TWI259086B - Pharmaceutical formulation adapted for intra-muscular injection - Google Patents
Pharmaceutical formulation adapted for intra-muscular injection Download PDFInfo
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- TWI259086B TWI259086B TW090100514A TW90100514A TWI259086B TW I259086 B TWI259086 B TW I259086B TW 090100514 A TW090100514 A TW 090100514A TW 90100514 A TW90100514 A TW 90100514A TW I259086 B TWI259086 B TW I259086B
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Classifications
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- A—HUMAN NECESSITIES
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Description
1259086 A7
本發明適合注射給藥之新較— 人 々穎緩釋百樂調配物,其包含化 。物7α-[9-(4,4,5,5,5-五氟戊美凸於賊甘、 二 ^ 鼠戍基亞嶒醯基)壬基]雌-^5(10)- := 較特別是關於萬麻油酸醋賦形劑中含有 ^t7(H9-(4,4,5,5,5-五氟戍基亞石黃酸基)壬基]^500)- : ,17β-一醇溶液之適合注射給藥的調配物,其中該賦 形劑另外包含至少一 _醢$ 知及了與蓖麻油酸酯賦形劑互容之 非水性酯溶劑。 1激素缺乏是治療許多良性及惡性乳房及生殖管疾病的 ί礎。在停經期前的婦女,經由外科手術、放射治療或醫 干方法除去卵巢機能而達到,而且在停經期後的婦女可藉 芳香酶抑制劑的使用而達到。 另-種斷除雌激素的方法是以抗雌激素對中和雌激素。 這些是可與雌激素應答組織核中所存在的雌激素受體(ER) 結合並競爭之藥物。慣用的非類固醇抗雌激素,如三苯氧 胺(tamoxifen),可完全有效地與£11鍵結,但他們的效力 經常文到他們所呈現的部份促動作用所限制,其結果造成 調節雌激素的活性無法完全被阻斷(Fun^J〇rdan 1984,
May 及 Westley 1987)。 非類醇抗激素呈現對抗性質的能力激勵可以高親和力與 E R鍵結而不會活化任何正常轉錄荷爾蒙應答及造成雌激 素顯示結果之新穎化合物的尋找。此種分子可能為“純,,抗 雌激素,明白地與似三苯氧胺配位基不同,其有能力引發 完全去除雌激素的營養作用。此種化合物係相當於雌激素 受體-抑制調節劑(Downregulators)(E.R.D·)。新穎、純抗雕 -4- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1259086 A7 B7 五、發明説明( ) 激素的基本設計及測試原理曾描述於:Bowler等人1989, Wakeling 1990a、1990b、1990c,Wakeling及Bowler 1987、 1988。 在7 α處具有烷基亞磺醯基側鏈之雌二醇的類固醇同系 物提供第一個缺乏雌激素活性之化合物實例(Bowler等人 1989)。這些實例之一,7〇6-[9-(4,4,5,5,5-五氟戊基亞磺醯 基)壬基]雌-1,3,5(1〇)-三烯-3,17β-二醇,基於其純雌激素 對抗劑活性及明顯較其他可取得之抗雌激素高之抗雌激素 效價,故選擇其作深入研究。7α-[9_(4,4,5,5,5-五氟戊基亞 磺醯基)壬基]雌_1,3,5(10)_三婦·3,17β-二醇之相關體外發 現及早期臨床經驗促使有興趣發展作為治療依賴雌激素之 適應症如乳癌及一些良性婦科狀況之藥劑的藥物。 7α-[9-(4,4,5,5,5-五氟戊基亞磺醯基)壬基]雌-三稀-3,17β-二醇或ICI 182,780曾被冠上國際非專有名詞夫 維司川(fulvestrant),其被用於下文中。相對於夫維司川 日守’我們包括其醫藥上可接受的鹽類及其任何可能的溶劑 化物。 夫維司川以類似於雌二醇之親和力鍵結在E R上並完全阻 斷雌一醇在體外對人類乳癌細胞的生長刺激作用;其在此 ^面比三苯氧胺更有分化能力且更有效。夫維司川完全阻 ,隹一醇在鼠、鼷鼠及猴子的uter〇tr〇phic作用,同時也阻 斷二笨氧胺的uterotrophic活性。 / 口為夫維司川沒有任何在臨床上可抗雌激素如三苯氧胺 或拖瑞米芬之特徵,似雌激素刺激活性,其可以更快速、女 -5-
1259086 五 發明説明( A7 B7 $正或持久性腫瘤退化作用;低發病率或低治療耐藥性發 :速率’·及腫瘤侵入性的降低為特徵提供更好的治療活 性。 ’、 ^維司川在處女成鼠中以不會對骨f密度造成不利影響 ’增加刺激性腺之分泌物的劑量可達到最大的子宮退化^ 用。若在人類身上亦為真,這些發現在臨床上是極為重要 的。降低骨質密度限制子宮内膜異位症之去除雖激素的仏 :時間。夫維司川不會阻斷下丘腦ERe雌激素去除作用^ :引起或惡化成熱潮紅及其他停經期症狀;夫維司川將不 5引起這些作用,因為其無法跨越血管-腦屏障。 L州專利申睛案編號〇 138 5〇4揭示一些類固醇街生物 有效的抗雌激素齊卜此揭示内容包括製備此類固醇衍生物 :相關資料。特別是在實例35中揭示化合物7α_[9_ ,4,5,5,5-五氟戊基亞磺醯基)壬基]雌],3,5(⑼·三烯· 3 17β-二# ’該化合物係於申請專利範圍第4項中被特別 =。其也揭示本發明化合物可以同時含有本發明類固醇 ^物與醫藥上可接受之稀釋劑或攜帶物之醫藥組合物形 線 c吏用…陳述該組合物可為適合經口或非經腸方 式給藥之形式。 伴隨其他以類固醇為基質之化合物的夫維司川表現出一 些使這些化合物不易調配之物理性質。夫維司川是 別親脂肪的分子’即使與其他類固醇化合物相&,而且苴 水性溶解度非常低,約10毫微克/毫升(這是_個由水/; 劑混合物溶質中所獲得的估計值,因為在只有水的溶質中 -6 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐Υ ------------- 1259086 A7 發明説明( 無法達到這麼低的測量值)。 一七有許夕已商業化之緩釋可注射的類固醇調配物。 :這些調配物使用油作為溶劑,而且其中存在附加賦形 二:列表!係描述一些已商業化之緩釋可注射調配物。 在表1内的調配物,择用却之 Ά m,3, 〇 不同種類的油料以溶解化 合物及附加賦形劑如苯甲基苯甲酸 而且曾使用過乙醇。溶解此類固醇活^基料乙酵, 積如下。可獲得從1JL8週之延長釋❸項需的油料體
1259086 A7 B7五、發明説明(5 ) BENZ9 菩娟热憩 GYNOESTRYL PROGESTERONE-潞;&球雜15熟憩 250»£/ RETARD»半
Roussel Diet. Vidal i£:i >*a- 19900 Pharlon Diet. Vidal ^¾ 神 1999 TOnOGESTAM^^^fisIenantate 200»> 邻斧 Theramax Diet. Vidal >3-龄(>*40% 冰m 1999 節 _ftI5o»> a.'SB. 250 THOPHOBOLENE Estrapronicate 1.3»^5a命 Theriax Diet. vidals^>s-45% 1997 Nandrolone —蘇荈 50»^§ ^•錁1洚疼鵾〇〇0»> N02STERAT 渖雒逾洚龄憩 200 »> 庠嘞Schering ABPIf莽鰣势穿斜 一 #一 HC λ>>'· 1999
PllOLUTON DEPOT 遛;&难錄16 热gs SUSTANONS0 30昝泽Organon ABPI烊 19s §*> 60峥> 100 250»^·/^绎 Schering ΑΒΡΙ»:^辦势 >'a-»-it »半 _»HC _>>3β , 1999 雜激>>3 陰 λΐ :^穿駟^硝^砮胸^客宮3*^耸鮮 0.1 * 半 -# 8iS半 1 ί: 一 庳 卑· 一洚2 1筚 »半 一咖 15冲 丰 30沙 1卑2 1筚 $
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BzBz BzOH Eton s s -8- 本紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1259086 A7 B7 五、發明説明(6 BZBZ=^-9^·辦-9_雖 BZOH=^-9s«EtOH=66| DicrvidaTDictionnairevidal %^時# / 錄織aiJL *ii^H-^^^l^^4:M^s DELALAJT2 ,40 楸 JL/» 半 250 *>/ 嗍鋒 DMS »半 ί 鸿滁麥吟鲥勢穿斜 (1964)53(8 )S1 »·» 2%
GRAVI1 PARABOLAN DELESTHOGEN 秦卜^17-13-/¾^¾5柳^/柳詾命 Schering Diet· Vidal n^s^^· 半 an J995 激啉竦雜1淨決龄戤250柳>/ 恭给雜 76州> >iHltzegma Diet vidal;f£:i.^ 20州^/拗^hraMS 半 恭 75州 45州 1.5州2趨 S7 半 雔滁孩呤鲥势^78% 20% 2% (1964)53(8 )891 58% 40% 2% li5v2r2ia 9 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1259086 發明説明( 在US 5,183,814實例3中描述_ ^ j./ 碎垔以油為基質的夫维g m 注射调配物’其包含5〇毫克夫 甲川 及足量的i麻油使該溶液的體積^毫升。us=甲切 以,央二 物將因高醇濃度變得複雜。所 人 夫、、隹司川调配物中雲i 一 厅 替“* ?而㈣低的醇濃度以防止夫維司川自 调配物中沈澱出來。 J ;丨自 表2顯示夫維司川在許多不 同溶劑中的溶解度。 表2 -夫維司川沾、、办& 溶劑 水 溶解度(2、5t下毫克/毫升) 0.001 花生油 0.45 芝麻油 0.58 蓖麻油 -20* Miglyol 810 3.06 Miglyol 812 2.72 油酸乙酯 1.25 苯甲酸苯甲基酯 6.15 肉豆蔻酸異丙基酯 0.80 Span 85(界面活性劑) 3.79 乙醇 >200 苯曱基醇 >200 如所見,夫維司川在蓖麻油中明顯比在任何其他所測試 的油料更易溶解。蓖麻油對類固醇化合物有較大溶劑化 -10 - 本紙張尺度適用中國國家標準(CNS) A4規格(2i〇x297公釐)_ 1259086
所知的並歸因於萬麻油酸醋的高經基數目,其中 ==醋係為萬麻油中所存在之甘油三酸醋内脂肪酸的 891^成份_參見(Riffkin等人’醫藥協會期刊,_),53, 但是’即使利用最好的油質 π由貝,合劑1麻油,我們發現不 夫維司川單獨溶於以油為基質的溶劑中,而達到在 液中達到配給病人足夠高濃度的藥及獲得有效 了達到治療上有效的釋放速率,夫維司川 較:、二:要回達’至少1 〇亳升之調配物體積。這需要 = = 積大幅過量的調配物予以明顯高於人類治療所 高之^劑I 0 ,夜1月i才曰導方針建議在單一次注射中不可將超過5毫升之 :=入肌内。藥理上1個月長期運作沈積夫維司川調配物 :::活性劑量係約2 5 0毫克。因此,只溶於萬麻油時, :而要以至少1 0毫升的蓖麻油量服入夫維司川。 可添加可自由溶解夫維司川之有機溶劑,如醇,其中該 ,機溶劑可與t麻油互容。隨高濃度醇的添加,可獲得濃 宅克’毫升之夫維司川的^麻油調配物,因此可獲得 15 =《注射體積-參見下列表3。我們驚舒地發現非水 I -曰冷相導入思外地使夫維司川容易溶解變成濃度為至 二50毫克/毫升.參見下列表3的溶液,其中該非水性醋溶 :可與萬麻油及醇互容。此發現是令人驚訝的,因為夫維 :川在非水性醋溶劑中的溶解度_參見下列表2_明顯低於 、准司川在醇中的溶解度。夫維司川在非水性醋溶劑中的溶
11 - A4規格(210 X 297公釐) 1259086 五、發明説明(9 解度也比夫維司川在莲麻油中的溶解度低。 因此,我們呈現一種f藥調配物作 該醫藥調配物包含溶於萬麻油酸妒^特徵,其令 夫維司川的存在量為3 1Π。/#胃 賦形蜊之夫維司川(最好 什隹里馮3-10%重量/體積、4·9 8%重量/體積、4_7%重量/體積、 體積、 約5¾重量/體積)、醫荜上可 里/體積及*佳係 上可接受之醇,其中;t二接非水性醋溶劑及醫藥
Hi 血聚夫維司川濃度達至少2星期之久。 中兮二配項特徵為含有夫維司川的㈣調配物,其 經由肌内注入人體,而且其注射後可獲得 療有效的血漿夫維司川濃度達至少2星期之久。 人明其他特徵包括適合肌内注射的醫藥調配物,其包 3,、准司川、30%重量/調配物體積或更低之醫藥上可接受 ^ ^ 1 /〇重里/調配物體積之可溶於蓖麻油酸酯賦形 劑之醫:藥卜γ β /添_ Γ接受的非水性酯溶劑及足量的蓖麻油酸酯賦 形Μ以製備注射後可獲得治療上有效的血漿夫維司川濃度 違至少2星期之久的調配物。 _本^月其他特徵包括適合肌内注射的醫藥調配物,其 S夫維司川;35〇/〇(較佳為3 0 %,理想為2 5 % )重量/調配 體積或更低之醫藥上可接受的醇,至少1%(較佳為至 5 /〇或理想為1 〇 %)重量/調配物體積之可溶於蓖麻油酸 賦形劑内之醫藥上可接受的非水性酯溶劑及足量的蓖麻 义6曰賦1幵》劑以製備含有至少4 5毫克/毫升夫維司川之調 物。 -12- 本紙張尺度遇州中國國宏---- 豕標準(CNS) A4規格(210X297公釐) # 裝_ 玎 包 物 少 酯 油 1259086 A7 B7 五、發明説明(1〇 ) 將%重量/調配物體積—詞用於調配物之組成份時,為了 避免產生任何疑惑’我們係指在單位調配物體積内,將存 在特疋百分比之組成份重’例如丄%重量/調配物體積為在 100毫升調配物體積内將包含1克該組成份。以進一步說 明的方式
1毫升調配物中的X重 ~_ ·--—τ_ 20% ___晃兄 200毫克 10% 100毫克 5% 50毫克 1% 10毫克 1·調配物的總體積是6毫升或更少,而且夫維司川的濃度 至少為45毫克/亳升。 2·調配物中夫維司川的總量為25〇毫克或更多,而且此調 配物的總體積是6亳升或更少。 3.調配物中夫維司川的總量為25〇亳克,而且此調配物的 總體積是5-5.25毫升。 可了解在調配物中可包含過量的調配物以使主治醫師或 照顧者可輸入所需劑量。因此,需要5亳升劑量時,須可 了解調配物中也可包含高達〇·25毫升,較佳係高達〇15毫 升之超多量。一般而言,該調配物可能裝在於小玻璃瓶或 預先裝入含有在此上述單位劑量之調配物的注射筒中,最 -13- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公爱) 1259086 A7 B7
五、發明説明( 好是預充填注射筒,這些是本發明另幾項特徵。 任何上述調配物中醫藥上可接受醇之較 至少3%重量/體積,至少5%重量/ ,辰又為· 里/體積,至少7 %重量/體 積’至少10%重量/體積,至少η%重量/體積,至少12〇/ 重量/體積,至少13%重量/體積,至少14%重量/體積,0 =少15%重量/體積及較佳係至少16%重量/體積。調配物 中醫藥上可接受醇之較佳最高存在濃度為:28%重量/體 積或更低,22%重量/體積或更低及2〇%重量/體積或更 低。任何上述調配物中醫藥上可接受醇之較佳存在範圍係 選自上述任何最小或對大值,較佳係3_35%重量/體積,仁 35%重量/體積,5-35%重量/體積,5_32%重量/體積,/ 32%重量/體積,10_30%重量/體積,12_28%重量/體積, 15-25%重量/體積,17_23%重量/體積’ 18_22%重量/體積 及理想地19-21 %重量/體積。 ' 醫學上可接受之醇係由一種醇或兩或多種醇之混合物所 組成的’較佳係由兩種醇之混合物所組成的。供非經腸方 式給藥之較佳醫學上可接受的醇是乙醇、苯甲基醇或乙醇 及苯甲基醇之混合物,較佳係乙醇與苯甲基醇以相同的重 1 /體積比同時存在於調配物中。此調配物醇最好包人 10 %重量/體積之乙醇及10 %重量/體積之苯甲基醇。 酉學上可接受之非水性酯溶劑係由一種非水性酯溶劑或 兩或多種醫學上可接受之非水性酯溶劑的混合物所組成 的’較佳係只由一種非水性酯溶劑組成。供非經腸方式终 藥之較佳醫學上可接受之非水性酯溶劑係選自苯甲酸笨甲 -14- 本紙張尺度適用中國國家標準((:^3) A4規格(210X 297公釐) ' ----- 1259086 A7 _____B7 五、發明説明(12 ) 基酯、油酸乙基酯、肉豆蔻異丙基酯、棕櫚酸異丙基酯或 其混合物。 蓖麻油酸酯賦形劑在調配物中的存在比例最好為至少 3 0 %重量/調配物體積,理想為至少4 〇 %或至少5 〇 %重量/ 調配物體積。 熟諳此技者應了解醫學上可接受之醇的品質應可使其符 合藥典的標準(如U S、英國、歐洲及日本藥典中所描述 的),此將包含一些水及可能其他有機溶劑,例如在u s藥 典中’在1 5 . 5 6 °c下測量乙醇時,其包含不低於9 4.9體積0/〇 及不超過96.0體積%之乙醇。在us藥典中,在15.56 °C下 測量脫水醇時,其包含不低於99·5體積。/〇之乙醇。 醫學上可接受之非水性酯溶劑在上述任一調配物中之較 佳存在濃度為:至少5 %重量/體積,至少8 %重量/體積, 至少1 0 %重量/體積,至少1 1 〇/〇重量/體積,至少1 2 %重量 /體積,至少1 3 %重量/體積,至少丨5 %重量/體積,至少 1 6 %重量/體積,至少1 7 %重量/體積,至少i 8 %重量/體 積至少19%重量/體積及至少2〇 %重量/體積。醫學上可 接叉之非水性酯溶劑的較佳最大濃度為·· 6 〇 %重量/體積 或更低,5 0 %重量/體積或更低,4 5 %重量/體積或更低, 40%重量/體積或更低,35%重量/體積或更低,3〇%重量 /體積或更低及2 5 %重量/體積或更低。較佳濃度為1 5 %重 量/體積。醫學上可接受之非水性酯溶劑在上述任一調配 物中之較佳存在範圍係選自上述任何最小或最大值,較佳 為· 5-60%重量/體積,7-55%重量/體積,^50%重量/體 -15-
1259086 A7
—--------— B7 五、發明説明(13 ) 積,10-50%重量/體積,1〇_45%重量/體積,1〇_4〇%重量/ 體積,10-35%重量/體積,1〇·3〇%重量/體積,1〇-25%重量 /體積,12-25%重量/體積,12-22%重量/體積,12_2〇%重 體積,12-18%重量/體積,η·17%重量/體積及理想地 14-16%重量/體積。較佳的酯溶劑是苯甲酸苯甲基酯,最 佳濃度為約1 5 %重量/體積。 熟諳此技者應了解醫學上可接受之非水性酯溶劑應具有 付合藥典標準(如U S、英國、歐洲及曰本藥典中所描述的) 之品質。 調配物中醫學上可接受之 溶劑之較佳組合係表示於下 醫學上可接受之醇 ί%重量/體積) 10-30 醇與醫學上可接受之非水性酯 -------- =了上可接X之非水性酯溶劑(% 重:S/體積) /〇,7·55,8·50,ΗΜο,ι〇-45,ιο-40,10-35 in 1 5 °'3〇^〇-25,12-25,12-22,12^20 η ΐδ ^ ,hl8,l3_17及理想的
3-35,4-35,5-35,5-32,7-32: 10-30,12-28,15-25,17-23, 18-22及理想的19-21 14-16 40,10_35,1G_3(U()_ 22,12-20 I? 1 14- 1 6 5 8,13-17 及理想的 10-35 12-18 3-35,4-35,5-35,5-32,7-32, 10-30,12-28,15-25,17-23, -16-
1259086
18-22及理想的19-21 乙醇及苯甲基醇,最佳係各為 約10% 本甲酉文本甲基酯,最佳係為約 15% 藉莲麻油酸酯賦形劑一詞的使用,我們意指一種組成中 具有一定比例(至少 20%,30%,4〇。/❶,5〇%,6〇%,7〇%, 80% ’ 90%或95% W/V)之萬麻酸之甘油三酸酯的油料。此 藥麻油酸酯賦形劑可為合成油或慣用的萬麻油,其如上所 述對藥典標準而言是理想的。 我們驚訝地發現上述本發明調配物經肌内注入之後提供 夫維司川令人滿意的釋放一段較長的時間。 ^ 因下列理由確實對此發現感到驚訝。 L先前申請者所作的試驗曾經由肌内注入水性懸浮物形 式之夫維司川。我們在注射部位發現蔓延著局部組織刺激 性以及釋放曲線不佳。相信該組織刺激性/發炎係由於夫 維司川以固體粒子形式存在。釋放曲線明白地可藉注射部 位所存在的發炎/刺激程度測得,而且這是多變的且不易 控制。而且,此夫維司川釋放速率也不夠高得足以具有臨 床有效性。 ^我們從利用標有之苯甲基醇所作的研究發現顯示其 從注射部位迅速消散並在給藥後的24小時内從 i 除。 戈 預期乙醇若無法非常快,則至少快速地從注射部位 散。 / 已知苯甲酸苯曱基酯可被人類的肺藉共軛鍵結至氨基醋 -17 1259086五、發明説明(15 A7 B7 酸以形成馬尿酸的方式代謝並排泄至尿液中-黯: 超越藥典,第32版,第1103頁,因此,使用苯甲酸苯甲 基醋時,其不同地在整個延長釋放期間皆存在於注射部位 上。 我們已發現除了附加溶解職形劑,即該醇及醫藥上 受之非水性醋溶劑從調配物職形劑中快速消失^卜> 注射該調配物後的注射部位藉由本發明調配物仍可獲得延 長釋放治療上有效量之夫維司川一段延伸期間。 藉“治療上有效量,,-詞的使用,我們意指病人身 =度可達到至少2.5毫微克/毫升,理想為至少3毫微克/ 笔升,至;8.5笔微克/毫升及高達12毫微克/毫升.^ 司川。較佳的血漿程度應低於15毫微克/毫升。 、’, 二巾週U及幸父佳為至少四週。在較佳特徵中 可達36天。最料長㈣A|M;|丨 ^放 (週一一、…佳為至少 :可主治醫師可能希望以分次劑量方式給予肌内 ^ P 5军升调配物係以連續給予兩個2 5毫升不因 射液的方式給藥,這是本發明另一項特徵。 问 簡單溶解夫維司川於油質液體調 有良好釋放曲線或無藥物沈;殿。1不預射後注射部位 示夫維司川編油賦形 含有醇類如乙醇及苯,基醇與苯以 文本T暴酉日。結果清楚地顯示苯f酸笨 血 川 放 注 注 蓖 曱 甲 -18- 本紙張尺度適用中國 豕標準(CNS) A4規格(2!(}χ297公釐) 1259086 A7 B7 五、發明説明(16 ) 基酯對夫維司川在蓖麻油賦形劑中的溶解度有正面作用, 除了夫維司川在蓖麻油賦形劑中具有比在醇或蓖麻油中低 的溶解度。 -19- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1259086 A7 B7 五、發明説明(17 ) s(96%) 5 5 5 5 舛-€踝^ 琳 sa-to· so ㈣ 100 >«3)11 27 36 S荈赛誶【柑 Α/ί;半】 10 10 10 5 5 10 15 5. 100 JL 100 i 100 払6 ^ ^ o15 一5 s 15 ^ 15 15 5. 100 5.100 JL 100 65 76 102 >3 :^25o°M_f 嬅 f^撖凉>谘3 竺(&lvestrgt)私琳iaifi-te 終瑭綷苏饮榷 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) -20- 1259086 五、發明説明(18 甲ί旦司:在含有相同量之醇及j甲酸苯 u 此_也顯確去_之後的溶解度。 1在含與不含聽 >、、丄# > ----調配物中的溶解度比較_ 調配物⑷ 夫維㈣的溶解度毫克/毫升@25°C 以蓖麻油為基質 以 Miglyol 812-N 為基 質 以芝麻籽油/蓖麻油(1 : 1)為基質 以芝麻籽油為基質 上乂花生油為基質_ 本甲酉夂本甲基酉曰(15%)並以所列油料加至體積。 加入各溶劑混合物中並測得溶解度。 八+ 調配物對夫維司川沈殿__ 賦形劑 賦形劑減去醇 81.2 12.6 86.8 70.1 45.7 40.2 1.7 4.4 0.7 <0.2 裝· 訂 天 線 調配物 2 調配物F1 以Ιί麻油為基質
-21 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)
1259086 A7 B7 五、發明説明(19 言周酉己斗勿F + 2 ++fc 以 Miglyol 812-N為基質 調配物F3 芝麻籽油/蓖麻油 為基質 _ 〇、+、++、+++=沈澱程度(未測得,溫和,中度,嚴重) a調配物包含夫維司川(5%)、乙醇[96%](1〇%)、苯甲基醇 (10%)及苯甲酸苯甲基酯(15%)並以所列油料加至體積。 b主要為大針狀結晶 C小針及/或結晶束 在兔子的體外研究中以上述調配物測得夫維司川的沈搬 及釋放曲線。 q 圖1顯示四種取自表4第二部份之調配物的體内稀釋輪摩 並顯示固定油成份經由肌内方式給予兔子藥之後五天對夫 維司川血漿輪廓的影響(數據被常態化成每3公斤5 〇毫克,· 平均給予;每時間點的動物數目=8,溶劑萃取後利用 ms/ms偵測分析電漿樣品的夫維司川含量)。如可見,蓖麻 油調配物顯示特別平坦的釋放曲線,即沒有夫維司川沈2 在注射部位之證據。 ' 因此,我們呈現一種適合肌内注射之延長釋放的醫藥調 配物作為另一項本發明特徵,其中該調配物包含夫維司 川,·35%(較佳係30%或理想的25%)重量/調配物體積或^ + + + + + + + + + + + + + + + + + + + + + + + + 22- 本紙張尺度適财® Η家標準(CNS) A4規格㈣X挪公茇) 1259086 A7 B7 五、發明説明(2〇 ) 少之醫藥上可接受的醇,至少1 % (較佳為至少5 %或理想 為1 0 /〇)重里/調配物體積之可溶於蓖麻油酸酉旨賦形劑之醫 藥上可接受的非水性酯溶劑及足量的蓖麻油酸酯賦形劑, 考慮添加任何其他視情況選用醫藥上可接受的賦形劑以製 備含有至少5 〇亳克/毫升夫維司川之調配物。 本發明的另一項特徵是一種如上所定義適合醫學治療用 之肌内注射液的醫藥調配物。 本1明的另一項特徵是一種藉由肌内注入一種延長釋放 以蓖麻油酸酯賦形劑為基礎之醫藥調配物給予需要此類治 療之人藥物的方式治療良性或惡性乳房及生殖管疾病,較 佳係治療乳癌的方法,其中該醫藥調配物包含至少4 5毫 克/毫升之夫維司川,35%(較佳係3 〇 0/。或理想的2 5 〇/〇 )重量/ 凋配物體積或更少之醫藥上可接受的醇,至少丨% (較佳為 至v 5 %或理想為丨〇 q/。)重量/調配物體積之可溶於蓖麻油 酸醋賦形劑之醫藥上可接受的非水性醋溶劑。 最好給予5毫升肌内注射液。 本發明的另一項特徵是夫維司川在製備如上文中所描述 &用於⑺療良f生或惡性乳房及生殖管疾病,較佳係治療乳 癌之醫藥調配物的用途。 藉“選用醫藥上可接受的睡彡 又的馱形劑一詞的使用,我們參考 在調配領域中慣用的可台色i 月1^加贼形劑,其包括,例如抗氧 化劑防腐劑、著色劑或界而 A界面,舌性劑。較佳的選用賦形劑為 界面活性劑。 如上所述,夫維司川可用 丨」用於治療依賴雌激素之適應症如 張尺度適用中國國家標準(CNS) 23- 1259086 -— 五、發明説明(21 乳癌及一些婦科狀況,如子宮内膜異位症。 除了夫維司川之外,目前另一種類似分子也在臨床研究 中。推定 SH_646(1 1P-氟-7心(14,14,15,15,15-五氣一6-甲基-噻吖十五碳烷基)雌_1,3,5(10)-三烯_3,17β·二醇)也 是一種具有與夫維司川相同的行為模式及極相似之化學結 j的化合物。相信該化合物也與夫維司川分享類似物理性 夤’因此,本發明也將有此化合物之應用。 本务明的另一項特徵是一種適合肌内注射之醫藥調配 物,其包含11β-氟-7心(14,14,15,15,15_五氣_6_甲基魯魂· Ρ 丫十五碳烧基)雌],3,5⑽-三稀〜7卜二醇;35%重量 :调配物體積《更少之醫藥上可接受的醇,纟少1%重量/ 調配物體積之可溶於萬麻油酸酯賦形劑内之醫藥上可接受 的非水性酯溶劑及足量的蓖麻油酸酯賦形劑以製備含有至 少 45 亳克/亳升之 llPn(14,14,15,i5,m6n 丫十五碳烧基)雌义3,5叫三稀乂導二醇的調 本發明的其他特徵係為上述這些特徵,但其中以阳摘 取代夫維司川。 調配物竇例 $維司川與醇及苯甲基醇混合,授拌直到完全溶解。加 入本甲酸甲基醋並以萬麻油將此溶液加至最終重 之(為了方便,利用重量相對於體積的比,使用重量而 體積)。讓此分散溶液籠罩在氮氣下。此溶液利用一或兩 張孔隙度為0.2微求的I紙過遽滅菌。在無菌狀態下將此 -24 張尺度適财國a家標準(CNS) Μ規4(21GX297公董「 i2_n〇0514號專利 中文說明書替換頁(95年5月) A7 ---------— B7 五、發明説明(2^ — 減菌濾液虞入已清洗並非致熱的滅菌一級容器巾,例如小 "或預充填左射筒時,該滅菌濾液被保存在氮氣下。 將過剩物包含在_級包裝中以幫助劑量體積的移除。該一 級包裝在無菌密封之前,以滅菌氮氣覆蓋之。 也參見圖2之程序流程圖 旦根據上述所需調配物規格、實例選擇調配物中各成份的 里例如加入各成份量以製備含有下列組成份之調配物 1 〇 %重量/體積之苯曱基醇 10 %重量/體積之乙醇 1 5 %重量/體積之苯甲酸苯甲基酯 各5宅升製成調配物有2 5 〇毫克夫維司川 及剩餘量之蓖麻油 -25- 68407-950517.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1259086
第090100514號專利申請案 中文說明書替換頁(95年5月) H 五、發明説明(23 ) 圖式說明 圖1顯示四種調配物的體内稀釋輪廓。 圖2顯示根據本發明之調配物的製造流程圖。
68407-950517.doc - 26 - 訂
本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1259086 A7 B7 五、發明説明(24 ) 參考文獻 1. Bowler J,Lilley TJ,Pittam JD,Wakeling AE,新穎類 固醇純抗雌激素,類固醇989 ; 5471-99。 2. Wakeling AE,新穎純抗雌激素:作用模式及治療期待. 美國紐約學術科學1990a ; 595 : 348-56。 3· Wakeling AE,類固醇純抗雌激素,在Lippman M, Dickson R編著者,乳癌中的調整機制。波士頓:Kluwer學 術,1990b : 239-57 ° 4. Wakeling AE,純抗雌激素在治療乳癌上的治療效力, 類固醇生物化學期刊1990c ; 37 : 771-5。 5· Wakeling AE,Bowler J,類固醇純抗雌激素,内分泌學 期刊 1987 ; 112 : R7-10。 6· Wakeling AE,Bowler J,純抗雌激素之生物學及作用模 式,類固醇生物化學期刊1988 ; 3 : 141-7。 -27- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
Claims (1)
1259086 六、申請專利範園 種適a肌内注射之醫藥調配物,其包含夫維司川 (fUlVeStrant)、30%或更少重量/調配物體積之醫藥上可接 受的醇、至少1%重量/調配物體積之可溶於莲麻油酸酯 =形劑之醫藥上可接受的非水性酯溶劑及足量的蓖麻油 酸酉旨賦形劑,以製備注射後可獲得治療上有效的血聚夫 維司川濃度達至少2星期之久的調配物,其中醫藥上可接 受的非水性酯溶劑係選自苯甲酸苯甲基酯、油酸乙基 =、肉豆蔻酸異丙基酯、棕櫚酸異丙基酯或其任何之混 s物,其條件為,調配物包含至少3 %之醫藥上 a 的醇。 ”炊又 2. 根據申請專利範圍第μ之醫藥調配物,其令所獲得的 2漿夫維司川濃度為至少2.5毫微克/毫升達至少2星期之 3. 一種適合肌内注射之醫藥調配物,其包含夫維司川、魏 或更少重量/調配物體積之醫藥上可接受的醇、至少1% 重量/調配物體積之可溶於t麻油酸酯賦形劑之醫藥上0 可接受的非水性醋溶劑及足量的菜麻;由酸醋賦形劑了以 以肴夫維司川濃度為至少45毫克/毫升之調配物,其中醫 =上可接受的非水性酯溶劑係選自苯甲酸苯甲基酯、油 酉欠乙基S曰、肉丑寇酸異丙基酯、棕櫊酸異丙基酯或其任 何之此口物’其條件為,調配物包含至少3 % 可接受的醇。 苗糸上 4. 根據申請專利範圍第⑷項之醫藥調配物,其包含 重量/體積或更少之醫藥上可接受的醇。 〇 本紙張尺度適用中國國家標準(CNS) A4規格 1259086 、申請專利範圍 A8 B8 C8 D8 5· t據中請專利範圍第4項之醫藥調配物,其包含20%重 體積或更少之醫藥上可接受的醇。 6 ·根據申請專利範圍第】十 固弟1或3項之醫藥調配物,其包含6 0 % 重量/體積或更少之醫筚 n丄上 西聚上可接受的非水性酯溶劑。 7 ·根據申請專利範圍第& 曰 ㈤弟6項之醫藥調配物,其包含5 0 %重 1/體積或更少之醫筚 梁上可接受的非水性酯溶劑。 8.根據申請專利範圍第 員之醫藥調配物,其包含4 5 %重 1/體積或更少之醫荦Pi w +上可接受的非水性酯溶劑。 9·根據申請專利範圍第6 ㈤弟6項之醫藥調配物,其包含4 0 %重 量/體積或更少之㈣上可接受的非水性㈣劑。 ι〇·根據申請享利範圍第6 5 曰 寸〜乾園弟6項之醫藥調配物,其包含3 5 %重 里/體積或更少之醫藥上可接受的非水性酯溶劑。 11·二據申請專利範圍第6項之醫藥調配物,其包含3〇%重 1/體積或更少之醫藥上可接受的非水性酯溶劑。 12·:據申請專利範圍第6項之醫藥調配物,其包含25%重 !/體積或更少之醫藥上可接受的非水性酯溶劑。 1 3 ·根據申明專利範圍第丨或3項之醫藥調配物,其中醫藥 上可接受的醇是乙醇與笨曱基醇之混合物。 14·根據申印專利範圍第!或3項之醫藥調配物,其中醫藥上 可接受的非水性酯溶劑是苯甲酸苯甲基酯。 15·根據申請專利範圍第1或3項之醫藥調配物,其中調配物 的總體積為6毫升或更少,而且夫維司川的濃度為至少4 5 毫克/毫升。 16.根據申请專利範圍第i或3項之醫藥調配物,其中夫維司 -2 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A B c D 1259086 六、申請專利範圍 川在調配物中的總量為2 5 0毫升或更多,而且該調配物 的總體積為6毫升或更少。 17·根據申請專利範圍第i 6項之醫藥調配物,其中夫維司川 在調配物中的總量為2 5 0毫升,而且該調配物的體積為 5-5.25毫升。 18·根據申請專利範圍第}或3項之醫藥調配物,其中醫藥上 可接受的醇是1 0 %重量/調配物體積之乙醇、1 0 %重量/ 調配物體積之苯甲基醇及1 5 %重量/調配物體積之笨甲 酸苯曱基s旨所形成的混合物,而且ϋ麻油酸自旨職形劑是 蓖麻油。 19·申請專利範圍第1或3項之醫藥調配物,其適合醫學治療 使用之肌内注射。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
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Families Citing this family (92)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0000313D0 (en) * | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
GB0116620D0 (en) * | 2001-07-07 | 2001-08-29 | Astrazeneca Ab | Formulation |
PL367624A1 (en) * | 2001-07-07 | 2005-03-07 | Astrazeneca Ab | Pharmaceutical formulation for the intramuscular administration of fulvestrant |
KR101086533B1 (ko) | 2002-05-24 | 2011-11-23 | 쉐링 코포레이션 | 중화 사람 항-igfr 항체, 이를 제조하는 방법 및 이를 포함하는 조성물 |
TW200404552A (en) * | 2002-05-30 | 2004-04-01 | Akzo Nobel Nv | Self administered contraception |
US20050152858A1 (en) * | 2003-07-11 | 2005-07-14 | Isp Investments Inc. | Solubilizing agents for active or functional organic compounds |
PE20050928A1 (es) * | 2003-11-21 | 2005-11-08 | Schering Corp | Combinaciones terapeuticas de anticuerpo anti-igfr1 |
EP1623713A1 (en) * | 2004-07-09 | 2006-02-08 | Proskelia SAS | Cominations of pure anti-estrogen with aromatase inhibitors |
EP1879587A2 (en) * | 2005-04-15 | 2008-01-23 | Schering Corporation | Methods and compositions for treating or preventing cancer |
US20090227552A1 (en) * | 2005-09-26 | 2009-09-10 | Kellie Ann Hooley | Fulvestrant formulations |
CA2716576A1 (en) * | 2008-03-07 | 2009-09-11 | Nageswara R. Palepu | Fulvestrant formulations |
AU2014200332B2 (en) * | 2008-04-28 | 2016-10-06 | Diurnal Limited | Lipid composition |
GB0807605D0 (en) | 2008-04-28 | 2008-06-04 | Diurnal Ltd | Lipid composition |
UA104147C2 (uk) * | 2008-09-10 | 2014-01-10 | Новартис Аг | Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань |
US20100317635A1 (en) | 2009-06-16 | 2010-12-16 | Endorecherche, Inc. | Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators |
CN102939287B (zh) | 2010-06-10 | 2016-01-27 | 塞拉根制药公司 | 雌激素受体调节剂及其用途 |
US8853423B2 (en) | 2010-06-17 | 2014-10-07 | Seragon Pharmaceuticals, Inc. | Indane estrogen receptor modulators and uses thereof |
EP2616078B1 (en) | 2010-09-16 | 2019-12-25 | Shimoda Biotech (Pty) Ltd | Fulvestrant compositions and methods of use |
CA2836831C (en) | 2011-05-20 | 2015-06-02 | Capital, Business Y Gestion De Finanzas S.L. | Pharmaceutical composition |
CN102391341B (zh) * | 2011-08-09 | 2013-05-22 | 福建省微生物研究所 | 制备6,7-脱氢-17β-烃酰氧基诺龙的方法 |
CN103070871B (zh) * | 2011-10-26 | 2015-04-15 | 正大天晴药业集团股份有限公司 | 一种氟维司群的药物组合物 |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
EP3936133A1 (en) | 2011-11-23 | 2022-01-12 | TherapeuticsMD, Inc. | Natural combination hormone replacement formulations and therapies |
BR112014014124A2 (pt) | 2011-12-14 | 2017-08-22 | Seragon Pharmaceutical Inc | Moduladores do receptor de estrogênio fluorados e usos dos mesmos |
MX2014007198A (es) | 2011-12-16 | 2014-10-13 | Olema Pharmaceuticals Inc | Compuestos novedosos de benzopirano, composiciones y usos de los mismos. |
CN102600064A (zh) * | 2012-03-31 | 2012-07-25 | 西安力邦制药有限公司 | 氟维司群或其衍生物缓释制剂及其制备方法 |
CN102600073B (zh) * | 2012-03-31 | 2014-01-01 | 莱普德制药有限公司 | 以乳酸酯为基础的氟维司群或其衍生物油性制剂及其制备方法 |
US11179468B2 (en) | 2012-04-09 | 2021-11-23 | Eagle Pharmaceuticals, Inc. | Fulvestrant formulations |
EP2836199B1 (en) * | 2012-04-09 | 2024-06-19 | Eagle Pharmaceuticals, Inc. | Fulvestrant formulations |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
JP6356218B2 (ja) | 2013-04-18 | 2018-07-11 | シーアン リーバン ファーマシューティカル テクノロジー シーオー., エルティーディー.Xi’An Libang Pharmaceutical Technology Co., Ltd. | 抗腫瘍活性を有する7−α−[9−(4,4,5,5,5−ペンタフルオロペンチルスルフィニル)ノニル]−エストラ−1,3,5(10)−トリエン−3,17β−ジオールのエステル誘導体及びその調製方法 |
WO2014195032A1 (en) | 2013-06-07 | 2014-12-11 | Medical Prognosis Institute A/S | Methods and devices for predicting treatment efficacy of fulvestrant in cancer patients |
WO2014203129A1 (en) | 2013-06-19 | 2014-12-24 | Olema Pharmaceuticals, Inc. | Combinations of benzopyran compounds, compositions and uses thereof |
WO2014203132A1 (en) | 2013-06-19 | 2014-12-24 | Olema Pharmaceuticals, Inc. | Substituted benzopyran compounds, compositions and uses thereof |
CN104337761B (zh) * | 2013-08-07 | 2019-03-26 | 江苏豪森药业集团有限公司 | 氟维司群药物组合物 |
US20160213682A1 (en) * | 2013-09-06 | 2016-07-28 | Salah Uddin Ahmed | Fulvestrant compositions |
US9271990B2 (en) | 2014-02-14 | 2016-03-01 | Fresenius Kabi Usa, Llc | Fulvestrant formulations |
AU2015228859A1 (en) | 2014-03-13 | 2016-07-07 | F. Hoffmann-La Roche Ag | Therapeutic combinations with estrogen receptor modulators |
WO2015179782A1 (en) | 2014-05-22 | 2015-11-26 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
EP3174542A4 (en) | 2014-07-29 | 2018-01-03 | TherapeuticsMD, Inc. | Transdermal cream |
AU2015367509B2 (en) | 2014-12-18 | 2020-01-02 | F. Hoffmann-La Roche Ag | Tetrahydro-pyrido(3,4-b)indole estrogen receptor modulators and uses thereof |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
BR122023020677A2 (pt) | 2015-10-01 | 2023-12-12 | Olema Pharmaceuticals, Inc. | Compostos de tetra-hidro-1h-pirido[3,4-b]indol, composições compreendendo os referidos compostos e usos dos mesmos |
CA3001526A1 (en) | 2015-10-13 | 2017-04-20 | Themis Medicare Limited | Fulvestrant compositions |
RU2747802C2 (ru) | 2015-12-09 | 2021-05-14 | Зе Боард Оф Трастис Оф Зе Юниверсити Оф Иллинойс | Бензотиофеновые селективные блокаторы эстрогеновых рецепторов |
WO2017173044A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd Inc. | Steroid hormone compositions in medium chain oils |
RU2018133932A (ru) | 2016-04-01 | 2020-05-12 | Терапьютиксмд, Инк. | Фармацевтическая композиция стероидного гормона |
CN108883118B (zh) | 2016-04-06 | 2021-06-15 | 富士胶片株式会社 | 医药组合物 |
CN109219604B (zh) | 2016-04-08 | 2021-09-24 | 豪夫迈·罗氏有限公司 | 四氢异喹啉雌激素受体调节剂及其用途 |
US11590077B2 (en) | 2016-05-06 | 2023-02-28 | Eagle Pharmaceuticals, Inc. | Fulvestrant formulations and methods of their use |
WO2019094650A1 (en) * | 2017-11-08 | 2019-05-16 | Eagle Pharmaceuticals, Inc | Fulvestrant formulations and methods of their use |
JP2019516789A (ja) * | 2016-05-06 | 2019-06-20 | イーグル ファーマスーティカルズ、インク. | フルベストラント配合物およびその使用方法 |
WO2017208847A1 (ja) * | 2016-05-31 | 2017-12-07 | 富士フイルム株式会社 | 医薬組成物 |
US20180002344A1 (en) | 2016-06-16 | 2018-01-04 | Genentech, Inc. | Heteroaryl estrogen receptor modulators and uses thereof |
US20170362228A1 (en) | 2016-06-16 | 2017-12-21 | Genentech, Inc. | TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
WO2017216279A1 (en) * | 2016-06-16 | 2017-12-21 | F. Hoffmann-La Roche Ag | Heteroaryl estrogen receptor modulators and uses thereof |
CN107789320B (zh) * | 2016-08-31 | 2021-06-22 | 鲁南制药集团股份有限公司 | 一种氟维司群缓释注射液及其制备工艺 |
MX2020002649A (es) | 2017-09-11 | 2020-09-25 | Atossa Therapeutics Inc | Metodos para hacer y usar endoxifeno. |
CA3081602A1 (en) | 2017-11-16 | 2019-05-23 | Novartis Ag | Combination therapies |
CN111465398A (zh) * | 2018-01-31 | 2020-07-28 | 富士胶片株式会社 | 注射用制剂的制造方法 |
RU2684330C1 (ru) * | 2018-02-02 | 2019-04-08 | Закрытое Акционерное Общество "Биокад" | Композиции фулвестранта |
CA3101421A1 (en) | 2018-05-24 | 2019-11-28 | Kashiv Biosciences, Llc | Prodrugs of fulvestrant |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
CN111035613A (zh) * | 2018-10-12 | 2020-04-21 | 江苏恒瑞医药股份有限公司 | 一种包含氟维司群的可注射的药物组合物及其制备方法 |
EP3873477A4 (en) | 2018-11-01 | 2022-09-07 | Syros Pharmaceuticals, Inc. | CYCLINE-DEPENDENT KINASE 7 (CDK7) INHIBITORS |
KR20210106437A (ko) | 2018-12-20 | 2021-08-30 | 노파르티스 아게 | 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 및 약학적 조합물 |
EP3924054A1 (en) | 2019-02-15 | 2021-12-22 | Novartis AG | 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
CA3123519A1 (en) | 2019-02-15 | 2020-08-20 | Novartis Ag | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
PE20220218A1 (es) | 2019-05-20 | 2022-02-02 | Novartis Ag | Conjugados de anticuerpo-farmaco inhibidores de mcl-1 y sus metodos de uso |
RU2722988C1 (ru) * | 2019-11-19 | 2020-06-05 | федеральное государственное бюджетное образовательное учреждение высшего образования "Башкирский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Способ моделирования проканцерогенного действия фулвестранта на яичники потомства женского пола у лабораторных мышей |
CN113260353A (zh) * | 2019-12-11 | 2021-08-13 | 上海博志研新药物技术有限公司 | 氟维司群药物组合物、其制备方法及应用 |
US20230057071A1 (en) | 2019-12-20 | 2023-02-23 | Novartis Ag | Combination of anti tim-3 antibody mbg453 and anti tgf-beta antibody nis793, with or without decitabine or the anti pd-1 antibody spartalizumab, for treating myelofibrosis and myelodysplastic syndrome |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
CA3182346A1 (en) | 2020-06-23 | 2021-12-30 | Novartis Ag | Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives |
EP4188549A1 (en) | 2020-08-03 | 2023-06-07 | Novartis AG | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
CR20230283A (es) | 2020-11-24 | 2023-07-27 | Novartis Ag | Anticuerpos anti-cd48, conjugados de anticuerpo-fármaco, y usos de los mismos |
EP4251208A1 (en) | 2020-11-24 | 2023-10-04 | Novartis AG | Mcl-1 inhibitor antibody-drug conjugates and methods of use |
JP2024505562A (ja) | 2021-02-02 | 2024-02-06 | レス ラボラトイレス セルビエル | 選択的bcl-xl protac化合物及び使用の方法 |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
WO2023121232A1 (ko) * | 2021-12-20 | 2023-06-29 | 주식회사 삼양홀딩스 | 용해도가 개선된 풀베스트란트의 약학 조성물 및 그 제조 방법 |
WO2023225336A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Met bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
WO2023225320A1 (en) | 2022-05-20 | 2023-11-23 | Novartis Ag | Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof |
Family Cites Families (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB817241A (en) | 1957-08-21 | 1959-07-29 | Vismara Francesco Spa | Oily solutions for parenteral administration containing adreno-cortical hormones |
FR6241E (fr) | 1905-04-19 | 1906-10-10 | Ktiengesellschaft | Système de refroidissement du piston des moteurs à explosions et des compresseurs |
DE947335C (de) | 1954-10-19 | 1956-08-16 | Schering Ag | Verfahren zur Herstellung stabiler oeliger Loesungen von Oestron |
US2983649A (en) | 1957-10-15 | 1961-05-09 | Francesco Vismara Societa Per | Ricinoleic acid ester solutions of adreno-cortical hormones |
GB1060632A (en) * | 1962-09-11 | 1967-03-08 | Olin Mathieson | Steroid compositions |
US3164520A (en) † | 1962-10-29 | 1965-01-05 | Olin Mathieson | Injectable steroid compositions containing at least 75% benzyl benzoate |
JPS4327327Y1 (zh) | 1965-01-07 | 1968-11-12 | ||
NL151903B (nl) | 1965-03-24 | 1977-01-17 | Schering Ag | Werkwijze ter bereiding van een injectievloeistof door een steroid op te lossen in een mengsel van ricinusolie en benzylbenzoaat. |
USRE28690E (en) * | 1965-05-05 | 1976-01-20 | Schering Aktiengesellschaft | 17α-Ethinyl-18-methyl-19-nortestosterone esters |
GB1207571A (en) * | 1967-01-13 | 1970-10-07 | Takeda Chemical Industries Ltd | Injectable composition |
SU549118A1 (ru) | 1973-04-02 | 1977-03-05 | Способ синхронизации половой охоты у циклирующих свиноматок | |
SU676284A1 (ru) | 1975-06-26 | 1979-07-30 | Научно-Исследовательский Институт Животноводства | Способ синхронизации половой охоты у самок домашних животных |
DE2548413A1 (de) | 1975-10-27 | 1977-04-28 | Schering Ag | Depotpraeparate in oeliger ungesaettigter loesung zur intramuskulaeren injektion |
US4048310A (en) | 1976-02-24 | 1977-09-13 | E. R. Squibb & Sons, Inc. | Topical steroid formulation in form of lotion or cream |
US4048309A (en) | 1976-02-24 | 1977-09-13 | E. R. Squibb & Sons, Inc. | Topical steroid ointment formulations |
NL7711916A (nl) * | 1977-10-29 | 1979-05-02 | Akzo Nv | Werkwijze ter bereiding van sterk geconcen- treerde farmaceutische preparaten van steroiden. |
DE2907460A1 (de) * | 1978-03-07 | 1979-09-13 | Sandoz Ag | Neue resorbierbare galenische kompositionen |
GB8327256D0 (en) | 1983-10-12 | 1983-11-16 | Ici Plc | Steroid derivatives |
DE3708942A1 (de) | 1987-03-18 | 1988-09-29 | Schering Ag | 19,11ss-ueberbrueckte steroide, deren herstellung und diese enthaltende pharmazeutische praeparate |
EP0310542B1 (de) * | 1987-10-01 | 1994-06-08 | Schering Aktiengesellschaft | Antigestagen- und antiöstrogenwirksame Verbindungen zur Behandlung hormonabhängiger Tumoren |
DE3733478A1 (de) | 1987-10-01 | 1989-04-13 | Schering Ag | Antigestagen- und antioestrogenwirksame verbindungen zur geburtseinleitung und zum schwangerschaftsabbruch sowie zur behandlung gynaekologischer stoerungen und hormonabhaengiger tumore |
GB8813353D0 (en) * | 1988-06-06 | 1988-07-13 | Ici Plc | Therapeutic product |
JPH04327327A (ja) | 1991-04-25 | 1992-11-16 | Toyoda Gosei Co Ltd | スリーブとホースの加締め用ダイス |
CN1102095A (zh) | 1993-10-30 | 1995-05-03 | 浙江医科大学 | 长效雄激素类制剂——十一酸睾丸注射液 |
IL111991A (en) | 1994-01-28 | 2000-07-26 | Abbott Lab | Liquid pharmaceutical composition of HIV protease inhibitors in organic solvent |
ZA9510926B (en) * | 1994-12-23 | 1996-07-03 | Schering Ag | Compounds with progesterone-antagonistic and antiestrogenic action to be used together for female contraception |
DE19510861A1 (de) | 1995-03-16 | 1996-09-19 | Schering Ag | Einmonatsspritze als Depot-Kontrazeptivum und für die Hormonersatztherapie für peri- und praemenopausale Frauen |
US20010006963A1 (en) | 1995-03-16 | 2001-07-05 | Ursula Lachnit-Fixson | Once-a-month injection as a depot contraceptive and for hormone replacement therapy for perimenopausal and premenopausal women |
EP0760237A1 (en) | 1995-08-30 | 1997-03-05 | Cipla Limited | Oil-in-water microemulsions |
GB9525194D0 (en) * | 1995-12-12 | 1996-02-07 | Zeneca Ltd | Pharmaceutical composition |
JPH09208496A (ja) * | 1996-01-30 | 1997-08-12 | Takeda Chem Ind Ltd | Lh−rh拮抗物質含有組成物 |
DE19613972A1 (de) | 1996-04-09 | 1997-10-16 | Bayer Ag | Injektionsformulierungen von Avermectinen und Milbemycinen auf Basis von Rizinusöl |
GB9608719D0 (en) | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
JPH10203982A (ja) * | 1996-07-05 | 1998-08-04 | Takeda Chem Ind Ltd | 視機能障害の予防・治療剤 |
US5952338A (en) | 1996-07-05 | 1999-09-14 | Takeda Chemical Industries, Ltd. | Agent for prophylaxis and treatment of disturbance of visual function |
DE19635525A1 (de) * | 1996-08-20 | 1998-02-26 | Schering Ag | 7alpha-(xi-Aminoalkyl)-estratriene, Verfahren zu deren Herstellung, pharmazeutische Präparate, die diese 7alpha(xi-Aminoalkyl-estratriene enthalten sowie deren Verwendung zur Herstellung von Arzneimitteln |
DE19638045A1 (de) | 1996-09-18 | 1998-03-19 | Bayer Ag | Injektionsformulierungen von Avermectinen und Milbemycinen |
JPH10152438A (ja) * | 1996-11-22 | 1998-06-09 | Takeda Chem Ind Ltd | 1−アザキサントン誘導体またはその塩の安定化方法および1−アザキサントン誘導体含有組成物 |
JPH11158200A (ja) * | 1997-09-26 | 1999-06-15 | Takeda Chem Ind Ltd | ヒト成長ホルモン・亜鉛複合体及びその用途 |
US6191107B1 (en) | 1997-09-26 | 2001-02-20 | Takeda Chemical Industries, Ltd. | Complex of human growth hormone and zinc |
WO1999027906A1 (en) | 1997-12-03 | 1999-06-10 | Merck & Co., Inc. | Long acting injectable formulations containing hydrogenated castor oil |
EP2266537B1 (en) | 1999-04-01 | 2014-09-03 | Hana Biosciences, Inc. | Compositions for treating cancer |
GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
JP4327327B2 (ja) | 2000-04-03 | 2009-09-09 | ロボテック株式会社 | 固定スプレー揺動装置 |
PL367624A1 (en) | 2001-07-07 | 2005-03-07 | Astrazeneca Ab | Pharmaceutical formulation for the intramuscular administration of fulvestrant |
GB0912999D0 (en) | 2009-07-27 | 2009-09-02 | Astrazeneca Ab | Method-803 |
-
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