the packaging unit. with 81. The kit according to any one of claims 73-80, in which the content of drospirenone in the dosage units is the same in each dosage unit in the package unit. h- 82. The kit according to any one of claims 73-81, in which drospirenone is sprayed from its solution onto particles of an inert carrier. 83. The kit according to any one of claims 73-82, in which the estradiol is in micronized form or sprayed from a solution onto particles of an inert carrier. 84. The kit according to any of claims 73 and 77-83, in which the number of daily dosage units is at least 21 or a multiple of 21. - s 85. The kit according to claim 84, in which the number of daily dosage units is a multiple of 21, such as from 2 to 12. 86. The kit according to any of claims 73-83, in which the number of daily dosage units is 28 or a multiple of 28. 87. The kit according to claim 86, in which the number of daily dosage units is a multiple of 28, such as from 2 to 12. 88. The kit according to claim 87, in which the number of daily dosage units is a multiple of 28, such as from 2 to 6. 89. The kit according to any one of claims 73-88, in which the oral dosage form is a tablet, capsule or pill. 90. The method of treatment of diseases, disorders and symptoms associated with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary insufficiency of ovarian function in women, where the diseases, disorders and symptoms are selected from the group consisting of hot flushes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue, decreased drive, irritability, urogenital atrophy, breast atrophy, cardiac -vascular disease, changes in hair growth, hair thickness, changes in the condition of the skin and osteoporosis, which involves the oral administration of a drug that includes a combination of estrogen and drospirenone, where drospirenone is present in quantities sufficient to protect the endometrium from the adverse effects of estrogen, and in the form, which has a surface area of more than 10,000 cm/g. 91. The method according to claim 90, in which drospirenone is sprayed from its solution onto particles of an inert carrier. (F) 92. The method according to claim 90 or 91, in which the estrogen is in micronized form. with 93. The method according to claim 92, where the micronized estrogen is characterized by a size distribution according to which 100 to particles have a diameter of "15.0 μm. 60 94. The method according to claim 93, where the micronized estrogen is characterized by a size distribution according to which 95 95 particles have a diameter of "10.0 μm. 95. The method according to any one of claims 90-94, in which estrogen is used in an amount sufficient to treat diseases, disorders and symptoms selected from the group consisting of hot flashes, sweating, palpitations, sleep disorders, mood swings, nervousness, anxiety, urogenital atrophy, breast atrophy or 65 for the prevention or treatment of osteoporosis. 96. The method according to claim 95, in which estrogen is used in an amount sufficient to treat hot flashes, sweating, palpitations. 97. The method according to any one of claims 90-96, in which an estrogen selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate, and conjugated estrogens is used. 98. The method according to claim 97, in which an estrogen selected from the group consisting of estrone sulfate, 17B-estradiol sulfate, 17A-estradiol sulfate, equiline sulfate, 17B-dihydroequiline sulfate, 17A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequiline sulfate and 17A is used. -dihydroequilenin sulfate. 99. The method according to claim 97, in which the estrogen is selected from the group consisting of estradiol, /o estradiol sulfamates, estradiol valerate, estradiol benzoate and their mixtures. 100. The method according to claim 99, in which the estrogen is estradiol. 101. The method according to any one of claims 90-100, in which the amount of drospirenone corresponds to a daily dose in the range from 0.5 to 4.5 mg. 102. The method according to claim 101, in which the amount of estrogen corresponds to a daily dose in the range from 0.1 to 5 mg. 103. The method according to any one of claims 90-102, in which the drug is administered orally in the form of a tablet, capsule or pill. 104. The method according to any one of claims 90-102, in which the drug is present in the form of a number of individually packaged daily dosage units that are individually removed from the package, placed in the package unit and intended for oral administration for a period of time that is at least 21 day, 2o mostly 28 days. 105. The method according to claim 104, in which the dose of estrogen is the same in each dosage unit in the package unit. 106. The method according to claim 104 or 105, in which the dose of drospirenone is the same in each dosage unit in the package unit. 107. The method according to any one of claims 104-106, in which the individually withdrawn dosage units are in the form of a composition characterized in any one of claims 1-13. 108. The method according to any one of claims 104-106, in which the dosage units, which are withdrawn individually, (o) are in the form of a composition characterized in any one of claims 14-26. 109. The method according to any one of claims 104-106, in which the individually withdrawn dosage units are in the form of a composition characterized in any one of claims 27-38. so so 110. The method according to any one of claims 107-109, in which the medicinal product is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are placed in a unit of packaging and constitute a co-pharmaceutical kit according to any one of claims 39- 55. with 111. The method according to any of claims 107-109, in which the medicinal product is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are placed in a packaging unit and represent a pharmaceutical kit according to any of claims 56 -72. co 112. The method according to any of claims 107-109, in which the medicinal product is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are contained in a packaging unit and constitute a pharmaceutical kit according to any of claims 73-89 . 113. The method of treatment of diseases, disorders and symptoms associated with natural menopause, perimenopause, postmenopause, hypogonadism, castration or primary insufficiency of ovarian function in women, where diseases, disorders and symptoms are selected from the group consisting of hot flushes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue, reduced drive, irritability, urogenital atrophy, breast atrophy, cardio- vascular disease, changes in hirsutism, hair thickness, changes in the condition of the skin and osteoporosis, which involves the oral administration of a drug that includes a combination of estrogen and drospirenone, where drospirenone is present in amounts sufficient to protect the endometrium from the adverse effects of estrogen, and in a form that characterized by the fact that at least 70-90% of drospirenone dissolves within 30 min. when conducting a test for dissolving a dosage unit in 900 ml of water at 37 2С and at a stirring speed of 50 rpm. according to the method of the Pharmacopoeia of the United States (O5P) XXII! Radae Mayo I. co 114. The method according to claim 113, in which drospirenone is sprayed from its solution onto particles of an inert carrier. at 115. The method according to claim 113 or 114, in which the estrogen is in micronized form. 116. The method according to claim 115, where the micronized estrogen is characterized by a size distribution according to which 100 95 particles have a diameter of "15.0 μm. 117. The method according to claim 116, where the micronized estrogen is characterized by a size distribution according to which 95% of the particles have a diameter of "10.0 μm. F) 118. The method according to any one of claims 113-117, in which estrogen is used in an amount sufficient to treat diseases, disorders and symptoms selected from the group consisting of hot flashes, sweating, palpitations, sleep disorders, mood swings, nervousness , anxiety, urogenital atrophy, mammary gland atrophy or for the prevention or treatment of osteoporosis. 119, The method according to claim 118, in which estrogen is used in an amount sufficient to treat hot flashes, sweating, palpitations. 120. The method according to any one of claims 113-119, in which an estrogen selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, 65 estrone, estriol, estriol succinate, and conjugated estrogens is used. 121. The method according to claim 120, in which an estrogen selected from the group consisting of estrone sulfate is used, 17B-estradiol sulfate, 17A-estradiol sulfate, equiline sulfate, 17B-dihydroequiline sulfate, 17A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequilenine sulfate, and 17A-dihydroequilenine sulfate. 122. The method according to claim 120, in which the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, and mixtures thereof. 123. The method according to claim 122, in which the estrogen is estradiol. 124. The method according to any one of claims 113-123, in which the amount of drospirenone corresponds to a daily dose in the range from 0.5 to 4.5 mg. 125. The method according to claim 124, in which the amount of estrogen corresponds to a daily dose in the range from 0.1 to 5 mg. 70 126. The method according to any one of claims 113-125, in which the drug is administered orally in the form of a tablet, capsule or pill. 127. The method according to any one of claims 113-125, in which the drug is present in the form of a number of individually packaged daily dosage units that are individually removed from the package, placed in the package unit and intended for oral administration for a period of time that is at least 21 /5 day, preferably 28 days. 128. The method according to claim 127, in which the dose of estrogen is the same in each dosage unit in the package unit. 129. The method according to claim 127 or 128, in which the dose of drospirenone is the same in each dosage unit in the package unit. 130. The method according to any one of claims 127-129, in which the individually withdrawn dosage units are in the form of a composition characterized in any one of claims 1-13. 131. The method according to any one of claims 127-129, in which the individually dispensed dosage units are in the form of a composition described in any one of claims 14-26. 132. The method according to any one of claims 127-129, in which the individually dispensed dosage units are in the form of a composition described in any one of claims 27-38. with 133. The method according to any of items 130-132, in which the drug is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are included in the packaging unit and are a pharmaceutical kit according to any of claims 39- 55. 134. The method according to any of items 130-132, in which the medicinal product is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are included in the packaging unit and the container is a pharmaceutical kit according to any of claims 56 -72. 135. The method according to any of clauses 130-132, in which the drug is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are contained in a packaging unit and are a pharmaceutical kit according to any of claims 73 -89. 136. The method of treatment of diseases, disorders and symptoms associated with natural menopause, h-perimenopause, postmenopause, hypogonadism, castration or primary insufficiency of ovarian function in women, where the diseases, disorders and symptoms are selected from the group consisting of hot flushes, sweating, palpitations, sleep disturbances, mood swings, nervousness, anxiety, poor memory, loss of self-confidence, loss of libido, difficulty concentrating, fatigue, decreased drive, irritability, urogenital atrophy, breast atrophy, cardiovascular disease, changes in hair growth, thickness « Hair, changes in the condition of the skin and osteoporosis, which involves the oral administration of a drug that includes a combination of estrogen and drospirenone, where drospirenone is in micronized form in amounts sufficient to protect the endometrium from the adverse effects of estrogen. with 137. The method according to claim 136, in which the estrogen is in micronized form. 138. The method according to claim 137, where the micronized estrogen is characterized by a size distribution according to which 100 95 particles have a diameter of "15.0 μm. Go! 139. The method according to claim 138, where the micronized estrogen is characterized by a size distribution according to which 95% of the particles have a diameter of "10.0 μm. - 140. The method according to any one of claims 136-139, in which estrogen is used in an amount sufficient to treat diseases, disorders and symptoms selected from the group consisting of hot flashes, sweating, palpitations, sleep disorders, mood swings, nervousness , anxiety, urogenital atrophy, atrophy of mammary glands or for the prevention or treatment of osteoporosis. with 141. The method according to claim 140, in which estrogen is used in an amount sufficient to treat hot flashes, sweating, palpitations. 142. The method according to any one of claims 136-141, in which an estrogen selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate, and conjugated estrogens is used. (F. 143. The method according to claim 142, in which an estrogen selected from the group consisting of estrone sulfate, co 17B-estradiol sulfate, 17A-estradiol sulfate, equiline sulfate, 17B-dihydroequiline sulfate, 17A-dihydroequiline sulfate, equilenin sulfate, 17B-dihydroequilenine sulfate and 17A-dihydroequilenin sulfate. 60 144. The method according to claim 142, in which the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, and mixtures thereof. 145. The method according to claim 144, in which the estrogen is estradiol. 146. The method according to any one of claims 136-145, in which the amount of drospirenone corresponds to a daily dose in the range from 0.5 to 4.5 mg. 65 147. The method according to claim 146, in which the amount of estrogen corresponds to a daily dose in the range from 0.1 to 5 mg. 148. The method according to any one of claims 136-147, in which the drug is administered orally in the form of a tablet, capsule or pill. 149. The method according to any one of claims 136-147, in which the drug is present in the form of a number of individually packaged daily dosage units that are individually removed from the package, placed in the package unit and intended for oral administration for a period of time that is at least 21 day, preferably 28 days. 150. The method according to claim 149, in which the dose of estrogen is the same in each dosage unit in the package unit. 151. The method according to claim 149 or 150, in which the dose of drospirenone is the same in each dosage unit in the package unit. 70 152. The method according to any one of claims 149-151, in which the individually dispensed dosage units are in the form of a composition described in any one of claims 1-13. 153. The method according to any one of claims 149-151, in which the individually dispensed dosage units are in the form of a composition described in any one of claims 14-26. 154. The method according to any one of claims 149-151, in which the individually withdrawn dosage units are in the form of a composition characterized in any one of claims 27-38. 155. The method according to any of items 152-154, in which the drug is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are included in the packaging unit and constitute a pharmaceutical kit according to any of claims 39-55 . 156. The method according to any of items 152-154, in which the medicinal product is present in the form of a number of individually packaged 200 mg daily dosage units, which are individually removed, which are contained in a packaging unit and constitute a pharmaceutical kit according to any of claims 56- 72. 157. The method according to any of items 152-154, in which the drug is present in the form of a number of individually packaged daily dosage units, which are individually removed, which are included in the packaging unit and constitute a pharmaceutical kit according to any of claims 73-89 . high school 0. and and and and. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated (8) microcircuits", 2008, M 1, 10.01.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. (ge) (ge) (ze) «-- Zo so - with . and? so - (55) so ii») F) ko 60 b5