TWI307627B - Drospirenone for hormone replacement therapy - Google Patents

Description

1307627 V. INSTRUCTIONS OF THE INVENTION (1 Field of the Invention The present invention relates to a hormonal reduction treatment comprising a medicinal composition comprising two snail feeding and estrogen = 'and a stimulating administration of a female stimulating red _ with estrogen The general background of the present invention is due to an increase in life expectancy, and the consequent increase in the number of women before and after menopause, which has led to menopause transitions in the public and medical plus women during the birth period. Menopause (last-menstrual period) In most women, between the ages of 45 and 55. A variety of factors (including ethnic 'genetic' nutrition, altitude of residence, smoking, number of children born, hormonal contraceptive use, number of menstrual cycles, and onset of puberty) The age) has an effect, positive or negative, to affect the age of the last menstrual period. In various physiological stages, female endocrine activities undergo a series of changes, resulting in the physical and mental health of women. Negatively affected. The goal of hormonal reduction therapy is to improve the health of women during this natural aging process. The symptoms associated with the period, as well as reducing the abnormalities or diseases that may or may be associated with this decline in hormonal activity. X. Consumer Cooperatives printed by the Ministry of Economic Affairs X. Consumer Cooperatives have been known by DE 26 52 761, in which case It has been revealed that it is used as a diuretic. Dispirone has a similar progestational activity, which is therefore used as a contraceptive, in the range of 0.5-50 mg, as disclosed in DE 30 22 In the case of 337. The use of progesterone in the form of antagonism with hormonal reduction therapy and the use of this paper scale for the Chinese National Standard (CNS) A4 specification (210 X 2 Machicho) 4

5. The role of the l3〇7627 invention has been developed by the scientific team (Lobo RA, 1992; Sobel NB., 1994), which is an ingestive therapy containing estrogen and progesterone (c〇rs〇n SL, 1993; Jones KP, 1992) ° Revealed in PCT/EP94/02997 for the use of a preparation for replacement therapy and oral contraceptives (which contain at least one progestogen and at least one estrogen, wherein the estrogen dose changes with a cycle Sexuality, thereby avoiding substantial blood loss.) SUMMARY OF THE INVENTION The first aspect of the invention relates to a pharmaceutical composition comprising a first active agent which is an estrogen (which may be natural or such Synthetic derivatives) in sufficient quantities to treat diseases, abnormalities and symptoms associated with insufficient amounts of endogenous estrogen in women, and a second active agent is 6Ρ,7β;15β;16β-dimethylene_3_one -17α•孕_4_ene_21,17_ carbonyl lactone (Drospirenone), in a sufficient amount to protect the endometrium from the negative effects of estrogen, and with pharmaceutically acceptable excipients or Carrier In a first aspect, the invention relates to a pharmaceutical composition comprising a female glycol as a first active agent in an amount equivalent to one to three milligrams per sputum for treatment and treatment Diseases, abnormalities and symptoms associated with insufficient endogenous estrogen, and 6β,7β;15β;16β-dimethylene-3-one_17α·pregn-4-ene-21,17 as a second active agent Carbolactone (Drospirenone) in an amount equivalent to a daily dose of 3.5 mg to protect the endometrium from the negative effects of estrogen' and pharmaceutically acceptable excipients Or a carrier. The invention is based on the use of an estrogen and a snail to the Chinese National Standard (CNS) A4 specification (210 X 297 liters) 1 rir··---- ---Order--------- (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13〇7627

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperation, printing system: To injure a drug, in which the amount of estrogen is sufficient to treat diseases, abnormalities and symptoms associated with the amount of estrogen in women, and the amount of snail is sufficient to protect the endometrium from estrogen. effect. In a further method, the present invention relates to a disease, an abnormality and a symptom associated with a deficiency in the amount of estrogen in women, which comprises a sufficient amount of estrogen to reduce the symptom and a sufficient amount. It can protect the endometrium from the negative effects of estrogen. Furthermore, the present invention relates to a method for treating and preventing diseases, abnormalities and symptoms associated with a woman's endogenous hormonal quantity, which comprises administering estradiol (equivalent to a daily dose of (1) The amount of milligrams, such as 2 or 3 milligrams, and the second, are equivalent to a daily dose of milligrams, such as "small to ^ or "mg". The details of the invention are disclosed in the text of the case, the rhetoric of the cycle itself or the words of the relevant period, which refers to the number of days between women's menstruation. The possible range is 21-31 days, typically 28 days. In the text of this case, the rhetoric of menopause is understood as the last natural (ovarian-induced) menstruation. It is a simple event and is an ovary that ages; it is a dysfunction of the bubble. The menopause reduces the production of sex hormones (estrogen and progesterone) by the nest. When the number of follicles falls below a certain threshold (one passes through the jk threshold), the ovaries are unable to produce mature vesicles and sex hormones. The fertility ability is terminated at the same time as the menopause. The beginning of the menopause period begins with menopausal symptoms. It is the time of the menstrual cycle. The Chinese National Standard (CNS) A4 specification (210 X 297 mm) ΜI, .14 Μ--------^ --------- {Please read the notes on the back and fill in this page.) 6 l3〇7627 V. Invention Description (4) Period becomes irregular, and closes to _ menstruation after one year of menopause The termination of the period can be judged after a long period of no menstrual blood. The postmenopausal period begins with menopause and continues until death. One of the theoretical goals of hormonal reduction therapy is to reduce steroid hormone levels in women with natural or early onset menopause, menopause or menopause, or to establish such hormone levels in women with hypogonadism. Monotherapy (also known as no-resistance therapy) is the treatment of estrogen alone. Exogenous estrogen stimulates the growth of the endometrium. In the monotherapy of estrogen, the anti-resistance of progesterone (which terminates proliferation) does not occur. The shedding period (the surface layer of the endometrium is detached during this period) does not occur, and the proliferation of the endometrium progresses to a much greater extent than in various periods (even before the period of menopause, the result is genital hyperplasia, which is - seed endometrial cancer) The risk factor. Combination therapy (also known as reverse resistance therapy) is a treatment in which #-progestogens are added for protection + endometrium from proliferative organ enlargement. The use of natural luteinizing hormones is limited by the low organisms of natural luteinizing hormones, even in the form of ultra-microtypes. Significantly, the inventors have discovered that the combination of diphthyl snails as a progestogen It is clearly effective. Dispiroxone (DRsp), a derivative of streptolactone, is a synthetic progestogen that has a physiological characteristic similar to that of lutein, and a better organism. It is the first synthetic progesterone that can have a pharmacological specialty such as progesterone. It is a reverse-resistance estrogen, a retrograde androgen, and has a mineral-resistant kidney-based paper scale. _Reduction (C; NS) A4 (21〇TiT^7 7 l3〇7627 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperation Du printing A7 B7 V. Description of invention (5) Activity of glandular lipid alcohol. A pharmaceutical composition comprising a spiking hormone, or a natural or synthetic derivative thereof, in a sufficient amount to treat diseases, abnormalities and symptoms associated with insufficient amounts of endogenous estrogen in women; 1 and - 6 as a second active agent (5,7(^叩;16b dimethylene phase_17〇1_pregnant·4·ene·21,17_ carbonyl lactone (Dr〇Spirenone), A sufficient amount to protect the endometrium from the negative effects of estrogen, and with a pharmaceutically acceptable excipient or carrier. In addition to the active substance itself, a vinegar or two-segment pre-drug drug has been envisaged. It can be used in the composition of the present invention, for example, OXyimin〇pregnane carbolactone disclosed in 98/24801. The amount of estrogen deficiency can be caused by various diseases. In order to meet the lack of estrogen, the cause is not considered. The disease is, but not limited to, natural menopause, near menopause, postmenopausal, hypogonadism, castration or primary ovarian dysfunction. Low estrogen amount 'regardless of its cause, leading to a decline in the overall quality of life of women Symptoms, diseases, and abnormalities range from simple discomfort to life-threatening. The composition of this treatment is expected to effectively reduce all physiological and psychological signs of estrogen deficiency. Transitional symptoms such as vasoconstriction Symptoms and psychological symptoms are specifically defined within the scope of treatment. Symptoms of vasoconstrictive nerves include but are not limited to flushing fever, night sweats (such as night sweats), and palpitations. Psychological symptoms of estrogen deficiency include but are not limited For insomnia and other sleep disorders, this paper is the national standard (CNS) A4 specification (210 X 297 public hair) r II' 4^-装-------- set-------- - (Please read the notes on the back and fill out this page) 1307627 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print A7 B7 V. Invention Description (6) Bad, poor memory, lack of confidence, emotion Ups and downs, anxiety 'lack of sexual desire, difficulty concentrating, difficult to make decisions, lack of energy and fatigue, irritability, and crying. Treatment of the aforementioned symptoms may involve a woman's life near the menopause or after that period, sometimes beyond the menopause for a long time. It is desirable that the present invention can be used in these menopause, menopause or postmenopausal periods and other transitional symptoms. In addition, if the estrogen deficiency is caused by hypogonadism, castration or primary ovarian dysfunction, the aforementioned symptoms can be alleviated. In another embodiment of the invention, the treatment is used to treat the permanent effects of estrogen deficiency. Permanent effects include physiological changes such as urogenital atrophy, breast atrophy, cardiovascular disease, altered hair distribution, hair thinning 'changing skin's skin and osteoporosis. Genitourinary atrophy, associated with symptoms (such as vaginal dryness, increased vaginal pH and subsequent intestinal microbial changes), or physiological changes that can cause such atrophy (such as multi-vascularization, elastic fiber wear, collagen) Fiber fusion) or cell shrinkage is thought to be particularly relevant to the treatment of the present invention. Furthermore, the invention is believed to be related to other genitourinary changes associated with estrogen deficiency, such as shortening of the length and/or inner diameter of the vagina, reduction of mucus secretion, alteration of cell number, reduction of glycogen production, reduction of growth of lactic acid bacteria or Increase the growth of streptococcus, staphylococcus or coliforms. Other changes that are believed to be preventable by the present invention are such that the vagina becomes susceptible to injury or infection, such as exudate discharge, vaginitis, and dyspareunia. Furthermore, urinary tract infections and incontinence are other common symptoms associated with insufficient estrogen levels. A II. Packing -------- Order --------- rtt first read the back of the note and then fill out this page}

1307627 A7

Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperatives, Printed Clothes, Other Specific Examples include prevention or alleviation of physiological changes associated with hormonal deficiency such as changes in skin, changes in hair distribution, hair sparseness, breast atrophy or bone mass loose. Prevention and control of osteoporosis (especially osteoporosis after menopause) is a particular example of particular interest in the present invention. Furthermore, (iv) demineralization' reduction in bone weight and density, thinning and discontinuity of the separation zone, and/or subsequent fracture or increased bone deformation are considered to be particularly relevant. The preventive treatment of osteoporosis is a particularly interesting application of the present invention. Specific examples of the present invention include the use of the composition of the present invention to reduce flushing, fever, convulsions, heart palpitations, sleep disorders, emotional ups and downs, anxiety, poor memory, lack of self-confidence, lack of sex, and lack of attention Concentration, fatigue, weakness, urogenital atrophy, breast atrophy, heart and blood S disease, hair distribution changes, hair sparseness, skin changes and osteoporosis (especially flushing, night sweats, palpitations, sleep disorders, mood Prevention and treatment of undulation, neuroticism, anxiety, urogenital atrophy, breast atrophy or osteoporosis. The pharmaceutical composition for HRT (hormone reduction therapy) disclosed in the present case contains estrogen. In a preferred embodiment, estrogen selection Since the group consisting of: estradiol, estradiol amide sulfonate, estradiol pentoxide, estradiol benzoate, ethinyl estradiol, estradiol, Estrogenol 'estragalol succinate and co-estrogen (contains conjugated-horse-derived estrogens such as estradiol sulfate, 17β-estipenone sulfate 17α-Estradiol Diester Sulfate, Estradiol Sulfate, 17β_Dihydroestradiol Sulfur Paper Size Applicable to China National Standard (CNS) A4 Specification (210x297 mm) — — — — — tt I ! ( Please read the notes on the back and fill out this page.)

IIS IIS, 10 1307627 A7 B7 V. Description of invention (8 C, please read the notes on the back and fill out this page) Acid Sa, 17α-dihydroestradiol sulfate, estrone ketone sulfate, ρβ-: hydrogen Estradiol ketone sulfate, 17α-dihydroestritol ketone sulfate' or a mixture of these. Estrogens of particular interest are selected from the group consisting of: estradiol, estradiol amide sulfonate, estradiol pentyl ester, estradiol benzoate, estradiol , a female ketone sulfate and a mixture of these 'especially estradiol, estradiol pentoxide, estradiol benzoate and estradiol amide sulfonate. Most preferred are the estradiol and the estradiol diol amino acid esters, especially the estradiol. Of particular interest are particulate type estrogens, such as particulate estrogen diol, particulate estradiol amide sulfonate, particulate estradiol pentyl ester, particulate estradiol benzoquinone Acid ester, microparticulate female ketone, microparticulate female ketone sulfate or a mixture of such 'preferably microparticulate estradiol, microparticulate estradiol amyl ester, microparticulate estradiol stuper formic acid The ester or microparticulate epartic acid glycol sulfonate oxime is preferably a microparticulate estradiol and a microparticulate estradiol amino acid ester, especially a particulate estradiol. In some embodiments of the present invention, wherein the composition comprises more than one estrogen, one or more estrogens (e.g., two or all estrogens) may be in a particulate form. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing and Clothing Co., Ltd. 'An interesting example of the present invention is to include a composition in which drospirenone (DRSP) is in a particulate form such as estrogen and drospirenone. (DRSP) either or both of them are in a particulate form, preferably both estrogen and drospirenone (DRSP) are in a particulate form. Dispirosone (DRSP) (which can be prepared in general as described in US 4,129,564 or WO 98/06738) is a Chinese National Standard (CNS) A4 specification (210 X 297 metrics) that is difficult to dissolve on this paper scale. PCT) 11 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 ^^ ____B7____ V. INSTRUCTIONS (9) Water and a variety of liquid buffers with different pH values. Further, the spirone is recombined into an inactive isomer in an acidic state and hydrolyzed in an alkaline state. In order to ensure that the compound has good bioavailability, it is advantageously provided in a form which contributes to such rapid dissolution. It has been found that when dispirosone is provided in a particulate form of a pharmaceutical composition, the inactive compound is rapidly dissolved from the composition. A particulate material is a granule such as a test batch (approximately 2 mM), in this case a snail granule having a surface area of more than 1 〇, 〇〇〇 cm ^ 2 / gram, and having the following The dipyridone of the particle size distribution observed under the microscope: in a certain batch (about 2 mg), no more than 2 particles have a particle size larger than 30 μm, and preferably $ 2 〇 The particles have a 210 μm and ^30 μm. , "quick dissolution" is defined as having a solubility of at least 70% in about 30 minutes, especially at least 80% in about 2 minutes, which is 371: the next contains 3 milligrams of drospirenone. The drug key is dissolved in 900 ml of water and is determined by a USP XXIII paddle method using a usp dissolution tester No. 2 (at 50 revolutions per minute) because it is a selective particle-based supply of dispirosone. It is capable of dissolving a spiro_ in a soluble solvent (such as decyl alcohol or ethyl acetate), and spraying the dispiroxone onto the inert carrier particles, and then incorporating the particles containing the surface of the snail. In the composition. It is not intended to be limited by any particular theory, which shows that the dissolution rate of the non-in vivo dispirosone is related to the dissolution rate in vivo, and the oral administration of the compound in vivo yields the dispiroxone. Absorption. This is a paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) I* Pack--------Book--------- (Please read the back first Note on this page) 12 Ministry of Economic Affairs Intellectual Property Office staff consumption Printed by the Society 1307627 A7 ----- B7____ V. INSTRUCTIONS (10) Benefits 'Because the isomerization of compounds in the stomach and/or the hydrolysis in the small intestine is actually reduced, directing a compound to a high organism Efficacy. Because estrogen may also be a poorly soluble substance, although it is generally not easily decomposed in the general gastrointestinal tract, it is also advantageous to spray in a particulate form or from a solvent such as ethanol. To the surface of the inert carrier particles to provide estrogen. This has a distribution that promotes a more uniform state of estrogen in the composition. When estrogen is provided in a particulate form, it is determined under a microscope, preferably It has the following particle size: 100% of the particles have a particle size of $15.0μηι, 99% of the particles have a particle size of $12.5μιη '95% of the particles have a particle size of $ΐ〇.〇μιη, and 50% of the particles have One particle size is $3.0μηι. Further, there are no particles larger than ζομη!, and $10 particles have a particle size of 15μηι5 $2〇μηι. Particle size of estradiol or estradiol hemihydrate The distribution is preferably: in a particular batch, 1% of the particles have a particle size of $15·0μηι, 99% of the particles have a particle size; ^Ι2·5μηι, 95% of the particles have a particle size^ 10. Ομηι, and 50% of the particles have a particle size of $3·0 μιη or 40% with a particle size of less than ι.ιμιη. In order to obtain a faster dissolution rate, preferably comprising a carrier or excipient It is used to enhance the dissolution of the two active substances. Specific examples of such carriers and excipients include substances which are easily soluble in water (for example, cellulose derivatives, hydroxydecyl cellulose, hydroxypropyl cellulose, hydroxypropyl groups). Methylcellulose, colloidal starch, gelatin or polyvinyl ketone: In particular, it is desirable that polyvinylpyrrolidone can contribute to improved dissolution. The dose of the second snail in each of the compositions, preferably the protectors--^----------^----- - (Please read the notes on the back and fill out this page) 13 1307627

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

Endometrium exempts estrogen from AA. Dithioglycol (DRSP), a sufficient amount of meat, is used as an antagonist of estrogen to protect the endometrium from hypogonadism or cancer. In some cases, 'dropodone (DRSP) can be sufficient to stabilize the menstrual cycle and the form of menstruation. In such cases, the amount of estrogen can be very low or absent. The estrogen produced by adipose tissue may be ''', or a low amount of androgen may be required to be in the form of axis and stroke. In some specific cases, women suffer and use an exogenous estrogen. Other symptoms of phase 4 (such as severe liver disease and pregnancy with absolute contrast, or endometrial cancer and endometriosis, breast cancer, venous thrombosis, hypertension, diabetes, Osteoporosis and melanoma), no or very low amounts of estrogen can be present in the composition. In these specific cases, (4) of the snails (DRSp) is capable of alleviating abnormalities, diseases, or symptoms. In a preferred embodiment, the dose of snail (DRSP) is equivalent to 15 to 70 mg per cycle (e.g., 6 (mg) per cycle), particularly 40 to 60 mg per cycle. The length of the cycle, called s-a, can range from 21 to 31 days. In other respects, the amount of a composition that can contain a drospirenone (DRSP) is equivalent to a daily dose ranging from 〇25 to 1〇 (eg, about 0.25 to 8, 〇·25 to 6, 0.25). Up to 5, 0.5 to 4.5, i to 4 and 1.5 to 3.5 mg). The dose of estrogen may vary from woman to woman, depending on the woman's physiology (near menopause or menopause), the amount of estrogen in the body, the severity of the symptoms (abnormal or disease), symptoms (abnormal or disease) ), for other purposes, the paper size is based on the Chinese National Standard (CNS) A4 specification (210 X 297 public) ---Ί1----参-装-------- order-- ------- (Please read the notes on the back and fill out this page) 14 1307627 A7

Other drugs and other pharmacokinetic variables used by women in the Ministry of Economic Affairs' Intellectual Property Office employees' consumption cooperatives. In other specific examples, the dose of estrogen and / or drospirenone (DRSp) is sufficient for / σ treatment of flushing fever, night sweats, palpitations, sleep disorders, emotional ups and downs, nervousness, anxiety, poor memory, lack of self-confidence Lack of sexual desire, lack of concentration, fatigue, weakness, urogenital atrophy, breast atrophy, "blood s disease, changes in hair distribution, sparseness of hair, changes in skin texture or prevention or control of osteoporosis. The dose of hormone and / or drospirenone (DRSP) may be treated according to the treatment, it is used to protect the endometrium (such as the shape of the passage), to prevent or control osteoporosis, to treat symptoms of menopause (such as reducing flushing) Fever, night sweats, emotional ups and downs, insomnia and other sleep disorders, emotional changes, nervousness, anxiety, poor memory, lack of self-confidence, lack of sexual desire, lack of concentration, fatigue, weakness, irritability, frequency and frequency The estrogen in the specific example is estradiol, and the amount of the estradiol is equivalent to the daily dose range of 〇.1 to 5 mg, for example. About 至2 to 4 5, 〇5 to 4, 1 to 3, especially 1, 2 or 3 mg. Regarding the dose aspect of a more potent estradiol derivative (for example, estradiol maleate) The proportional dose can be calculated by adjusting the doses described above according to their relative potency. For women in specific cases, the dose of estrogen and/or snail (DRSP) can be close to the menopause. According to the cycle of the day, it means: whether the woman is in the period before or after ovulation, and how long it is in each period. The women in the specific case are after menopause or even before menopause. At the time, although the dose of hormone and / or drospirenone (DRSP) can be regarded as the last time according to the paper size, the Chinese National Standard (CNS) A4 specification (210 X 297 mil) - ------ Order ---------^9. (Please read the notes on the back and fill out this page)

I 15

V. Description of the invention (Determining the time of printing by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. In some specific examples of the invention, the type of the drug is to place a number of separately shifted and individually removable dosage units. a packing list (4) and intended for oral administration for at least 21 days (eg at least days, for example at least 30-31 days). In these specific examples, snails (DRsp) & / or female The amount of hormone may be the same or different in each dosage unit. In a specific example, the amount of dispirosone (DRSP) and/or estrogen in each dosage unit varies according to a period of at least 21 days (eg, The dosage unit of the administration, the method of treatment and preparation of the composition is referred to as multi-phase in a period or day of at least 28 days. The ratio of the dose may vary depending on the use thereof. In a preferred embodiment, the dose ratio of estrogen and drospirenone used to prepare a drug is such that an estrogen dose can treat diseases, abnormalities, and symptoms associated with insufficient estrogen endocrine levels, and the amount of dispirosone is sufficient. Protect the endometrium In addition to the negative effects of estrogen. In a preferred embodiment, the dose ratio is sufficient to treat flushing fever, night sweats, palpitations, sleep disorders, emotional ups and downs, nervousness, anxiety, poor memory, lack of self-confidence, lack of sexual desire, and lack of concentration. , fatigue, weakness, urogenital atrophy, breast atrophy, cardiovascular disease, hair distribution changes, hair sparseness, skin damage or osteoporosis prevention or control. The present invention relates to a treatment of women and estrogen A method for the treatment of diseases, abnormalities, and symptoms associated with insufficient endocrine volume, which comprises administering estrogen (in sufficient amount to alleviate such symptoms), and dispirosone (in sufficient amount to protect the endometrium of the paper. Standard (CNS) A4 specification (210 X 297 mil) Μ — ί —.1 Μ.--------^---------. (Please read the precautions on the back and fill in This page) -16 - A7 A7 Ministry of Economic Affairs Intellectual Property Office Employees' Consumption Cooperation Du-Printing Clothing ^ --- 2L____ V. Invention Description (14) - Eliminating the Negative Effects of Estrogen). Preferably, the method of the present invention is applied. It Insufficient stimuli, caused by menstruation, near menopause, menopause, hypogonadism, castration or primary or nestal dysfunction. Diseases, abnormalities and symptoms using the method of the invention include flushing fever, night sweats, Heart #, sleep disorders, mood fluctuations, nervousness, anxiety, poor memory, lack of self-confidence, lack of sexual desire, lack of concentration, fatigue, weakness, genitourinary atrophy, breast atrophy, cardiovascular disease, hair distribution changes The degree of sparsity, change of skin texture or prevention or control of osteoporosis. In particular, the method of the present invention is intended to be applied to flushing fever, night sweats, palpitations, sleep disorders, emotional ups and downs, nervousness, anxiety, urogenital atrophy, breasts Atrophy, cardiovascular disease, changes in hair distribution, sparseness of hair, alteration of skin texture or prevention or control of osteoporosis. The method of the present invention is used to administer an estrogen, which is preferably a female lipid, a drunk female glycol hydroxy amide, an estradiol pentoxide, an estradiol benzoate, an ethynyl female Alcohol, estradiol, estroglycerol, estroglycerol and conjugated estrogen (contains conjugated-horse-derived estrogens such as estradiol sulfate, 17β-female disulfate Vinegar, 17α-Although lipid bis-sulfate vinegar, equine estrone sulfate, 17β-dihydroequine estrone decanoate, ΐ7α-dihydroequene estrone sulfate, catechol sulfate, 17β- Dihydro horse tea, female sulphuric acid vinegar, 17α-dihydro horse tea _ sulphuric acid vinegar or a mixture of these), most of which are estradiol, estradiol sulfonate, estradiol pentane Ester, estradiol benzoate, estradiol, estradiol sulfate or a mixture of these, especially estradiol. A particularly attractive specific example of the present invention comprises drospirenone (DRSP). This paper scale applies to Chinese national standards (CNS > A4 size (210 X 297 mm) T i , 1 t pack -------- Order --------- (Please read the notes on the back and fill out this page) 17 1307627

V. Description of invention (15) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs and the administration of oxo-estrogens in a particulate form. Further, it is particularly interesting that estrogen is a particulate type of female lipid II. In this specific example, single or two active ingredients are administered in a particulate form. In some embodiments, the method of the present invention comprises a dose of two snails (DRSP) of (iv) 15 to 7 gram per _ cycle (eg, 20 to (four) grams per cycle, particularly per - a period of avoidance of 6. mg). Preferably, the method of the present invention comprises a dose of a drospirenone (DRsp), a dose of a snail ketone (DRSP) equivalent to a daily dose ranging from 0.25 to 10 mg (eg, about 0.25 to 8, 〇25). To 6, 〇.5 to 45, a# or 1.5 to 3.5 mg). The amount of estradiol administered can be equivalent to a daily dose ranging from 〇·1 to 5 mg (e.g., about 〇.2 to 至至扣(1), especially 2 or 3 mg). - a specific example of a pharmaceutical composition comprising a first active agent which is an estrogen in an amount equivalent to one to three milligrams per dose to treat an insufficient amount of endogenous estrogen in women Related diseases, abnormalities and symptoms, as well as - the first active agent is 6β, 7β; 15β; 16β_ dimethylene m17a. Pregnancy _4_ women _2117 vinegar (Drospirenone) The negative effect of protecting the endometrium from estrogen at a daily dose to 3.5 mg is equivalent to a pharmaceutically acceptable excipient or carrier.

In some preferred embodiments of the active ingredient in the composition, wherein the estrogen is estradiol, and 1 mg of estradiol is contained in 5 mg of drospirenone (DRSP) W mg estradiol. There is a milligram of snail ketone (DRS)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public recovery (please read the note on the back and fill out this page)

Installation-----Book II 18 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1307627 A7 ^_________B7 V. Invention Description (16) 1 mg of estradiol has 1.5 mg of snail brewing j (DRSP), 1 In milligrams of estradiol with 2 mg of drospirenone (DRSP), 1 mg of estradiol with 25 mg of dispironet (DRSP) and 1 mg of estradiol with 3 mg of dispiroxone (DRSP) ), 2 mg of dextran (drsp) in 2 mg of estradiol and 4 mg of drospirenone (DRSP) in 2 mg of estradiol. In a preferred embodiment, a preferred embodiment of the invention relates to a pharmaceutical composition comprising a first active agent which is a female glycol diol in an amount equivalent to a daily dose of from 1 to 3 mg (eg, 1, 1.5, 2, 2.5 or 3 mg of estradiol), and a second active agent is 60,70; 150; 160-di-indenyl_3_嗣_17〇1-pregn-4-ene -21,17-lactone (Drospirone, Drospirenone), in an amount equivalent to one to each dose of i to 3.5 mg (eg 1 ' ι·5, 2, 2.5 or 3 mg of spirulina (orsP) And, together with a pharmaceutically acceptable excipient or carrier. According to a preferred embodiment of the present invention, a method for treating and preventing diseases, abnormalities and symptoms associated with insufficient amounts of endogenous estrogen in women comprises administering estradiol (equivalent to each The daily dose is 1 to 3 mg (for example, 丨, 2, or 3 mg), and the drospirenone is equivalent to 1 to 3 to 5 mg per dose (for example: 1, 1.5, 2, 2.5, 3 or 3.5 mg)). It is known that the lack of endogenous estrogen may be related to (from among other factors). Natural menopause, near menopause, postmenopausal, hypogonadism, castration or primary ovarian dysfunction, treatment and prevention with diseases, abnormalities The method associated with the symptoms may persist until the individual dies. In other words, the composition may be administered to the individual's life from the diagnosis of the disease, abnormality or symptoms. MJ-111-i^va------------I----^Aw. (Please read the notes on the back and fill out this page)

-19 - 13〇7627

The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed the end of life. In some embodiments, the methods and compositions of the present invention may be based on the rhythm of the menstrual cycle. In other embodiments, the method of the present invention may completely ignore the natural cycle. The method of the invention is preferably multi-phase. The method of the invention may comprise administration for a period of from 1 to 12 days: a daily dosage unit comprising estradiol (in an amount equivalent to from 1 to 5 mg per dose); and further 10 to 12 days Dosing: A daily dosage unit containing estradiol (equivalent to a daily dose ranging from 0.1 to 5 mg) and bisphedine (equivalent to a daily dose ranging from 〇25 to 6 mg) Plus for 4 to 8 days of administration: a daily dosage unit containing estradiol (equivalent to a dose ranging from 0. 25 to 5 mg per dose). Similarly, the multi-stage method of the present invention can comprise administration over a period of up to j 2 days: one dose unit per dose comprising estradiol (equivalent to a dose ranging from 0.1 to 5 mg per dose); Plus 10 to 12 days of dosing: one dose per unit contains estradiol (in an amount equivalent to 0.1 to 5 mg per dose) and dispiroxone (equivalent to the dose per dose) 0.25 to 6 mg); plus 4 to 8 days of dosing: one dose per unit of placebo or none. A dosing schedule for the method of the invention can comprise administration for at least 2 days: a daily dosage unit comprising estradiol (in an amount equivalent to from 0.1 to 5 mg per dose) and drospirenone ( It is equivalent to a dose ranging from 0_25 to 6 mg per dose; and plus no more than 7 days of administration: one daily dose unit contains placebo or no drug. A dosing schedule similar to the method of the present invention can comprise a drug that lasts for at least 21 days: a paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) - Μ 丨 - MJ - Pack - -----Order--------- (Please read the notes on the back and fill out this page) 20 1307627 V. Inventions (18) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed Dosage unit comprises estradiol (in an amount equivalent to 0.1 to 5 mg per dose) and drospirenone (in an amount equivalent to 0.25 to ό mg per dose); and the duration does not exceed 7-day dosing: A daily dosage unit contains estradiol (in an amount equivalent to a daily dose ranging from 0-1 to 5 mg). Alternatively, a dosing schedule of the method of the invention can comprise administration for at least 21 days: a daily dosage unit comprising estradiol (in an amount equivalent to from 1 to 5 mg per dose) And drospirenone (in an amount equivalent to 0.25 to 6 mg per dose); and none of the dosage units are administered for less than 7 days. A specific example of one of the methods of the present invention comprises administration for a period of 21 to 28 days: one dose per unit containing estradiol (in an amount equivalent to from 0 to 5 mg per dose) and drospirenone ( It is equivalent to a dose of 0.25 to 6 mg per dose. The dosing schedule can include a continuous administration; in other words, a daily dosage unit of estradiol is administered throughout the period of 21 to 28 days. Similarly, drospirenone can also be administered continuously, whereby estrogen and/or drospirenone (DRSP) alone or both can be administered continuously. In another specific example, the estrogen is administered continuously and the spiroxone is administered in a phased manner in a specific case, and the estrogen is administered in a continuous manner. The snail ketone (DRSP) is in the period of 〖to the day. The regular intervals in the process are as follows: 3 to 15 days, 5 to 14 days, especially 6 to 14 days. In another interesting specific example of the dosing schedule of the method of the present invention, immediately after the stage of the second job, the dose of estrogen is reduced by the calendar to the amount of IIΗI*. — Μ------------—Book·------- (Please read the notes on the back and fill out this page) 21 V. Intellectual Property Office of the Ministry of Economic Affairs Cooperative printing

1307627 DESCRIPTION OF THE INVENTION (19 days. Further, in a specific example of the present invention, a method for treating and preventing diseases, abnormalities and symptoms associated with a deficiency in the amount of sexual estrogen in women (4) comprises a continuous estrogen administration. And the intermittent administration of the progesterone. The method of the invention is particularly that the estrogen can be administered continuously for 21 to 30 days, and the dispirosone is administered as a three-day administration for 3 days to stop the drug. A specific example of a human is included in the selective dispirosone to be administered on days 4 to 6, 10 to 12, 16 to 18, 22 to 24, and 28 to 3 〇天' is administered continuously in the form of estrogen (e.g., estradiol). The composition of the dosage unit can be formulated in any conventional manner in the pharmaceutical arts. In particular (as indicated above) the composition can be A method is formulated comprising providing dispirosone and (e.g., a desired estrogen (e.g., estradiol): in a particulate form, in a unit dosage form, or from a solution Spraying onto the particles of an inert carrier Forming a mixture with one or several pharmaceutically acceptable excipients to enhance the solubility of the snail and the hormonal hormone, so as to promote the rapid dissolution of the bismuth and especially the female diol in the oral administration. Examples of shaped agents include fillers (eg, sugars (such as lactose, glucose or sucrose), sugar alcohols (such as mannitol), secrets (such as ^ 或 or 钤 淀粉 starch starch), lubricants (such as talc) Or stearic acid) and binders (such as polyethylene (4), cellulose derivatives, benzyl cellulose, light propyl cellulose, propyl propyl methyl cellulose or vitamins) (eg: medicinal ingots, pills _. medicines (4) conveniently (10) over one;;'

Mlil. Aw- ^--------^---------^9 (Please read the notes on the back and fill out this page)

The paper size turns t _ (four) CNS) A4 specifications (2) G x 297 ~ 22 13〇7627

Description of the Invention (20) Membrane-type reagents (for example: (iv) propylmethylcellulose) printed by the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative. The composition of the present invention can also be (4) (for example, a material, f, a float or an emulsifier), and incorporates a conventional agent or excipient for a method known in the art of pharmacy. ° A multi-stage pharmaceutical preparation - a particularly interesting administration (4) Μ contains phased administration of both estrogen and drospirenone. An attractive example of such a dosing schedule would include a period of no treatment's (four) time (four) quantity units being «, such as containing a dose of 20 f for 24 days: "a daily dose unit contains Estradiol (in an amount equivalent to from 0.1 to 5 mg per dose) and snail (in an amount equivalent to a daily dose ranging from 〇.25 to 6 mg); At least 10 to 12 days in 24 days' and no dose of one dose unit is administered for a period of (8) days. Alternatively, there is no drospirenone (DRSP) or estrogen-free administration for any period of time, with one placebo or no dose. Such a dosing schedule for hormonal reduction therapy can effectively comprise a method comprising administering a dose of 20 to 24 days: a daily dosage unit comprising estrogen (equivalent to a daily dose ranging from 〇1 to 5 mg) The amount), and the last 12 days of the period of 20 to 24 days plus the administration of: drospirenone (equivalent to a daily dose ranging from 0.25 to 6 mg); and plus 4 to 8 days Dosing: A dosage unit does not contain active ingredients. An optional dosing schedule comprising administration of from 2 to 24 days: one dose per unit of estradiol (equivalent to a dose ranging from 0.1 to 5 mg per dose), and the duration The last 10 to the paper scale from 2〇 to 24 days applies to the Chinese National Standard (CNS) A4 specification (2〗 0 X 297 mm) Μ !*'1---Μ--------^- -------- (Please read the notes on the back and fill out this page) 23 1307627 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 -------------- V. Description of the invention (21) 12 days plus administration: drospirenone (in the range of 〇25 to 6 mg per dose range); and 4 to 8 days of administration: one dose contains female fat A diol (less than the amount of estradiol administered per one dose unit of 2 to 24 days). In the specific example of the present invention, the 'drug administration mode is to place a plurality of separately packaged and individually removable dosage units in one packaging unit, and to be used for oral administration for at least 21 days (for example, at least 28 days, for example at least 30-3 1 day), and wherein the estrogen is a female diol, preferably a combination of at least 21 days in a dosage unit comprising estradiol (approximately 0.1 to 5) The amount of milligrams) and drospirenone (in an amount ranging from 〇25 to 6 mg); and the amount of estradiol in each dosage unit that lasts 7 days (or less than 7 days) (approx. 〇_1) To a quantity of 5 mg). Alternatively, the mode of administration of the drug is to place a plurality of separately packaged and individually removable dosage units in one packaging unit and to be administered orally for at least 28 days, and for at least 21 days each. The 曰 dosage unit comprises a combination of estradiol (in an amount of about 11 to 5 mg) and drospirenone (in an amount ranging from 0.25 to 6 mg); and a duration of 7 days (or less than 7) Day) The daily dosage unit contains no administration or placebo. Following the drug, it may be formulated to place a plurality of separately packaged and individually removable dosage units in one packaging unit and to be administered orally for at least 28 days, and at least 21 The daily dosage unit of the day contains a combination of estradiol (in an amount of about 1 to 5 mg) and dispiroxone (in an amount ranging from 0.25 to 6 mg). There is no one dosage unit for the last 7 days (or less than 7 days) of the dosing schedule. 0. .Ί*------------Book --------- {Please read the notes on the back and fill out this page)

24 13〇7627

A patient who follows a specific example of several dosing schedules can be modified by the method of pharmaceutical preparation to the needs or habits of the patient. One such preparation can include several individually packaged and individually removable dosage units. - in a packaging unit, and intended for oral administration for a period of at least 21 days (eg, to > 28 days) 'where each of the dosage units contains a combination of estradiol (in the range of approximately 〇. One of 1 to 5 mg) and drospirenone (in an amount ranging from 0. 25 to 6 mg). The Ministry of Economic Affairs, the Intellectual Property Office, the Employees' Cooperatives, and the Clothing Co., Ltd. can be used to assist patients in taking medications with a multi-stage pharmaceutical preparation schedule. A parental administration schedule can be easily added in a multi-stage pharmaceutical preparation (such as a unit containing several individually packaged and individually removable dosage units in one packaging unit and intended for oral administration for 28 days). The period of time wherein the daily dosage unit comprises a combination of estradiol (in an amount ranging from about 0.1 to 5 mg) and dispiroxone (in an amount ranging from 0.25 to 6 mg). In such a preparation, the amount of active ingredient is varied over a period of 28 days. An attractive and specific example relates to a multi-stage pharmaceutical preparation comprising a plurality of individually packaged and individually removable dosage units placed in a single unit and intended for oral administration for 21 to 3 consecutive doses. A period of time 'of which 10 to 15 of these daily dosage units contain a combination of estradiol (in an amount ranging from about 〇丨 to 5 mg) and drospirenone (in the range of 〇_) One of 25 to 6 mg); and 10 to 15 of these daily dosage units contain estradiol (in an amount ranging from about 1 to 5 mg). This specific example is particularly suitable for preparation, in which the size of the female paper is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). install tr----- ----Φ. 25 l3〇7627 A7 B7 V. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing Instructions (23) It was administered continuously for 21 to 30 days, and the drug was administered for 3 days. The cycle of stopping the drug for 3 days. Preferably, in this specific example, the preparation is designed such that the drospirenone is administered on days 4 to 6, 10 to 12, 16 to 18, 22 to 24, and 28 to 30th day. Furthermore, the number of dosage units per ampule in a multi-stage pharmaceutical preparation is 21 or 28, or a multiple of (21 or 28) (eg 2 to 24, 2 to 12, especially 2 to 8 (eg 2 to 6) Multiples)) Similarly, the present invention relates to a method of treating diseases, disorders and symptoms associated with insufficient amounts of estrogen comprising a multi-stage pharmaceutical preparation comprising a daily dosage unit for administration over a period of time 1 to 12. Preferably, 2 to 8 such as 2, 3, 4, 5, 6, 7, and 8) are 28 days. A packaging unit containing a daily dosage unit as described above can be similar to the method of making an oral contraceptive or a hormonal resetting administration schedule by one method. This may be, for example, a conventional blister pack (package of articles with a raised transparent cover on a hard bottom) or any other type known for such purposes (eg, a package containing an appropriate number of dosage units) (In this case, at least 28, or a multiple of 28 for a specific application), the device is packaged in a Φ-encapsulated hood, plus a cardboard, cardboard, packaged flute or plastic liner, and sealed in a suitable In the envelope, each blister pack can be conveniently numbered or labeled. It is also envisaged that the composition of the invention may be in a form of parenteral formulation (such as a subcutaneous implant or a skin-penetrating formula). To produce an implant lingual agent, it may be appropriately corroded or decomposed by the polymers together with one or more polymers, which are --- MJI 1,]-- --0. --------BOOK--------- (Please read the notes on the back and fill out this page) 297 mm) 26 1307627

V. INSTRUCTIONS INSTRUCTIONS (24) The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints compounds such as ketonic polymer, ethyl acetoxyacetate, polyethylene or t-acryl. When it comes to formulas that penetrate the skin, these may be prepared in the form of matrices or membranes, or in fluid or mucus formulations in oil or hydrated colloids. For penetrating dermal patches, 'should be included with a skin-compatible adhesive (eg, polyacrylate, a ketone adhesive or polyisobutylene, and one by (eg, polyethylidene, polypropylene) a packaging foil made of dilute, vinyl ethylene acetate, polystyrene, polyvinylidene chloride, or polyester, and a removable protective packaging foil (made of, for example, polyester or having Anthrone or a fluorinated polymer coated paper. To prepare a solution or colloid that penetrates the skin, water or an organic solvent or a mixture of the same may be used. The colloid that penetrates the skin may further comprise one or more suitable a gelling agent or a toluene agent (for example: anthrone, Tragacons gum, starch or starch derivatives, cellulose or cellulose derivatives or polyacrylic acid or derivatives thereof). One or more substances may suitably be included to enhance absorption through the skin (e.g., bile salts or derivatives thereof, and/or phospholipids). For example, a suitable transdermal formula can be similarly described in w. 〇94/041 Case 57 (used to make 3_1^〇<1£18〇§6 also 61). Optionally, the skin-wearing formula can be disclosed in (BW Barry, ''Dermatological Formulations, Percutaneous Absorption,” Marcel Dekker Inc., New York-Basel, 1983 or YW Chien, "Transdermal Controlled Systemic Medications," Marcel Dekker Inc., New York-Basel, 1987). The invention is further described in the following examples. In these examples, the paper size applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 public f) (please read the note on the back and then fill out this page) n I If n buckle-0, · a_l · ϋ 1 ϋ ϋ ^1 II . -27 1307627

Micronized snail _ micronized female lipoprotein lactose monohydrate corn powder modified starch polyvinylpyrrole 115) 25,000 magnesium stearate no, how to not limit the invention as defined in the scope of the patent application category. Test Example 1 A nucleus containing a drug solution of dispirosone and estradiol can be prepared in the following manner: 3.00 mg 1·〇〇, 2.00, 3.00 mg 45.2, 46.2, 47.2 mg 14.40 mg 9 · 60 mg 4 · 〇〇 mg 0.80 mg was prepared by using 31.68 kg of corn starch, 21.12 kg of modified starch, 6.60 kg of micronized drospirenone, 22 〇, 4.4 〇 or 66 〇 kg of microparticulated female Lipid diol (for the preparation of 丨mg, 2mg and 3mg negative respectively), and 99.44, 〇1.64 or 103.84 kg of lactose monohydrate (differentiated to prepare 1 mg, 2 mg and 3 mg doses) Load the granulator into a fluid j-slot and activate the fluid sump. Continuously spraying a 8 8 kg of polyethylene π ketone ketone 25, hydrazine dissolved in 46_20 kg of pure water in water to the fluid bottom tank, and by heating the fluid bottom tank Air line to dry. At the end of the process, magnesium stearate is pumped into the bead machine' and then mixed with the granules by maintaining a fluid bottom tank. The resulting granules are compressed into tablets by pressing using a rotary tablet. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mil). (Please read the notes on the back and fill in the form. Page) Pack--------Book--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 28 1307627 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description ( 26) For tablets containing 1 mg of estradiol, 2.22464 kg of propyl sulfhydryl cellulose and 0.44528 kg of macrogol 600 were dissolved in 14.67 kg of pure water. 0.44528 kg of talc, 1.25906 kg of titanium dioxide and 0.02575 kg of ferric oxide pigment were suspended in 10.26 kg of pure water by stirring and homogenization. The solutions and suspensions are combined and the core of the tablet is wrapped by continuous injection of the coating suspension in the coating machine. For tablets containing 2 or 3 mg of estradiol, the proportion by weight of the reagents used to coat the preparation can be easily calculated. An optional formula for coating 1 mg of tablet contains 2.22464 kg of hydroxypropyl decyl cellulose, 0.44528 kg of macrogol 6000, 0.44528 kg of talc, 1.17326 kg of titanium dioxide and 0.07634 kg of ferric oxide. Pigment (yellow) and 0.03520 kg of ferric oxide pigment (red). One formula that may be used to coat 2 mg of tablets contains 2.22464 kg of hydroxypropyl decyl cellulose, 0.44528 kg of macrogol 600, 0.44528 kg of talc, 1,19636 kg of titanium dioxide and 0.08844 kg of ferric oxide. Pigment (red). One formulation that may be used to coat a 3 mg tablet contains 2.22464 kilograms of propyl fluorenyl cellulose, 0.44528 kilograms of macrogol 600, 0.44528 kilograms of talc, 1.25906 kilograms of titanium dioxide, and 0.02574 kilograms of ferric oxide pigment. (red). Example 2: Relative Bioavailability The relative bioavailability of estradiol (E2) and drospirenone (DRSP) was assessed by volunteers using a freely participating random two-way crossover test. In [2 mg estradiol (E2) + 2 mg drospirenone (DRSP)] or [2 mg female (please read the back of the note before you fill out this page) -------- order -- ------· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 29 l3〇7627 -- A7 -------B7_ V. Invention description (27 ) Alcohol (E2H6 mg drospirenone (DRSP)) coated with ingots treated with estradiol/dispirone (E2/DRSP) ρ·〇., comparing [2 mg of estradiol (E2) Oral solution of +2 mg of drospirenone (DRSP). Example 3: Repeated doses were evaluated for pharmacokinetics (cumulative) of repeated doses and possible interactions between estradiol and dispirosone. Two dose combinations were used for open-label, randomized, intra-individual cross-linking test (with one interval of 4 weeks interval and 'multiple administration in 28 days). After the last dose A period of 4 weeks of observation. Treatment of A. 1 mg of estradiol (E2) + 1 mg of diphthoquinone (DRSp), daily, via oral remedy B · 1 house glucitol (E2) + 4 mg dispirosone (DRSP), daily, via oral therapy C: 2 mg estradiol (E2) + 1 mg drospirenone (drsP), daily, via oral therapy D: 2 g of estradiol (E2 + 1 mg of drospirenone (drsP), daily, via oral evaluation: no statistically significant interaction was observed between the two active ingredients. Example 4: Protection of the endometrium t target · Evaluation of 13 consecutive 28-day persistent estradiol/dispirone (E2/DRSP) combinations versus persistent estradiol (E2) by analyzing endometrial hyperplasia in women after protection from menopause The effectiveness of the main criteria: evaluation of the endometrial morphology, the type of menstrual blood, on behalf of the paper scale applies the Chinese National Standard (CNS) A4 specifications (210 X 297 public meals) (please read the back of the precautions before Fill in this page) -----Order - - ----- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 30 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed clothing 13〇7627 A7 ^------ 2L___ — V. Description of the invention (28) The effect of the test parameters of the hemostatic agent. The physical and mental health of women after menopause is borrowed. Women's Health Questionnaire (WHQ) and Medical Efficacy Trial 36 items short health survey (SF-36) were evaluated. The effect on the frequency and severity of flushing fever' and its effect on reducing genitourinary symptoms. The content of drospirenone (DRSP) and estradiol (E2). The metabolic parameters were evaluated in detail in the subgroup. Summary: Dose group: 1 mg of estradiol (E2); 1 mg of estradiol (E2) + 0.5 mg drospirenone (DRSP); 1 mg estradiol (E2) + 1 mg drospirenone (DRSP); 1 mg estradiol (E2) + 2 mg drospirenone (DRSP) 1 mg of estradiol (E2) + 3 mg of drospirenone (DRSP). A menopausal woman with or without menopause will perform one of five dosing procedures. The effect on the endometrium is assessed by biopsy to determine the incidence of endometrial hyperplasia. Symptoms and patterns of menstrual blood will be assessed from the topical daily record. The safety of general health and the effects on specific biochemical and blood parameters will be assessed. At the same time, an assessment of post-menopausal health status and assessment of patient satisfaction will be conducted. A two-hour glucose tolerance test and a 15-minute insulin resistance test were performed in some cases. Data analysis Endometrial biopsy was performed on the first visit and the last visit. Throughout the trial, the type of menstrual blood was recorded in a daily record. The primary effect parameters will be analyzed in two ways: i) two-way comparison of treatments' and ii) unilateral, intra-group dose-effect (reliance) interval estimates. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ί厂-II 1——«—ΐ II -------I ^ · IIIIIII — {Please read the notes on the back first Fill in this page again. 31 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Ϊ 307627 A7 B7____ V. INSTRUCTIONS (29) The incidence rate table is generated for these visits with endometrial biopsy. These tables will show that the number and percentage of subjects in each endometrial response type in each treatment group (and the test station when the case is an interaction between a treatment and a test station) is in all groups. The overall incidence of organ hyperplasia between the whole group and the group will be carried out. This analysis will be used for therapeutic purposes, as well as for testing the workstation to test the original hypothesis: there is no difference in response to treatment (no adverse resistance versus reverse resistance, although lipodiol). The dose-response (trust) area is evaluated by the probability of each dose of dispirosone (DRSP) (t0 〇, 〇.5, 1 〇, 2 〇, 3·〇) (8). Further, the upper limit value of the 95% confidence interval of the single side of each probability (6) is calculated separately. This means that the confidence interval will have non-bilateral coexistence. Example 5: Prevention of Osteoporosis Straight _ Zen: The mineral density of the buttocks bones after 104 days of treatment. Primary ilA: Hip mineral density (BMD) after treatment at 12, 28, 52, and 80 weeks. Lumbar spine, the backbone of the tibia and the bone mass of the whole body (BMD) ^ The effect on bone metabolism parameters. The type of menstrual blood. Safety for general health. The survey was a double-blind, placebo-controlled trial in which “women with healthy, postmenopausal women (after payment of their informed consent) were randomly assigned to 4 groups (6 per group) One of the groups. The following groups are as follows: 1 mg of estradiol (Ε2) + 1 mg of snail (DRSP) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1 fri η ΙΓ ------ ------------ <Please read the notes on the back and fill out this page) ^91. 32 1307627 A7 B7 V. Description of invention (30) 1 mg of female fat Alcohol (E2) + 2 mg drospirenone (DRSP) 1 mg of estradiol (E2) + 3 mg of drospirenone (DRSP) (please read the notes on the back and fill out this page) There must be 40 patients with bone loss (bone mineral density (BMD) hip T-level data (T-score) between -1 and -2.5) and 20 non-bone loss patients over the course of 2 years ( In the absence of treatment-free period of treatment, all treatments will be administered daily on each bone. In addition, calcium tablets (500 mg of calcium per sputum) will be provided. Suffering. The mineral density (BMD) of the hip bone was measured at 12, 28, 52, and 80 weeks after screening, basal line, and treatment. The measurement was performed on the left side using a double energy X-ray absorptiometer. Biochemical markers for bone remodeling. Assessment of bone-specific alkaline acidase in serum, N-micro osteocalcin in serum, intra-calcium/creatine in urine (second morning urination), Cross Laps in urine ® / Creatine (second morning urination). Example 6: Menopause Symptoms Objective: To demonstrate that the therapeutic utility of E2-DRSP (estradiol-dispirone) in menopause symptoms is superior to that of the placebo Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives print the primary goal: Chaohong fever three owe to witness: night sweats, sleep disorders, emotional depression, nervousness, genitourinary symptoms (vaginal dryness, frequent urination, nocturia), perineal metamorphosis, general health safety Abstract: Double-blind, placebo-controlled group trial: randomized post-menopausal women to one of four groups. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mil. ) 33 130762 7 A7 _ B7_ V. Description of invention (31 ) 1 mg of estradiol (E2) + 1 mg of drospirenone (DRSP) 1 mg of estradiol (E2) + 2 mg of drospirenone (DRSP) 1 mg of female Lipiddiol (E2) + 3 mg drospirenone (DRSP) placebo summary: Main inclusion criteria: at least 7 moderate to severe flushing fevers at least 7 days per day for 2 weeks prior to treatment Treatment will last for 16 weeks (4 28-day cycles). Assessment of flushing fever will be recorded by recording the frequency and severity of the attack (mild, moderate, and severe) and then recording these between the dosing group and the placebo. comparing. The patient will record the number and severity of flushing fever on the day card. In addition, the visitor will ask the patient about other typical symptoms of menopause (night sweats, sleep disorders, emotional depression, neuroticism, urogenital symptoms) at each visit. The intensity of the symptoms will be assessed as mild, moderate or severe. If the patient has a fully functional uterus, the menstrual blood that will occur on each day of the test period is recorded on the log card. The patient will fill in the daily record on the log card based on the definition of the following blood status. (Please read the notes on the back and then fill out this page) --------Book ---------. Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed code type definition 0 no vaginal bleeding 1 point is less than normal menstrual flow, according to the experience of the subject, there is no need to use sanitary napkins (excluding sanitary pads) 2 Small amount is less than normal menstrual flow, according to the experience of the subject, use sanitary cotton 3 Normal The amount according to the experience of the subject is similar to the normal menstrual volume of more than 4 according to the experience of the subject is more than the normal menstrual volume. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 34 1307627 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (32) For the genitourinary symptoms, the following parameters and classification are used: Parameter type vaginal dryness yes / no / do not know how to increase the number of urination yes / no nocturia yes / no ("Yes" A night data analysis representing at least 2 or more (at least 2 night urinations) in a previous week, for effectiveness parameters, a validity case analysis (VCA) and an enterprise Figure for the treatment of (ITT) analysis. The primary target variable is the relative probability of the number of times of flushing fever (C). C is defined as the number (TB) / B, where T and B are represented by different. The average number of weekly flushing fevers was calculated from the number of observations from the third week to the 16th week of the treatment period. B is the average number of weekly flushing fevers, which is calculated from the number of observations 2 weeks before treatment. Example 7: Fat Configuration Target: The primary goal of this trial was to compare the two methods of treatment with estradiol/two snail (E2/DRSP) and Premique®/Premelle® in a fat configuration. Accepted as the ultimate indicator for assessing heart disease. Primary goal: Fat configuration with high density fat (HDL) cholesterol and low density fat (LDL) cholesterol Secondary goal: Contains all cholesterol, triglycerides, high density fat 2 (HDL2) cholesterol, high-density fat 3 (HDL3) cholesterol, very low-density fat (VLDL) cholesterol, apo lipoprotein (Al, A-2, B, E), Lp (a) fat configuration; menopause symptoms ; blood type; the safety of the endometrium The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ▼ — --------Book --------- · 35 1307627 A7 B7_ V. INSTRUCTIONS (33) Sex; safety to general health. Design: The test was conducted in a public solicitation, multi-station, and comparative test method, which will be used by 300 post-menopausal women. After submitting their informed consent, they are randomly arranged into one of three groups (100 in each group). Group: 1 mg estradiol (E2) + 2 mg drospirenone (DRSP) 1 mg estradiol (E2) + 3 mg drospirenone (DRSP) Premique®/Premelle® : 0.625 mg conjugated female Glycol + 5 mg MPA All treatments were administered orally daily for the entire treatment period without treatment vacancies and over 2 years of treatment. The fat configuration was measured after screening, treatment for 12, 28, 52, and 104 weeks (and 6 weeks of treatment). —7—1^—Installation--------Book--------- (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperation, printing The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 36

Claims (1)

Patent Application No. 1 076+7090101039 Patent Application U / ✓ ✓ ✓ ✓ 申请 申请 申请 ( ( ( ( 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 Estrogen; (1) equivalent to a daily dose ranging from 25 to 1 mg of Drospirenone; and iii) a pharmaceutically acceptable excipient or carrier, wherein the snail is having a surface area greater than (10) The type of cm2/g. 2. An oral dosage form of a pharmaceutical composition comprising i) an estrogen selected from the group consisting of estradiol, estradiol sulfonate, estradiol pentoxide, estradiol benzene a group of formate, lactool, lactotriol, lactotriol succinate, conjugated estrogen or a mixture thereof; ii) equivalent to 25 to 1 mg of snail per dose range a ketone; and iii) a pharmaceutically acceptable excipient or carrier, wherein the snail is in a fast-dissolving form such that the spirone has at least 70% solubility in 30 minutes (when used) Usp χχπι Paddle Method II tests the solubility of a composition of 37 parts of water in 9 liters of water at 50 rpm. 3. An oral dosage form of a pharmaceutical composition comprising i) an estrogen selected from the group consisting of estradiol, estradiol sulphate, estradiol, estradiol a group of benzoate, estradiol, lactotriol, estroglycerol succinate, conjugated estrogen or a mixture thereof; 84562-971111.doc Common Chinese National Standard (CNS) A4 specification for this paper scale (210X297 mm) 1307627 A8 B8 C8 The sputum is prepared in a daily dose ranging from 0.25 to 10 mg of microparticulate form; and a pharmaceutically acceptable excipient or carrier. For example, in the pharmaceutical group of patent application No. 2 or 2, = in the form of particles or sprayed from the solution of the snail solution to the surface of the carrier. The pharmaceutical composition according to any one of claims 1 to 3, wherein the estrogen is selected from the group consisting of estradiol and estradiol sulfonate: although the glycol diol is brewed, Glycol aglycolic acid vinegar, estradiol, estroglycerol, estradiol, conjugate # hormone or a mixture thereof. The pharmaceutical composition of the fifth aspect of the invention, wherein the total estrogen is selected from the group consisting of estrogen sulphate sulphate, estrogen diketone sulphate, ηα: ipodione sulphate sulphate, succinyl sulphate vinegar, "β_ Dihydroestradiol sulphuric acid vinegar, dihydroestradiol sulphuric acid vinegar, female sterol _ sulphuric acid vinegar, = ^ (4) her purpose and heart: hydrogen female solid 7. As claimed in the scope of the pharmaceutical composition of claim 6, The estradiol is a micronized form in the pharmaceutical composition of any one of the above-mentioned claims, wherein the pharmaceutical composition of any one of claims (1) The second snail is sufficient to protect the endometrium from the negative effects of estrogen. For example, the pharmaceutical composition of any of the above-mentioned patents (1) is as follows: 6. Its 84546-971111.doc. 2 paper scale Applicable to China National Standard (CNS) Α 4 specifications (210X 297 mm) A8 B8 C8 The 1 crotonone content in 1307627 is equivalent to a daily dose ranging from 0.5 to 4.5 mg. 11. The pharmaceutical composition of any of the items in paragraph (1) of the patent scope is provided, and the estrogen is sufficient to treat the diseases, diseases and symptoms associated with insufficient endogenous estrogen levels in women. 12. The pharmaceutical composition according to any one of claims (1), wherein the estrogen is present in a sufficient amount to treat a woman's natural menopause, near menopause, after stagnation, hypogonadism, castration or primary ovarian dysfunction Diseases, disorders and symptoms, which are selected from the group consisting of flushing fever, night sweats, palpitations, sleep disorders, emotional ups and downs, left mass, anxiety, poor memory, lack of self-confidence, lack of sexuality/mainness Groups consisting of inhomogeneity, fatigue, weakness, irritability, urogenital atrophy, ritual atrophy, cardiovascular disease, changes in hair distribution, hair sparseness, skin texture changes, and osteoporosis. The pharmaceutical composition according to any one of claims 3 to 3, wherein the lipodiol content is equivalent to a daily dose ranging from 0.1 to 5 mg. 14. The pharmaceutical composition according to any one of claims 1-3 to 3, wherein the oral dosage form is in the form of a lozenge, capsule or pill. 15. A medical kit consisting of several individually packaged and individually removable dosage units, each of which is placed in a packaging unit and intended for a period of at least 21 days. Oral administration; wherein each dosage unit comprises estradiol (content ranging from about 〇_1 to 5 mg) and snail content ranging from about 〇25 to όp克' and The surface area is greater than 1〇〇〇〇crn2/g). 1 6 . — A medical kit ' is made up of several individually packaged and individually removable 84062-971111.doc _ 3 _ ΐ paper scale using China National Standard (CNS) A4 specification (21〇Χ297 public wheat) ) ---~ 1307627 VI. Apply for the patent Fan Garden II composition, the dosage units are placed in a package and intended for use - for at least 21 days of oral administration '· about the dose of early contains estradiol ( The content range is from ancient times and dispiroxone (the content range is from about 〇25 g, and the system has a fast dissolving pattern, so that the snail has a solubility of at least 7 G% at 30 minutes (four) (when using USP XXIII addle) Method II tests η at a speed of 5 rpm. The solubility of the dosage unit in the lower milliliters of water.) The medical kit consists of several individually packaged and individually removable dosage units. The dosage unit is placed in a pack = position and is intended for oral administration for a period of at least 21 days; the 4 daily dosage unit comprises estradiol (content ranging from about 0.1 to 5 mg in ancient times) Dioxone (the content range is from about 〇 Όmg), and its system is in the form of microparticles. 18. - The medical kit 'is composed of several separately packaged and individually removable daily dosage units'. The dosage units are placed in a package. Within the unit, and intended for oral administration for at least 21 days; wherein the daily dosage unit comprises estradiol (content ranging from about 0.1 to 5 mg) and snail _ (the content range thereof) From approximately 〇25 to 6 mg) 'The dosage of estradiol per unit dose in the packaging unit is the same. 19. For the medical kit of any of items 15 to 18 of the patent application, oral The drug administration system lasts for 28 days. 20. The medical kit of the 19th patent scope is intended for use in an 84562-971111.doc > This paper scale uses the Chinese National Standard (CNS) Α 4 specification (210X297 PCT) A8 B8 C8 D8 1307627 ------ VI. The patent application period is 28 days for oral administration; at least 21 of each dosage unit contains a range of estradiol from about 〇 to 5 mg. Content ranges from approximately 〇25 to 6 mg two snails A combination of no more than 7 dosage units comprising a drug-free, placebo or a content of from about 0.1 to 5 mg of estradiol. 21. A medical kit according to any one of claims 15 to 18. a group, which is intended for oral administration for at least 28 consecutive days, wherein at least 10 of the dosage units each comprise a concentration of estradiol from about 〇 to 5 mg; at least 10 Each dosage unit comprises a combination of estradiol in an amount ranging from about 〇" to 5 mg with a spiroxone in an amount ranging from about 至25 to 6 mg; and no more than 8 of the daily dosage unit comprising a consolation Or no medicine. 2 2. A medical kit according to any one of claims 5 to 18, which is intended for oral administration for at least 28 consecutive days, at least 10 of which are contained per dose unit The content ranges from about 〇 to 5 mg of estradiol; at least 10 of the dosage units per unit contains a content of estradiol from about 〇. j to 5 mg and a content ranging from about 〇25 to A combination of 6 mg of spiroxone; and no more than 8 of the daily dosage unit comprise estradiol in an amount ranging from about 0.1 to 5 mg. 84562-971111.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 8 8 8 8 A BCD 1307627 Patent application scope 23. If any of the patent scopes 15 to 18 The medical kit of the item is intended for oral administration for a continuous period of 2 to 30 days, « at least 1 0-1 of the daily dosage units contain a content ranging from about 0.1 to 5 mg. The combination of estradiol with a content ranging from about 0.25 to 6 mg of snail; and 10 to 15 of the dosage unit per unit containing a range of estradiol from about 〇" to 5 mg. A medical kit according to any one of claims 15 to 17, wherein the female diol content of the dosage unit differs depending on the period of at least 21 days. 25. The medical kit of any one of claims 15 to 17, wherein the content of the female glycol in each unit dose in the packaging unit is the same. 26. A pharmaceutical kit according to any one of claims 15 to 18, wherein the hexanone content per unit dose in the packaging unit is the same. 2 7. The pharmaceutical kit of claim 5 or 6 wherein the spiroxane is in a particulate form or is sprayed from the snail solution onto the surface of the inert carrier. The pharmaceutical kit of any one of claims 15 to 18, wherein the female glycol is in a micronized form or sprayed from a solution onto particles of an inert carrier. [beta] 29. A medical kit according to any one of claims 15 to 18, wherein the number of daily dosage units is at least 21 or a multiple of 21. 30. A pharmaceutical kit according to any one of claims 5 to 8 wherein the number of daily dosage units is 28 or a multiple of 28. , 84562-971111.doc Λ This paper size applies to the S national standard (CNS) Α 4 specifications (2 ι〇Χ 297 羡). 1307627 A8 B8 C8 D8 夂, apply for the patent garden 3 1 · If the scope of patent application is 15医药A medical kit of any one of the eight items, wherein the dosage unit of δ海母曰 is in an oral form. 3 2. For the medical kit of claim 31, the oral dosage form is in the form of a lozenge, capsule or pill. 3 3. Combination of estrogen and dispirosone for the preparation of oral medications for the treatment of natural menopause, near menopause, postmenopausal, gonadal dysfunction or primary ovarian dysfunction-related diseases, disorders and symptoms Uses, wherein the diseases, conditions and symptoms are selected from the group consisting of flushing fever, night sweats, palpitations, sleepiness, sleepiness, dizziness, divine, quality, anxiety, poor memory, lack of self-confidence, lack of sexual desire, lack of concentration, fatigue, no a group of stimuli, irritability, genitourinary atrophy, breast atrophy, cardiovascular disease, hair distribution changes, hair sparsity, skin texture changes and osteoporosis, one of which is sufficient to protect the endometrium It is free from the negative action of estrogen, and the dispirosone is of a type having a surface area greater than 1 〇 and 〇〇〇 cm 2 /g. Combination of 34' estrogen and dispirosone for the preparation of oral medications for the treatment of women with natural menopause, near menopause, postmenopausal, hypogonadism, castration or primary ovarian dysfunction-related disease conditions and symptoms It 'where the diseases, conditions and symptoms are selected from the group consisting of flushing fever, night sweats, palpitations, sleepy eye disorders, emotional ups and downs, nervousness, anxiety, poor memory, lack of self-confidence, lack of sexual desire, lack of concentration, fatigue, and lack of energy. Irritable, genitourinary atrophy, breast atrophy, cardiovascular disease, hair distribution changes, hair thinness 84062-9711H.doc -7 _ This paper scale applies T-closed home (CNS) A4 specifications (2 offer 297 public Chu ) --------- 1307627 a group consisting of sparseness, skin texture changes, and osteoporosis, in which the content of the two snails is sufficient to protect the endometrium from the negative effects of estrogen' and the snail is a form with rapid dissolution. The drospirenone has a solubility of at least 7% in 30 minutes (the solubility of the drug in 900 ml of water at 37 C was tested at 50 rpm using the usp XXIII Paddle Method II). 3 5 . A combination of estrogen and dispirosone for the preparation of oral, macroscopic menopause, near menopause, postmenopausal, hypogonadism, castration or primary ovarian dysfunction-related diseases, conditions and symptoms The use of the drug, wherein the diseases, conditions and symptoms are selected from the group consisting of flushing fever, night sweats, palpitations, sleepy eye disorders, emotional ups and downs, nervousness, anxiety, poor memory, lack of self-confidence, lack of sexual desire, lack of concentration, fatigue, no a group consisting of strength, irritability, genitourinary atrophy, breast atrophy, cardiovascular disease, changes in hair distribution, hair sparseness, skin texture changes and osteoporosis, in which the content of dispirosone is sufficient to protect the endometrium It is free from the negative effects of estrogen, and the dispirosone is in a particulate form. 36. The use of claim 33, wherein the spiroxone is in the form of a particulate form or is sprayed from a solution of the dispirorone to the surface of the inert carrier particle. 37. The use of any one of claims 33 to 35, wherein the estrogen is in a micronized form. 38. The use of any one of claims 33 to 35, wherein the estrogen content is sufficient to treat a condition selected from the group consisting of flushing fever, night sweats, palpitations, sleepy eye disorders, emotional ups and downs, nervousness, anxiety, genitourinary contracture 84562- 971111.doc - 8 - General Chinese National Standard (CNS) A4 Specification (210 X 297 DON) for this paper size ABCD 1307627 VI. Prevention or control of diseases, illnesses or symptoms or osteoporosis in patent gardens and breast atrophy. 3 9 _ As used in the scope of patent application No. 38, where estrogen is sufficient to treat flushing fever, night sweats or palpitations. 40. The use of any one of claims 33 to 35, wherein the estrogen is selected from the group consisting of estradiol, estradiol amide, lactate, estradiol, estradiol A group of benzoic acid S, ethinyl estradiol, estradiol, estroglycerol, estroglycerol succinate, conjugated estrogen. 41. The use of claim 40, wherein the conjugated estrogen is selected from the group consisting of estradiol sulfate, 17 β-virotione sulfate, 17 α-estradione sulfate, and female solids Alcohol sulfate, 17β-dihydroestradiol sulfate, 17 α-dihydroestradiol sulfate, estrone ketone sulfate, 17 β-dihydroestritol ketone sulfate, 17α-dihydrogen a group consisting of estrone ketone phthalate). 42. The use of claim 40, wherein the estrogen is selected from the group consisting of estradiol, estradiol sulfonate, estradiol, estradiol, and mixtures thereof. 4 3 The use of the fourth aspect of the patent application, wherein the estrogen is estradiol 0 44. The use of any one of claims 33 to 35, wherein the drospirenone (DRSP) The dose is equivalent to from 0.25 to 10 mg per dose range. 45. For the purposes of application No. 43 of the patent application, the content of the female glycol diol is 84562-971111.doc. 9. The paper scale is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm). From 0.1 to 5 mg per dose range. The use of any one of claims 33 to 35, wherein the medicament is in the form of a lozenge, capsule or pill. 47. The use of any one of claims 33 to 35, wherein the drug is placed in a package unit in a plurality of separately packaged and individually removable daily dosage unit forms and is intended for use in a package Oral administration for at least 21 days is preferably at least 28 days. 48. For the purposes of section 47 of the patent application, the estrogen content of each dosage unit in the packaging unit is the same. 49. For example, the use of item 47 of the scope of patents, in which the spirone content of each dosage unit in the packaging unit is the same. 50. For the use of claim 47, wherein each of the individually removable dosage units is a composition as claimed in claims 1 to 3. 51. If the application of the scope of patent application is 47, please select several individually packaged and individually removable daily dosage units as defined in any of the items in the patent scope. 84562-971111.doc ^ Medium country material (CNS) A4 specification (21GX297 male cage ^