Title of Invention	A PHARMACEUTICAL COMPOSITION IN THE FORM OF AN ORAL DOSAGE
Abstract	A pharmaceutical composition in the fonn of an oral dosage fonn comprising an estrogen with the exception of ethyl estradiol; drospirenone in an amount from 0.25 to 10 mg; and a pharmaceutically acceptable excipient or carrier, wherein said drospirenone is in a fonn having rapid dissolution such that at least 70% of said drospirenone is dissolved within 30 minutes when the composition is subjected to dissolution testing in 900 ml of water at 37°C using USP XXIII Paddle Method II operated at a stirring rate of 50 rpm.

Title of Invention

A PHARMACEUTICAL COMPOSITION IN THE FORM OF AN ORAL DOSAGE

Abstract

A pharmaceutical composition in the fonn of an oral dosage fonn comprising an estrogen with the exception of ethyl estradiol; drospirenone in an amount from 0.25 to 10 mg; and a pharmaceutically acceptable excipient or carrier, wherein said drospirenone is in a fonn having rapid dissolution such that at least 70% of said drospirenone is dissolved within 30 minutes when the composition is subjected to dissolution testing in 900 ml of water at 37°C using USP XXIII Paddle Method II operated at a stirring rate of 50 rpm.

Full Text	The use of a preparation for substitution therapy and for oral contraception comprising at bleast one progestagen and at least one estrogen wherein the estrogen dose varies with a dicity such that blood loss is substantially avoided is disclosed in PCT/EP94/02997. SUMMARY OF THE INVENTION The invention relates in a first aspect to a pharmaceutical composition comprising as a first active agent, an estrogen (or naturally or synthetic derivative thereof) in sufficient amounts to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent, 6B,7p;15p;16B-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbolactone (drospirenone) in sufficient amounts to protect the endometrium from the adverse effects of estrogen, together with pharmaceuticalJy acceptable excipients or carriers. In a second aspect, the invention relates to a pharmaceutical composition comprising as a first active agent estradiol in amounts corresponding to a daily dose of 1 to 3 mg to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent 6p,7p;15B;16p-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbo!actone (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 excipient or carrier. Another aspect of the invention relates to the use of a combination of estrogen and irospirenone for the preparation of a medicament wherein the amount of estrogen is sufficient to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in and the amount of drospirenone is sufficient to protect he endometrium from the adverse effects of estrogen. n a further aspect, the invention relates to a method of treating diseases, disorders and lymptoms associated with deficient endogenous levels of estrogen in women comprising idministering estrogen in sufficient amounts to alleviate said symptoms and drospirenone i sufficient amounts to protect the endometrium from adverse effects of estrogen. ;urthermore, the invention relates to a method of treating and preventing diseases, isorders and symptoms associated with deficient endogenous levels of estrogen in women comprising administering estradiol in amounts corresponding to daily doses of 1 to 13 mg, such as 1, 2 or 3 mg, and drospirenone in amounts corresponding to daily doses of 11,3.5 mg, such as 1,1.5, 2, 2.5, 3, or 3.5 mg. DETAILED DISCLOSURE OF THE INVENTION In the present context, the term cycle itself or when associated with the term menstrual is intended to mean the number of days between menses in a woman. It can range from 21-31 days, typically 28 days. In the present context, the term menopause is understood as the last natural (ovary -induced) menstruation. It is a single event and a result of an age-dependent dysfunction of the ovarian follicles. Menopause results from the ovaries decreasing their production of the sex hormones estrogen and progesterone. When the number of follicles falls below a certain threshold (a bleeding threshold), the ovaries can no longer produce mature follicles and sex hormones. The ability to reproduce capability ends with menopause. The peri-menopausal phase begins with the onset of climacteric symptoms when the cycle becomes irregular and ends one year after menopause. The end of peri-menopausal phase can be identified after a protracted period of time without bleeding. Post-menopause is the phase that begins at menopause and continues until death. One principal aim of hormone replacement therapy is to restore levels of the sex steroid hormones in naturaily or prematurely pre-menopausal, menopausal and post-menopausal women or to establish these levels in hypogonadal females. Monotherapy, also referred to as unopposed therapy, is the treatment with estrogens alone. Exogenous estrogens stimulate the proliferation of the endometrium. In estrogen monotherapy, the opposing effect of progesterone, which terminates proliferation, is absent. The desquamation phase, during which the top layers of the endometrium are shed, does not occur and proliferation of the endometrium occurs to a greater extent than in the phases up to an including the pre-menopausal phase. The result is hyperplasia, a risk factor for endometrial cancer. Combination therapy, also referred to as opposed therapy, is a treatment where a progestagen 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. Significantly, it has been found that combination therapy comprising the use of drospirenone as a progestagen, is remarkably effective. Drospirenone (DRSP), a 17-a-spirolactone derivative, is a synthetic progestagen that has a surprisingly similar physiological profile to progesterone yet notably better bioavailability. It is the first synthetic progestagen to have a progesterone-like pharmacological profile in that it is antiestrogenic, antiandrogenic, and has antimineralcorticoid activity. The invention embodies a pharmaceutical composition comprising an estrogen, or naturally or synthetic derivative thereof, in sufficient amounts to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent, 6p,7\|J;15p;16^dimethylene-3-oxo-17a-preg-4-ene-21,17-arbolactone (drospirenone) in sufficient amounts to protect the endometrium from the adverse effects of estrogen, together with pharmaceutical^ acceptable excipients or carriers. Apart form the active substances themselves, it is envisaged that an ester or prodrug of drospirenone may be employed in the present composition, e.g. an oxyiminopregnane carbolactone as disclosed in WO 98/24801. Deficient levels of estrogen can occur for a variety of reasons. The composition can be suoh that it is adequate for deficient levels of estrogen, regardless of the cause. Causes anticipated by the therapy are, but not limited to, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian failure. Low levels of estrogen, irrespective of the cause, lead to an overall decreased quality of life for women. Symptoms, diseases and disorders range from merely being inconvenient to life threatening. The composition of this therapy anticipates the effective alleviation of all physiological and psychological signs of estrogen deficiency. Transient symptoms, such as vasomotor signs and psychological symptoms are certainly embodied with the realm of therapy. Vasomotor signs comprise but are not limited to hot fjjjshes, sweating attacks such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency comprise, but are not limited to, insomnia and other sleep disorders, poor memory, loss of confidence, mood changes, anxiety, loss of libido, difficulties in concentration, difficulty in making decisions, diminished energy and drive, irritability, and crying spells. The treatment of the aforementioned symptoms can be associated with the peri-menopausal phase of a woman"s life or after, sometimes long after menopause. It is anticipated that the invention is applicable to these and other transient symptoms during the peri-menopausal phase, menopause, or post-menopausa) phase. Moreover, the aforementioned symptoms can be alleviated if the cause of the estrogen deficiency is hypogonadism, castration or primary ovarian failure. In another embodiment of the invention, the therapy is used for the treatment of permanent effects of estrogen deficiency. Permanent effects comprise physical changes such as urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis. Urogenital atrophy, conditions associated with it such as vaginal dryness, increase in vaginal pH and subsequent changes in flora, or events which lead to such atrophy, such as decreases in vascularity, fragmentation of elastic fibres, fusion of collagen fibres, or decreases in cell volume are symptoms thought to be particularly relevant to this therapy. Furthermore, the invention is thought to be relevant to other urogenital changes associated estrogen deficiency such as decreases in the length and/or diameter of the vagina, decreases mucus production, changes in celt population, decreases in glycogen production, decreases in growth of lactobacilli or increases in growth of streptococci, staphylococci, or coliform bacilli. Other associated changes that are thought to be preventable by the invention are those that may render the vagina susceptible to injury or infection, such as exudative discharges, vaginitis, and dyspareunia. Furthermore, infections of the urinary tract and incontinence are other common symptoms associated with lowered estrogen levels. .Other embodiments of the invention include the prevention or alleviation of physical Changes associated with estrogen deficiency, such as changes in the skin, changes in h^r distribution, thickness of hair, atrophy of the breasts, or osteoporosis. The prevention and management of osteoporosis, most notably postmenopausal osteoporosis, is a particularly interesting embodiment of the invention. Furthermore, bone demineralisation, reduction of bone mass and density, thinning and interruption of trabecule, and/or consequent increase in bone fractures or bone deformations are thought to be particularly relevant. The prophylactic treatment of osteoporosis is an interesting therapeutic application of the invention. A particularly interesting embodiment of the invention comprises the use of the composition for lessening the frequency, persistence, duration and/or severity of hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis, most notably hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts or for the prevention or management of osteoporosis. The pharmaceutical composition for HRT disclosed herein comprises estrogen. In preferred embodiments, the estrogen is selected from the group consisting of estradiol, estradiol sutfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17ft-estradiol sulfate, 17o>estradio! sulfate, equilin sulfate, 17f> dihydroequilin sulfate, 17a-dihydroequilin sulfate, equilenin sulfate, 17p-dihydroequilenin sulfate and17a-dihydroequllenin sulfate or mixtures thereof. Particularly interesting estrogens are selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof, notably estradiol, estradiol valerate, estradiol benzoate and estradiol sulfamates. Most preferred are estradiol or estradiol sulfamates, particularly estradiol. Thought to be particularly relevant are micranized forms of estrogens, such as micronized estradiol, micronized estradiol sulfamates, micronized estradiol valerate, micronized estradiol benzoate, micronized estrone, or micronized estrone sulfate or mixtures thereof, fcrotably micronized estradiol, micronized estradiol valerate, micronized estradiol benzoate or^iicronized estradiol sulfamates. Most preferred is micronized estradiol or micronized estradiol sulfamates, particularly micronized estradiol. In certain embodiments of the invention, wherein the composition comprises more than one estrogen, one or more estrogen may be in micronized form, such as 2 or ail of the estrogen. Moreover, an interesting embodiment of the invention comprises a composition wherein the drospirenone (DRSP) is in micronized form, such that one or both estrogen and DRSP are in micronized form, preferably both estrogen and DRSP are in micronized form. Drospirenone, which may be prepared substantially as described in, e.g., US 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof. It has been found that when drospirenone is provided in micronized form in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro. A micronized substance is such that a test batch (ca. 200 mg) of the particles, herein drospirenone particles, has a surface area of more than 10,000 cnrVg, and has the following particle size distribution for drospirenone as determined under the microscope: not more than 2 particles in a given batch (ca. 200 mg) with a diameter of more than 30 u,m, and preferably <. particles with a diameter of and urn. the term dissolution is defined as at least over about minutes in particular drospirenone from tablet preparation containing mg ml water determined by usp xxiii paddle method using test apparatus rpm.> As an alternative to providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition. V Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound. With respect to the estrogen which may also be a sparingly soluble substance, though usually less sensitive to degradation than drospirenone under conditions prevailing in the gastrointestinal tract, it is also an advantage to provide it in micronized form or sprayed from a solution, e.g. in ethanol, onto the surface of inert carrier particles. This has the added advantage of facilitating a more homogenous distribution of the estrogen throughout the composition. When the estrogen is provided in micronized form, it preferably has the following particle size distribution as determined under the microscope: 100% ofthe particles have a diameter of 15 p.m and The particle size distribution for estradiol or estradiol hem"ihydrate is preferably such that 100% ofthe particles in a given batch have a diameter less than 15.0 pm, 99% have a diameter less than 12.5 urn, 95% have a diameter less than 10.0 pm, 50% have a diameter less than 3.0 pm, or 40% have a diameter less than 1.1 pm. To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients, which act to promote dissolution of both active substances. Examples of such carriers and sxcipients include substances that are readily soluble in water such as cellulose ierivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl ;ellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it is anticipated that polyvinylpyrrolidone might be particularly helpful to promote dissolution. The dose of the drospirenone in each composition is preferably such as to protect the -endometrium from the adverse effects of estrogen. DRSP, in sufficient doses, may be u\|jd as an opponent to estrogen to protect the endometrium form hyperplasia or cancer. In some cases, however, the dose of DRSP may be sufficient so as to stabilise the menstrual cycle and bleeding pattern. In such cases, doses of estrogen may be low or nil. Adipose tissue production of estrogen may be such that no or very low doses of estrogen are required to stabilise the menstrual cycle and bleeding pattern. Moreover, in certain embodiments, where the woman suffers from other disorders not compatible with the use of an exogenous source of estrogen (such as for the absolute contraindications of severe liver diseases and pregnancy or for the relative contraindications endometrial carcinoma and endometriosis, mammary carcinoma, venous thromboembolism, hypertension, diabetes mellitus, otosclerosis and melanoma) no or very low amounts of estrogen may be in the composition. In such embodiments, the dose of DRSP may be such that the disorder, disease, or symptom is alleviated. In preferred embodiments, the dose of DRSP corresponds to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The length of the cycle, as stated supra may vary from 21 to31 days". Viewed otherwise, a composition may comprise of an amount of DRSP corresponding to a daily dose ranging from 0.25 to 10, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg. The dose of estrogen may vary from woman to woman, depending on the phase of her life (peri-menopausal or post-menopausal), endogenous levels of estrogen, the severity of the symptom(s), disorder or disease, the disorder, disease or symptom targeted, the use by the woman of other medicaments for other purposes, and other pharmacokinetic variables. In other embodiments, the dose of estrogen andfor DRSP is sufficient to treat hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition or for the prevention or management of osteoporosis. The dose of estrogen and/or DRSP may depend on the treatment, be it for endometrial protection such as bleeding pattern, for osteoporosis prevention or management, for the treatment of menopausal symptoms, such as the for the reduction in the number, frequency, and severity of hot flushes, night sweats, mood swings palpitations, insomnia and other sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive and irritability. In embodiments wherein the estrogen is estradiol, the amount of estradiol corresponds to a daily dose ranging from 0.1 to5mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, in particular 1, 2, or3mg. With regards to the doses of estradiol derivatives with greater potency, e.g. estradiol valerate, the comparable dosage may be calculated by adjusting the above-mentioned dosages in accordance to the relative potency. In embodiments where the woman is peri-menopausal the dose of estrogen and/or DRSP may depend on the day of the cycle, that is, whether she is in the preovulatory or postovulatory phase of the cycle, and how advanced within each phase. In embodiments where the woman is post-menopausal or even pre-menopausal, the dose of estrogen and/or DRSP may depend on the time since the last menstruation. In certain embodiments of the invention, the medicament is administered in the form a of a number of separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 21, such as at least 28 days, such as at least 30 or 31 days. In such embodiments, the dose of DRSP and/or estrogen may be the same within each dosage unit or may vary. In embodiments where the amount of DRSP and/or estrogen in the dosage unit varies according to the phase or day within the period of at least 21 days, such as at least 26 days that said dosage unit is to be administered, such compositions, methods of treatments and preparations are termed multi-phased. The dose proportionality may vary according to its use. In preferred embodiments the dose proportionality of estrogen and drospirenone for the preparation of a medicament is such that estrogen doses are to treat diseases, disorders and symptoms associated with W,MBI ,l ei"oogenous levels ot estrogen and the amount of drospirenone is sufficient to protect the endometrium from the adverse effects of estrogen. V In preferred embodiments, the dose proportionality is sufficient to treat hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition or for the srevention or management of osteoporosis. The invention relates to a method of treating diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women comprising administering estrogen in sufficient amounts to alleviate said symptoms and drospirenone n sufficient amounts to protect the endometrium from adverse effects of estrogen. Preferably, the deficient levels of estrogen to which the method applies are caused by laturai menopause, peri-menopause, post-menopause, hypogonadism, castration or srimary ovarian failure. "he diseases, disorders and symptoms to which the method applies comprise hot flushes, iweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, loor memory, loss of confidence, loss of libido, poor concentration, diminished energy, liminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular lisease, changes in hair distribution, thickness of hair, changes in skin condition or for the trevention or management of osteoporosis. Specifically, the method is anticipated to pply to hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, ervousness, anxiety, urogenital atrophy, atrophy of the breasts or for the prevention or nanagement of osteoporosis. he method applies to the administration of an estrogen, preferably estradiol, estradiol ulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol uccinate and conjugated estrogens, including conjugated equine estrogens such as strone sulfate, 17p-estradiol sulfate, l7a-estradioi sulfate, equilin sulfate, 17(3-ihydroequilin sulfate, 17a-dihydroequilin sulfate, equilentn sulfate, -tTp-dihydroequilerun ulfate and17a-dihydroequilenin sulfate or mixtures thereof, most estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or fixtures thereof, particularly estradiol. A particularly attractive embodiment of the invention comprises the administration of drospirenone (DRSP) and/or the estrogen in micronized form. Furthermore, of particular interest is where the estrogen is estradiol in micronized form. In such embodiments, one or both active ingredients are administered in micronized form. In certain embodiments, the method comprises the administration of a dose of DRSP corresponding to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The method preferably comprises the administration a dose of DRSP the amount of DRSP corresponding to a daily dose ranging from 0.25 to 10 mg, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, or 1.5 to 3.5 mg. The amount of estradiol administered may correspond to a daily dose ranging from 0.1 to 5 mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, in particular 1, 2 or 3 mg. A particularly pertinent embodiment relates to a pharmaceutical composition comprising, as a first active agent, estradiol in amounts corresponding to a daily dose of 1 to 3 mg to treat diseases, disorders and symptoms associated with deficient endogenous levels of sstrogen in women and as a second active agent 6p,7p;15f5;16f3-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbolactone (drospirenone) in amounts corresponding to a daily dose of 1 to 3.5 mg sufficient amounts to protect the endometrium from the adverse effects of estrogen together with a pharmaceutical^ acceptable excipient or carrier. Certain preferred combinations with regards to the active ingredients in the composition, wherein the estrogen is estradiol comprise 1 mg of estradiol with 0.5 mg of DRSP, 1 mg of estradiol with 1 mg of DRSP, 1 mg of estradiol with 1.5 mg of DRSP, 1 mg of estradiol with 2 mg of DRSP, 1 mg of estradiol with 2.5 mg of DRSP, 1 mg of estradiol with 3 mg of DRSP, 2 mg of estradiol with 1 mg of DRSP and 2 mg of estradiol with 4 mg of DRSP. In a preferred embodiment, a preferred embodiment of the invention relates to a pharmaceutical composition comprising as a first active agent estradiol in amounts corresponding to a daily dose of 1 to 3 mg, such as 1,1.5,2,2.5, or 3 mg of estradiol, and as a second active agent 6p,7p;15p;16J3-dimethylene-3-oxo-17a-preg-4-ene-21,17- ;arbolactone (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 of DRSP, together with a pharmaceutical^ acceptable ?\|sipient or carrier. Accordingly, a preferred embodiment of the invention relates to a method of treating and ireventing diseases, disorders and symptoms associated with deficient endogenous svels of estrogen in women comprising administering estradiol in amounts corresponding a daily doses of 1 to 3 mg, such as 1, 2 or 3 mg, and drospirenone in amounts corresponding to daily doses of 1 to 3.5 mg, such as 1, 1.5, 2, 2.5, 3, or 3.5 mg. Given that deficient endogenous levels of estrogens may be associated with, amongst other conditions, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian failure, the method of treating and preventing associated diseases, disorders and symptoms may persist until the death of the individual. That is to say that the composition may be administered from the diagnosis of the disease, disorder or symptoms for the entirety of the individual"s life. In certain embodiments, the method and the composition may be based on rhythm of the menstrual cycle. In other embodiments, the method may totally disregard the natural cycle. The method is preferably multi-phased. The method may comprise administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0,1 to 5 mg; and further administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for 4 to 8 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.25 to 5 mg. Similarly, the multi-phased method may comprise administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5mg; and further administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for 4 to 8 days a daily dosage unit comprising of a placebo or blank. A regimen of the method may comprise administering for at least 21 days a daily dosage »>unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 r^jj and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for no more than 7 days a daily dosage unit comprising of a placebo or blank. A similar regimen of method may comprise administering for at least 21 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for no more than 7 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg. Alternatively, a regimen of the method may comprise administering for at least 21 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and not administering a dosage unit for no more than 7 days. An alternative embodiment of the method comprises administering for 21 to 28 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg. The regimen may comprise of a continuous administration; that is to say that throughout "he 21 to 28 days, a daily dose of estrogen is administered. Likewise, drospirenone may administered continuously, such that either one or both of estrogen and DRSP is/are administered continuously. n another embodiment, estrogen is administered continuously and drospirenone is administered sequentially. In such an embodiment, throughout the continuous administration of estrogen, DRSP is administered at regular intervals, for 1 to 20 days, ;uch as for 3 to 15 days, 5 to 14 days, particularly for 6 to 14 days. In another interesting imbodiment of the regimen of the method, the estrogen dosage is lower for the 1 to 7 lays immediately following said sequential administration of drospirenone. :urthermore, in one embodiment of the invention, the method of treating and preventing iseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women comprises continuous administration of estrogen and interrupted administration of progestin. Specifically the method may estrogen being administered c^finuousfy for 21 to 30 days and drospirenone being administered in a 3-day-on-3-day-off cycle. A particularly attractive embodiment within this alternative drospirenone being administered on days 4 through 6, 10 through 12, 16 through 18, 22 through 24, and 28 through 30, whilst estrogen, such as estradiol is administered continuously. The composition of the dosage unit may be formulated in any way conventional in the Pharmaceutical art. In particular, as indicated above, the composition may be formulated >y a method comprising providing drospirenone and, if desired, an estrogen such as estradiol in micronized form in said unit dosage form, or sprayed from a solution onto ^articles of an inert carrier in admixture with one or more pharmaceutically acceptable ixcipients that promote dissolution of the drospirenone and an estrogen so as to promote aptd dissolution of drospirenone and preferably estradiol on oral administration. Examples of suitable excipients include fillers, e.g. sugars such as lactose, glucose or iucrose, sugar alcohols such as mannitol, starch such as corn or potato starch or nodified starch, lubricants such as talc or magnesium stearate and binders such as lolyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl ellulose, hydroxypropylmethyl cellulose, methyl cellulose, or gelatin for making oral losage forms such as tablets, pills or capsules. Tablets may conveniently be coated with i suitable film-forming agent, e.g. hydroxypropylmethylcellulose. The present composition nay also be formulated in liquid form, e.g. as solutions, suspensions or emulsions, Dgetherwith conventional diluents or excipients in a manner known perse in the "harmaceutical art. k particularly interesting regimen of a multi-phased pharmaceutical preparation comprises le sequential administration of both estrogen and drospirenone. An attractive mbodiment of such as regimen will comprise a treatment free interval wherein no dosage nit is administered such as a comprising administering for 20 to 24 days a daily dosage nit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, and not administering any dosage units for 4 to 8 days. Aiternatively, any interval wherein neither DRSP nor estrogen is administered, a placebo or blank is administered. Such a regimen of hormone replacement therapy can effectively l^mprise a method comprising administering for 20 to 24 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg, and further administering drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, and further administering for 4 to 8 days a daily dosage unit comprising no active ingredient. An alternative regimen comprises administering for 20 to 24 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0,1 to 5 mg, and further administering drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, followed by administering for 4 to 8 days a daily dosage of unit comprising estradiol in amounts less than daily dosage unit taken for said 20 to 24 day administration of estradiol. In embodiments where the medicament is in the form a of a number of separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 21, such as at least 28 days and wherein the estrogen is estradiol, preferably at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and 7 or less daily dosage units comprise estradiol in an amount from about 0.1 to 5 mg. Alternatively, the medicament may be in the form of a numberof separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 days and at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg and 7 or less daily dosage units comprise a blank or placebo. It easily follows that the medicament may be in the form of a number of separately packaged and individually removable dosage units placed In a packaging unit and intended for oral administration for a period of at least 28 days and at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg. There may not be any dosage units for the last 7 or less days of the regimen. Patient compliance of the many embodiments of the regimen may be aided by means of a pharmaceutical preparation tailored to the patients needs or habits. One such preparation may consist of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of at least 21 days, such as at least 28 days, wherein said 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. Furthermore, patient compliance may be aided by a regimen comprising a multi-phase pharmaceutical preparation. Every regimen may be easily be adhered to by a multi-phased pharmaceutical preparation such as one consisting of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of 28 days wherein said 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. In such a preparation, the amount of active ingredient varies through the 28-day period. An attractive embodiment relates to multi-phased pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of 21 to 30 consecutive days wherein 10 to 15 said 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 10 to 15 said daily dosage units comprise estradiol in an amount ranging from about 0.1 to 5 mg. This embodiment is particularly suited for preparations wherein estrogen is administered continuously for 21 to 30 days and drospirenone is administered in a 3-day-on-3-day-off cycle. Preferably, within this embodiment, the preparation is designed so that drospirenone is administered on days 4 through 6,10 through 12, 16 through 18, 22 through 24, and days 28 through 30. Moreover, a multi-phased pharmaceutical preparation wherein the number of daily dosag Jnits is 21 or 28, or a multiple of 21 or 28, such as 2 to 24, such as 2 to 12, particularly 21 B^uch as multiples of 2 to 6. Likewise, the invention relates to a method of treating diseases, disorders, and symptom; associated with estrogen deficiency comprising a multi-phased pharmaceutical preparation comprising daily dosage units which are administered for 1 to 12, preferably; to 8, such as 2, 3, 4 5, 6, 7, and 8 multiples of 28 days. A packaging unit comprising the daily dosage units described above may be prepared in It is also envisaged that the present composition may be in the form of a parenteral formulation such as a subcutaneous implant or transdermal formulation. For making implants, the active agents may suitably be formulated together with one or more polymers that are gradually eroded or degraded when in use, e.g. silicone polymers, ethylene vinylacetate, polyethylene or polypropylene. Where transdermal formulations are concerned, they may be prepared in the form of matrices or membranes or as fluid or viscous formulations in oil or hydrogels. For transdermal patches, an adhesive which is compatible with the skin should be included, such as polyacrylate, a silicone adhesive or polyisobutylene, as well as a foil made of, e.g, polyethylene, polypropylene, ethylene vinylacetate, polyvinylchloride, polyvinylidene chloride or polyester, and a removable protective foil made from, e.g., polyester or paper coated with silicone or a fluoropolymer. For the preparation of transdermal solutions or gels, water or organic solvents or mixtures thereof may be used. Transdermal gels may :urthermore contain one or more suitable gelling agents or thickeners such as silicone, ragacanth, starch or starch derivatives, cellulose or cellulose derivatives or polyacrylic acids or derivatives thereof. Transdermal formulations may also suitably contain one or riore substances that enhance absorption though the skin, such as bile salts or derivatives thereof and/or phospholipids. Suitable transdermal formulations may, for "instance, be made in a manner analogous to that described in WO 94/04157 for 3-kspdesogestrel. Alternatively, transdermal formulations may be prepared according to a method disclosed in, e.g., BW Barry, "Dermatologica! Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York - Basel, 1983, or YW Chien, "Transdermal Controlled Systemic Medications", Marcel Dekker Inc., New York - Basel, 1987. The present invention is further described In the following examples which are not in any way intended to limit the scope of the invention as claimed. EXPERIMENTAL i^ample 1 Preparation of tablets containing drospirenone and estradiol may be performed in the "ollowing manner Tablet cores of the following composition micronized drospirenone 3.00 mg micronized estradiol 1.00, 2.00, 3.00 mg lactose monohydrate 45.2,46.2, 47.2 mg cornstarch 14.40 mg modified starch 9.60 mg polyvinylpyrrolidone 25,000 4.00 mg magnesium stearate 0.30 mg are prepared by charging a fluidised bed granulator with 31.66 kg corn starch, 21.12 kg modified starch, 6.60 kg micronized drospirenone, 2,20, 4.40 or 6.6 kg of micronized estradiol (for 1 mg, 2 mg, and 3 mg dose, respectively) and 99.44,101.64, or 103.84 kg of lactose monohydrate (for 3 mg, 2 mg, and 1 mg dose, respectively) and activating the fluidised bed. An aqueous solution of 8.80 kg polyvinylpyrrolidone 25,000 in 46.20 kg purified water is sprayed continuously onto the fluidised bed while drying by heating the air stream of the fiuidised bed. At the end of the process 1.76 kg magnesium stearate is sucked into the granulator and mixed with the granules by maintaining the fluidised bed. The resulting granulate is pressed into tablet cores by compression using a rotary tablet press. For tablets comprising 1 mg of estradiol, 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol 6000 are dissolved in 14,67 kg purified water. 0.44528 kg talc, 1.25906 kg titanium dioxide and 0.02575 kg ferric oxide pigment are suspended in 10.26 kg purified water with stirring and homogenised. The solution and suspension are combined and used to coat the tablet cores by continuous application of the coating suspension in a coater. For tablets comprising 2 or 3 mg of estradiol, the specific weights of the reagents for the preparation of the coating can easily be calculated. An alternative formulation for the coatings of 1 mg tablets comprises 2.22464 kg of rhydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.17326 of tijanium dioxide, 0.07634 kg of ferric oxide pigment, yellow, and 0.03520 kg of ferric oxide pigment, red. A possible formulation for the coatings of 2 mg tablets comprises of 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.19636 of titanium dioxide and 0.08844 kg of ferric oxide pigment, red. A possible formulation for the coatings of 3 mg tablets comprises of 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.25906 of titanium dioxide and 0.02574 kg of ferric oxide pigment, red. Example 2: Relative bioavailability The evaluation of relative bioavailability of estradiol Example 3; Repeated Dose The evaluation of repeated dose pharmokinetics (accumulation) and potential interaction between estradiol and drospirenone was performed. This open-label, randomised, intra-individuat cross-over study of two dose level combinations with an intervening wash-out phase (4 weeks), and multiple application over 28 days was done with 4 dose combinations. A 4-week observation period was performed after the last dose. Treatment A: 1 mg E2 + 1 mg DRSP, daily, p.o. Treatment B: 1 mg E2 + 4 mg DRSP, daily, p.o. Treatments. 2 mg E2 + 1 mg DRSP, daily, p.o. Treatment D: 2 mg E2 + 4 mg DRSP, daily, p.o. Assessment: No statistically significant interaction was observed between the two active ingredients. Example 4: Endometrial Protection Primary Objective-. To evaluate the efficacy of thirteen, 28 day cycles of continuous E2-"DRSP combinations compared to continuous E2 by analysis of protection against hyperplasia in postmenopausal women. Secondary Objectives: To evaluate the effect of endometrial morphology, bleeding patterns, metabolic and hemostatic laboratory parameters. Weil-being of post¬menopausal women as assessed by the Women"s Health Questionnaire (WHQ) and The Medical Outcomes Study 36-ltem Short-Form Health Survey (SF-36). Effect on the frequency and severity of hot flushes, and on the relief of urogenital symptoms. Drug levels of DRSP and E2. Detailed evaluation of the metabolic parameters in subgroup. Synopsis: Dose Groups: E2 1 mg; E2 1 mg + DRSP 0.5 mg; E2 1 mg + DRSP 1 mg; E2 1 mg + DRSP 2 mg; E2 1 mg + DRSP 3 mg. 3ost-menopausal women with or without menopausal symptoms will be assigned 1 of 5 egimens. Endometrial effects will be evaluated by biopsy to determine the incidence of :ndometrial hyperplasia. Symptoms and bleeding patterns will be evaluated from subject iiaries. General safety, and effects on specific biochemical and hematological larameters will be evaluated. A postmenopausal quality of life assessment and ivaluation of patient satisfaction will also be made. "wo-hour glucose tolerance tests, and 15-minute insulin tolerance tests were performed ,t certain sites. >ata Analysis indometrial biopsy at Visit 1 and Final Visit. Bleeding pattern information is recorded in a aily diary throughout the study. wo analyses will be performed for the primary efficacy variable: i) 2-sided comparison of eatments and ii) 1-sided, within group interval estimation of doso effect, requency tables will be generated for visits at which endometrial biopsies are performed, hese tables will display the number and percent of subjects in each endometrial jsponse category for each treatment group (and by centre in case-of a treatment-by-sntre interaction). Overall and between group comparison of the incidence of Hyperplasia among the treatment groups will be performed. This analysis will be intent-to treat and will test the null hypothesis of no difference in response to treatments (unopposed vs. opposed estradiol) when adjusted for centre. Interval estimation of dose response The probability it( will be estimated for each dose of DRSP (t 0.0,0.5,1.0, 2.0, 3.0). Additionally, the upper limit of the one-sided 95% confidence interval will be calculated for each 7rt separately. This means that the confidence intervals will be non-simultaneous. Example 5: Osteoporosis Prevention Primary Objective: Bone mineral density of the hip after 104 weeks of treatment. Secondary Objectives: Bone mineral density (BMD) of the hip after 12, 28, 52, and SO weeks of treatment. BMD of the lumbar spine, of the midshaft of the radius, of the total body. Effects on parameters for bone metabolism. Bleeding pattern. General safety. The study will be performed as a double blind, placebo-controlled trial with 240 healthy, lost-menopausal women randomly assigned to one of 4 groups of 60 after giving their nformed consent. The groups will be as follows; 1 mg E2 + 1 mg DRSP 1 mg E2 + 2 mg DRSP 1 mg E2 + 3 mg DRSP Synopsis rorty osteopenic patients (BMD hip T-score between -1 and -2.5) and 20 non-osteopenic patients should be enrolled in each group. All treatments will be applied daily per os juring the whole treatment of 2 years without a treatment-free interval. In addition, the patients will be supplied with calcium tablets (500 mg of calcium daily). Measurements of sone mineral density of the hip will be measured on the left side utilising dual-energy x-ray absorptiometry at screening, baseline, and after 12, 28, 52,80, and 104 weeks of reatment. Biochemical markers of bone remodelling will be measured at intervals. Serum bone specific alkaline phosphatase, serum N-mid osteocalcin, urinary calcium/creatine (second morning void), and urinary CrossLaps® /creatine (second iteming void) will additionally be evaluated. Example 6: Menopausal Symptoms Objective: To demonstrate that the therapeutic efficacy of E2-DRSP regarding menopausal symptoms is superior to placebo Primary Objective: Hot flushes Secondary Objectives: Sweating episodes, sleep problems, depressed moods, nervousness, urogenital symptoms (vaginal dryness, pollakisuria, nocturia), bleeding patterns. General safety. Synopsis Double-blind, placebo controlled trial with healthy, post-menopausal women randomly assigned to one of 4 groups 1 mg E2 + 1 mg DRSP 1 mg E2 + 2 mg DRSP 1 mg E2 + 3 mg DRSP placebo Synopsis: Vlain inclusion criterion: A minimum of 5 moderate to severe hot flushes per day on at east 7 days of the 2-week pre-treatment period. The duration of the treatment will be 15 weeks (4 28-day cycles). Hot flushes will be assessed by means of recording the frequency and severity (mild, noderate and severe) and comparing these between the verum groups and placebo. The jatient will record the incidence and severity of the hot flushes and diary cards. In addition, the investigator will ask the patient at each visit about other typical menopausal symptoms (sweating episodes, sleep problems, depressed moods, nervousness, Data Analysis For the efficacy parameters, both a valid-case analysis (VCA) and an intention to treat (ITT) analysis will be performed. The primary target variable is the individual relative change (C) in the number of hot flushes. C is defined as (T-B) / B, where T and B are individual means. T is the mean number of hot flushes per week, calculated by the observations during the weeks 3 through 16 of the treatment phase. B is the mean number of hot flushes per week, calculated from the observations of the 2-week pre-treatment phase. Example 7: Lipid Profile ojective The primary goal of this study is to compare two E2/DRSP treatments and Premique®/Preme!le8" regarding lipid profile. Lipid profile is generally accepted as the surrogate endpointto estimate cardiovascular risk. Primary Objectives: Lipid pattern including HDL cholesterol, LDL cholesterol Secondary Objectives: Lipid pattern including total cholesterol, triglycerides, HDL2 cholesterol, HDL3 cholesterol, VLDL cholesterol, apolipoproteins (A-1, A-2, B, E), Lp(a); Menopausal symptoms; Bleeding pattern; Endometrial safety; General safety Design; The study is performed as an open-label, multicentre, comparative study in 300 post-menopausal women randomly assigned to one of 3 groups of 100 after giving their informed consent. Groups: 1 mgE2 + 2mgDRSP 1 mg E2 + 3 mg DRSP Premique®/Premelle(3: 0,625 mg conjugated estrogens + 5 mg MPA All treatments are applied daily orally during the whole treatment period of 2 years without a treatment free interval. Measurements of lipid profile are performed at screening and after 12, 28, 52, and 104 weeks of treatment as well as six weeks after treatment. WE CLAIM: 1. A pharmaceutical composition in the form of an oral dosage form comprising i) an estrogen with the exception of ethinyl estradiol; ii) micronised drospirenone in an amount from 0.25 to 10 mg; and iii) a pharmaceutically acceptable excipient or carrier, wherein said drospirenone has rapid dissolution such that at least 70% of said drospirenone is dissolved within 30 minutes when the composition is subjected to dissolution testing in 900 ml of water at 37°C using USP XXIII Paddle Method II operated at a stirring rate of 50 rpm. 2. A pharmaceutical composition as claimed in claim 1 wherein said micronized drospirenone has a surface area of more than 10,000 cma/g. 3. The composition as claimed in any of claims 1 or 2, wherein said estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate, conjugated estrogens and mixtures thereof. 4. The composition as claimed in claim 3, wherein the conjugated estrogen is selected from the group consisting of estrone sulfate, 17(1 -estradiol sulfate, 17a-estradiol sulfate, equilin sulfate, 17p" -dihydroequilin sulfate, 17a -dihydroequilin sulfate, equilenin sulfate, 17fl -dihydroequilenin sulfate and 17a-dihydroequilenin sulfate. 5. The composition as claimed in claim 3, wherein the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate and mixtures thereof. 6. The composition as claimed in claim 5, wherein the estrogen estradiol. 7. The composition as claimed in claim 6, wherein estradiol is in an amount from 0.1 to 5 mg. 8. The composition as claimed in any of claims 1 to 7, wherein the estrogen is in micronised form. 9. The composition as claimed in any of claims 1 to 8, wherein drospirenone is in an amount from 0.5 to 4.5 mg. 10. The composition as claimed in any of claims 1 to 9, wherein the oral dosage form is in the form of a tablet, a capsule or a pill. 11. The composition as claimed in claim 10, wherein the oral dosage form is in the form of a tablet. 12. A pharmaceutical preparation consisting of a number of separately packaged and individually removable oral dosage forms placed into a packaging unit, wherein said oral dosage forms are as defined in any of claims 1 to 11.

Full Text

The use of a preparation for substitution therapy and for oral contraception comprising at
bleast one progestagen and at least one estrogen wherein the estrogen dose varies with a
dicity such that blood loss is substantially avoided is disclosed in PCT/EP94/02997.
SUMMARY OF THE INVENTION
The invention relates in a first aspect to a pharmaceutical composition comprising as a first active agent, an estrogen (or naturally or synthetic derivative thereof) in sufficient amounts to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent, 6B,7p;15p;16B-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbolactone (drospirenone) in sufficient amounts to protect the endometrium from the adverse effects of estrogen, together with pharmaceuticalJy acceptable excipients or carriers.
In a second aspect, the invention relates to a pharmaceutical composition comprising as a first active agent estradiol in amounts corresponding to a daily dose of 1 to 3 mg to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent 6p,7p;15B;16p-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbo!actone (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 excipient or carrier.
Another aspect of the invention relates to the use of a combination of estrogen and irospirenone for the preparation of a medicament wherein the amount of estrogen is sufficient to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in and the amount of drospirenone is sufficient to protect he endometrium from the adverse effects of estrogen.
n a further aspect, the invention relates to a method of treating diseases, disorders and lymptoms associated with deficient endogenous levels of estrogen in women comprising idministering estrogen in sufficient amounts to alleviate said symptoms and drospirenone i sufficient amounts to protect the endometrium from adverse effects of estrogen.
;urthermore, the invention relates to a method of treating and preventing diseases, isorders and symptoms associated with deficient endogenous levels of estrogen in

women comprising administering estradiol in amounts corresponding to daily doses of 1 to 1*3 mg, such as 1, 2 or 3 mg, and drospirenone in amounts corresponding to daily doses of 11,3.5 mg, such as 1,1.5, 2, 2.5, 3, or 3.5 mg.
DETAILED DISCLOSURE OF THE INVENTION
In the present context, the term cycle itself or when associated with the term menstrual is intended to mean the number of days between menses in a woman. It can range from 21-31 days, typically 28 days.
In the present context, the term menopause is understood as the last natural (ovary -induced) menstruation. It is a single event and a result of an age-dependent dysfunction of the ovarian follicles. Menopause results from the ovaries decreasing their production of the sex hormones estrogen and progesterone. When the number of follicles falls below a certain threshold (a bleeding threshold), the ovaries can no longer produce mature follicles and sex hormones. The ability to reproduce capability ends with menopause.
The peri-menopausal phase begins with the onset of climacteric symptoms when the cycle becomes irregular and ends one year after menopause. The end of peri-menopausal phase can be identified after a protracted period of time without bleeding. Post-menopause is the phase that begins at menopause and continues until death.
One principal aim of hormone replacement therapy is to restore levels of the sex steroid hormones in naturaily or prematurely pre-menopausal, menopausal and post-menopausal women or to establish these levels in hypogonadal females.
Monotherapy, also referred to as unopposed therapy, is the treatment with estrogens alone. Exogenous estrogens stimulate the proliferation of the endometrium. In estrogen monotherapy, the opposing effect of progesterone, which terminates proliferation, is absent. The desquamation phase, during which the top layers of the endometrium are shed, does not occur and proliferation of the endometrium occurs to a greater extent than in the phases up to an including the pre-menopausal phase. The result is hyperplasia, a risk factor for endometrial cancer.

Combination therapy, also referred to as opposed therapy, is a treatment where a progestagen 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. Significantly, it has been found that combination therapy comprising the use of drospirenone as a progestagen, is remarkably effective. Drospirenone (DRSP), a 17-a-spirolactone derivative, is a synthetic progestagen that has a surprisingly similar physiological profile to progesterone yet notably better bioavailability. It is the first synthetic progestagen to have a progesterone-like pharmacological profile in that it is antiestrogenic, antiandrogenic, and has antimineralcorticoid activity.
The invention embodies a pharmaceutical composition comprising an estrogen, or naturally or synthetic derivative thereof, in sufficient amounts to treat diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women, and as a second active agent, 6p,7|J;15p;16^dimethylene-3-oxo-17a-preg-4-ene-21,17-arbolactone (drospirenone) in sufficient amounts to protect the endometrium from the adverse effects of estrogen, together with pharmaceutical^ acceptable excipients or carriers.
Apart form the active substances themselves, it is envisaged that an ester or prodrug of drospirenone may be employed in the present composition, e.g. an oxyiminopregnane carbolactone as disclosed in WO 98/24801.
Deficient levels of estrogen can occur for a variety of reasons. The composition can be suoh that it is adequate for deficient levels of estrogen, regardless of the cause. Causes anticipated by the therapy are, but not limited to, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian failure.
Low levels of estrogen, irrespective of the cause, lead to an overall decreased quality of life for women. Symptoms, diseases and disorders range from merely being inconvenient to life threatening. The composition of this therapy anticipates the effective alleviation of all physiological and psychological signs of estrogen deficiency.

Transient symptoms, such as vasomotor signs and psychological symptoms are certainly embodied with the realm of therapy. Vasomotor signs comprise but are not limited to hot fjjjshes, sweating attacks such as night sweats, and palpitations. Psychological symptoms of estrogen deficiency comprise, but are not limited to, insomnia and other sleep disorders, poor memory, loss of confidence, mood changes, anxiety, loss of libido, difficulties in concentration, difficulty in making decisions, diminished energy and drive, irritability, and crying spells.
The treatment of the aforementioned symptoms can be associated with the peri-menopausal phase of a woman"s life or after, sometimes long after menopause. It is anticipated that the invention is applicable to these and other transient symptoms during the peri-menopausal phase, menopause, or post-menopausa) phase. Moreover, the aforementioned symptoms can be alleviated if the cause of the estrogen deficiency is hypogonadism, castration or primary ovarian failure.
In another embodiment of the invention, the therapy is used for the treatment of permanent effects of estrogen deficiency. Permanent effects comprise physical changes such as urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis.
Urogenital atrophy, conditions associated with it such as vaginal dryness, increase in vaginal pH and subsequent changes in flora, or events which lead to such atrophy, such as decreases in vascularity, fragmentation of elastic fibres, fusion of collagen fibres, or decreases in cell volume are symptoms thought to be particularly relevant to this therapy. Furthermore, the invention is thought to be relevant to other urogenital changes associated estrogen deficiency such as decreases in the length and/or diameter of the vagina, decreases mucus production, changes in celt population, decreases in glycogen production, decreases in growth of lactobacilli or increases in growth of streptococci, staphylococci, or coliform bacilli. Other associated changes that are thought to be preventable by the invention are those that may render the vagina susceptible to injury or infection, such as exudative discharges, vaginitis, and dyspareunia. Furthermore, infections of the urinary tract and incontinence are other common symptoms associated with lowered estrogen levels.

.Other embodiments of the invention include the prevention or alleviation of physical Changes associated with estrogen deficiency, such as changes in the skin, changes in h^r distribution, thickness of hair, atrophy of the breasts, or osteoporosis.
The prevention and management of osteoporosis, most notably postmenopausal osteoporosis, is a particularly interesting embodiment of the invention. Furthermore, bone demineralisation, reduction of bone mass and density, thinning and interruption of trabecule, and/or consequent increase in bone fractures or bone deformations are thought to be particularly relevant. The prophylactic treatment of osteoporosis is an interesting therapeutic application of the invention.
A particularly interesting embodiment of the invention comprises the use of the composition for lessening the frequency, persistence, duration and/or severity of hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition and osteoporosis, most notably hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, urogenital atrophy, atrophy of the breasts or for the prevention or management of osteoporosis.
The pharmaceutical composition for HRT disclosed herein comprises estrogen. In preferred embodiments, the estrogen is selected from the group consisting of estradiol, estradiol sutfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol succinate and conjugated estrogens, including conjugated equine estrogens such as estrone sulfate, 17ft-estradiol sulfate, 17o>estradio! sulfate, equilin sulfate, 17f> dihydroequilin sulfate, 17a-dihydroequilin sulfate, equilenin sulfate, 17p-dihydroequilenin sulfate and17a-dihydroequllenin sulfate or mixtures thereof. Particularly interesting estrogens are selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or mixtures thereof, notably estradiol, estradiol valerate, estradiol benzoate and estradiol sulfamates. Most preferred are estradiol or estradiol sulfamates, particularly estradiol.
Thought to be particularly relevant are micranized forms of estrogens, such as micronized estradiol, micronized estradiol sulfamates, micronized estradiol valerate, micronized

estradiol benzoate, micronized estrone, or micronized estrone sulfate or mixtures thereof, fcrotably micronized estradiol, micronized estradiol valerate, micronized estradiol benzoate or^iicronized estradiol sulfamates. Most preferred is micronized estradiol or micronized estradiol sulfamates, particularly micronized estradiol.
In certain embodiments of the invention, wherein the composition comprises more than one estrogen, one or more estrogen may be in micronized form, such as 2 or ail of the estrogen.
Moreover, an interesting embodiment of the invention comprises a composition wherein the drospirenone (DRSP) is in micronized form, such that one or both estrogen and DRSP are in micronized form, preferably both estrogen and DRSP are in micronized form.
Drospirenone, which may be prepared substantially as described in, e.g., US 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.
It has been found that when drospirenone is provided in micronized form in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro. A micronized substance is such that a test batch (ca. 200 mg) of the particles, herein drospirenone particles, has a surface area of more than 10,000 cnrVg, and has the following particle size distribution for drospirenone as determined under the microscope: not more than 2 particles in a given batch (ca. 200 mg) with a diameter of more than 30 u,m, and preferably <. particles with a diameter of and urn. the term dissolution is defined as at least over about minutes in particular drospirenone from tablet preparation containing mg ml water determined by usp xxiii paddle method using test apparatus rpm.> As an alternative to providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the

surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition. V
Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound.
With respect to the estrogen which may also be a sparingly soluble substance, though usually less sensitive to degradation than drospirenone under conditions prevailing in the gastrointestinal tract, it is also an advantage to provide it in micronized form or sprayed from a solution, e.g. in ethanol, onto the surface of inert carrier particles. This has the added advantage of facilitating a more homogenous distribution of the estrogen throughout the composition. When the estrogen is provided in micronized form, it preferably has the following particle size distribution as determined under the microscope: 100% ofthe particles have a diameter of 15 p.m and The particle size distribution for estradiol or estradiol hem"ihydrate is preferably such that 100% ofthe particles in a given batch have a diameter less than 15.0 pm, 99% have a diameter less than 12.5 urn, 95% have a diameter less than 10.0 pm, 50% have a diameter less than 3.0 pm, or 40% have a diameter less than 1.1 pm.
To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients, which act to promote dissolution of both active substances. Examples of such carriers and sxcipients include substances that are readily soluble in water such as cellulose ierivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl ;ellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it is anticipated that polyvinylpyrrolidone might be particularly helpful to promote dissolution.

The dose of the drospirenone in each composition is preferably such as to protect the -endometrium from the adverse effects of estrogen. DRSP, in sufficient doses, may be u|jd as an opponent to estrogen to protect the endometrium form hyperplasia or cancer.
In some cases, however, the dose of DRSP may be sufficient so as to stabilise the menstrual cycle and bleeding pattern. In such cases, doses of estrogen may be low or nil. Adipose tissue production of estrogen may be such that no or very low doses of estrogen are required to stabilise the menstrual cycle and bleeding pattern. Moreover, in certain embodiments, where the woman suffers from other disorders not compatible with the use of an exogenous source of estrogen (such as for the absolute contraindications of severe liver diseases and pregnancy or for the relative contraindications endometrial carcinoma and endometriosis, mammary carcinoma, venous thromboembolism, hypertension, diabetes mellitus, otosclerosis and melanoma) no or very low amounts of estrogen may be in the composition. In such embodiments, the dose of DRSP may be such that the disorder, disease, or symptom is alleviated.
In preferred embodiments, the dose of DRSP corresponds to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The length of the cycle, as stated supra may vary from 21 to31 days". Viewed otherwise, a composition may comprise of an amount of DRSP corresponding to a daily dose ranging from 0.25 to 10, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, and 1.5 to 3.5 mg.
The dose of estrogen may vary from woman to woman, depending on the phase of her life (peri-menopausal or post-menopausal), endogenous levels of estrogen, the severity of the symptom(s), disorder or disease, the disorder, disease or symptom targeted, the use by the woman of other medicaments for other purposes, and other pharmacokinetic variables.
In other embodiments, the dose of estrogen andfor DRSP is sufficient to treat hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition or for the prevention or management of osteoporosis.

The dose of estrogen and/or DRSP may depend on the treatment, be it for endometrial protection such as bleeding pattern, for osteoporosis prevention or management, for the
treatment of menopausal symptoms, such as the for the reduction in the number,
frequency, and severity of hot flushes, night sweats, mood swings palpitations, insomnia and other sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of
confidence, loss of libido, poor concentration, diminished energy, diminished drive and
irritability.
In embodiments wherein the estrogen is estradiol, the amount of estradiol corresponds to a daily dose ranging from 0.1 to5mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, in particular 1, 2, or3mg.
With regards to the doses of estradiol derivatives with greater potency, e.g. estradiol valerate, the comparable dosage may be calculated by adjusting the above-mentioned dosages in accordance to the relative potency.
In embodiments where the woman is peri-menopausal the dose of estrogen and/or DRSP may depend on the day of the cycle, that is, whether she is in the preovulatory or postovulatory phase of the cycle, and how advanced within each phase. In embodiments where the woman is post-menopausal or even pre-menopausal, the dose of estrogen and/or DRSP may depend on the time since the last menstruation.
In certain embodiments of the invention, the medicament is administered in the form a of a number of separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 21, such as at least 28 days, such as at least 30 or 31 days. In such embodiments, the dose of DRSP and/or estrogen may be the same within each dosage unit or may vary. In embodiments where the amount of DRSP and/or estrogen in the dosage unit varies according to the phase or day within the period of at least 21 days, such as at least 26 days that said dosage unit is to be administered, such compositions, methods of treatments and preparations are termed multi-phased.
The dose proportionality may vary according to its use. In preferred embodiments the dose proportionality of estrogen and drospirenone for the preparation of a medicament is such that estrogen doses are to treat diseases, disorders and symptoms associated with

W,MBI ,l ei"oogenous levels ot estrogen and the amount of drospirenone is sufficient to protect the endometrium from the adverse effects of estrogen.
V
In preferred embodiments, the dose proportionality is sufficient to treat hot flushes,
sweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, poor memory, loss of confidence, loss of libido, poor concentration, diminished energy, diminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular disease, changes in hair distribution, thickness of hair, changes in skin condition or for the srevention or management of osteoporosis.
The invention relates to a method of treating diseases, disorders and symptoms associated with deficient endogenous levels of estrogen in women comprising administering estrogen in sufficient amounts to alleviate said symptoms and drospirenone n sufficient amounts to protect the endometrium from adverse effects of estrogen. Preferably, the deficient levels of estrogen to which the method applies are caused by laturai menopause, peri-menopause, post-menopause, hypogonadism, castration or srimary ovarian failure.
"he diseases, disorders and symptoms to which the method applies comprise hot flushes, iweating attacks, palpitations, sleep disorders, mood changes, nervousness, anxiety, loor memory, loss of confidence, loss of libido, poor concentration, diminished energy, liminished drive, irritability, urogenital atrophy, atrophy of the breasts, cardiovascular lisease, changes in hair distribution, thickness of hair, changes in skin condition or for the trevention or management of osteoporosis. Specifically, the method is anticipated to pply to hot flushes, sweating attacks, palpitations, sleep disorders, mood changes, ervousness, anxiety, urogenital atrophy, atrophy of the breasts or for the prevention or nanagement of osteoporosis.
he method applies to the administration of an estrogen, preferably estradiol, estradiol ulfamates, estradiol valerate, estradiol benzoate, ethinyl estradiol, estrone, estriol, estriol uccinate and conjugated estrogens, including conjugated equine estrogens such as strone sulfate, 17p-estradiol sulfate, l7a-estradioi sulfate, equilin sulfate, 17(3-ihydroequilin sulfate, 17a-dihydroequilin sulfate, equilentn sulfate, -tTp-dihydroequilerun ulfate and17a-dihydroequilenin sulfate or mixtures thereof, most estradiol, estradiol

sulfamates, estradiol valerate, estradiol benzoate, estrone, and estrone sulfate or fixtures thereof, particularly estradiol.
A particularly attractive embodiment of the invention comprises the administration of drospirenone (DRSP) and/or the estrogen in micronized form. Furthermore, of particular interest is where the estrogen is estradiol in micronized form. In such embodiments, one or both active ingredients are administered in micronized form.
In certain embodiments, the method comprises the administration of a dose of DRSP corresponding to 15 to 70 mg per cycle, such as 20 to 60 mg per cycle, particularly 40 to 60 mg per cycle. The method preferably comprises the administration a dose of DRSP the amount of DRSP corresponding to a daily dose ranging from 0.25 to 10 mg, such as about 0.25 to 8, 0.25 to 6, 0.25 to 5, 0.5 to 4.5, 1 to 4, or 1.5 to 3.5 mg.
The amount of estradiol administered may correspond to a daily dose ranging from 0.1 to 5 mg, such as about 0.2 to 4.5, 0.5 to 4, 1 to 3, in particular 1, 2 or 3 mg.
A particularly pertinent embodiment relates to a pharmaceutical composition comprising, as a first active agent, estradiol in amounts corresponding to a daily dose of 1 to 3 mg to treat diseases, disorders and symptoms associated with deficient endogenous levels of sstrogen in women and as a second active agent 6p,7p;15f5;16f3-dimethylene-3-oxo-17a-preg-4-ene-21,17-carbolactone (drospirenone) in amounts corresponding to a daily dose of 1 to 3.5 mg sufficient amounts to protect the endometrium from the adverse effects of estrogen together with a pharmaceutical^ acceptable excipient or carrier.
Certain preferred combinations with regards to the active ingredients in the composition, wherein the estrogen is estradiol comprise 1 mg of estradiol with 0.5 mg of DRSP, 1 mg of estradiol with 1 mg of DRSP, 1 mg of estradiol with 1.5 mg of DRSP, 1 mg of estradiol with 2 mg of DRSP, 1 mg of estradiol with 2.5 mg of DRSP, 1 mg of estradiol with 3 mg of DRSP, 2 mg of estradiol with 1 mg of DRSP and 2 mg of estradiol with 4 mg of DRSP.
In a preferred embodiment, a preferred embodiment of the invention relates to a pharmaceutical composition comprising as a first active agent estradiol in amounts corresponding to a daily dose of 1 to 3 mg, such as 1,1.5,2,2.5, or 3 mg of estradiol, and as a second active agent 6p,7p;15p;16J3-dimethylene-3-oxo-17a-preg-4-ene-21,17-

;arbolactone (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 of DRSP, together with a pharmaceutical^ acceptable ?|sipient or carrier.
Accordingly, a preferred embodiment of the invention relates to a method of treating and ireventing diseases, disorders and symptoms associated with deficient endogenous svels of estrogen in women comprising administering estradiol in amounts corresponding a daily doses of 1 to 3 mg, such as 1, 2 or 3 mg, and drospirenone in amounts corresponding to daily doses of 1 to 3.5 mg, such as 1, 1.5, 2, 2.5, 3, or 3.5 mg.
Given that deficient endogenous levels of estrogens may be associated with, amongst other conditions, natural menopause, peri-menopause, post-menopause, hypogonadism, castration or primary ovarian failure, the method of treating and preventing associated diseases, disorders and symptoms may persist until the death of the individual. That is to say that the composition may be administered from the diagnosis of the disease, disorder or symptoms for the entirety of the individual"s life. In certain embodiments, the method and the composition may be based on rhythm of the menstrual cycle. In other embodiments, the method may totally disregard the natural cycle.
The method is preferably multi-phased. The method may comprise administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0,1 to 5 mg; and further administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for 4 to 8 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.25 to 5 mg.
Similarly, the multi-phased method may comprise administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5mg; and further administering for 10 to 12 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for 4 to 8 days a daily dosage unit comprising of a placebo or blank.

A regimen of the method may comprise administering for at least 21 days a daily dosage »>unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 r^jj and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for no more than 7 days a daily dosage unit comprising of a placebo or blank. A similar regimen of method may comprise administering for at least 21 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and further administering for no more than 7 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg.
Alternatively, a regimen of the method may comprise administering for at least 21 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg; and not administering a dosage unit for no more than 7 days.
An alternative embodiment of the method comprises administering for 21 to 28 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg.
The regimen may comprise of a continuous administration; that is to say that throughout "he 21 to 28 days, a daily dose of estrogen is administered. Likewise, drospirenone may administered continuously, such that either one or both of estrogen and DRSP is/are administered continuously.
n another embodiment, estrogen is administered continuously and drospirenone is administered sequentially. In such an embodiment, throughout the continuous administration of estrogen, DRSP is administered at regular intervals, for 1 to 20 days, ;uch as for 3 to 15 days, 5 to 14 days, particularly for 6 to 14 days. In another interesting imbodiment of the regimen of the method, the estrogen dosage is lower for the 1 to 7 lays immediately following said sequential administration of drospirenone.
:urthermore, in one embodiment of the invention, the method of treating and preventing iseases, disorders and symptoms associated with deficient endogenous levels of

estrogen in women comprises continuous administration of estrogen and interrupted administration of progestin. Specifically the method may estrogen being administered c^finuousfy for 21 to 30 days and drospirenone being administered in a 3-day-on-3-day-off cycle. A particularly attractive embodiment within this alternative drospirenone being administered on days 4 through 6, 10 through 12, 16 through 18, 22 through 24, and 28 through 30, whilst estrogen, such as estradiol is administered continuously.
The composition of the dosage unit may be formulated in any way conventional in the Pharmaceutical art. In particular, as indicated above, the composition may be formulated >y a method comprising providing drospirenone and, if desired, an estrogen such as estradiol in micronized form in said unit dosage form, or sprayed from a solution onto ^articles of an inert carrier in admixture with one or more pharmaceutically acceptable ixcipients that promote dissolution of the drospirenone and an estrogen so as to promote aptd dissolution of drospirenone and preferably estradiol on oral administration. Examples of suitable excipients include fillers, e.g. sugars such as lactose, glucose or iucrose, sugar alcohols such as mannitol, starch such as corn or potato starch or nodified starch, lubricants such as talc or magnesium stearate and binders such as lolyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl ellulose, hydroxypropylmethyl cellulose, methyl cellulose, or gelatin for making oral losage forms such as tablets, pills or capsules. Tablets may conveniently be coated with i suitable film-forming agent, e.g. hydroxypropylmethylcellulose. The present composition nay also be formulated in liquid form, e.g. as solutions, suspensions or emulsions, Dgetherwith conventional diluents or excipients in a manner known perse in the "harmaceutical art.
k particularly interesting regimen of a multi-phased pharmaceutical preparation comprises le sequential administration of both estrogen and drospirenone. An attractive mbodiment of such as regimen will comprise a treatment free interval wherein no dosage nit is administered such as a comprising administering for 20 to 24 days a daily dosage nit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg, and drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, and not administering any dosage units for 4 to 8 days.

Aiternatively, any interval wherein neither DRSP nor estrogen is administered, a placebo or blank is administered. Such a regimen of hormone replacement therapy can effectively l^mprise a method comprising administering for 20 to 24 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0.1 to 5 mg, and further administering drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, and further administering for 4 to 8 days a daily dosage unit comprising no active ingredient.
An alternative regimen comprises administering for 20 to 24 days a daily dosage unit comprising estradiol in amounts corresponding to daily doses ranging from 0,1 to 5 mg, and further administering drospirenone in amounts corresponding to daily doses ranging from 0.25 to 6 mg for the last 10 to 12 days of said 20 to 24 day, followed by administering for 4 to 8 days a daily dosage of unit comprising estradiol in amounts less than daily dosage unit taken for said 20 to 24 day administration of estradiol.
In embodiments where the medicament is in the form a of a number of separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 21, such as at least 28 days and wherein the estrogen is estradiol, preferably at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg; and 7 or less daily dosage units comprise estradiol in an amount from about 0.1 to 5 mg.
Alternatively, the medicament may be in the form of a numberof separately packaged and individually removable dosage units placed in a packaging unit and intended for oral administration for a period of at least 28 days and at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg and drospirenone in an amount ranging from about 0.25 to 6 mg and 7 or less daily dosage units comprise a blank or placebo.
It easily follows that the medicament may be in the form of a number of separately packaged and individually removable dosage units placed In a packaging unit and intended for oral administration for a period of at least 28 days and at least 21 daily dosage units comprise a combination of estradiol in an amount from about 0.1 to 5 mg

and drospirenone in an amount ranging from about 0.25 to 6 mg. There may not be any dosage units for the* last 7 or less days of the regimen.

Patient compliance of the many embodiments of the regimen may be aided by means of a pharmaceutical preparation tailored to the patients needs or habits. One such preparation may consist of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of at least 21 days, such as at least 28 days, wherein said 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.
Furthermore, patient compliance may be aided by a regimen comprising a multi-phase pharmaceutical preparation.
Every regimen may be easily be adhered to by a multi-phased pharmaceutical preparation such as one consisting of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of 28 days wherein said 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. In such a preparation, the amount of active ingredient varies through the 28-day period.
An attractive embodiment relates to multi-phased pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed into a packaging unit and intended for oral administration for a period of 21 to 30 consecutive days wherein 10 to 15 said 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 10 to 15 said daily dosage units comprise estradiol in an amount ranging from about 0.1 to 5 mg. This embodiment is particularly suited for preparations wherein estrogen is administered continuously for 21 to 30 days and drospirenone is administered in a 3-day-on-3-day-off cycle. Preferably, within this embodiment, the preparation is designed so that drospirenone is administered on days 4 through 6,10 through 12, 16 through 18, 22 through 24, and days 28 through 30.

Moreover, a multi-phased pharmaceutical preparation wherein the number of daily dosag Jnits is 21 or 28, or a multiple of 21 or 28, such as 2 to 24, such as 2 to 12, particularly 21 B^uch as multiples of 2 to 6.
Likewise, the invention relates to a method of treating diseases, disorders, and symptom; associated with estrogen deficiency comprising a multi-phased pharmaceutical preparation comprising daily dosage units which are administered for 1 to 12, preferably; to 8, such as 2, 3, 4 5, 6, 7, and 8 multiples of 28 days.
A packaging unit comprising the daily dosage units described above may be prepared in It is also envisaged that the present composition may be in the form of a parenteral formulation such as a subcutaneous implant or transdermal formulation. For making implants, the active agents may suitably be formulated together with one or more polymers that are gradually eroded or degraded when in use, e.g. silicone polymers, ethylene vinylacetate, polyethylene or polypropylene.
Where transdermal formulations are concerned, they may be prepared in the form of matrices or membranes or as fluid or viscous formulations in oil or hydrogels. For transdermal patches, an adhesive which is compatible with the skin should be included, such as polyacrylate, a silicone adhesive or polyisobutylene, as well as a foil made of, e.g, polyethylene, polypropylene, ethylene vinylacetate, polyvinylchloride, polyvinylidene chloride or polyester, and a removable protective foil made from, e.g., polyester or paper coated with silicone or a fluoropolymer. For the preparation of transdermal solutions or gels, water or organic solvents or mixtures thereof may be used. Transdermal gels may :urthermore contain one or more suitable gelling agents or thickeners such as silicone, ragacanth, starch or starch derivatives, cellulose or cellulose derivatives or polyacrylic acids or derivatives thereof. Transdermal formulations may also suitably contain one or riore substances that enhance absorption though the skin, such as bile salts or

derivatives thereof and/or phospholipids. Suitable transdermal formulations may, for "instance, be made in a manner analogous to that described in WO 94/04157 for 3-ks*pdesogestrel. Alternatively, transdermal formulations may be prepared according to a method disclosed in, e.g., BW Barry, "Dermatologica! Formulations, Percutaneous Absorption", Marcel Dekker Inc., New York - Basel, 1983, or YW Chien, "Transdermal Controlled Systemic Medications", Marcel Dekker Inc., New York - Basel, 1987.
The present invention is further described In the following examples which are not in any way intended to limit the scope of the invention as claimed.

EXPERIMENTAL
i^ample 1
Preparation of tablets containing drospirenone and estradiol may be performed in the "ollowing manner
Tablet cores of the following composition
micronized drospirenone 3.00 mg
micronized estradiol 1.00, 2.00, 3.00 mg
lactose monohydrate 45.2,46.2, 47.2 mg
cornstarch 14.40 mg
modified starch 9.60 mg
polyvinylpyrrolidone 25,000 4.00 mg
magnesium stearate 0.30 mg
are prepared by charging a fluidised bed granulator with 31.66 kg corn starch, 21.12 kg modified starch, 6.60 kg micronized drospirenone, 2,20, 4.40 or 6.6 kg of micronized estradiol (for 1 mg, 2 mg, and 3 mg dose, respectively) and 99.44,101.64, or 103.84 kg of lactose monohydrate (for 3 mg, 2 mg, and 1 mg dose, respectively) and activating the fluidised bed. An aqueous solution of 8.80 kg polyvinylpyrrolidone 25,000 in 46.20 kg purified water is sprayed continuously onto the fluidised bed while drying by heating the air stream of the fiuidised bed. At the end of the process 1.76 kg magnesium stearate is sucked into the granulator and mixed with the granules by maintaining the fluidised bed. The resulting granulate is pressed into tablet cores by compression using a rotary tablet press.
For tablets comprising 1 mg of estradiol, 2.22464 kg of hydroxypropylmethylcellulose and 0.44528 macrogol 6000 are dissolved in 14,67 kg purified water. 0.44528 kg talc, 1.25906 kg titanium dioxide and 0.02575 kg ferric oxide pigment are suspended in 10.26 kg purified water with stirring and homogenised. The solution and suspension are combined and used to coat the tablet cores by continuous application of the coating suspension in a coater. For tablets comprising 2 or 3 mg of estradiol, the specific weights of the reagents for the preparation of the coating can easily be calculated.

An alternative formulation for the coatings of 1 mg tablets comprises 2.22464 kg of rhydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.17326 of tijanium dioxide, 0.07634 kg of ferric oxide pigment, yellow, and 0.03520 kg of ferric oxide pigment, red. A possible formulation for the coatings of 2 mg tablets comprises of 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.19636 of titanium dioxide and 0.08844 kg of ferric oxide pigment, red. A possible formulation for the coatings of 3 mg tablets comprises of 2.22464 kg of hydroxypropylmethylcellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1.25906 of titanium dioxide and 0.02574 kg of ferric oxide pigment, red.
Example 2: Relative bioavailability
The evaluation of relative bioavailability of estradiol Example 3; Repeated Dose
The evaluation of repeated dose pharmokinetics (accumulation) and potential interaction between estradiol and drospirenone was performed. This open-label, randomised, intra-individuat cross-over study of two dose level combinations with an intervening wash-out phase (4 weeks), and multiple application over 28 days was done with 4 dose combinations. A 4-week observation period was performed after the last dose.
Treatment A: 1 mg E2 + 1 mg DRSP, daily, p.o. Treatment B: 1 mg E2 + 4 mg DRSP, daily, p.o. Treatments. 2 mg E2 + 1 mg DRSP, daily, p.o. Treatment D: 2 mg E2 + 4 mg DRSP, daily, p.o.
Assessment: No statistically significant interaction was observed between the two active
ingredients.
Example 4: Endometrial Protection

Primary Objective-. To evaluate the efficacy of thirteen, 28 day cycles of continuous E2-"DRSP combinations compared to continuous E2 by analysis of protection against hyperplasia in postmenopausal women.
Secondary Objectives: To evaluate the effect of endometrial morphology, bleeding patterns, metabolic and hemostatic laboratory parameters. Weil-being of post¬menopausal women as assessed by the Women"s Health Questionnaire (WHQ) and The Medical Outcomes Study 36-ltem Short-Form Health Survey (SF-36). Effect on the frequency and severity of hot flushes, and on the relief of urogenital symptoms. Drug levels of DRSP and E2. Detailed evaluation of the metabolic parameters in subgroup.
Synopsis:
Dose Groups: E2 1 mg; E2 1 mg + DRSP 0.5 mg; E2 1 mg + DRSP 1 mg; E2 1 mg +
DRSP 2 mg; E2 1 mg + DRSP 3 mg.
3ost-menopausal women with or without menopausal symptoms will be assigned 1 of 5 egimens. Endometrial effects will be evaluated by biopsy to determine the incidence of :ndometrial hyperplasia. Symptoms and bleeding patterns will be evaluated from subject iiaries. General safety, and effects on specific biochemical and hematological larameters will be evaluated. A postmenopausal quality of life assessment and ivaluation of patient satisfaction will also be made.
"wo-hour glucose tolerance tests, and 15-minute insulin tolerance tests were performed ,t certain sites.
>ata Analysis
indometrial biopsy at Visit 1 and Final Visit. Bleeding pattern information is recorded in a
aily diary throughout the study.
wo analyses will be performed for the primary efficacy variable: i) 2-sided comparison of eatments and ii) 1-sided, within group interval estimation of doso effect, requency tables will be generated for visits at which endometrial biopsies are performed, hese tables will display the number and percent of subjects in each endometrial jsponse category for each treatment group (and by centre in case-of a treatment-by-sntre interaction). Overall and between group comparison of the incidence of

Hyperplasia among the treatment groups will be performed. This analysis will be intent-to *treat and will test the null hypothesis of no difference in response to treatments (unopposed vs. opposed estradiol) when adjusted for centre.
Interval estimation of dose response
The probability it( will be estimated for each dose of DRSP (t 0.0,0.5,1.0, 2.0, 3.0). Additionally, the upper limit of the one-sided 95% confidence interval will be calculated for each 7rt separately. This means that the confidence intervals will be non-simultaneous.
Example 5: Osteoporosis Prevention
Primary Objective: Bone mineral density of the hip after 104 weeks of treatment.
Secondary Objectives: Bone mineral density (BMD) of the hip after 12, 28, 52, and SO weeks of treatment. BMD of the lumbar spine, of the midshaft of the radius, of the total body. Effects on parameters for bone metabolism. Bleeding pattern. General safety.
The study will be performed as a double blind, placebo-controlled trial with 240 healthy, lost-menopausal women randomly assigned to one of 4 groups of 60 after giving their nformed consent.
The groups will be as follows; 1 mg E2 + 1 mg DRSP
1 mg E2 + 2 mg DRSP
1 mg E2 + 3 mg DRSP Synopsis
rorty osteopenic patients (BMD hip T-score between -1 and -2.5) and 20 non-osteopenic patients should be enrolled in each group. All treatments will be applied daily per os juring the whole treatment of 2 years without a treatment-free interval. In addition, the patients will be supplied with calcium tablets (500 mg of calcium daily). Measurements of sone mineral density of the hip will be measured on the left side utilising dual-energy x-ray absorptiometry at screening, baseline, and after 12, 28, 52,80, and 104 weeks of reatment. Biochemical markers of bone remodelling will be measured at intervals.

Serum bone specific alkaline phosphatase, serum N-mid osteocalcin, urinary calcium/creatine (second morning void), and urinary CrossLaps® /creatine (second iteming void) will additionally be evaluated.
Example 6: Menopausal Symptoms
Objective: To demonstrate that the therapeutic efficacy of E2-DRSP regarding menopausal symptoms is superior to placebo
Primary Objective: Hot flushes
Secondary Objectives: Sweating episodes, sleep problems, depressed moods, nervousness, urogenital symptoms (vaginal dryness, pollakisuria, nocturia), bleeding patterns. General safety.
Synopsis
Double-blind, placebo controlled trial with healthy, post-menopausal women randomly
assigned to one of 4 groups
1 mg E2 + 1 mg DRSP
1 mg E2 + 2 mg DRSP
1 mg E2 + 3 mg DRSP
placebo
Synopsis:
Vlain inclusion criterion: A minimum of 5 moderate to severe hot flushes per day on at
east 7 days of the 2-week pre-treatment period.
The duration of the treatment will be 15 weeks (4 28-day cycles).
Hot flushes will be assessed by means of recording the frequency and severity (mild, noderate and severe) and comparing these between the verum groups and placebo. The jatient will record the incidence and severity of the hot flushes and diary cards. In addition, the investigator will ask the patient at each visit about other typical menopausal symptoms (sweating episodes, sleep problems, depressed moods, nervousness,

Data Analysis
For the efficacy parameters, both a valid-case analysis (VCA) and an intention to treat (ITT) analysis will be performed. The primary target variable is the individual relative change (C) in the number of hot flushes. C is defined as (T-B) / B, where T and B are individual means. T is the mean number of hot flushes per week, calculated by the observations during the weeks 3 through 16 of the treatment phase. B is the mean number of hot flushes per week, calculated from the observations of the 2-week pre-treatment phase.

Example 7: Lipid Profile
ojective The primary goal of this study is to compare two E2/DRSP treatments and Premique®/Preme!le8" regarding lipid profile. Lipid profile is generally accepted as the surrogate endpointto estimate cardiovascular risk.
Primary Objectives: Lipid pattern including HDL cholesterol, LDL cholesterol
Secondary Objectives: Lipid pattern including total cholesterol, triglycerides, HDL2 cholesterol, HDL3 cholesterol, VLDL cholesterol, apolipoproteins (A-1, A-2, B, E), Lp(a); Menopausal symptoms; Bleeding pattern; Endometrial safety; General safety
Design; The study is performed as an open-label, multicentre, comparative study in 300 post-menopausal women randomly assigned to one of 3 groups of 100 after giving their informed consent.
Groups:
1 mgE2 + 2mgDRSP
1 mg E2 + 3 mg DRSP
Premique®/Premelle(3: 0,625 mg conjugated estrogens + 5 mg MPA
All treatments are applied daily orally during the whole treatment period of 2 years without a treatment free interval. Measurements of lipid profile are performed at screening and after 12, 28, 52, and 104 weeks of treatment as well as six weeks after treatment.

WE CLAIM:
1. A pharmaceutical composition in the form of an oral dosage form
comprising
i) an estrogen with the exception of ethinyl estradiol;
ii) micronised drospirenone in an amount from 0.25 to 10 mg;
and
iii) a pharmaceutically acceptable excipient or carrier, wherein said drospirenone has rapid dissolution such that at least 70% of said drospirenone is dissolved within 30 minutes when the composition is subjected to dissolution testing in 900 ml of water at 37°C using USP XXIII Paddle Method II operated at a stirring rate of 50 rpm.
2. A pharmaceutical composition as claimed in claim 1 wherein said micronized drospirenone has a surface area of more than 10,000 cma/g.
3. The composition as claimed in any of claims 1 or 2, wherein said estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate, estrone, estriol, estriol succinate, conjugated estrogens and mixtures thereof.
4. The composition as claimed in claim 3, wherein the conjugated estrogen is selected from the group consisting of estrone sulfate, 17(1 -estradiol sulfate, 17a-estradiol sulfate, equilin sulfate, 17p" -dihydroequilin sulfate, 17a -dihydroequilin sulfate, equilenin sulfate, 17fl -dihydroequilenin sulfate and 17a-dihydroequilenin sulfate.
5. The composition as claimed in claim 3, wherein the estrogen is selected from the group consisting of estradiol, estradiol sulfamates, estradiol valerate, estradiol benzoate and mixtures thereof.

6. The composition as claimed in claim 5, wherein the estrogen
estradiol.
7. The composition as claimed in claim 6, wherein estradiol is in an
amount from 0.1 to 5 mg.
8. The composition as claimed in any of claims 1 to 7, wherein the
estrogen is in micronised form.
9. The composition as claimed in any of claims 1 to 8, wherein drospirenone is in an amount from 0.5 to 4.5 mg.
10. The composition as claimed in any of claims 1 to 9, wherein the oral dosage form is in the form of a tablet, a capsule or a pill.
11. The composition as claimed in claim 10, wherein the oral dosage
form is in the form of a tablet.
12. A pharmaceutical preparation consisting of a number of separately
packaged and individually removable oral dosage forms placed into a
packaging unit, wherein said oral dosage forms are as defined in any of
claims 1 to 11.

Documents:

in-pct-2002-1096-che abstract.pdf

in-pct-2002-1096-che claims-duplicate.pdf

in-pct-2002-1096-che claims.pdf

in-pct-2002-1096-che correspondnece-others.pdf

in-pct-2002-1096-che correspondnece-po.pdf

in-pct-2002-1096-che description(complete)-duplicate.pdf

in-pct-2002-1096-che description(complete).pdf

in-pct-2002-1096-che form-1.pdf

in-pct-2002-1096-che form-13.pdf

in-pct-2002-1096-che form-18.pdf

in-pct-2002-1096-che form-26.pdf

in-pct-2002-1096-che form-3.pdf

in-pct-2002-1096-che form-5.pdf

in-pct-2002-1096-che others.pdf

in-pct-2002-1096-che pct.pdf

in-pct-2002-1096-che petition.pdf

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Patent Number

218867

Indian Patent Application Number

IN/PCT/2002/1096/CHE

PG Journal Number

23/2008

Publication Date

06-Jun-2008

Grant Date

16-Apr-2008

Date of Filing

17-Jul-2002

Name of Patentee

SCHERING AKTIENGESELLSCHAFT

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	LIPP, RALPH
2	SCHURMANN, ROLF
3	HEIL, Wolfgang
4	HILMANN, JURGEN

PCT International Classification Number

A61K 31/585

PCT International Application Number

PCT/IB01/00041

PCT International Filing date

2001-01-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	00200183.2	2000-01-18	U.S.A.
2	09/484,026	2000-01-18	U.S.A.