TWI307627B - Drospirenone for hormone replacement therapy - Google Patents

Drospirenone for hormone replacement therapy Download PDF

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TWI307627B
TWI307627B TW90101039A TW90101039A TWI307627B TW I307627 B TWI307627 B TW I307627B TW 90101039 A TW90101039 A TW 90101039A TW 90101039 A TW90101039 A TW 90101039A TW I307627 B TWI307627 B TW I307627B
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estradiol
estrogen
content
days
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TW90101039A
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Chinese (zh)
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Heil Wolfgang
Hilman Jurgen
Lipp Ralph
Schurmann Rolf
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Bayer Schering Pharma Ag
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1307627 五、發明說明(1 發明之領域 本發明係關於-種包含有二螺飼及雌激素之藥學組成 =’以及供㈣素分料足婦女使狀藉红_與雌激 素投藥的荷爾蒙復位治療方法。 本發明之一般性背景 由於對生命健康期許的增強,以及隨之增加的停經前 與停經後婦女人數,已導向大眾及醫學加則注生育期婦 女的更年期轉變。停經(最後-次月經),於多數之婦女發 生在45-55歲之間。多種因素(包括族裔 '遺傳 '營養、居 住之海拔、吸煙、生育子女數、使用荷爾蒙避孕法、月經 周期之日數及青春期起始之年齡)皆有影響,正面或負面 地,來影響到最後一次月經的年齡。 於諸等生理階期中,女性内分泌活動進行一系列之變 隨之產生的疋g午多婦女的身體及心理健康受到負面的 影響。荷爾蒙復位治療的目標為改善婦女在此種自然老化 過程中之健康狀況,俾以減輕與此轉變期有關之症狀,以 及降低可能或減緩與此荷爾蒙活動下降有關之異常或疾 病。 經 濟 部 智 慧 財 產 局 員 X. 消 費 合 作 社 印 製 一螺酮已由DE 26 52 761案而被熟知,於該案中二螺 酿1疋以其做為利尿劑之用途被揭示。 二螺酮具有類似促孕素活性,其因此而被使用為一種 避孕藥,劑量範圍在0.5-50毫克,係揭示於DE 30 22 337 案中。 與荷爾蒙復位治療呈拮抗型態之孕激素的用途及扮演 本紙張尺度適用中關家標準(CNS)A4規格(210 X 2町公餐) 41307627 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

五、 l3〇7627 發明說明( 的角色,已被科學團隊(Lobo R. A.,1992; Sobel N.B·,1994) 所研發,其為包含雌激素及孕激素之攝取治療法(c〇rs〇n S.L., 1993; Jones K.P., 1992) ° 揭示於PCT/EP94/02997案中為使用一種製備用於取 代治療及口服避孕藥(其包含至少一種孕激素及至少一種 雌激素,其中雌激素劑量之變化具有週期性,藉此來避免 實質之血液流失)。 發明之概要說明 本發明於第一個方面係關於一種藥學組成物,其包含 的一個第一活性試劑為一種雌激素(可為天然或此等之合 成性衍生物),呈足夠數量來供治療與婦女内因性雌激素量 不足有關之疾病、異常及症狀,以及一個第二活性試劑為 6Ρ,7β;15β;16β-二亞甲基 _3_ 酮-17α•孕 _4_烯_21,17_ 羰内酯 (二螺酮,Drospirenone),呈足夠數量來保護子宮内膜免於 雌激素之負面作用,併同藥學上可接受之賦形劑或載劑。 於第一個方面,本發明係關於一個藥學組成物,其包 含一個作為第一活性試劑之雌脂二醇,呈相當於一個每曰 劑篁為1至3毫克之數量來供治療與婦女内因性雌激素量不 足有關之疾病、異常及症狀,以及一個作為第二活性試劑 之 6β,7β;15β;16β-二亞甲基-3-酮 _17α·孕-4-烯-21,17-羰内 酯(二螺酮,Drospirenone),呈相當於一個每日劑量為】至 3.5毫克之數量來供保護子宮内膜免於雌激素之負面作 用’併同藥學上可接受之賦形劑或載劑。 本發明於另一方面係關於使用一個雌激素與二螺_之 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮) 1 rir·· 裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 13〇76275. 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

經濟部智慧財產局員工消費合作杜印製 :。來製傷-個藥物,其中雌激素之量足夠用來治療與婦 女内因性雌激素量不^有關之疾病、異常及症狀,且二螺 嗣之量足夠用來保護子宮内膜免除雌激素之負面作用。 於-個更進一步之方法,本發明係關於與婦女内因性 雌激素量不足有關之疾病、異常及症狀之方法,其包含投 樂為呈足量可減輕該症狀之雌激素,及呈足量可保護子宮 内膜免除雌激素之負面作用的二螺酮。 再者,本發明係關於一種治療及預防與婦女内因性雖 激素量不;1有關之疾病、異常及症狀之方法,其包含之投 藥有雌脂二醇(呈相當於一個每日劑量為⑴毫克之量,諸 如卜2或3毫克)及二_(呈相當於一個每日劑量為 毫克之量’諸如卜“小以^或“毫克)。 發明之詳細内容揭露 於本案之文字内容中,週期本身之辭意或設若關連月 經一辭時,係欲意指一婦女月經之間相隔的日數。其可能 之範圍為21-31天,典型為28天。 於本案之文字内容中,停經之辭意被瞭解為最後一次 自然(卵巢誘發)之月經。其為一個單純事件,且為一種隨 年齡產生之卵巢;慮泡的功能障礙。停經係由於印巢減少其 等之性荷爾蒙(雌激素及黃體激素)的產生。當濾泡之數量 落在一某種閥值點(一個行經jk之閥值點)以下時,卵巢則 無法產生成熟之遽泡及性荷爾蒙。可生育之能力與停經同 時終止。 接近-停經期之起始是由更年期症狀開始,是時月經週 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ΜI, .14 Μ--------^--------- {請先閲讀背面之注意事項再填寫本頁) 6 l3〇7627 五、發明說明(4 ) 期變為不規則,且於停經後一年結束❶接近_停經期之終止 能夠經由一段長時間無經血之後來判別。後停經期是由停 經開始持續至死亡。 荷爾蒙復位治療之一個理論目標為復位自然性或早發 性停經前、停經或停經後婦女之固醇類性荷爾蒙含量,或 在性腺功能減退之女性身上建立此等荷爾蒙含量。 單一治療(亦被稱之為無逆阻治療)係為單獨使用雌激 素之治療。外源性雌激素刺激子宮内膜之増生。於雌激素 之單一治療中,黃體激素之逆阻作用(其終止增生)不會出 現。脫落期(於此期間子宮内膜之表層脫落)不會發生,且 子宮内膜之增生進展至—程度遠大於多種時期(甚至於停 經前之時期結果為性器官增生,為—種子宮内膜癌之危 險因子。 組合治療(亦被稱之為逆阻治療)係為一種治療,其中 # -種孕激素類被添加來供保護+宮内膜免於增生性器官增 大。 於組口…療中使用天然之黃體激素,會受天然黃體激 素之低生物體可利錄之限制,甚至於呈超微量之型態。 顯著地’本發明人已發現包含有二螺嗣當做一個孕激素之 組合治療為明顯地有效。二螺酮(DRsp),一個心螺内酯 之衍生物,為-個合成之孕激素,其具有一另人驚舒之與 黃體激素類似之生理特性,還有更好之生物體可利用性。 其為第-個合成之孕激素能具有一個如黃體激素之藥學特 I·生在其為逆阻雌激素、逆阻雄激素且具有抑制礦物性腎上 本紙張尺度_ _减準(C;NS)A4 (21〇TiT^7 7 l3〇7627 經濟部智慧財產局員工消費合作杜印製 A7 B7 五、發明說明(5 ) 腺皮質類脂醇之活性。 本發明具體化—個藥學組成物,該組成物包含一個雕 激素,或為其天然或合成的衍生物,呈足夠數量來供治療 與婦女内因性雌激素量不足有關之疾病、異常及症狀;1以 及-個作為第二活性試劑之6(5,7(^叩;16卜二亞甲基相 _17〇1_孕·4·烯·21,17_ 羰内酯(二螺酮,Dr〇Spirenone),呈足 夠數量來供保護子宮内膜免於雌激素之負面作用,併同藥 學上可接受之賦形劑或載劑。 除活性物質本身之外,已設想有一個醋或二螺網之前 驅藥物可以被使用在本發明之組成物中,例如揭示於 98/24801中之種氧亞胺基孕燒幾内醋(OXyimin〇pregnane carbolactone) 〇 雌激素量不足可因多種病因而發生。組成物可以為滿 足雌激素量不足所需,不計其病因。治療所期望之病因為, 但不限制為,自然性停經、接近停經、停經後、性腺功能 減退、去勢或原發性卵巢機能障礙。 低雌激素量’不論其病因,導致婦女之生命品質有一 整體性之下降。症狀、疾病及異常之範圍由單純之不適至 危及生命。此種治療之組成物所期望的是有效減低雌激素 不足之所有的生理及 心理的癍兆。 過渡性症狀’諸如血管收縮神經之癥候及心理性症狀 被確定地具體化在治療之範疇内。血管收縮神經之癥候包 含但不限制為潮紅發熱、盜汗(如夜間盜汗)、及心悸。雌 激素不足之心理性症狀包含但不限制為失眠及其他睡眠障 本紙張尺錢巾國國家標準(CNS)A4規格(210 X 297公髮) r I-I' 4^-裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1307627 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(6 ) 礙、記憶力不佳、缺乏自信、情緒起伏、焦慮 '缺乏性慾、 難以集中注意力、難以做決策、無勁且乏力、易怒、以及 愛哭。 治療前述症狀可能涉及一個婦女生命中接近停經期或 該時期之後,有時超越停經後甚久。所期望的是本發明可 被使用在接近停經期、停經或後停經期中的此等及其他過 渡性症狀。此外,設若雌激素不足之病因為性腺功能減退、 去勢或原發性卵巢機能障礙時,則前述之症狀能夠被減輕。 於本發明之另一個具體例中,本治療被用來治療雌激 素不足之永久性作用。永久性作用包含生理變化,諸如泌 尿生殖器萎縮、乳房萎縮、心血管疾病、改變毛髮分布、 毛髮稀疏度'改變皮膚之膚質及骨質疏鬆。 泌尿生殖器萎縮,與其相關之症候(諸如陰道乾澀、陰 道酸鹼值增高及繼之腸内微生物改變),或可導致此等萎縮 之生理變化(諸如多血管化、彈性纖維之戴段化、膠原纖維 融合)’或者是細胞體積縮小被認為是與本發明治療特別有 關。再者,本發明被認為係關於與雌激素不足有關之其他 泌尿生殖器變化,諸如陰道之長度及/或内徑變短、黏液分 泌減少、細胞數量改變、減少產生醣原、減少乳酸菌之生 長或增加鏈球菌、葡萄球菌或大腸菌之生長。其他被認為 可以藉由本發明來預防之相關性改變為該等可使陰道成為 易於又傷害或受感染,諸如滲出液排出、陰道炎、及性交 疼痛。再者,尿道感染及大小便失禁為其他與雌激素量不 足有關之常見的症狀。 一 II. 裝--------訂--------- rtt先閱讀背面之注意事項再填寫本頁}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 A71307627 A7

經濟部智慧財產局員工消費合作社印制衣 本發月其他之具體例包含預防或減輕與雖激素不足有 關之生理改變’諸如皮膚的改變、毛髮分布的改變、毛髮 的稀疏度、乳房萎縮或骨質疏鬆。 預防及控制骨骨質疏鬆(尤其是停經後骨質疏鬆)為本 發明之-個特別令人關注的具體例。再者,㈣去礦物質 化'骨骼重量及密度減低、分隔帶變薄及間斷、及/或繼而 生之骨折或骨路變形增多被認為是特別有關的。骨質疏料 之預防性治療為本發明之—個特別令人關注的應用性^ 療。 本發明-個特別令人關注的具體例包含使用本發明之 組成物來減低潮紅發熱、奸、心悸、睡眠障礙、情緒起 伏神經質、焦慮、記憶力不佳、缺乏自信、缺乏性您、 注意力不集中、乏力、無勁、泌尿生殖器萎縮、乳房萎縮、 心血S疾病、毛髮分布的改變、毛髮的稀疏度、改變皮膚 之膚質及骨質疏鬆(尤其是潮紅發熱、盜汗、心悸、睡眠障 礙、情緒起伏、神經質、焦慮、泌尿生殖器萎縮、乳房萎 縮或骨質疏鬆之防治。 藥學組成物用於H RT (荷爾蒙復位治療)於本案之揭示 包含有雌激素。於較佳之具體例中,雌激素係選自於包含 下列之群組:雌脂二醇、雌脂二醇胺基磺酸酯、雌脂二醇 戊酯、雌脂二醇苯甲酸酯、乙炔基雌脂二醇、雌脂酮、雌 脂三醇 '雌脂三醇琥珀酸酯及共輛雌激素(包含共軛-源自 馬的雌激素,諸如雌脂酮硫酸酯、17β_雌脂二酮硫酸酯、 17α-雌脂二酮硫酸酯、雌固醇硫酸酯、17β_二氫雌固醇硫 本紙張尺度適用中國國豕標準(CNS)A4規格(210x297公釐) — — — — — t t I ! (請先閱讀背面之注意事項再填寫本頁)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.)

ϋ I I S, 10 1307627 A7 B7 五、發明說明(8 C請先閲讀背面之注意事項再填寫本頁) 酸Sa、17α-二氫雌固醇硫酸酯、雌固醇酮硫酸酯、ρβ-: 氫雌固醇酮硫酸酯、17α-二氫雌固醇酮硫酸酯’或是此等 之混合物。特別受到關注之雌激素是選自於包含下列之群 組:雌脂二醇、雌脂二醇胺基磺酸酯、雌脂二醇戊酯、雌 脂二酵苯甲酸酯、雌脂酮、雌脂酮硫酸酯及此等之混合物’ 尤其是雌脂二醇、雌脂二醇戊酯、雌脂二醇苯甲酸酯及雌 脂二醇胺基磺酸酯。最佳為雌脂二醇及雌脂二醇胺基續酸 酯,特別是雌脂二醇。 被認為特別有關的是微粒型態之雌激素,諸如微粒型 雌脂二醇、微粒型雌脂二醇胺基磺酸酯、微粒型雌脂二醇 戊酯、微粒型雌脂二醇苯曱酸酯、微粒型雌脂酮、微粒型 雌脂酮硫酸酯或此等之混合物’較佳為微粒型雌脂二醇、 微粒型雌脂二醇戊酯、微粒型雌脂二醇笨甲酸酯或微粒型 雌脂二醇胺基磺酸酯◊最佳為微粒型雌脂二醇及微粒型雌 脂二醇胺基確酸酯,特別是微粒型雌脂二醇。 於本發之某些具體例中,其中之組成物包含超過一個 雌激素’一個或多個雌激素(例如2個或所有的雌激素)可以 呈微粒型態。 經濟部智慧財產局員工消費合作社印制衣 再者’本發明的一個令人感興趣的具體例為包含一個 組成物,其中二螺酮(DRSP)呈微粒型態,諸如雌激素及二 螺酮(DRSP)二者之一或二者皆呈微粒型態,較佳為雌激素 及二螺酮(DRSP)皆呈微粒型態。 二螺酮(DRSP)(其製備大體上係可以參照如us 4,129,564或W0 98/06738中所描述者)’為一個難以溶解於 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 11 經濟部智慧財產局員工消費合作社印製 A7 ^^ ____B7____ 五、發明說明(9 ) 水及多種不同酸鹼值之液態緩衝液之物質。更進一步而 言,二螺酮在酸性之狀態下重組為一個不具活性之異構 物,且於鹼性之狀態下水解。為了確保化合物有良好之生 物可利用性,因而採取有利地提供其呈有助於此等可快速 溶解之一種型態。 已發現當二螺酮以一個藥學組成物之微粒型態被提供 時’於非活體内’活性化合物自組成物中快速溶解。一個 微粒型物質為諸如一個測試批組(大约2〇〇毫克)之顆粒 體,於本案為二螺酮顆粒體,具有一個表面積為超過1〇,〇〇〇 平方公分/公克,且具有下列以顯微鏡下觀測到之粒徑尺寸 分布的二螺酮:於一定量批組(大約2〇〇毫克)中,不超過2 個顆粒具有一個大於30微米之粒徑,且較佳為$ 2〇個顆粒 具有一個210μιη且^30μιη。,,快速溶解”之辭意定義為在約 30分鐘内有至少70%的溶解度,尤其是在約2〇分鐘内有至 少80%的溶解度,其為371:下一含有3毫克二螺酮之藥鍵溶 於900毫升之水,藉由使用一種usp溶解測試儀2號(以每分 鐘50轉)之USP XXIII paddle方法來測定。 因其是一種選擇性以微粒型態提供二螺酮,故其能夠 將一螺_溶解於一種可溶之溶劑中(例如曱醇或醋酸乙 酯),且可將二螺酮喷灑於惰性之載體顆粒上,再將此表面 含有二螺嗣之顆粒併入組成物之中。 不欲為任何一種特定之理論所限制,所顯示為非活體 内之二螺酮的溶解速率關連到活體内之溶解速率,產生活 體内化合物之口服投藥下二螺酮被快速吸收。此為一個 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) I* 裝--------訂--------- (請先閲讀背面之注意事項再填寫本頁) 12 經濟部智慧財產局員工消費合作社印製 1307627 A7 ----- B7____ 五、發明說明(10 ) 利點’因為於胃中化合物之異構化及/或小腸中之水解被實 際地消減,導向一個化合物有高的生物可利用度。 由於雌激素亦可能為一難溶之物質,雖然其於一般腸 胃道中通常較二螺酮不易被分解,其亦為一有利點是以微 粒型態或自一種溶劑(如乙醇)噴灑至惰性載體顆粒之表面 來提供雌激素。此具有增添促進雌激素在組成物中有一個 更均勻態之分布。當雌激素是以微粒型態被提供時,其以 顯微鏡下測定出來,較佳是具有下列粒徑尺寸:100%的顆 粒具有一個粒徑$15.0μηι,99%的顆粒具有一個粒徑 $12.5μιη ’ 95%的顆粒具有一個粒徑$ΐ〇.〇μιη,且50%的顆 粒具有一個粒徑$3.0μηι。更進一步而言,沒有大於ζομη! 的顆粒,且$10個顆粒具有一個15μηι5粒徑$2〇μηι。 雌脂二醇或雌脂二醇半水合物之粒徑尺寸分布較佳 為:在一個特定之批組中,1〇〇%的顆粒具有一個粒徑 $15·0μηι,99%的顆粒具有一個粒徑;^Ι2·5μηι,95%的顆粒 具有一個粒徑^10.Ομηι,且50%的顆粒具有一個粒徑 $3·0μιη或40%具有一粒徑為小於ι.ιμιη。 為了得到一個更快之溶解速率,較佳地是包含載體或 賦形劑’該等用來增進兩種活性物質之溶解。此等載體及 賦形劑之具體例包含易溶於水之物質(例如纖維素衍生 物、羥基曱基纖維素、羥基丙基纖維素、羥基丙基甲基纖 維素、膠體化之澱粉、明膠或聚乙稀吼Ρ各酮:特別是希望 聚乙烯吡咯酮能夠有助益於增進溶解。 於每一種組成物中之二螺酮劑量,較佳為諸等保護子 --^--·-------^ --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 13 1307627IIS 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

經濟部智慧財產局員工消費合作社印製Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

宫内膜免除雌激素之έ AA 爻貝面作用。二螺酮(DRSP),呈足量 肉月b夠破用來當做雌激素之一種结抗劑,用來保護子宮 内膜免於性腺功能減退或癌症。 子呂 …、而於某些案例中’二螺酮(DRSP)可以為充足之 俾^穩疋月經週期及行經之形態。於此種案例中’雌 素之齊丨量可旎很低或無。由脂肪組織產生之雌激素可能 為’’’、或低量之雄激素會被需*來軸及行經之形 態再者,於某些具體例中之婦女係蒙受與使用一種外源 性雌激素不相4之其他病症(諸如有絕對相衝之嚴重性肝 病及懷孕,或有相當相衝之子宮内膜癌及子宮内膜異位、 乳癌、靜脈ok栓性检塞症、高血壓、糖尿病、骨質疏鬆及 黑色素瘤),無或非常低量之雌激素能夠存在組成物之中。 於此等具體例巾,二螺_(DRSp)之㈣為能夠使異常、病 變或症狀被減輕。 於較佳之具體例中,二螺嗣(DRSP)之劑量相當於每一 個週期15至70毫克(例如每—個週期跑6()毫克),特別是 每一個週期40至60毫克。週期之長短,被稱為s-a可以由 21至31天而有*同。在其他方面來看,一個組成物能夠包 含有-個二螺酮(DRSP)之數量是相當於每日劑量由〇 25至 1〇之範圍(例如約0.25至8、〇·25至6、0.25至5、0.5至4·5、i 至4及1.5至3.5毫克)。 雌激素之劑量可因不同之婦女而異,端視該婦女之生 理階期(接近停經或停經後)、體内之雌激素含量、症狀(異 常或疾病)之嚴重性、症狀(異常或疾病)之標的、因其他目 本纸張尺度漣用中國國家標準(CNS)A4規格(210 X 297公爱) ---Ί1----參-裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 14 1307627 A7Endometrium 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

經濟部智慧財產局員工消費合作社印制衣 的而被婦女所使用之其他藥物、及其他藥物動力學變數。 於其他之具體例中,雌激素及/或二螺酮(DRSp)之劑量 係足夠用以/σ療潮紅發熱、盜汗、心悸、睡眠障礙、情緒 起伏、神經質、焦慮、記憶力不佳、缺乏自信、缺乏性慾、 注意力不集中、乏力、無勁、泌尿生殖器萎縮、乳房萎縮、 “血s疾病、毛髮分布的改變、毛髮的稀疏度、改變皮膚 之膚質或骨質疏鬆之預防或控制。 雌激素及/或二螺酮(DRSP)之劑量可以視治療而定,其 有用於保護子宮内膜(如行經之形態)、用於預防或控制骨 質疏鬆、用於治療停經之症狀(如降低潮紅發熱、夜間盜 汗、情緒起伏心悸、失眠及其他睡眠障礙、情緒轉變、神 經質、焦慮、記憶力不佳、缺乏自信、缺乏性慾、注意力 不集中、乏力、無勁及易怒煩躁之次數、頻率及嚴重度。 於具體例之中的雌激素為雌脂二醇,該雌脂二醇的數 量相當於每日劑量範由〇.1至5毫克,例如大約〇 2至4 5、〇 5 至4、1至3,特別是1、2或3毫克。 關於具有較強效力之雌脂二醇衍生物(例如:雌脂二醇 戊酯)的劑量方面,成比例之劑量可以依照其相對之效力來 調整上文所述之劑量而計算出來。 於具體例之中的婦女為接近停經期時,雌激素及/或二 螺嗣(DRSP)之劑量可以視該日之週期巾定,意即:該婦女 是在排卵前或排卵後之週期内,及處在每一期内有多久。 於具體例之中的婦女為停經後或者甚至為前停經期時,雖 激素及/或二螺酮(DRSP)之劑量可以視距離最後一次經 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮) -ί 裝--------訂---------^9. (請先閱讀背面之注意事項再填寫本頁)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 15I 15

五、發明說明( 經濟部智慧財產局員工消費合作社印製 的時間而定。 於本發明之某些具體例中,藥物之型態為將數個分別 移且個別可移取之劑量單位置於—個包裝單㈣,且欲用 於-為期至少21天之口服投藥(例如至少以天、例如至少 30-31天)。於此等具體例中,二螺_(DRsp)&/或雌激素之 數量在每-個劑量單位中可以為相同或不同。於具體例中 二螺酮(DRSP)及/或雌激素之數量在每一個劑量單位中的 變化是依據週期為至少21天(例如至少2 8天)中之階期或 日,該給藥之劑量單位、此組成物' 治療及製備之方法被 稱為多階段式(multi-phase)。 劑量之比例可以依據其用途而改變。於較佳之具體例 中,用以製備一個藥物之雌激素及二螺酮的劑量比例為諸 如雌激素劑量可治療與雌激素内分泌量不足有關之疾病、 異常及症狀,且二螺酮之數量足以保護子宮内膜免除雌激 素之負面作用。 於較佳之具體例中’劑量之比例足以治療潮紅發熱、 盜汗、心悸、睡眠障礙、情緒起伏、神經質、焦慮、記憶 力不佳、缺乏自信、缺乏性慾、注意力不集中、乏力、無 勁、泌尿生殖器萎縮、乳房萎縮、心血管疾病、毛髮分布 的改變、毛髮的稀疏度、改變皮膚之膚質或骨質疏鬆之預 防或控制。 本發明係關於一種治療婦女與雌激素内分泌量不足有 關之疾病、異常及症狀的方法,其包含之投藥有雌激素(呈 足量來減輕該等症狀),及二螺酮(呈足量來保護子宮内膜 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮) Μ —ί —.1 Μ.--------^---------. (請先閲讀背面之注意事項再填寫本頁) -16 - A7 A7 經濟部智慧財產局員工消費合作杜印制衣 ^ ---—2L____ 五、發明說明(14) - 免除雌激素之負面作用)。較佳地,應用本發明方法之雌激 、量不足是由自,然停經、接近停經、停經後、性腺功能減 退、去勢或原發性即巢機能障礙所引起的。 應用本發明方法之疾病、異常及症狀包含潮紅發熱、 盜汗、心#、睡眠障礙、情绪起伏、神經質、焦慮、記憶 力不佳、缺乏自信、缺乏性慾、注意力不集中、乏力、無 勁、泌尿生殖器萎縮、乳房萎縮、心血管疾病、毛髮分布 的改變'毛髮的稀疏度、改變皮膚之膚質或骨質疏鬆之預 防或控制。特別地,本發明之方法希望能應用在潮紅發熱、 盜汗、心悸、睡眠障礙、情緒起伏、神經質、焦慮、泌尿 生殖器萎縮、乳房萎縮、心血管疾病、毛髮分布的改變、 毛髮的稀疏度、改變皮膚之膚質或骨質疏鬆之預防或控制。 應用本發明之方法來投藥一種雌激素,其較佳為雌脂 一醉雌脂二醇胺基續酸酯、雌脂二醇戊酯、雌脂二醇苯甲 酸酯、乙炔基雌脂二醇、雌脂酮、雌脂三醇、雌脂三醇號 拍酸酯及共軛雌激素(包含共軛-源自馬的雌激素,諸如雌 脂酮硫酸醋、17β-雌脂二綱硫酸醋、17α-雖脂二_硫酸醋、 馬稀雌酮硫酸酯、17β-二氫馬稀雌酮琉酸酯、ΐ7α-二氫馬 烯雌酮硫酸酯、馬茶雌酮硫酸酯、17β-二氫馬茶雌剩硫酸 醋、17α-二氫馬茶雌_硫酸醋或此等之混合物),大部份為 雌脂二醇、雌脂二醇胺基磺酸酯、雌脂二醇戊酯、雌脂二 醇苯甲酸酯、雌脂酮、雌脂酮硫酸酯或此等之混合物,特 別是雌脂二醇。 本發明一個特別吸引人的具體例包含有二螺酮(DRSP) 本紙張尺度適用中國國家標準(CNS〉A4規格(210 X 297公釐) T i ,1 t 裝--------訂--------- (請先閲讀背面之注意事項再填寫本頁) 17 1307627V. 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

五、發明說明(15 ) 經濟部智慧財產局員工消費合作社印製 及/氧雌激素以微粒型態的投藥。更進一步而言,特別令人 感興趣的是雌激素為呈微粒型態之雌脂二I於此等具體 例中,單一或兩種活性成份呈微粒型態被投藥。 於某些具體例中,本發明之方法包含有—個二螺嗣 (DRSP)之投藥劑量為㈣於每_個週期15至7〇毫克(例如 每-個週期20至㈣克,特別是每—個週期避6。毫克)。 本發明之方法較佳為包含有—個二螺酮(DRsp)之投藥劑 量一螺酮(DRSP)之數量為相當於一個每日劑量範圍由 0.25至10毫克(例如大約0.25至8、〇25至6、〇.5至45、a# 或1.5至3.5毫克)。 雌脂二醇之投藥數量可以為相當於一個每日劑量範圍 由〇·1至5毫克(例如大約〇.2至以^至扣⑴特別是卜 2或3毫克)。 -個特別有關的具體例係關於一個藥學組成物,其包 含的一個第一活性試劑為一種雌激素,以數量相當於一個 每曰劑量為1至3毫克來治療與婦女内因性雌激素量不足有 關之疾病、異常及症狀,以及—個第:活性試劑為 6β,7β;15β;16β_二亞甲 m17a.孕 _4_婦_2117幾内醋 (二螺剩,Drospirenone)’以數量相當於一個每日劑量韌 至3.5毫克來保護子宮内膜免除雌激素之負面作用,併同藥 學上可接受之賦形劑或載劑。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.

關於組成物中之活性成份的某些較佳具體例中,其中 雌激素為雌脂二醇,包含1毫克雌脂二醇中有〇 5毫克之二 螺酮(DRSP) W毫克雌脂二醇中有〗毫克之二螺酮(DRSIn 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)

本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公复 (請先閱讀背面之注意事項再填寫本頁)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)

裝-----訂II 18 經濟部智慧財產局員工消費合作社印製 1307627 A7 ^_________B7 五、發明說明(16 ) 1毫克雌脂二醇中有1.5毫克之二螺酿j(DRSP)、1毫克雌脂二 醇中有2毫克之二螺酮(DRSP)、1毫克雌脂二醇中有25毫克 之二螺網(DRSP) 1毫克雌脂二醇中有3毫克之二螺酮 (DRSP)、2毫克雌脂二醇中有1毫克之二螺酮(drsp)、2毫 克雌脂二醇中有4毫克之二螺酮(DRSP)。 於較佳之具體例中,本發明一個較佳之具係關於一個 藥學組成物’其包含的一個第一活性試劑為一種雌脂二 醇’以數量相當於一個每日劑量為1至3毫克(例如1、1.5、 2、2.5或3毫克之雌脂二醇),以及一個第二活性試劑為 60,70;150;160-二亞曱基_3_嗣_17〇1-孕-4-烯-21,17-幾内酯 (二螺酮,Drospirenone),以數量相當於一個每曰劑量為i 至3.5毫克(例如1 ' ι·5、2、2.5或3毫克之二螺酮(orsP)), 併同藥學上可接受之賦形劑或載劑。 依據地,本發明之一個較佳的具體例係關於一種治療 及預防與婦女内因性雌激素量不足有關之疾病、異常及症 狀的方法,其包含之投藥有雌脂二醇(呈相當於每日劑量為 1至3毫克之數量(例如丨、2、或3毫克)),以及二螺酮(呈相 當於每曰劑量為1至3_5毫克之數量(例如:1、1.5、2、2.5、 3或3.5毫克))。 已知之内因性雌激素量不足可能有關為(於其他眾因 素之中).自然停經、接近停經期、停經後、性腺功能減退、 去勢或原發性卵巢機能障礙,治療及預防與疾病、異常及 症狀有關之方法可能會持續至個體死亡為止。換句話說, 組成物可能自診斷出疾病、異常或症狀而投藥至個體之生 M J— — 111 — i^va -------—訂 ----I---—^Aw. (請先閱讀背面之注意事項再填寫本頁)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 - 13〇7627-19 - 13〇7627

經濟部智慧財產局員工消費合作社印製 命結束。於某些具體例中,本發明之方法及組成物可能是 以月經週期之節奏為基準。於其他之具體例中,本發明之 方法可能完全忽略天生之週期。 本發明之方法較佳為多階段性(multi-phase)。本發明 之方法可能包含歷時1〇至12天的投藥:一個每日劑量單位 包含雌脂二醇(呈相當於每曰劑量範圍由〇1至5毫克之數 量);以及再加之10至12天的投藥:一個每日劑量單位包含 雌脂二醇(呈相當於每日劑量範圍由0.1至5毫克之數量)及 二螺明(呈相當於每日劑量範圍由〇 25至6毫克之數量);再 加之歷時4至8天的投藥:一個每日劑量單位包含雌脂二醇 (呈相當於每曰劑量範圍由0·25至5毫克之數量)。 類似地,本發明之多階段性方法能夠包含歷時丨〇至j 2 天的投藥:一個每曰劑量單位包含雌脂二醇(呈相當於每曰 劑量範圍由0.1至5毫克之數量);以及再加歷時10至12天的 投藥:一個每曰之劑量單位包含雌脂二醇(呈相當於每曰劑 量範圍由0.1至5毫克之數量)及二螺酮(呈相當於每曰劑量 範圍由0.25至6毫克之數量);再加歷時4至8天的投藥:一 個每曰劑量單位包含安慰劑或無。 本發明方法之一種給藥程序表能夠包含歷時至少2 i天 的投藥:一個每日劑量單位包含雌脂二醇(呈相當於每曰劑 量範圍由0.1至5毫克之數量)及二螺酮(呈相當於每曰劑 量範圍由0_25至6毫克之數量);以及再加歷時不超過7天的 投藥:一個每日劑量單位包含安慰劑或無藥。一個類似本 發明方法之給藥程序表能夠包含歷時至少21天的投藥:一 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) —Μ 丨-—M J—裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 20 1307627 五、發明說明(18 ) 經濟部智慧財產局員工消費合作社印製 個每曰劑量單位包含雌脂二醇(呈相當於每曰劑量範圍由 0.1至5毫克之數量)及二螺酮(呈相當於每曰劑量範圍由 0.25至ό毫克之數量);以及再加歷時不超過7天的投藥:一 個每日劑量單位包含雌脂二醇(呈相當於每日劑量範圍由 0-1至5毫克之數量)。 可擇地,本發明方法之一種給藥程序表能夠包含歷時 至少21天的投藥:一個每日劑量單位包含雌脂二醇(呈相當 於每曰劑量範圍由〇·1至5毫克之數量)及二螺酮(呈相當於 每曰劑量範圍由0.25至6毫克之數量);且無一個劑量單位 為歷時少於7天之投藥。 本發明方法之一選擇性的具體例包含為期21至28天的 投藥:一個每曰劑量單位包含雌脂二醇(呈相當於每曰劑 範圍由0_1至5毫克之數量)及二螺酮(呈相當於每曰劑量 圍由0.25至6毫克之數量)。 給藥程序表能夠包含一個持續性投藥;換句話說, 整個為期21至28天中,給予一個每日劑量單位的雌脂 醇。相同地,二螺酮亦能夠持續性投藥,藉此雌激素及/ 或二螺酮(DRSP)單一或兩者可被持續性投藥。 於另一個具體例中,雌激素被持續性投藥而二螺酮 階段性投藥6於一個此種具體例中,全程做雌激素之持 性投藥,二螺酮(DRSP)於為期〖至加天中的規律性間隔 如3至15天、5至14天、特別是6至14天)投藥。本發明方法 之給藥程序表的另一個令人感興趣之具體例中,緊接於該 等二職之階段性«後,雌激素之劑量被減低歷則'至Λ7 量範 於 二 以 續 IIΗI*. — Μ------------—訂·------- (請先閱讀背面之注意事項再填寫本頁) 21 五、 經濟部智慧財產局員工消費合作社印製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 發明說明(19 天。 此外,於本發明之具體例中,本發明之一種治療及預 防與婦女㈣性雌激素量不足有關之疾病、異常及症狀的 方法’係包含持續性之雌激素投藥及助孕素之間歇性投 藥。本發明方法之特別為雌激素可以被持續性投藥歷時21 至30天,且二螺酮被投藥為3天給藥3天停藥之循環。—個 特別吸引人之具體例’係包含於此選擇性二螺酮被投藥在 第4至第6天、第10至第12天、第16至第18天、第22至第24 天及第28至第3〇天’於雌激素(例如雌脂二醇)方面則做持 續性投藥。 劑量單位之組成物可以任何一種藥學技藝中傳統的方 法來配方。特別是(如上文所指示)組成物能夠藉由一種方 法被配方,該方法包含提供二螺酮及(如為所需卜種雌激 素(例如雌脂二醇):呈微粒型態,以該等之單位劑量型態, 或自-種溶液被喷壤至一個惰性載體之顆粒上,與一個或 數個藥學上可接受之賦形劑形成混合物來增進二螺嗣及— 個雖激素之溶解度,俾以促使二_及特別是雌脂二醇在 口服投藥能夠快速溶解。適合之賦形劑的範例包含填充物 (例如··糖類(諸如乳糖、葡萄糖或蔗糖)、糖醇類(諸如甘 露醇)、祕(諸如^轉或馬鈐¥澱粉纽f澱粉)、潤滑 劑(諸如滑石或硬脂酸鎮)及結合劑(諸如聚乙料㈣、纖 維素衍生物、幾基甲基纖維素、輕基丙基纖維素、經基丙 基甲基纖維素m维素或明膠)用 (例如:藥錠、藥丸_。藥㈣方便地⑽覆一;;'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 (請先閱讀背面之注意事項再填寫本頁)Mlil. Aw- ^--------^---------^9 (Please read the notes on the back and fill out this page)

本纸張尺度翻t _㈣CNS)A4規格⑵G x 297 ~ 22 13〇7627The paper size turns t _ (four) CNS) A4 specifications (2) G x 297 ~ 22 13〇7627

發明說明(20 ) 經濟部智慧財產局員工消費合作社印製 口之膜衣型成試劑(例如:㈣丙基甲基纖維素)。本發明 之組成物亦能心㈣被㈣(例如:為料、f、浮液或乳 化劑),兼併有傳統之_劑或賦形劑,以就藥學技藝而言 為已知之方法。 ° 一個多階段性藥學製備的-個特別令人感興趣之給藥 ㈣Μ包含雌激素及二螺酮兩者之階段性投藥。一個此 種給藥程序表的-個吸引人的具體例會包含—個無治療之 時段’㈣時財㈣量單位被«,其諸如包含歷時20 f 24天的投藥:―個每日劑量單位包含雌脂二醇(呈相當於 每曰劑量範圍由0·1至5毫克之數量)及二螺嗣(呈相當於每 日劑量範圍由〇.25至6毫克之數量);於該歷時20至24天中 至少10至12天’且無任何一個劑量單位之投藥為歷時⑻ 天。 可擇地,於任何一段期間中既無二螺酮(DRSP)亦無雌 激素之投藥,而以一個安慰劑或無投藥。如此之一個荷爾 蒙復位治療的給藥程序表可以有效地包含一個方法,其包 含歷時20至24天的投藥:一個每日劑量單位包含雌激素 (呈相當於每日劑量範圍由〇1至5毫克之數量),及於該歷 時20至24天中最後的至12天再加之投藥:二螺酮(呈相當 於每日劑量範圍由0.25至6毫克之數量);以及再加之歷時4 至8天的投藥:一個劑量單位中不包含有活性成份。 一個可擇之給藥程序表包含歷時2〇至24天的投藥:一 個每曰劑量單位中包含雌脂二醇(呈相當於每曰劑量範圍 由0.1至5毫克之數量),及於該歷時2〇至24天中最後的10至 本紙張尺度適用中國國家標準(CNS)A4規格(2〗0 X 297公釐) Μ !*'1---Μ--------^--------- (請先閱讀背面之注意事項再填寫本頁) 23 1307627 經濟部智慧財產局員工消費合作社印製 A7 -------------- 五、發明說明(21 ) 12天再加之投藥:二螺酮(呈相當於每曰劑量範圍由〇25至 6毫克之數量);以及隨繼歷時4至8天的投藥:一個劑量單 位中包含雌脂二醇(呈小於該歷時2〇至24天之一個每曰劑 量單位中的雌脂二醇投藥量)。 於本發明之具體例中’藥物之投藥型態為將數個分別 包裝且個別可移取之劑量單位置於一個包裝單位内,且欲 用於口服投藥供至少21天之一段時間(例如至少28天、例如 至少30-3 1天),且其中之雌激素為雌脂二醇,較佳為歷時 至少21天的每曰劑量單位中包含一個組合為雌脂二醇(呈 大約0.1至5毫克之數量)與二螺酮(呈範圍由〇25至6毫克之 一個數量);以及歷時7天(或少於7天)的每曰劑量單位中包 含雌脂二醇(呈大約〇_1至5毫克之一個數量)。 可擇地,藥物之投藥型態為將數個分別包裝且個別可 移取之劑量單位置於一個包裝單位内,且欲用於口服投藥 供至少28天之一段時間,且至少21天的每曰劑量單位中包 含一個組合為雌脂二醇(呈大約〇.1至5毫克之數量)與二螺 酮(呈範圍由0.25至6毫克之一個數量);以及歷時7天(或少 於7天)的每日劑量單位中包含無給藥或安慰劑。 易隨繼在該藥物之後,可以呈型態為將數個分別包裝 且個別可移取之劑量單位置於一個包裝單位内,且欲用於 口服投藥供至少28天之一段時間,且至少21天的每日劑量 單位中包含一個組合為雌脂二醇(呈大約〇1至5毫克之數 量)與二螺酮(呈範圍由0.25至6毫克之一個數量)。於給藥程 序表之最後7天(或少於7天)的無任何一個劑量單位。 0. .Ί*------------訂--------- {請先閱讀背面之注意事項再填寫本頁)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 13〇762724 13〇7627

遵照數個給藥程序表之具體例的病患能夠藉由藥學製 備之方法來修改為病患之需求或習慣…個此種製備可包 含有數個分別包裝且個別可移取之劑量單位置於—個包裝 單位内,且欲用於口服投藥供至少21天之一段時間(例如至 > 28天)’其中該每曰劑量單位中包含一個組合為雌脂二醇 (呈範圍由大約〇.1至5毫克之一個數量)與二螺酮(呈範圍由 0·25至6毫克之一個數量)。 經濟部智慧財產局員工消費合作社印制衣 再者’能夠以一個包含有一多階段性藥學製備之給藥 程序表來輔助病患服藥。 母一個給藥程序表可被容易地附加以一個多階段性藥 學製備(諸如一個包含有數個分別包裝且個別可移取之劑 量單位置於一個包裝單位内,且欲用於口服投藥供28天之 段時間’其中該每日劑量單位中包含一個组合為雌脂二 醇(呈範圍由大約0.1至5毫克之一個數量)與二螺酮(呈範圍 由0.25至6毫克之一個數量))。於如此之一個製備中,活性 成份的數量在28天之期間内做變化。 一個吸引人的具體例係關於多階段性藥學製備,其包 含有一個包含有數個分別包裝且個別可移取之劑量單位置 於一個包裝單位内,且欲用於口服投藥供連續21至3〇天之 一段時間’其中10至15個該等之每日劑量單位中包含一個 組合為雌脂二醇(呈範圍由大約〇丨至5毫克之一個數量)與 二螺酮(呈範圍由〇_25至6毫克之一個數量);以及10至15個 該等之每日劑量單位中包含雌脂二醇(呈範圍由大約〇1至 5毫克之一個數量)。此具體例特別適用之製備,其中雌激 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閲讀背面之注意事項再填寫本頁) 裝 tr---------Φ. 25 l3〇7627 A7 B7 五、 經濟部智慧財產局員工消費合作社印製 發明說明(23 ) 素以連續21至30天被投藥,且二螺酮被投藥為3天給藥3天 停藥之循環。較佳地,於此具體例中,製備被設計來使二 螺酮被投藥在第4至第6天、第10至第12天、第16至第18天、 第22至第24天及第28至第30天。 此外,一個多階段性藥學製備中的每曰劑量單位之數 量為21或28、或者(21或28)的一個倍數(例如2至24、2至 12、特別是2至8(例如2至6個倍數))》 相同地,本發明係關於一種治療與雌激素量不足有關 之疾病、異常及症狀的方法,其包含一個多階段藥學製備 (係包含每日劑量單位被用以投藥歷時1至12、較佳為2至8 諸如2、3、4、5、6、7及8)個28天。 一個包裝單位包含有如上文所述之每日劑量單位,係 可藉由一種方法類似於製造口服避孕藥或荷爾蒙復位給藥 程序表。此可以舉例而言為一個傳統之罩板包裝(硬底上有 凸起透明罩的物品包裝)或任何一種其他型態被已知用於 此種目的(例如一個包裝包含有適當數量之劑量單位(於本 案例為至少28、或用於特定應用為28之一個倍數),裝置於 、個Φ封之罩板包裝,加有一卡紙、紙板、包裝笛或塑 襯墊,且封入一個適當之封套中。每一個罩板包裝皆可 方便地編號或標記。 亦有設想為本發明組成物可以呈一個非經腸道之配方 的型態(諸如一個皮下植入物或穿透皮膚之配方)。為製造 植入物舌性試劑可以適當地與-個或多個聚合物共同被 該等聚合物於使用時會漸次地腐蝕或分解,該等聚 膠 以 ---MJI 1,]----0. --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 297公釐) 26 1307627A 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

五、發明說明(24 ) 經濟部智慧財產局員工消費合作社印製 合物例如梦酮聚合物、乙嫦基乙婦醋酸醋、聚乙稀或t丙 炼。 當涉及穿透皮膚之配方時,該等可以呈基質(matrices) 或膜片、或為流體、黏液配方於油或水合膠體中的型態被 製備。對於穿透皮膚貼片而言’應該被包含一個與皮膚可 相容之黏貼物(例如聚丙稀酸酯、一種碎酮黏貼物或聚異丁 稀、及一個由(例如:聚乙婦、聚丙稀、乙烯基乙稀醋酸酯、 聚氣乙烯、聚偏氯乙烯、或聚酯)製成之包裝箔、以及一個 可移除之保護性包裝箔(其製成係由例如:聚酯或者具有矽 酮或一個氟化聚合物塗覆之紙)。為製備穿透皮膚之溶液或 膠體,可使用水或有機溶劑或此等之混合物。穿透皮膚之 膠體可進一步地包含一個或數個適合之膠化試劑或桐化劑 (例如:矽酮、特拉加康斯樹膠、澱粉或澱粉衍生物、纖維 素或纖維素衍生物或聚丙烯酸或此等之衍生物。穿透皮膚 之配方亦可以適合地包含一個或數個物質來增進經由皮膚 之吸收(例如膽鹽或此等之衍生物、及/或磷脂)。舉例而 言,適合之穿透皮廣配方可以一個方法類似描述於w〇 94/04157案(用以製造3_1^〇<1£18〇§6也61)來製造。任擇地’ 穿皮配方可以依據被揭示於(BW Barry, ’’Dermatological Formulations, Percutaneous Absorption,” Marcel Dekker Inc.,New York-Basel,1983 或 YW Chien,”Transdermal Controlled Systemic Medications,’’ Marcel Dekker Inc.,New York-Basel,1987)之一種方法來予以製備。 本發明進一步被描述在以下之實施例中,該等實施例 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公f ) (請先閲讀背面之注意事項再填寫本頁) n I If n 扣-0, · a_l ·ϋ 1 ϋ ϋ ^1 I I . -27 1307627V. 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

微粒化之二螺_ 微粒化之雌脂二酵 乳糖單水合物 玉米激粉 改質澱粉 聚乙烯吡咯115)25,000 硬脂酸鎂 無,如何皆不欲限制如申請專利範圍所界定之本發明的範 疇。 試驗 實施例1 可以下列方式來製備包含二螺酮及雌脂二醇之藥錠藥 旋之核體為下列組成: 3.00毫克 1·〇〇、2.00、3.00毫克 45.2、46.2、47.2毫克 14.40毫克 9·60毫克 4·〇〇毫克 0.80毫克 之製備係經由將31.68公斤之玉米澱粉、21.12公斤之改| 澱粉、6.60公斤之微粒化二螺酮、22〇、4.4〇或66〇公斤戈 微粒化雌脂二醇(分別用以製備丨毫克、2毫克及3毫克負 量)、及99.44、1〇 1.64或103.84公斤之乳糖單水合物(分另 用以製備1毫克、2毫克及3毫克劑量)裝載至一個流體式j 槽之顆粒機,並活化流體式底槽。以持續性喷灑一個8 8 公斤之聚乙稀π比嘻酮25,〇〇〇溶於46_20公斤之純水的水个 溶液至流體式底槽之上,並藉由加熱流體式底槽之空氣 線來予以乾燥。於製程結尾時,硬脂酸鎂被抽吸進入顆珠 機内’然後藉由維持流體式底槽來與顆粒混合。產生之澤 粒係經由使用一旋轉式藥錠壓鑄的壓製而被壓製成藥錠 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮) (請先閱讀背面之注意事項再填寫本頁) 裝--------訂--------- 經濟部智慧財產局員工消費合作社印製 28 1307627 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(26 ) 對於包含有1毫克雌脂二醇之藥錠而言,係將2.22464 公斤之經基丙基曱基纖維素及0.44528公斤之macrogol 600 溶解於14.67公斤之純水中。以攪拌及均質化將0.44528公 斤之滑石、1.25906公斤之二氧化鈦及0.02575公斤之三氧 化二鐵顏料懸浮在10.26公斤之純水中。合併溶液與懸浮液 並藉由於裹覆機中持續注入裹覆懸浮液來裹覆藥錠之核 體。對於包含有2或3毫克雌脂二醇之藥錠而言,則可容易 地計算出用以袠覆製備之試劑的比例重量。 一個選擇性之用以裹覆1毫克藥錠的配方係包含 2.22464公斤之羥基丙基曱基纖維素、0.44528公斤之 macrogol 6000、0.44528公斤之滑石、1.17326公斤之二氧 化鈦及0.07634公斤之三氧化二鐵顏料(黃色)及0.03520公 斤之三氧化二鐵顏料(紅色)。一個可能用以裹覆2毫克藥錠 的配方係包含2.22464公斤之羥基丙基曱基纖維素、 0.44528公斤之 macrogol 600、0.44528 公斤之滑石、1,19636 公斤之二氧化鈦及0.08844公斤之三氧化二鐵顏料(紅 色)。一個可能用以裹覆3毫克藥錠的配方係包含2.22464公 斤之經基丙基曱基纖維素、0.44528公斤之macrogol 600、 0.44528公斤之滑石、1.25906公斤之二氧化鈦及0.02574公 斤之三氧化二鐵顏料(紅色)。 實施例2 :相對之生物可利用度 以志願者藉由一個可自由參加之隨機雙向交叉測試, 評估雌脂二醇(E2)及二螺酮(DRSP)之相對生物可利用度。 於[2毫克雌脂二醇(E2)+2毫克二螺酮(DRSP)]或[2毫克雌 (請先閱讀背面之注意事項再填寫本頁) --------訂--------· 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 29 l3〇7627 -- A7 -------B7_ 五、發明說明(27 ) 脂二醇(E2H6毫克二螺酮(DRSP)]之具有裹覆的藥錠治療 後以雌脂二醇/二螺酮(E2/DRSP) ρ·〇.,對比[2毫克雌脂二 醇(E2)+2毫克二螺酮(DRSP)]之口服溶液。 實施例3 :重覆劑量 進行評估重覆劑量之藥物動力學(累積性)及雌脂二醇 與二螺酮之間可能的交互作用。以4個劑量組合來進行公開 徵求、隨機、個體内交聯測試兩種劑量組合(具有一個歷時 4週之間隔停歇期’並在28天中做多次性投藥)。於最後一 個劑量之後進行一段歷時4週之觀察。 冶療法A . 1毫克雌脂二醇(E2)+l毫克二螺輞(DRSp), 每日,經由口服 冶療法B · 1宅克雌脂二醇(E2)+4毫克二螺酮(DRSP), 每日,經由口服 治療法C : 2毫克雌脂二醇(E2)+l毫克二螺酮(drsP), 每日,經由口服 治療法D : 2耄克雌脂二醇(E2)+l毫克二螺酮(drsP), 每日,經由口服 評估:於兩種活性成份之間沒有觀察到統計上為顯著 之交互作用。 實施例4 :對子宮内膜的保護作用 t要目標·:藉由分析停經後婦女受保護而免除子宮内 膜增生來評估13個週期為28天之持續性雌脂二醇/二螺酮 (E2/DRSP)組合對比持續性雌脂二醇(E2)之效力。 主要-標:評估對子宮内膜形態、行經血之型態、代 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公餐) (請先閱讀背面之注意事項再填寫本頁) -----訂- - ----- 經濟部智慧財產局員工消費合作社印製 30 經濟部智慧財產局員工消費合作社印制衣 13〇7627 A7 ^------2L___ — 五、發明說明(28 ) 謝及止血劑檢驗參數的效應。停經後婦女的身心健康係藉 由婦女保健問卷調查表(WHQ)及醫藥療效試驗36個項目簡 短型健康調查表(SF-36)予以評估。對潮紅發熱之頻率及嚴 重度的效應’及對減輕泌尿生殖器症狀的效應。藥物中二 螺酮(DRSP)及雌脂二醇(E2)的含量。於子群組中詳盡評估 代謝參數。 摘要說明: 劑量組別:1毫克雌脂二醇(E2) ; 1毫克雌脂二醇 (E2)+0.5毫克二螺酮(DRSP) ; 1毫克雌脂二醇(E2)+l毫克二 螺酮(DRSP); 1毫克雌脂二醇(E2)+2毫克二螺酮(DRSP); 1 毫克雌脂二醇(E2)+3毫克二螺酮(DRSP)。 具有或不具有停經症狀之停經婦女將進行5種給藥程 序之1種。評估對子宮内膜之效應,係藉由切片檢查法來決 定子宮内膜增生之發生率。症狀及行經血之型態將自主題 式每日記錄來評估。對一般健康之安全性、及對特定生化 及血液參數之效應將予以評估。同時將進行一個停經後生 活健康狀態的評估及病患滿意度的評估。 於某些情況進行兩小時葡萄糖耐受性測試、及15分鐘 胰島素耐受性測試。 數據分析 於第1次訪視及最後1次訪視做子宮内膜切片檢查。於 試驗全程中,行經血之型態被記錄在一個每日記錄内。 首要效應之參數將進行兩項分析:i)治療法的雙向比 較’及ii)單邊、組内劑量效應之(信賴)區間估算。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ί 厂 -I I 1— —«—ΐ I I -------I ^ · I I I I I I I — {請先閱讀背面之注意事項再填寫本頁) 31 經濟部智慧財產局員工消費合作社印製 Ϊ307627 A7 B7____ 五、發明說明(29 ) 發生率表格之產生係用於該等進行有子宮内膜切片檢 查之訪視。此等表格會顯示出每一個治療組(及測試工作 站係當案例為一個治療法與測試工作站之交互作用時)在 每一種子宮内膜反應類型中的受測物數量及百分比◊於所 有組別中比較整體及組間的器官增生發生率將被進行。此 分析將欲用於治療之用途,以及以測試工作站調整時,用 來測試原始假設:對治療法(無逆阻對比受逆阻之雖脂二 醇)所產生之反應沒有差異。 劑量效應之(信賴)區問仕▼ 估算每一種二螺酮(DRSP)劑量(t0 〇、〇.5、1 〇、2 〇、 3·〇)的機率⑻。此外,分別地計算出每一個機率⑹之單 邊95%信賴區間的上限值。此意指信賴區間將具非雙邊共 存性。 實施例5 :預防骨質疏鬆 直要_禪:治療104天後之臀部骨骼礦物質密度。 主ilA:於12、28、52及80週之治療後的臀部骨骼 礦物質密度(BMD)。腰脊椎骨、橈骨之中骨幹及全身之骨 骼礦物質密度(BMD) ^對骨骼代謝參數之影響。行經血之 型態。對一般健康之安全性。 調查為一個雙盲、以安慰劑做控制組之試驗,其將“Ο 位健康、停經後之婦女(於繳交其等之知情同意書後)隨機 地編排至4組(每組有6 〇人)中之一組。 該等組別如下:1毫克雌脂二醇(Ε2)+1毫克二螺鲷 (DRSP) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱) 1 fri η ΙΓ 裝------------ <請先閱讀背面之注意事項再填寫本頁) ^91. 32 1307627 A7 B7 五、發明說明(30 ) 1毫克雌脂二醇(E2)+2毫克二螺酮(DRSP) 1毫克雌脂二醇(E2)+3毫克二螺酮(DRSP) (請先閱讀背面之注意事項再填寫本頁) 摘要說明 於每一組中必須有40位骨質流失病患(骨骼礦物質密 度(BMD)臀部T-分級數據(T-score)在-1與-2.5之間)及20位 非骨質流失病患。在整個2年(沒有無治療之間期)的治療 中,所有的治療將於每日被施用在每一根骨路上。此外, 會將鈣片藥錠(每曰500毫克之鈣)提供給病患。於篩選、基 底線及治療12、28、52及80週後量測臀部骨骼礦物質密度 (BMD),係於左侧使用雙倍能量X光射線吸收儀做量測。將 以定期性測量骨骼重建之生化標幟物。 外加地評估血清中具骨骼專一性的鹼性填酸酶、血清 中N-mid osteocalcin、尿液内鈣/肌酸(次晨排尿)、尿液内 Cross Laps®/肌酸(次晨排尿)。 實施例6 :停經症狀 目標:證明E2-DRSP(雌脂二醇-二螺酮)在停經症狀方 面之治療效用係優於安慰劑 經濟部智慧財產局員工消費合作社印製 首要目標:潮紅發熱 三欠要目撢:盜汗、睡眠障礙、情绪沮喪、神經質、泌 尿生殖器症狀(陰道乾溫、頻尿症、夜尿症)、行經血之变 態、一般健康之安全性。 摘要說明: 雙盲、以安慰劑做控制組之試驗:將健康、停經後婦 女隨機編排至4組中之1組 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮) 33 1307627 A7 _ B7_ 五、發明說明(31 ) 1毫克雌脂二醇(E2)+l毫克二螺酮(DRSP) 1毫克雌脂二醇(E2)+2毫克二螺酮(DRSP) 1毫克雌脂二醇(E2)+3毫克二螺酮(DRSP) 安慰劑 摘要說明: 主要之列入標準:於治療前之2週内至少7天有一個每 日至少5次中度至重度的潮紅發熱。 治療將歷時16週(4個28天週期) 潮紅發熱之評估,將藉由記錄發作頻率及嚴重度(溫 和、中度及重度),然後將給藥組與安慰劑之間的此等記錄 做比較。病患將記載潮紅發熱之次數及嚴重度於日諸卡 上。此外,訪查人員於每一次訪視將詢問病患有關其他典 型之停經症狀(盜汗、睡眠障礙、情緒沮喪、神經質、泌尿 生殖器症狀)。症狀之強度將被評定為溫和、中度或重度。 設若病患具有一功能完全之子宮時,於試驗期間的每 一天將發生之行經血記錄在日誌卡上。病患將依據下列行 經血狀態之定義來填寫日誌卡上的每日記錄。 (請先閱讀背面之注意事項再填寫本頁) --------訂---------. 經濟部智慧財產局員工消費合作社印製 代碼 類型 定義 0 無 無陰道出血 1 點狀 較諸正常月經量少,依照受測者之經驗為不需使用衛 生棉(不包括衛生護墊) 2 少量 較諸正常月經量少,依照受測者之經驗需使用衛生棉 3 正常量 依照受測者之經驗為類似正常月經量 4 多量 依照受測者之經驗為超過正常月經量 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 34 1307627 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(32 ) 對於泌尿生殖器症狀則使用下列參數及分類: 參數 類型 陰道乾澀 是/否/不知道 增加排尿次數 是/否 夜尿症 是/否(“是”代表至少在先前之一週内有2或 更多個(至少2次夜間排尿)的夜晚 數據分析 對於效力性參數而言,將進行一種有效性案例分析法 (VCA)及一種企圖用以治療(ITT)之分析法。首要標的變數 為潮紅發熱之次數上的個體相對機率(C)。C之定義為數 (T-B)/B,其中T及B所代表為各別不同。T為每週潮紅發熱 之平均次數,其係以治療期之第3週至第16週之觀測數來計 算。B為每週潮紅發熱之平均次數,其係以治療前2週之觀 測數來計算。 實施例7 :脂肪組態 目標:本試驗之首要目標係以脂肪組態來比較雌脂二 醇 /二螺嗣(E2/DRSP )及 Premique®/Premelle® 兩種治療法。 脂肪組態一般被接受為評估心企管疾病的終極指標。 首要目標:包含有高密度脂肪(HDL)膽固醇及低密度 脂肪(LDL)膽固醇之脂肪組態 次要目標:包含所有膽固醇、甘油三酸酯、高密度脂 肪2(HDL2)膽固醇、高密度脂肪3 (HDL3)膽固醇、甚低密 度脂肪(VLDL)膽固醇、apo脂蛋白(A-l、A-2、B、E)、Lp(a) 之脂肪組態;停經症狀;行經血型態;對子宮内膜之安全 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注意事項再填寫本頁) ▼— --------訂---------· 35 1307627 A7 B7_五、發明說明(33 ) 性;對一般健康之安全性。 設計:試驗係以一種公開徵求、多工作站據點、比較 試驗法進行,其將300位停經後婦女(於繳交其等之知情同 意書後)隨機地編排至3組(每組有100人)中之一組。 分組: 1毫克雌脂二醇(E2)+2毫克二螺酮(DRSP) 1毫克雌脂二醇(E2)+3毫克二螺酮(DRSP) Premique®/Premelle® : 0.625 毫克共輊雌脂二醇+ 5 毫克 MPA 於無治療空缺期且歷時2年之治療全程中,將所有的治 療法以每日口服之方式施行。脂肪組態之量測於於篩選及 治療12、28、52及104週(以及治療6週)後進行。 —7—1^—裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 36Micronized 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)

申請專利範圍 1^076+7090101039號專利申請案 U / Ο今✓文申請專利範圍替換本(97年 1· 一種口服劑量型式之醫藥組合物,其包含 1)不含乙炔基雌脂二醇之雌激素; ⑴相當於每日劑量範圍自〇 25至1〇毫克之二螺酮 (Drospirenone);及 iii)藥學上可接受之賦形劑或載劑, 其中該一螺酮係為具有表面積大於⑽cm2/g之 型式。 2. 一種口服劑量型式之醫藥組合物,其包含 i) 一雌激素,其係選自由雌脂二醇、雌脂二醇胺基磺 酸酯、雌脂二醇戊酯、雌脂二醇苯甲酸酯、雌脂 酮、雌脂三醇、雌脂三醇琥珀酸酯、共軛雌激素或 其混合之群組; ii) 相當於每曰劑量範圍自〇 25至1〇毫克之二螺酮; 及 iii) 藥學上可接受之賦形劑或載劑, 其中該一螺酮係為具.有快速溶解之型式,以致該二螺 酮在30分鐘内有至少70%的溶解度(當使用usp χχπι Paddle Method II在每分鐘50轉速下測試37它下9〇〇 毫升水中一組合物之溶解度)。 3. —種口服劑量型式之醫藥組合物,其包含 i) 一雌激素’其係選自由雌脂二醇、雌脂二醇胺基石黃 酸酯、雌脂二醇戊酯、雌脂二醇苯曱酸酯、雌脂 酮、雌脂三醇、雌脂三醇琥珀酸酯、共軛雌激素或 其混合之群組; 84562-971111.doc 本紙張尺度通用中國國家標準(CNS) A4規格(210X297公釐) 1307627 A8 B8 C8Patent 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 1〇相备於每日劑量範圍自0.25至10毫克微粒型態之 -螺網;及 出)藥學上可接受之職形劑或載劑。 如申請專利範圍第】或2項之醫藥組, =呈微粒型態或自二螺嗣溶液中喷至㈣載體^ 之表面。 1°申請專利範圍第1至3項中任-項之醫藥組合物,其 雌激素係選自由雌脂二醇、雌脂二醇胺基磺酸酯: 雖脂二醇戊酿、雌月旨二醇笨甲酸醋、雌脂閑、雌脂三 醇、雌脂三醇琥旨、共軛#激素或其混合 組。 π 利範圍第5項之醫藥組合物,其中共輛雌激素 是選自由雌脂酮硫酸醋、導雌脂二酮硫酸酯、ηα :脂二酮硫酸醋、雌固醇硫酸醋、”β_二氫雌固醇硫 酸醋、心二氫雌固醇硫酸醋、雌固醇_硫酸醋、 =之^㈣她旨及心:氫雌固 7. 如申請專利範圍第6項之醫藥組合物, 雌脂二醇。 n 8. 如申請專利範圍^至3項中任—項之醫藥組合物 中雌激素呈微粒化型態。 9. 如申請專利範圍第⑴項中任一項之醫藥組合物 中二螺鲷呈足量保護子宫内膜免於雌激素之負作用 .如申請專利範圍第⑴項中任—項之醫藥組合物 4 6. 其 其 其 84562-971111.doc . 2 本紙張尺度適用中酉國家揉準(CNS) Α4規格(210X 297公釐)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 C8A8 B8 C8 1307627 中二螺酮含量相當於每日劑量範圍自0.5至4.5毫克。 11·如中請專利範圍第⑴項中任—項之醫藥垣合物,且 中雌激素呈足量以治療婦女内因性雌激素含量不足之 相關疾病、病症及症狀。 12.如申請專利範圍第⑴項中任一項之醫藥組合物其 中雌激素呈足量以治療婦女自然性停經、接近停經、 停蛵後、性腺功能減退、去勢或原發性卵巢機能障礙 相關之疾病、病症及症狀,該等疾病、病症及症狀係 選自由潮紅發熱、盜汗、心悸、睡眠障礙、情緒起 伏神、左質、焦慮、記憶力不佳、缺乏自信、缺乏性 心/主忍力不集中、乏力、無勁、易怒、泌尿生殖器 萎縮、礼房萎縮、心血管疾病、毛髮分布的改變、毛 髮的稀疏度、膚質改變及骨質疏鬆所組成之群組。 1 3 .如申凊專利範圍第丨至3項中任一項之醫藥組合物,其 中雖脂二醇含量相當於每日劑量範圍自0.1至5毫克。 14. 如申請專利範圍第〗至3項中任一項之醫藥組合物,其 中口服劑量型式係呈錠劑、膠囊或藥丸型式。 15. —種醫藥套組,其係由數個分別包裝且個別可移取之 每曰劑量單位所組成,該等劑量單位係被置於一個包 裝單位内,且欲供用於一為期至少21天之口服投藥; 其中該等每曰劑量單位包含雌脂二醇(其含量範圍係自 大約〇_1至5毫克)與二螺其含量範圍係自大約〇25 至ό笔克’且其係具有表面積大於1〇〇〇〇 crn2/g)。 1 6 . —種醫藥套組’其係由數個分別包裝且個別可移取之 84562-971111.doc _ 3 _ ΐ紙張尺度逍用中國國家揉準(CNS) A4规格(21〇Χ297公麦) --—~ 1307627 六、申請專利範園 二 組成,該等劑量單位係被置於-個包 且欲供用於-為期至少21天之口服投藥’· 大约劑量早位包含雌脂二醇(其含量範圍係自 古 )與二螺酮(其含量範圍係自大約〇·25 克,且其係具有快速溶解型式,以致該二螺嗣在 30分鐘㈣至少7G%的溶解度(當使用USP XXIII addle Method II在每分鐘5〇轉速下測試η。。下川〇 毫升水中劑量單位之溶解度)。 種醫藥套組,其係由數個分別包裝且個別可移取之 每曰劑量單位所組成,該等劑量單位係被置於一個包 =位内,且欲供用於一為期至少21天之口服投藥; 該4每日劑量單位包含雌脂二醇(其含量範圍係自 大約古0.1至5毫克)與二螺酮(其含量範圍係自大約〇 至ό毫克),且其係呈微粒型態。 18. -種醫藥套組’其係由數個分別包裝且個別可移取之 每日劑量單位所組成’該等劑量單位係被置於一個包 裝單位内,且欲供用於一為期至少21天之口服投藥; 其中該等每日劑量單位包含雌脂二醇(其含量範圍係自 大約0·1至5毫克)與二螺_(其含量範圍係自大約〇 25 至6毫克)’其中包装單位内每一單位劑量之雌脂二醇 劑量係為相同。 19. 如申請專利範圍第15至18項中任_項之醫藥套組,其 中口服投藥係為期28天。 20. 如中請專利範圍第19項之醫藥套組,其係欲供用於一 84562-971111.doc > 本紙張尺度逄用中國國家標準(CNS) Α4規格(210X297公釐) A8 B8 C8 D8 1307627 ------ 六、申請專利範圍 為期28天之口服投藥;其中 有至少21個每曰劑量單位包含含量範圍自大約〇」至 5毫克之雌脂二醇與含量範圍自大約〇 25至6毫克二螺 酮之組合;以及 不超過7個之劑量單位包含無藥、安慰劑或含量範圍 自大約0.1至5毫克之雌脂二醇。 21·如申請專利範圍第15至18項中任一項之醫藥套組,其 係欲供用於一為期至少連續28天之口服投藥,其中至 少有1 0個該每曰劑量單位包含含量範圍自約〇」至5毫 克之雌脂二醇; 至少有1 0個該每曰劑量單位包含含量範圍自大約〇」 至5毫克之雌脂二醇與含量範圍自大約〇 25至6毫克之 二螺酮之組合;以及 不超過8個之該每日劑量單位包含一個安慰劑或無 藥。 2 2 .如申請專利範圍第丨5至1 8項中任一項之醫藥套組,其 係欲供用於一為期至少連續28天之口服投藥,其中至 少有1 0個該每曰劑量單位包含含量範圍係自大約〇」至 5毫克之雌脂二醇; 至少有1 0個該每曰劑量單位包含含量範圍自大約〇 . j 至5毫克之雌脂二醇與含量範圍自大約〇25至6毫克之 二螺酮之組合;以及 不超過8個之該每日劑量單位包含含量範圍自大約 0.1至5毫克之雌脂二醇。 84562-971111.doc 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐). 8 8 8 8 A BCD 1307627 申請專利範圍 23.如申請專利範圍第15至18項中任一項之醫藥套組,其 係欲供用於一為期連續2 1至3 0天之口服投藥, « 其中至少有1 0-1 5個每日劑量單位包含含量範圍自大 約0·1至5毫克之雌脂二醇與含量範圍自大約0.25至6毫 克之二螺醐之組合;以及 有10 -1 5個該每曰劑量單位包含含量範圍自大約〇」 至5毫克之雌脂二醇。 2 4 .如申請專利範圍第1 5至1 7項中任一項之醫藥套組,其 中該劑量單位之雌脂二醇含量係根據該至少2 1天期間 而不同。 25. 如申請專利範圍第15至17項中任一項之醫藥套組,其中 包裝單位内每一單位劑量之雌脂二醇含量係為相同。 26. 如申請專利範圍第1 5至1 8項中任一項之醫藥套組,其 中包裝單位内每一單位劑量之二螺酮含量係為相同。 2 7 .如申請專利範圍第丨5或丨6項之醫藥套組’其中該二螺 酮係呈微粒型態或自二螺_溶液中喷至惰性載體顆叔 之表面。 2 8.如申請專利範圍第15至18項中任一項之醫藥套組其 中該雌脂二醇係呈微粒化型態或自一溶液中噴至惰性 載體之顆粒上。 β 29.如申請專利範圍第15至18項中任—項之醫藥套組,其 中每日劑量單位數為至少21或者為21之倍數。 、 3 0.如申請專利範圍第丨5至丨8項中任一項之醫藥套組,其 中每日劑量單位數量為2 8或者為28之倍數。 、 84562-971111.doc Λ 本紙張尺度適用中S國家標準(CNS) Α4規格(2ι〇Χ297公羡). 1307627 A8 B8 C8 D8 夂、申請專利範園 3 1 ·如申請專利範圍第1 5至丨8項中任一項之醫藥套組,其 中δ亥母曰劑量單位係呈口服型式。 3 2.如申請專利範圍第31項之醫藥套組其中口服劑量型 式係呈錠劑、膠囊或藥丸型式。 3 3.種有關雌激素與二螺酮之組合供用於製備治療婦女 自然性停經、接近停經、停經後、性腺功能減退去 勢或原發性卵巢機能障礙相關之疾病、病症及症狀之 口服藥物的用途,其中該等疾病、病症及症狀係選自 由潮紅發熱、盜汗、心悸、睡眼障礙情緒起伏、神 、:質、焦慮、記憶力不佳、缺乏自信、缺乏性慾、注 意力不集中、乏力、無勁、易怒、泌尿生殖器萎縮、 乳房萎縮、心血管疾病、毛髮分布的改變、毛髮的稀 疏度、膚質改變及骨質疏鬆所組成之群組,其中 一螺酮含量足夠用來保護子宮内膜免於雌激素之負作 用,且該二螺酮係為具有表面積大於1〇,〇〇〇 cm2/g之 型式。 34'種有關雌激素與二螺酮之組合供用於製備治療婦女 自然性停經、接近停經、停經後、性腺功能減退、去 勢或原發性卵巢機能障礙相關之疾病病症及症狀之 口服藥物的用it ’其中該等疾病、病症及症狀係選自 由潮紅發熱、盜汗、心悸、睡眼障礙、情緒起伏、神 經質、焦慮、記憶力不佳、缺乏自信、缺乏性慾、注 意力不集中、乏力、無勁、易怒、泌尿生殖器萎縮、 乳房萎縮、心血管疾病、毛髮分布的改變、毛髮的稀 84562-9711H.doc -7 _ 本纸張尺度適用T關家料(CNS) A4規格(2獻297公楚)-------- 1307627The 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 疏度、膚質改變及骨質疏鬆所組成之群組,其中 二螺i同含量足夠用來保護子宮内膜免於雌激素之負作 用’且該二螺嗣係為具有快速溶解之型式,以致該二 螺酮在30分鐘内有至少7〇%的溶解度(當使用usp XXIII Paddle Method II在每分鐘50轉速下測試37 C下900毫升水中該藥物之溶解度)。 3 5 . —種有關雌激素與二螺酮之組合供用於製備治療婦女 自然性停經、接近停經、停經後、性腺功能減退、去 勢或原發性卵巢機能障礙相關之疾病、病症及症狀之 口服藥物的用途,其中該等疾病、病症及症狀係選自 由潮紅發熱、盜汗、心悸、睡眼障礙、情緒起伏、神 經質、焦慮、記憶力不佳、缺乏自信、缺乏性慾、注 意力不集中、乏力、無勁、易怒、泌尿生殖器萎縮、 乳房萎縮、心血管疾病、毛髮分布的改變、毛髮的稀 疏度、膚質改變及骨質疏鬆所組成之群組,其中 二螺酮含量足夠用來保護子宮内膜免於雌激素之負作 用,且該二螺酮係呈微粒型態。 36·如申請專利範圍第33或34項之用途,其中二螺酮係呈 微粒型態或自二螺酮溶液中喷至惰性載體顆粒表面。 37. 如申請專利範圍第33至35項中任一項之用途,其中雌 激素呈微粒化型態。 38. 如申請專利範圍第33至35項中任一項之用途,其中雌 激素含量係足以治療選自潮紅發熱、盜汗、心悸、睡 眼障礙、情緒起伏、神經質、焦慮、泌尿生殖器蒌縮 84562-971111.doc - 8 - 本紙張尺度通用中國國家標準(CNS) A4规格(210 X 297公董) ABCD 1307627 六、申請專利範園 及乳房萎縮之疾病、病症或症狀或骨質疏鬆之預防或 控制。 3 9 _如申請專利範圍第3 8項之用途,其中雌激素係足以治療 潮紅發熱、盜汗或心悸。 40. 如申請專利範圍第33至35項中任一項之用途,其中雌 激素係選自由雌脂二醇、雌脂二醇胺基續酸酯、雌脂 一醇戊醋、雌脂二醇笨甲酸S旨、乙炔基雌脂二醇、雌 脂酮、雌脂三醇、雌脂三醇琥珀酸酯、共軛雌激素之 群組。 41. 如申請專利範圍第40項之用途,其中共軛雌激素是選 自由雌脂酮硫酸酯、1 7 β -維脂二酮硫酸酯、1 7 α -雌脂 二酮硫酸酯、雌固醇硫酸酯、17β -二氫雌固醇硫酸 酯、1 7 α -二氫雌固醇硫酸酯、雌固醇酮硫酸酯、1 7 β -二氫雌固醇酮硫酸酯、17α-二氫雌固醇酮琉酸酯)所組 成之群組。 42. 如申請專利範圍第40項之用途,其中雌激素係選自由 雌脂二醇、雌脂二醇胺基磺酸酯、雌脂二醇戊酯、雌 脂酮及其混合之群組。 4 3 ·如申請專利範圍第4 2項之用途,其中該雌激素為雌脂 二醇0 44. 如申請專利範圍第33至35項中任一項之用途,其中二 螺酮(DRSP)之劑量相當於每曰劑量範圍自0.25至10毫 克。 45. 如申請專利範圍第43項之用途,其中雌脂二醇含量相 84562-971111.doc . 9 . 本紙張尺度適用中國國家標準(CNS) Α4规格(210X297公釐). 六、申請專利範圍 當於每曰劑量範圍自0.1至5毫克。 46·如申請專利範圍第33至35項中任一項之用途,其中該 藥物係呈錠劑、膠囊或藥丸型式。 47.如申請專利範圍第33至35項中任一項之用途,其中該 藥物係以數個分別包裝且個別可移取之每日劑量單位 型式置於一包裝單位内’且欲供用於一為期至少21天 之口服投藥’較佳係至少2 8天。 48. 如申請專利範圍第47項之用途,其中包裝單位内每一 劑量單位之雌激素含量係為相同。 49. 如_請專利範圍第47項之用途,其中包裝單位内每一 劑量單位之二螺酮含量係為相同。 50. 如申請專利範圍第47項之用途,其中個別可移除之每 日劑量单位係呈如申請專利範圍第1至3項中任_輕 疋義之組合物。 51·如申請專利範圍第47項之用途 請專利範圍第咖項中任-項所定 之數個分別包裝且個別可移取之每日劑量單位裝单位 84562-971111.doc ^ 本紙張尺度逍用中g國家料(CNS) A4規格(21GX297公笼^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 ^
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