TW202012381A - 奧德維希百(odevixibat)之結晶修飾物 - Google Patents
奧德維希百(odevixibat)之結晶修飾物 Download PDFInfo
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- TW202012381A TW202012381A TW108121584A TW108121584A TW202012381A TW 202012381 A TW202012381 A TW 202012381A TW 108121584 A TW108121584 A TW 108121584A TW 108121584 A TW108121584 A TW 108121584A TW 202012381 A TW202012381 A TW 202012381A
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Abstract
本發明係關於1,1-二側氧基-3,3-二丁基-5-苯基-7-甲硫基-8-(N-{(R)-α-[N-((S)-1-羧丙基)胺甲醯基]-4-羥基苯甲基}胺甲醯基甲氧基)-2,3,4,5-四氫-1,2,5-苯并噻二氮呯(奧德維希百) (odevixibat)之結晶修飾物,更特別是奧德維希百之結晶修飾物1及2。本發明亦關於一種製備奧德維希百之結晶修飾物1的方法,一種包含結晶修飾物1之醫藥組合物,及此結晶修飾物治療如本文所述之各種病狀的用途。
Description
本發明係關於一種1,1-二側氧基-3,3-二丁基-5-苯基-7-甲硫基-8-(N
-{(R)-α-[N-((S)-1-羧丙基)胺甲醯基]-4-羥基苯甲基}胺甲醯基甲氧基)-2,3,4,5-四氫-1,2,5-苯并噻二氮呯(奧德維希百) (odevixibat)之結晶修飾物,更具體言之奧德維希百之結晶修飾物1及2。本發明亦係關於一種製備奧德維希百之結晶修飾物1的方法,係關於一種包含結晶修飾物1之醫藥組合物,且係關於此結晶修飾物在如本文所描述之各種病狀的治療中的用途。
化合物1,1-二側氧基-3,3-二丁基-5-苯基-7-甲硫基-8-(N
-{(R)-α-[N
-((S)-1-羧丙基)胺甲醯基]-4-羥基苯甲基}胺甲醯基甲氧基)-2,3,4,5-四氫-1,2,5-苯并噻二氮呯(奧德維希百;亦稱為A4250)揭示於WO 03/022286中。下文顯示奧德維希百之結構。
作為迴腸膽汁酸轉運體(ileal bile acid transporter,IBAT)機制之抑制劑,奧德維希百抑制膽汁酸自迴腸天然再吸收進入肝門靜脈循環中。未自迴腸再吸收之膽汁酸替代地分泌至糞便中。膽汁酸自肝腸循環全部移除導致血清及肝臟中之膽汁酸含量降低。因此,奧德維希百或其醫藥學上可接受之鹽適用於治療或預防諸如血脂異常、便秘、糖尿病及肝病,且尤其與膽汁酸含量升高相關之肝病的疾病。
根據WO 03/022286之實驗章節,製備奧德維希百之最後一個步驟涉及在酸性條件下水解第三丁酯。藉由在減壓下蒸發溶劑隨後藉由製備型HPLC純化殘餘物來獲得粗化合物(實例29)。未鑑別出結晶材料。
非晶形材料可含有高含量之殘餘溶劑,其對於應用作藥劑之材料為極其不合需要的。此外,由於非晶形材料與結晶材料相比化學及物理穩定性較低,因此非晶形材料可顯現較快分解且可自發地形成具有可變結晶度之結晶。此可導致不可再現的溶解速率以及儲存及處理材料之困難。在醫藥製劑中,有效藥劑成份(active pharmaceutical ingredient,API)出於彼原因較佳以高度結晶狀態使用。因此,需要具有關於穩定性、主體處理及溶解性之改良特性的奧德維希百之結晶修飾物。特定言之,本發明之目的為提供一種不含高含量之殘餘溶劑之奧德維希百之穩定結晶修飾物,其具有經改良之化學穩定性且可以高水準結晶度獲得。
本發明提供一種奧德維希百之結晶修飾物。在第一態樣中,結晶修飾物為奧德維希百之結晶水合物。此結晶水合物為通道水合物,其可含有每莫耳奧德維希百多至2莫耳水與結晶結合。本文所計算之水的量不包括吸收至結晶表面之水。在一個實施例中,結晶水合物為倍半水合物,亦即含有每莫耳奧德維希百約1.5莫耳水與結晶結合。在另一態樣中,其可與第一態樣有關,本發明提供一種奧德維希百之結晶修飾物1。結晶修飾物1為在30%相對濕度(RH)下含有每莫耳奧德維希百約1.5莫耳水之穩定結晶水合物。
在另一態樣中,本發明提供一種奧德維希百之二水合物-溶劑合物。此混合溶劑合物可以不同的同構溶劑合物存在且可包含甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF或DMSO作為有機溶劑。當混合溶劑合物乾燥時,其失去其溶劑合物分子且轉化成奧德維希百之結晶修飾物1。在另一態樣中,其可與此態樣有關,本發明提供一種奧德維希百之結晶修飾物2A、2B及2C,在本文中統稱為奧德維希百之結晶修飾物2。在乾燥後,結晶修飾物2失去其有機溶劑分子且產生奧德維希百之結晶修飾物1。
本發明進一步提供一種奧德維希百之結晶修飾物1在治療本文所描述之病狀中之用途,一種包含奧德維希百之結晶修飾物1之醫藥組合物以及一種用於製備奧德維希百之結晶修飾物1之方法。
相關申請案之交叉引用
本申請案主張2018年6月20日申請之瑞典申請案第1850761-6號及2018年6月20日申請之瑞典申請案第1850762-4號之優先權,該等申請案之揭示內容以全文引用之方式併入本文中。
本文所述之本發明係關於在奧德維希百之廣泛研究中所發現之結晶修飾物。已觀測到,奧德維希百可藉由在其結構中併入溶劑合物分子而自多種有機溶劑(或溶劑之混合物)結晶,由此形成多種溶劑合物或混合溶劑合物。雖然大部分此等(混合)溶劑合物在空氣中不穩定且在乾燥後變成非晶形,但已出人意料地發現,可乾燥奧德維希百之某些混合溶劑合物且將其轉化成奧德維希百之穩定結晶形式。值得注意的是,此穩定形式(在下文中稱為奧德維希百之結晶修飾物1)可自奧德維希百之不同混合溶劑合物形成。
因此,在第一態樣中,本發明係關於一種奧德維希百之結晶修飾物1。 此穩定的結晶修飾物可自奧德維希百於水及有機溶劑(諸如乙醇)之混合物中之漿液獲得。在此等條件下,最初形成含有每莫耳奧德維希百約兩莫耳水及約一到約三莫耳,諸如約二到約三莫耳乙醇的混合溶劑合物(例如,二水合物-二乙醇合物或二水合物-三乙醇合物)。在一些實施例中,此混合溶劑合物稱為結晶修飾物2。當混合溶劑合物乾燥時,其失去其有機溶劑分子且變成結晶修飾物1。雖然不希望受理論束縛,但咸信可在無需結晶溶解及再結晶之情況下移除溶劑分子。
結晶修飾物1含有空隙體積,該等空隙體積視相對濕度而定能含有每莫耳奧德維希百至多約2莫耳與結晶相關聯之水。此形式因此形式上為通道水合物。然而,在約30%相對濕度下,結晶修飾物1含有實質上每莫耳有機化合物約1.5莫耳之水的化學計量之量,且因此為倍半水合物。實質上化學計量之量的水視為有利的,因為即使在約30%至約70% RH之正常相對濕度範圍內之濕度變化的情況下,結晶之含水量仍實質上保持恆定。實際上,在諸如約30與約70%之間RH之正常濕度下,結晶修飾物1展現相對低吸濕性。
在一個實施例中,本發明係關於具有用CuKα1-輻射獲得之X射線粉末繞射(XRPD)圖的奧德維希百之結晶修飾物1,其至少在°2θ位置5.6±0.2、6.7±0.2及/或12.1±0.2處具有特定峰值。
在其特定實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之結晶修飾物1,具有特定峰在°2θ位置5.6±0.2、6.7±0.2及12.1±0.2及一或多個以下特徵峰:4.1±0.2、4.6±0.2、9.3±0.2、9.4±0.2及10.7±0.2。
在其更特定實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之結晶修飾物1,其在°2θ位置4.6±0.2、5.6±0.2、6.7±0.2、9.3±0.2、9.4±0.2及12.1±0.2處具有特定峰值。
在其又一更具體實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之結晶修飾物1,其在°2θ位置4.1± 0.2、4.6±0.2、5.6±0.2、6.7±0.2、9.3±0.2、9.4±0.2、10.7±0.2及12.1±0.2以及8.1±0.2、8.6±0.2、13.4±0.2、13.8±0.2、13.9±0.2、16.6±0.2、17.3±0.2、17.7±0.2、18.3±0.2、18.9±0.2、19.4±0.2、19.7±0.2、20.5±0.2、20.8±0.2、21.6±0.2、23.2±0.2、24.3±0.2、29.8±0.2及30.6±0.2中之一或多者處具有特徵峰值。
在其又一甚至更特定實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之結晶修飾物1,其在°2θ位置4.1±0.2、4.6±0.2、5.6±0.2、6.7±0.2、8.1±0.2、8.6±0.2、9.3±0.2、9.4±0.2、10.7±0.2、12.1±0.2、13.4±0.2、13.8±0.2、13.9±0.2、16.6±0.2、17.3±0.2、17.7±0.2、18.3±0.2、18.9±0.2、19.4±0.2、19.7±0.2、20.5±0.2、20.8±0.2、21.6±0.2、23.2±0.2、24.3±0.2、29.8±0.2及30.6±0.2處具有特徵峰值。
在一特定實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之結晶修飾物1,基本上如圖1所示。
儘管結晶修飾物1為在約30%相對濕度下含有約3.5%水之倍半水合物,但已觀測到,當濕度增加至95% RH時結晶可吸收額外1.5%水。此額外水之吸收及解吸為完全可逆的(參見例如實例10)。額外水可吸收至表面上或可進一步填充結構之通道。在一些實施例中,術語「過度水合」係指結晶修飾物1含有每莫耳奧德維希百約1.5至約4莫耳之水,諸如每莫耳奧德維希百約1.5至約3.5,或諸如約1.5至3,或諸如約1.5至約2.5,或諸如約1.5至約2莫耳之水。在一些實施例中,術語「過度水合」係指結晶修飾物1含有每莫耳奧德維希百約2至約4莫耳之水,諸如每莫耳奧德維希百約2至約3.5,或諸如約2至約3,或諸如約2至2.5莫耳之水。
已觀測到,過度水合結晶修飾物1之XRPD圖當例如在真空中在50℃下乾燥時略有變化。如圖2及圖3中分別顯示,峰值之小位移在2θ範圍5-13°及18-25°中最清楚可見。將乾燥修飾物暴露於高相對濕度,諸如至多95% RH,使得過度水合修飾物之XRPD圖再次出現。峰值位移為單元晶胞體積變化之結果,其由於水分子進入及離開結晶結構而出現。
因此,在另一實施例中,本發明係關於具有用CuKα1-輻射獲得之X射線粉末繞射(XRPD)圖的過度水合結晶修飾物1,其至少在°2θ位置5.7±0.2、6.7±0.2及/或12.0±0.2處具有特定峰值。
在某些實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖的過度水合結晶修飾物1,其具有°2θ位置5.7±0.2、6.7±0.2及12.0±0.2處之特定峰值以及以下特徵峰值中之一或多者:4.0±0.2、9.4±0.2、9.6±0.2及10.8±0.2。
在一更特定實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之過度水合結晶修飾物1,其在°2θ位置4.0±0.2、5.7±0.2、6.7±0.2、9.4±0.2、9.6±0.2、10.8±0.2及12.1±0.2處具有特定峰值。
在另一實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之過度水合結晶修飾物1,其在°2θ位置4.0±0.2、5.7±0.2、6.7±0.2、9.4±0.2、9.6±0.2、10.8±0.2及12.1±0.2以及4.7±0.2、8.0±0.2、8.6±0.2、13.3±0.2、14.1±0.2、15.3±0.2、16.5±0.2、17.3±0.2、19.3±0.2、19.7±0.2、19.9±0.2、20.1±0.2、20.8±0.2、21.7±0.2、23.6±0.2、26.2±0.2、26.5±0.2、28.3±0.2及30.9±0.2中之一或多者處具有特徵峰值。
在又另一實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之過度水合結晶修飾物1,其在°2θ位置4.0±0.2、4.7±0.2、5.7±0.2、6.7±0.2、8.0±0.2、8.6±0.2、9.4±0.2、9.6±0.2、10.8±0.2、12.1±0.2、13.3±0.2、14.1±0.2、15.3±0.2、16.5±0.2、17.3±0.2、19.3±0.2、19.7±0.2、19.9±0.2、20.1±0.2、20.8±0.2、21.7±0.2、23.6±0.2、26.2±0.2、26.5±0.2、28.3±0.2及30.9±0.2處具有特徵峰值。
在又一實施例中,本發明係關於具有用CuKα1-輻射獲得之XRPD圖之奧德維希百之過度水合結晶修飾物1,基本上如圖2所示。
在一些實施例中,結晶修飾物1之結晶度大於約99%。結晶度可藉由例如實驗章節中所揭示之差示掃描熱量測定(DSC)方法量測。
結晶修飾物1具有優於非晶形奧德維希百之若干優勢。結晶修飾物1在諸如30-70% RH之正常濕度下的相對低吸濕性便於奧德維希百之處理及儲存。另外,結晶修飾物1不含高含量之殘餘溶劑。相比之下,已觀測到,粗非晶形奧德維希百之各批次可含有含量超過迄今為止之調節極限之殘餘溶劑(諸如甲酸)。穩定性實驗已進一步顯示,奧德維希百之結晶修飾物1展現比非晶形奧德維希百高的化學穩定性。
結晶修飾物1可具有一或多個額外優勢,諸如比非晶形奧德維希百高之物理及熱力學穩定性;比非晶形奧德維希百可再現之溶解性;或改良之處理成調配物之能力。此類特性與奧德維希百之醫藥調配物高度相關。
在第二態樣中,本發明係關於一種奧德維希百之結晶修飾物2。已發現,不僅可自乙醇及水之混合物(如上文所描述),且亦可自甲醇以及溶劑及水之某些其他混合物(包括甲醇及水、2-丙醇及水、丙酮及水、乙腈及水、1,4-二噁烷及水、DMF及水以及DMSO及水之混合物)獲得結晶修飾物2。結晶修飾物2為混合溶劑合物,含有每莫耳奧德維希百約兩莫耳水及約一至約三莫耳有機溶劑。在一些實施例中,混合溶劑合物包括約1.7至約2.3、約1.8至約2.2、約1.9至約2.1或約1.95至約2.05莫耳與結晶中之每莫耳奧德維希百相關聯之水(不包括可吸收至結晶表面之任何水)。
有趣的是,自此等不同混合物獲得之結晶修飾物之XRPD圖基本上相同(參見圖6-12)。因此,咸信結晶修飾物2可以不同的同構
溶劑合物(亦稱為同形
溶劑合物)存在。在此等同構溶劑合物中,結晶修飾物2適應不同溶劑(作為與水之混合物)。不同溶劑之存在造成單元晶胞體積的小變化,但不會另外導致結晶修飾物2之結晶結構之任何顯著變形。然而,針對同構溶劑合物之XRPD圖可略有不同。結晶修飾物2之三種相似但略微不同之形式在本文中稱為結晶修飾物2A、2B及2C,且統稱為「結晶修飾物2」。明顯地,已發現不管結晶修飾物2自哪種溶劑混合物結晶,結晶修飾物2A、2B及2C可在乾燥後形成結晶修飾物1。
在第一實施例中,結晶混合溶劑合物為如自乙醇及水、丙酮及水、1,4-二噁烷及水、DMF及水或2-丙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之X射線粉末繞射(XRPD)圖,其至少在°2θ位置5.0±0.2、5.1±0.2及/或11.8±0.2處具有特定峰值。
在其特定實施例中,本發明係關於如自乙醇及水、丙酮及水、1,4-二噁烷及水、DMF及水或2-丙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,其具有°2θ位置5.0±0.2、5.1±0.2及11.8±0.2處之特定峰值以及以下特徵峰值中之一或多者:6.4±0.2、6.6±0.2及9.5±0.2。
在其更特定實施例中,本發明係關於如自乙醇及水、丙酮及水、1,4-二噁烷及水、DMF及水或2-丙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置5.0±0.2、5.1±0.2、6.4±0.2、6.6±0.2、9.5±0.2及11.8±0.2處具有特定峰值。
在其又一更特定實施例中,本發明係關於如自乙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置5.0±0.2、5.1±0.2、6.4±0.2、6.6±0.2、9.5±0.2及11.8±0.2,以及5.9±0.2、8.8±0.2、9.8±0.2、10.1±0.2、11.0±0.2、11.2±0.2、11.4±0.2、12.7±0.2、13.9±0.2、14.7±0.2、15.1±0.2、15.8±0.2、16.3±0.2、17.2±0.2、17.9±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.3±0.2、22.1±0.2、22.5±0.2、22.9±0.2、23.2±0.2、23.6±0.2、24.0±0.2、24.1±0.2、24.7±0.2、25.3±0.2、26.7±0.2、26.9±0.2、29.8±0.2、30.4±0.2、30.8±0.2及31.6±0.2中之一或多者處具有特徵峰值。
在其又一更特定實施例中,本發明係關於如自乙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置5.0±0.2、5.1±0.2、5.9±0.2、6.4±0.2、6.6±0.2、8.8±0.2、9.5±0.2、9.8±0.2、10.1±0.2、11.0±0.2、11.2±0.2、11.4±0.2、11.8±0.2、12.7±0.2、13.9±0.2、14.7±0.2、15.1±0.2、15.8±0.2、16.3±0.2、17.2±0.2、17.9±0.2、19.7±0.2、20.2±0.2、20.7±0.2、21.3±0.2、22.1±0.2、22.5±0.2、22.9±0.2、23.2±0.2、23.6±0.2、24.0±0.2、24.1±0.2、24.7±0.2、25.3±0.2、26.7±0.2、26.9±0.2、29.8±0.2、30.4±0.2、30.8±0.2及31.6±0.2處具有特徵峰值。
在一個特定實施例中,本發明係關於如自乙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖6所示。
在另一特定實施例中,本發明係關於如自丙酮及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖7所示。
在又一特定實施例中,本發明係關於如自2-丙醇及水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖8所示。
在又一特定實施例中,本發明係關於如自1,4-二噁烷與水之混合物獲得之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖9所示。
在第二實施例中,結晶混合溶劑合物為如自甲醇或自甲醇及水或乙腈及水之混合物獲得之結晶修飾物2B,其具有用CuKα1-輻射獲得之X射線粉末繞射(XRPD)圖,其至少在°2θ位置4.8±0.2、5.1±0.2及/或11.6±0.2處具有特定峰值。
在一特定實施例中,本發明係關於如自甲醇或自甲醇及水或乙腈及水之混合物獲得的結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,其具有°2θ位置4.8±0.2、5.1±0.2及11.6±0.2處之特定峰值以及以下特徵峰值中之一或多者:6.2±0.2、6.7±0.2、9.5±0.2及20.3±0.2。
在其更特定實施例中,本發明係關於如自甲醇或自甲醇及水或乙腈及水之混合物獲得的結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置4.8±0.2、5.1±0.2、6.2±0.2、6.7±0.2、9.5±0.2、11.6±0.2及20.3±0.2處具有特定峰值。
在其又一更特定實施例中,本發明係關於自甲醇及水獲得之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置4.8±0.2、5.1±0.2、6.2±0.2、6.7±0.2、9.5±0.2、11.6±0.2及20.3±0.2以及5.8±0.2、8.7±0.2、9.7±0.2、10.1±0.2、10.7±0.2、11.5±0.2、13.4±0.2、13.5±0.2、14.4±0.2、14.5±0.2、15.2±0.2、16.5±0.2、16.8±0.2、19.4±0.2、20.6±0.2、21.2±0.2、21.5±0.2、23.8±0.2、23.9±0.2、25.4±0.2、26.3±0.2、26.7±0.2、30.1±0.2及30.6±0.2中之一或多者處具有特徵峰值。
在其又一甚至更特定實施例中,本發明係關於自甲醇及水獲得之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置4.8±0.2、5.1±0.2、5.8±0.2、6.2±0.2、6.7±0.2、8.7±0.2、9.5±0.2、9.7±0.2、10.1±0.2、10.7±0.2、11.5±0.2、11.6±0.2、13.4±0.2、13.5±0.2、14.4±0.2、14.5±0.2、15.2±0.2、16.5±0.2、16.8±0.2、19.4±0.2、20.3±0.2、20.6±0.2、21.2±0.2、21.5±0.2、23.8±0.2、23.9±0.2、25.4±0.2、26.3±0.2、26.7±0.2、30.1±0.2及30.6±0.2處具有特徵峰值。
在一個特定實施例中,本發明係關於如自甲醇獲得之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖10所示。
在另一特定實施例中,本發明係關於如自乙腈及水之混合物獲得之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖11所示。
在第三實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之X射線粉末繞射(XRPD)圖,其至少在°2θ位置5.0±0.2、6.2±0.2、9.4±0.2及/或23.9±0.2處具有特定峰值。
在其特定實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖,其具有°2θ位置5.0±0.2、6.2±0.2、9.4±0.2及23.9±0.2處之特定峰值以及以下特徵峰值中之一或多者:11.5±0.2、19.5±0.2及20.2±0.2。
在其更特定實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置5.0±0.2、6.2±0.2、9.4±0.2、11.5±0.2、19.5±0.2、20.2±0.2及23.9±0.2處具有特定峰值。
在其又一更特定實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置5.0±0.2、6.2±0.2、9.4±0.2、11.5±0.2、19.5±0.2、20.2±0.2及23.9±0.2以及4.9±0.2、5.8±0.2、6.6±0.2、8.6±0.2、9.7±0.2、10.0±0.2、10.8±0.2、13.5±0.2、15.1±0.2、17.7±0.2、17.9±0.2、19.0±0.2、19.3±0.2、20.7±0.2、21.1±0.2、21.2±0.2、21.2±0.2、22.8±0.2、25.3±0.2、26.6±0.2、27.3±0.2、27.4±0.2、28.6±0.2、30.1±0.2及30.2±0.2中之一或多者處具有特徵峰值。
在其又一甚至更特定實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖,其在°2θ位置4.9±0.2、5.0±0.2、5.8±0.2、6.2±0.2、6.6±0.2、8.6±0.2、9.4±0.2、9.7±0.2、10.0±0.2、10.8±0.2、11.5±0.2、13.5±0.2、15.1±0.2、17.7±0.2、17.9±0.2、19.0±0.2、19.3±0.2、19.5±0.2、20.2±0.2、20.7±0.2、21.1±0.2、21.2±0.2、21.3±0.2、22.8±0.2、23.9±0.2、25.3±0.2、26.6±0.2、27.3±0.2、27.4±0.2、28.6±0.2、30.1±0.2及30.2±0.2處具有特徵峰值。
在一個特定實施例中,本發明係關於如自DMSO及水之混合物獲得之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖,基本上如圖12所示。
如自上文將理解,穩定結晶修飾物1之分離及表徵並非直接的。儘管其為水合物,但不能藉由直接自水結晶獲得結晶修飾物1。在一些實施例中,例如藉由分離及乾燥結晶修飾物2間接獲得結晶修飾物1,結晶修飾物2藉由奧德維希百自水與特定有機溶劑之混合物結晶形成。在一些實施例中,在蒸發溶劑分子之後自結晶修飾物2獲得結晶修飾物1。在一些實施例中,結晶修飾物2經結晶中間體,亦即修飾物12轉化成結晶修飾物1 (參見圖5)。在一些實施例中,在未使結晶溶解及再結晶的情況下自修飾物2移除溶劑分子。
在另一態樣中,本發明係關於一種如本文中所描述之奧德維希百之結晶修飾物2 (2A、2B或2C)在用於製備奧德維希百之結晶修飾物1之方法中的用途。
在又一態樣中,本發明係關於一種製備奧德維希百之結晶修飾物1的方法。在一些實施例中,此方法涉及自奧德維希百於溶劑混合物中之溶液分離奧德維希百之結晶修飾物2,該溶劑混合物包含水及選自由以下組成之群的有機溶劑:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO,以及其混合物。在一些實施例中,該方法涉及自奧德維希百於溶劑混合物中之溶液分離奧德維希百之結晶修飾物2,該溶劑混合物包含水及選自由以下組成之群的有機溶劑:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO。
在一些實施例中,結晶修飾物1之結晶度視乾燥過程而定。如實驗章節中所示,已觀測到當在真空下(例如低於5 mbar)或在氮氣流下乾燥結晶修飾物2時,可獲得具有優良結晶度之結晶修飾物1。咸信在此等條件下乾燥結晶修飾物2產生脫水形式,其隨後自空氣快速吸收水。
因此,在一些實施例中,製備奧德維希百之結晶修飾物1的方法包含以下步驟:
a) 自奧德維希百於溶劑混合物中之溶液分離奧德維希百之結晶修飾物2,該溶劑混合物包含水及選自由以下組成之群之有機溶劑:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO;及
b) 在真空下或在氮氣流下乾燥該固體。
在一較佳實施例中,奧德維希百之結晶修飾物2為奧德維希百之結晶修飾物2A。在一更佳實施例中,奧德維希百之結晶修飾物2A係自水及乙醇之混合物獲得。
在一些實施例中,用於製備奧德維希百之結晶修飾物1的方法包含以下步驟:
a) 自奧德維希百於水及乙醇之混合物中之溶液分離奧德維希百之結晶修飾物2A;及
b) 在真空下或在氮氣流下乾燥該固體。
在一些實施例中,結晶修飾物1之結晶度視水及有機溶劑之混合物之組成而定。舉例而言,具有優良結晶度之結晶修飾物1可自結晶修飾物2A之樣品獲得,該等樣品在22℃下自奧德維希百於乙醇及水之60:40 (% v/v)混合物中之漿液獲得。在一較佳實施例中,溶劑混合物中之乙醇含量為約55至約75% (v/v),諸如約60至約70% (v/v)。在一些實施例中,溶劑混合物中之乙醇含量為約60% (v/v)。在一些實施例中,溶劑混合物中之乙醇含量為約65% (v/v)。在一些實施例中,溶劑混合物中之乙醇含量為約70% (v/v)。
在一些實施例中,當經分離結晶暴露於含有40至60% (v/v)乙醇之乙醇/水氛圍至少24小時之時間段時,結晶修飾物2A之結晶度提高。
在一些實施例中,該方法包含以下步驟:
a) 製備奧德維希百於水及有機溶劑之混合物中之飽和溶液,該有機溶劑選自由以下組成之群:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO;
b) 向步驟a)之飽和溶液中添加過量的奧德維希百,以便獲得漿液;
c) 將該漿液在約0至約25℃之溫度下保持攪拌至少24小時之時間段;
d) 回收在步驟c)中獲得之固體;
e) 在真空下或在氮氣流下乾燥該固體。
在一些實施例中,該方法包含以下步驟:
a) 製備奧德維希百於水及乙醇之混合物中之飽和溶液;
b) 向步驟a)之飽和溶液中添加過量的奧德維希百,以便獲得漿液;
c) 將該漿液在約20至約25℃、較佳約22℃之溫度下保持攪拌至少24小時之時間段;
d) 回收在步驟c)中獲得之固體;
e) 視情況將步驟d)之結晶暴露於乙醇/水氛圍;及
f) 在真空下或在氮氣流下乾燥該固體。
或者,可藉由將晶種添加至奧德維希百於水及適合有機溶劑之混合物中之飽和溶液中來獲得結晶修飾物1。因此,在另一實施例中,該方法包含以下步驟:
a) 製備奧德維希百於水及有機溶劑之混合物中之飽和溶液,該有機溶劑選自由以下組成之群:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO;
b) 將晶種添加至步驟a)之飽和溶液;
c) 將該漿液在約0至約25℃之溫度下保持攪拌至少24小時之時間段;
d) 回收在步驟c)中獲得之固體;
e) 在真空下或在氮氣流下乾燥該固體。
在一些實施例中,該方法包含以下步驟:
a) 製備奧德維希百於水及乙醇之混合物中之飽和溶液;
b) 將晶種添加至步驟a)之飽和溶液;
c) 將該漿液在約20至約25℃、較佳22℃之溫度下保持攪拌至少24小時之時間段;
d) 回收在步驟c)中獲得之固體;
e) 視情況將步驟d)之結晶暴露於乙醇/水大氣;及
f) 在真空下或在氮氣流下乾燥該固體。
結晶修飾物2之漿液樣品可用作晶種。或者,可使用結晶修飾物1。 咸信當此形式添加至結晶過程之溶劑混合物中時,快速轉化為結晶修飾物2。
在另一態樣中,本發明亦關於一種用於療法之如本文所描述之奧德維希百之結晶修飾物1。
奧德維希百為迴腸膽汁酸轉運體(IBAT)抑制劑。迴腸膽汁酸轉運體(IBAT)為用於自胃腸道再吸收膽汁酸之主要機制。該奧德維希百機制之部分或完全阻斷將導致小腸壁、門靜脈、肝實質、肝內膽管樹及肝外膽管樹,包括膽囊中之膽汁酸濃度較低。可受益於IBAT機制部分或完全阻斷之疾病可為血清及上述器官中膽汁酸過量濃度之症狀作為主要病理生理學缺陷之彼等疾病。如本文所述之奧德維希百之結晶修飾物1因此適用於治療或預防需要抑制膽汁酸循環之病狀、病症及疾病,諸如心血管疾病、脂肪酸代謝障礙及葡萄糖利用障礙、胃腸疾病及病症、肝臟疾病及病症。
脂肪酸代謝及葡萄糖利用之心血管疾病及病症包括(但不限於),高膽固醇血症;脂肪酸代謝障礙;1型及2型糖尿病;糖尿病併發症,包括白內障、微血管及大血管疾病、視網膜病變、神經病變、腎病變及傷口癒合延遲、組織局部缺血、糖尿病足、動脈硬化、心肌梗塞、急性冠狀動脈症候群、不穩定型心絞痛、穩定型心絞痛、中風、周邊動脈阻塞性疾病、心肌病變、心臟衰竭、心律異常及血管再狹窄;糖尿病相關疾病,諸如胰島素抗性(葡萄糖穩態受損)、高血糖症、高胰島素血症、脂肪酸或甘油血液含量升高、肥胖、血脂異常、包括高三酸甘油酯血症之高脂質血症、代謝症候群(症候群X)、動脈粥樣硬化及高血壓;及用於提高高密度脂蛋白含量。
胃腸疾病及病症包括便秘(包括慢性便秘、功能性便秘、慢性特發性便秘(CIC)、間歇性/偶發性便秘、繼發於糖尿病之便秘、繼發於中風之便秘、繼發於慢性腎病之便秘、繼發於多發性硬化症之便秘、繼發於帕金森氏病(Parkinson's disease)之便秘、繼發於全身性硬化症之便秘、藥物誘發之便秘、伴隨便秘之大腸急躁症(IBS-C)、混合型大腸急躁症(IBS-M)、小兒功能性便秘及類鴉片誘發之便秘);克羅恩氏病(Crohn's disease);原發性膽汁酸吸收障礙;大腸急躁症(IBS);發炎性腸病(IBD);迴腸發炎;及逆流病及其併發症,諸如巴雷特食道炎(Barrett's esophagus)、膽汁逆流性食道炎及膽汁逆流性胃炎。便秘之治療及預防亦已揭示於WO 2004/089350中,其以全文引用的方式併入本文中。
如本文所定義之肝病為肝臟中及與其連接之器官中之任何疾病,諸如胰臟、門靜脈、肝實質、肝內膽管樹、肝外膽管樹及膽囊。在一些實施例中,肝病為膽汁酸依賴性肝病。在一些實施例中,肝病涉及血清中及/或肝臟中之膽汁酸含量升高。在一些實施例中,肝病為膽汁鬱積性肝病。肝臟疾病及病症包括(但不限於)肝臟之遺傳性代謝障礙;膽汁酸合成之先天性缺陷;先天性膽管異常;膽管閉鎖;葛西手術後膽管閉鎖(post-Kasai biliary atresia);肝移植後膽管閉鎖;新生兒肝炎;新生兒膽汁鬱積;遺傳形式之膽汁鬱積;腦腱性黃瘤病;BA合成之繼發性缺陷;齊威格氏症候群(Zellweger´s syndrome);囊性纖維化相關之肝病;α1-抗胰蛋白酶缺乏症;阿拉吉歐症候群(Alagilles syndrome,ALGS);拜勒症候群(Byler syndrome);膽汁酸(BA)合成之原發性缺陷;漸進性家族性肝內膽汁鬱積(PFIC),包括PFIC-1、PFIC-2、PFIC-3及非特定PFIC、膽汁分流後PFIC及肝移植後PFIC;良性復發性肝內膽汁鬱積(BRIC),包括BRIC1、BRIC2及非特定BRIC、膽汁分流後BRIC及肝移植後BRIC;自體免疫性肝炎;原發性膽汁性肝硬化(PBC);肝纖維化;非酒精性脂肪性肝病(NAFLD);非酒精性脂肪變性肝炎(NASH);門靜脈高血壓;膽汁鬱積;唐氏症候群膽汁鬱積(Down syndrome cholestasis);藥物誘發之膽汁鬱積;妊娠肝內膽汁鬱積(懷孕期間之黃疸);肝內膽汁鬱積;肝外膽汁鬱積;非經腸營養相關之膽汁鬱積(PNAC);低磷脂相關之膽汁鬱積;淋巴水腫膽汁鬱積症候群1 (LSC1);原發性硬化性膽管炎(PSC);免疫球蛋白G4相關之膽管炎;原發性膽汁性膽管炎;膽石症(膽結石);膽管結石;輸膽管結石;膽石性胰臟炎;卡羅利病(Caroli disease);膽管惡性腫瘤;引起膽管樹阻塞之惡性腫瘤;膽管狹窄;AIDS膽管病變;缺血性膽管病變;由膽汁鬱積或黃疸引起之搔癢病;胰臟炎;引起漸進性膽汁鬱積之慢性自體免疫肝病;肝脂肪變性;酒精性肝炎;急性脂肪肝;妊娠之脂肪肝;藥物誘發之肝炎;鐵超負荷病症;先天性膽汁酸合成缺陷1型(BAS 1型);藥物誘發之肝臟損傷(DILI);肝纖維化;先天性肝纖維化;肝硬化;蘭格漢氏細胞組織細胞增多症(LCH);新生兒魚鱗癬硬化性膽管炎(NISCH);促紅血球形成性原紫質症(EPP);特發性成人期膽管缺失(IAD);特發性新生兒肝炎(INH);非綜合症性小葉間膽管缺乏(NS PILBD);北美印第安兒童肝硬化(NAIC);肝類肉瘤病;澱粉樣變性; 壞死性小腸結腸炎;血清膽汁酸引起之毒性,包括在異常血清膽汁酸概況中的心律不整障礙(例如心房纖維顫動)、與肝硬化相關之心肌病變(「膽心(cholecardia)」),及與膽汁鬱積性肝病相關之骨骼肌萎縮;病毒性肝炎(包括A型肝炎、B型肝炎、C型肝炎、D型肝炎及E型肝炎);肝細胞癌(肝癌);膽管癌;膽汁酸相關之胃腸癌;及由肝、膽管及胰臟之腫瘤及贅瘤引起之膽汁鬱積。肝病之治療及預防亦揭示於WO 2012/064266中,其以全文引用之方式併入本文中。
可由奧德維希百之結晶修飾物1治療或預防之其他疾病包括吸收過多症候群(包括無β脂蛋白血症、家族性低β脂蛋白血症(FHBL)、乳糜微粒滯留疾病(CRD)及豆固醇血症);維生素過多症及骨質石化病;高血壓;腎小球超微過濾;及腎衰竭相關性搔癢病。
膽管閉鎖為罕見兒科肝病,其涉及大膽管部分或完全阻塞(或甚至不存在)。此阻塞或不存在造成膽汁鬱積,其導致損害肝臟之膽汁酸積累。在一些實施例中,膽汁酸積聚在肝外膽管樹中發生。 在一些實施例中,膽汁酸積聚發生在肝內膽管樹中。當前照護標準為葛西程序,其為移除阻塞之膽管且將小腸之一部分直接連接至肝臟的手術。當前不存在審批通過的用於此病症之藥物療法。
本文提供用於治療有需要個體之膽管閉鎖的方法,該等方法包含投與治療有效量之奧德維希百之結晶修飾物I。在一些實施例中,個體在投與奧德維希百之結晶修飾物I之前已經歷葛西程序。在一些實施例中,在進行葛西程序之前向個體投與奧德維希百之結晶修飾物I。在一些實施例中,膽管閉鎖之治療降低個體內之血清膽汁酸含量。在一些實施例中,血清膽汁酸之含量藉由例如ELISA酶分析或如在Danese等人., PLoS One. 2017, 第12(6)卷: e0179200中所述之用於量測總膽汁酸之分析測定,其以全文引用之方式併入本文中。 在一些實施例中,血清膽汁酸之含量可在投與奧德維希百之結晶修飾物之前降低例如10%至40%、20%至50%、30%至60%、40%至70%、50%至80%或超過90%之血清膽汁酸含量。 在一些實施例中,對膽管閉鎖之治療包括搔癢病之治療。
PFIC為一種罕見的遺傳性病症,據估計,全世界每50,000至100,000名出生的兒童中就有一名患病,且引起漸進性的危及生命之肝病。
PFIC之一種表現為搔癢病,其常常導致生活品質嚴重降低。 在一些情況下,PFIC導致肝硬化及肝臟衰竭。當前療法包括部分膽汁外分流術(Partial External Biliary Diversion,PEBD)及肝臟移植,然而,此等選擇可帶來手術後併發症之實質風險,以及心理及社會問題。
已鑑別出三種替代性基因缺陷,其與三種各別PFIC亞型稱為1、2及3型相關。
• PFIC 1型,其有時稱為「拜勒疾病(Byler disease)」,由於ATP8B1基因中之突變所致之膽汁分泌受損引起,該基因編碼有助於維持膽管中之細胞膜中稱為磷脂之脂肪適當平衡的蛋白質。此等磷脂中之不平衡與肝臟中之膽汁鬱積及升高之膽汁酸相關。患有PFIC 1型之個體通常在生命的第一個月內發生膽汁鬱積,且在無手術治療的情況下,在生命的第一個十年結束之前進行至肝硬化及末期肝病。
• PFIC 2型,其有時稱為「拜勒症候群(Byler syndrome)」,由於ABCB11基因中之突變所致之膽汁鹽分泌受損引起,該基因編碼將膽汁酸移出肝臟之蛋白質,稱為膽汁鹽輸出泵。患有PFIC 2型之個體通常在生命的前幾年內發生肝臟衰竭且有增加發生一種類型稱為肝細胞癌之肝癌之風險。
• PFIC 3型,其通常在具有漸進性膽汁鬱積之兒童期的前幾年中出現,由ABCB4基因中之突變引起,該基因編碼使磷脂穿過細胞膜之轉運體。
另外,已提出TJP2基因、NR1H4基因或Myo5b基因突變為PFIC之原因。 另外,一些患有PFIC之個體在ATP8B1、ABCB11、ABCB4、TJP2、NR1H4或Myo5b基因之任一者中不具有突變。在此等情況下,病狀之起因未知。
ATP8B1基因或所產生蛋白質之例示性突變列於表1及2中,其中編號係基於人類野生型ATP8B1蛋白質(例如SEQ ID NO:1)或基因(例如SEQ ID NO:2)。ABCB11基因或所產生蛋白質之例示性突變列於表3及4中,其中編號基於人類野生型ABCB11蛋白質(例如SEQ ID NO:3)或基因(例如SEQ ID NO:4)。
如熟習此項技術者可瞭解,對應於SEQ ID NO:1或3中之特定胺基酸位置之參考蛋白質序列中的胺基酸位置可藉由將參考蛋白質序列與SEQ ID NO:1或3比對(例如使用軟體程式,諸如ClustalW2)來確定。此等殘基之變化(在本文中稱為「突變」)可包括單個或多個胺基酸取代、序列內插入或側接序列處之插入,以及序列內缺失或側接序列處之缺失。如熟習此項技術者可瞭解,對應於SEQ ID NO:2或4中之特定核苷酸位置的參考基因序列中之核苷酸位置可藉由將參考基因序列與SEQ ID NO:2或4比對(例如使用軟體程式,諸如ClustalW2)來確定。此等殘基之變化(在本文中稱為「突變」)可包括單個或多個核苷酸取代、序列內或側接序列處之插入,以及序列內或側接序列處之缺失。亦參見Kooistra,等人.,「KLIFS: A structural kinase-ligand interaction database,」 Nucleic Acids Res. 2016, 第44卷, 第D1期, 第D365-D371頁,其以全文引用的方式併入本文中。表 1. 例示性 ATP8B1 突變 表 2. 與 PFIC-1 相關之所選 ATP8B1 突變 A
「X」之突變表示早期終止密碼子表 1 及 2 之參考文獻 1
Folmer et al., Hepatology. 2009, vol. 50(5), p. 1597-1605.2
Hsu et al., Hepatol Res. 2009, vol. 39(6), p. 625-631.3
Alvarez et al., Hum Mol Genet. 2004, vol. 13(20), p. 2451-2460.4
Davit-Spraul et al., Hepatology 2010, vol. 51(5), p. 1645-1655.5
Vitale et al., J Gastroenterol. 2018, vol. 53(8), p. 945-958.6
Klomp et al., Hepatology 2004, vol. 40(1), p. 27-38.7
Zarenezhad et al., Hepatitis Monthly: 2017, vol. 17(2); e43500.8
Dixon et al., Scientific Reports 2017, vol. 7, 11823.9
Painter et al., Eur J Hum Genet. 2005, vol. 13(4), p. 435-439.10
Deng et al., World J Gastroenterol. 2012, vol. 18(44), p. 6504-6509.11
Giovannoni et al., PLoS One. 2015, vol. 10(12): e0145021.12
Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S180. Abstract Number: OP284.13
Togawa et al., Journal of Pediatric Gastroenterology and Nutrition 2018, vol. 67, Supp. Supplement 1, pp. S363. Abstract Number: 615.14
Miloh et al., Gastroenterology 2006, vol. 130, No. 4, Suppl. 2, pp. A759-A760. Meeting Info.: Digestive Disease Week Meeting/107th Annual Meeting of the American-Gastroenterological-Association. Los Angeles, CA, USA. May 19.15
Dröge et al., Zeitschrift fur Gastroenterologie 2015, vol. 53, No. 12. Abstract Number: A3-27. Meeting Info: 32. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Dusseldorf, Germany. 22 Jan 2016-23 Jan 201616
Mizuochi et al., Clin Chim Acta. 2012, vol. 413(15-16), p. 1301-1304.17
Liu et al., Hepatology International 2009, vol. 3, No. 1, p. 184-185. Abstract Number: PE405. Meeting Info: 19th Conference of the Asian Pacific Association for the Study of the Liver. Hong Kong, China. 13 Feb 2009-16 Feb 200918
McKay et al., Version 2. F1000Res. 2013; 2: 32. DOI: 10.12688/f1000research.2-32.v219
Hasegawa et al., Orphanet J Rare Dis. 2014, vol. 9:89.20
Stone et al., J Biol Chem. 2012, vol. 287(49), p. 41139-51.21
Kang et al., J Pathol Transl Med. 2019 May 16. doi: 10.4132/jptm.2019.05.03. [Epub ahead of print]22
Sharma et al., BMC Gastroenterol. 2018, vol. 18(1), p. 107.23
Uegaki et al., Intern Med. 2008, vol. 47(7), p. 599-602.24
Goldschmidt et al., Hepatol Res. 2016, vol. 46(4), p. 306-311.25
Liu et al., J Pediatr Gastroenterol Nutr. 2010, vol. 50(2), p. 179-183.26
Jung et al., J Pediatr Gastroenterol Nutr. 2007, vol. 44(4), p. 453-458.27
Bounford. University of Birmingham. Dissertation Abstracts International, (2016) Vol. 75, No. 1C. Order No.: AAI10588329. ProQuest Dissertations & Theses.28
Stolz et al., Aliment Pharmacol Ther. 2019, vol. 49(9), p. 1195-1204.29
Ivashkin et al., Hepatology International 2016, vol. 10, No. 1, Supp. SUPPL. 1, pp. S461. Abstract Number: LBO-38. Meeting Info: 25th Annual Conference of the Asian Pacific Association for the Study of the Liver, APASL 2016. Tokyo, Japan. 20 Feb 2016-24 Feb 201630
Blackmore et al., J Clin Exp Hepatol. 2013, vol. 3(2), p. 159-161.31
Matte et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 488-493.32
Squires et al., J Pediatr Gastroenterol Nutr. 2017, vol. 64(3), p. 425-430.33
Hayshi et al., EBioMedicine. 2018, vol. 27, p. 187-199.34
Nagasaka et al., J Pediatr Gastroenterol Nutr. 2007, vol. 45(1), p. 96-105.35
Wang et al., PLoS One. 2016; vol. 11(4): e0153114.36
Narchi et al., Saudi J Gastroenterol. 2017, vol. 23(5), p. 303-305.37
Alashkar et al., Blood 2015, vol. 126, No. 23. Meeting Info.: 57th Annual Meeting of the American-Society-of-Hematology. Orlando, FL, USA. December 05 -08, 2015. Amer Soc Hematol.38
Ferreira et al., Pediatric Transplantation 2013, vol. 17, Supp. SUPPL. 1, pp. 99. Abstract Number: 239. Meeting Info: IPTA 7th Congress on Pediatric Transplantation. Warsaw, Poland. 13 Jul 2013-16 Jul 2013.39
Pauli-Magnus et al., J Hepatol. 2005, vol. 43(2), p. 342-357.40
Jericho et al., Journal of Pediatric Gastroenterology and Nutrition 2015, vol. 60(3), p. 368-374.41
van der Woerd et al., PLoS One. 2013, vol. 8(11): e80553.42
Copeland et al., J Gastroenterol Hepatol. 2013, vol. 28(3), p. 560-564.43
Dröge et al., J Hepatol. 2017, vol. 67(6), p. 1253-1264.44
Chen et al., Journal of Pediatrics 2002, vol. 140(1), p. 119-124.45
Jirsa et al., Hepatol Res. 2004, vol. 30(1), p. 1-3.46
van der Woerd et al., Hepatology 2015, vol. 61(4), p. 1382-1391.
在一些實施例中,ATP8B1中之突變係選自L127P、G308V、T456M、D554N、F529del、I661T、E665X、R930X、R952X、R1014X及G1040R。表 3. 例示性 ABCB11 突變 表 4. 與 PFIC-2 相關之所選 ABCB11 突變 A
「X」之突變表示早期終止密碼子表 3 及 4 之參考文獻 1
Noe et al., J Hepatol. 2005, vol. 43(3), p. 536-543.2
Lam et al., Am J Physiol Cell Physiol. 2007, vol. 293(5), p. C1709-16.3
Stindt et al., Liver Int. 2013, vol. 33(10), p. 1527-1735.4
Gao et al., Shandong Yiyao 2012, vol. 52(10), p. 14-16.5
Strautnieks et al., Gastroenterology. 2008, vol. 134(4), p. 1203-1214.6
Kagawa et al., Am J Physiol Gastrointest Liver Physiol. 2008, vol. 294(1), p. G58-67.7
Byrne et al., Hepatology. 2009, vol. 49(2), p. 553-567.8
Chen et al., J Pediatr. 2008, vol. 153(6), p. 825-832.9
Davit-Spraul et al., Hepatology 2010, vol. 51(5), p. 1645-1655.10
Dröge et al., Sci Rep. 2016, vol. 6: 24827.11
Lang et al., Pharmacogenet Genomics. 2007, vol. 17(1), p. 47-60.12
Ellinger et al., World J Gastroenterol. 2017, vol. 23(29), p. :5295-5303.13
Vitale et al., J Gastroenterol. 2018, vol. 53(8), p. 945-958.14
Knisely et al., Hepatology. 2006, vol. 44(2), p. 478-86.15
Ellis et al., Hepatology. 2018, vol. 67(4), p. 1531-1545.16
Lam et al., J Hepatol. 2006, vol. 44(1), p. 240-242.17
Varma et al., Hepatology 2015, vol. 62(1), p. 198-206.18
Treepongkaruna et al., World J Gastroenterol. 2009, vol. 15(34), p. 4339-4342.19
Zarenezhad et al., Hepatitis Monthly: 2017, vol. 17(2); e43500.20
Hayashi et al., Hepatol Res. 2016, vol. 46(2), p. 192-200.21
Guorui et al., Linchuang Erke Zazhi 2013, vol. 31(10), 905-909.22
van Mil et al., Gastroenterology. 2004, vol. 127(2), p. 379-384.23
Anzivino et al., Dig Liver Dis. 2013, vol. 45(3), p. 226-232.24
Park et al., World J Gastroenterol. 2016, vol. 22(20), p. 4901-4907.25
Imagawa et al., J Hum Genet. 2018, vol. 63(5), p. 569-577.26
Giovannoni et al., PLoS One. 2015, vol. 10(12): e0145021.27
Hu et al., Mol Med Rep. 2014, vol. 10(3), p. 1264-1274.28
Lang et al,. Drug Metab Dispos. 2006, vol. 34(9), p. 1582-1599.29
Masahata et al., Transplant Proc. 2016, vol. 48(9), p. 3156-3162.30
Holz et al., Hepatol Commun. 2018, vol. 2(2), p. 152-154.31
Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S180. Abstract Number: OP284.32
Francalanci et al., Laboratory Investigation 2011, vol. 91, Supp. SUPPL. 1, pp. 360A. Abstract Number: 1526.33
Francalanci et al., Digestive and Liver Disease 2010, vol. 42, Supp. SUPPL. 1, pp. S16. Abstract Number: T.N.5.34
Shah et al., J Pediatr Genet. 2017, vol. 6(2), p. 126-127.35
Gao et al., Hepatitis Monthly 2017, vol. 17(10), e55087/1-e55087/6.36
Evason et al., Am J Surg Pathol. 2011, vol. 35(5), p. 687-696.37
Davit-Spraul et al., Mol Genet Metab. 2014, vol. 113(3), p. 225-229.38
Maggiore et al., J Hepatol. 2010, vol. 53(5), p. 981-6.39
McKay et al., Version 2. F1000Res. 2013; 2: 32. DOI: 10.12688/f1000research.2-32.v240
Liu et al., Pediatr Int. 2013, vol. 55(2), p. 138-144.41
Waisbourd-Zinman et al., Ann Hepatol. 2017, vol. 16(3), p. 465-468.42
Griffin, et al., Canadian Journal of Gastroenterology and Hepatology 2016, vol. 2016. Abstract Number: A200. Meeting Info: 2016 Canadian Digestive Diseases Week, CDDW 2016. Montreal, QC, United States. 26 Feb 2016-29 Feb 201643
Qiu et al., Hepatology 2017, vol. 65(5), p. 1655-1669.44
Imagawa et al., Sci Rep. 2017, 7:41806.45
Kang et al., J Pathol Transl Med. 2019 May 16. doi: 10.4132/jptm.2019.05.03. [Epub ahead of print]46
Takahashi et al., Eur J Gastroenterol Hepatol. 2007, vol. 19(11), p. 942-6.47
Shimizu et al., Am J Transplant. 2011, vol. 11(2), p. 394-398.48
Krawczyk et al., Ann Hepatol. 2012, vol. 11(5), p. 710-744.49
Sharma et al., BMC Gastroenterol. 2018, vol. 18(1), p. 107.50
Sattler et al., Journal of Hepatology 2017, vol. 66, No. 1, Suppl. S, pp. S177. Meeting Info.: International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver. Amsterdam, NETHERLANDS. April 19 -23, 2017. European Assoc Study Liver.51
Jung et al., J Pediatr Gastroenterol Nutr. 2007, vol. 44(4), p. 453-458.52
Sciveres. Digestive and Liver Disease 2010, vol. 42, Supp. SUPPL. 5, pp. S329. Abstract Number: CO18. Meeting Info: 17th National Congress SIGENP. Pescara, Italy. 07 Oct 2010-09 Oct 201053
Sohn et al., Pediatr Gastroenterol Hepatol Nutr. 2019, vol. 22(2), p. 201-206.54
Ho et al., Pharmacogenet Genomics. 2010, vol. 20(1), p. 45-57.55
Wang et al., Hepatol Res. 2018, vol. 48(7), p. 574-584.56
Shaprio et al., J Hum Genet. 2010, vol. 55(5), p. 308-313.57
Bounford. University of Birmingham. Dissertation Abstracts International, (2016) Vol. 75, No. 1C. Order No.: AAI10588329. ProQuest Dissertations & Theses.58
Stolz et al., Aliment Pharmacol Ther. 2019, vol. 49(9), p. 1195-1204.59
Jankowska et al., J Pediatr Gastroenterol Nutr. 2014, vol. 58(1), p. 92-95.60
Kim. Journal of Pediatric Gastroenterology and Nutrition 2016, vol. 62, Supp. SUPPL. 1, pp. 620. Abstract Number: H-P-045. Meeting Info: 49th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESPGHAN 2016. Athens, Greece. 25 May 2016-28 May 2016.61
Pauli-Magnus et al., Hepatology 2003, vol. 38, No. 4 Suppl. 1, pp. 518A. print. Meeting Info.: 54th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA. October 24-28, 2003. American Association for the Study of Liver Diseases.62
Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S362. Abstract Number: PP0347. Meeting Info: 26th Annual Conference of the Asian Pacific Association for the Study of the Liver, APASL 2017. Shanghai, China. 15 Feb 2017-19 Feb 2017.63
Rumbo et al., Transplantation 2018, vol. 102, No. 7, Supp. Supplement 1, pp. S848. Abstract Number: P.752. Meeting Info: 27th International Congress of The Transplantation Society, TTS 2018. Madrid, Spain. 30 Jun 2018-05 Jul 2018.64
Lee et al., Pediatr Gastroenterol Hepatol Nutr. 2017, vol. 20(2), p. 114-123.65
Sherrif et al., Liver international: official journal of the International Association for the Study of the Liver 2013, vol. 33, No. 8, pp. 1266-1270.66
Blackmore et al., J Clin Exp Hepatol. 2013, vol. 3(2), p. 159-161.67
Matte et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 488-493.68
Lin et al., Zhongguo Dang Dai Er Ke Za Zhi. 2018, vol. 20(9), p. 758-764.69
Harmanci et al., Experimental and Clinical Transplantation 2015, vol. 13, Supp. SUPPL. 2, pp. 76. Abstract Number: P62. Meeting Info: 1st Congress of the Turkic World Transplantation Society. Astana, Kazakhstan. 20 May 2015-22 May 2015.70
Herbst et al., Mol Cell Probes. 2015, vol. 29(5), p. 291-298.71
Moghadamrad et al., Hepatology. 2013, vol. 57(6), p. 2539-2541.72
Holz et al., Zeitschrift fur Gastroenterologie 2016, vol. 54, No. 8. Abstract Number: KV275. Meeting Info: Viszeralmedizin 2016, 71. Jahrestagung der Deutschen Gesellschaft fur Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten mit Sektion Endoskopie - 10. Herbsttagung der Deutschen Gesellschaft fur Allgemein- und Viszeralchirurgie. Hamburg, Germany. 21 Sep 2016-24 Sep 2016.73
Wang et al., PLoS One. 2016; vol. 11(4): e0153114.74
Hao et al., International Journal of Clinical and Experimental Pathology 2017, vol. 10(3), p. 3480-3487.75
Arnell et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 494-499.76
Sharma et al., Indian Journal of Gastroenterology 2017, vol. 36, No. 1, Supp. Supplement 1, pp. A99. Abstract Number: M-20. Meeting Info: 58th Annual Conference of the Indian Society of Gastroenterology, ISGCON 2017. Bhubaneswar, India. 14 Dec 2017-17 Dec 2017.77
Beauséjour et al., Can J Gastroenterol. 2011, vol. 25(6), p. 311-314.78
Imagawa et al., Journal of Pediatric Gastroenterology and Nutrition 2016, vol. 63, Supp. Supplement 2, pp. S51. Abstract Number: 166. Meeting Info: World Congress of Pediatric Gastroenterology, Hepatology and Nutrition 2016. Montreal, QC, Canada. 05 Oct 2016-08 Oct 2016.79
Peng et al., Zhonghua er ke za zhi (Chinese journal of pediatrics) 2018, vol. 56, No. 6, pp. 440-444.80
Tibesar et al., Case Rep Pediatr. 2014, vol. 2014: 185923.81
Ng et al., Journal of Pediatric Gastroenterology and Nutrition 2018, vol. 66, Supp. Supplement 2, pp. 860. Abstract Number: H-P-127. Meeting Info: 51st Annual Meeting European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESPGHAN 2018. Geneva, Switzerland. 09 May 2018-12 May 2018.82
Wong et al., Clin Chem. 2008, vol. 54(7), p. 1141-1148.83
Pauli-Magnus et al., J Hepatol. 2005, vol. 43(2), p. 342-357.84
Jericho et al., Journal of Pediatric Gastroenterology and Nutrition. 60, vol. 3, p. 368-374.85
Scheimann et al., Gastroenterology 2007, vol. 132, No. 4, Suppl. 2, pp. A452. Meeting Info.: Digestive Disease Week Meeting/108th Annual Meeting of the American-Gastroenterological-Association. Washington, DC, USA. May 19 -24, 2007. Amer Gastroenterol Assoc; Amer Assoc Study Liver Dis; Amer Soc Gastrointestinal Endoscopy; Soc Surg Alimentary Tract.86
Jaquotot-Haerranz et al., Rev Esp Enferm Dig. 2013, vol. 105(1), p. 52-54.87
Khosla et al., American Journal of Gastroenterology 2015, vol. 110, No. Suppl. 1, pp. S397. Meeting Info.: 80th Annual Scientific Meeting of the American-College-of-Gastroenterology. Honolulu, HI, USA. October 16 -21, 2015.88
Dröge et al., J Hepatol. 2017, vol. 67(6), p. 1253-1264.89
Liu et al., Liver International 2010, vol. 30(6), p. 809-815.90
Chen et al., Journal of Pediatrics 2002, vol. 140(1), p. 119-124.91
U.S. Patent No. 9,295,677
在一些實施例中,ABCB11中之突變係選自A167T、G238V、V284L、E297G、R470Q、R470X、D482G、R487H、A570T、N591S、A865V、G982R、R1153C及R1268Q。
提供治療個體之PFIC (例如PFIC-1及PFIC-2)之方法,該等方法包括對獲自個體之樣品進行分析,以確定個體是否具有與PFIC相關之突變(例如ATP8B1、ABCB11、ABCB4、TJP2、NR1H4或Myo5b突變),以及向確定具有與PFIC相關突變的個體投與(例如特定或選擇性地投與)治療有效量之式(I)化合物,或其藥學上可接受之鹽。在一些實施例中,突變為ATP8B1或ABCB11突變。舉例而言,如表1至4之任一者中所提供之突變。在一些實施例中,ATP8B1中之突變係選自L127P、G308V、T456M、D554N、F529del、I661T、E665X、R930X、R952X、R1014X及G1040R。在一些實施例中,ABCB11中之突變係選自A167T、G238V、V284L、E297G、R470Q、R470X、D482G、R487H、A570T、N591S、A865V、G982R、R1153C及R1268Q。
亦提供用於治療有需要個體之PFIC (例如PFIC-1及PFIC-2)之方法,該方法包含:(a)偵測個體內與PFIC相關之突變(例如ATP8B1、ABCB11、ABCB4、TJP2、NR1H4或Myo5b突變);及(b)向個體投與治療有效量之奧德維希百之結晶修飾物I。在一些實施例中,用於治療PFIC之方法可包括向具有與PFIC相關突變(例如ATP8B1、ABCB11、ABCB4、TJP2、NR1H4或Myo5b突變)之個體投與治療有效量之式(I)化合物或其醫藥學上可接受之鹽。在一些實施例中,突變為ATP8B1或ABCB11突變。舉例而言,如表1至4之任一者中所提供之突變。在一些實施例中,ATP8B1中之突變係選自L127P、G308V、T456M、D554N、F529del、I661T、E665X、R930X、R952X、R1014X及G1040R。在一些實施例中,ABCB11中之突變係選自A167T、G238V、V284L、E297G、R470Q、R470X、D482G、R487H、A570T、N591S、A865V、G982R、R1153C及R1268Q。
在一些實施例中,藉由使用任何此項技術中認知之檢驗,包括下一代測序(next generation sequencing,NGS),在個體內或來自個體之生檢樣品中測定個體具有與PFIC相關之突變。在一些實施例中,使用管理機構核准(例如FDA核准)之用於鑑別個體內或來自個體之生檢樣品中與PFIC相關突變的檢驗或分析,或藉由進行本文所述分析之非限制性實例中之任一者,測定個體具有與PFIC相關之突變。診斷PFIC之另外方法描述於Gunaydin, M.等人., Hepat Med. 2018, 第10卷, 第95-104頁,其以全文引用的方式併入本文中。
在一些實施例中,PFIC (例如PFIC-1或PFIC-2)之治療降低個體中血清膽汁酸之含量。在一些實施例中,血清膽汁酸之含量藉由例如ELISA酶分析或如Danese等人., PLoS One. 2017, 第12(6)卷: e0179200中所述之用於量測總膽汁酸之分析測定,其以全文引用之方式併入本文中。在一些實施例中,血清膽汁酸之含量可在投與奧德維希百之結晶修飾物I之前降低例如10%至40%、20%至50%、30%至60%、40%至70%、50%至80%或超過90%之血清膽汁酸之含量。在一些實施例中,PFIC之治療包括搔癢病之治療。
因此,在一個實施例中,本發明係關於本文所述之奧德維希百之結晶修飾物1,其用於治療或預防如上文所列之疾病或病症。
在另一實施例中,本發明係關於本文所述之奧德維希百之結晶修飾物1的用途,其用於製造用以治療或預防如上文所列之疾病或病症之藥物。
在又一實施例中,本發明係關於治療或預防溫血動物中如上文所列出之疾病或病症的方法,其包含向需要此類治療及/或預防之溫血動物投與治療有效量之本文所描述之奧德維希百之結晶修飾物1。
本發明之另一態樣係關於一種醫藥組合物,其包含治療有效量之本文所述之奧德維希百之結晶修飾物1,以及醫藥學上可接受之稀釋劑或載劑。
醫藥組合物可進一步包含至少一種其他活性物質,諸如選自以下之活性物質:IBAT抑制劑;腸內分泌肽或其增強劑;二肽基肽酶-IV抑制劑;雙胍;腸促胰液素模擬物;噻唑啶酮;PPAR促效劑;HMG Co-A還原酶抑制劑;膽汁酸結合劑;TGR5受體調節劑;前列酮類化合物之成員;鳥苷酸環化酶C促效劑;5-HT4血清素促效劑;或此等活性物質之任一者之醫藥學上可接受之鹽。此類組合之實例亦描述於WO2012/064268中。
可在約0.01至1.0 mg/kg,諸如約0.01至0.5 mg/kg,或諸如約0.01至0.2 mg/kg範圍內之單位劑量向溫血動物投與奧德維希百之結晶修飾物1,且此可提供治療有效劑量。諸如錠劑或膠囊之單位劑型可含有約0.1至20 mg,諸如約0.1至10 mg,或諸如約0.2至5 mg,或諸如約0.2至1.0 mg之活性成分。日劑量可以單次劑量投與或分成一個、兩個、三個或更多個單位劑量。經口投與之奧德維希百之日劑量較佳在約0.1至50 mg內,更佳在約0.1至20 mg內,諸如在約0.2至10 mg內,或諸如在約0.2至5.0 mg內。
奧德維希百之醫藥調配物可包含治療有效量之奧德維希百之結晶修飾物1及一或多種醫藥學上可接受之賦形劑。該等賦形劑可例如包括填充劑、結合劑、崩解劑、滑動劑及潤滑劑。一般而言,醫藥組合物可使用習知賦形劑以習知方式製備。
在一些實施例中,醫藥調配物為含有低劑量之奧德維希百之結晶修飾物1的多微粒調配物。此類調配物允許基於重量之劑量且可尤其適用於向兒科患者投與。在一些實施例中,醫藥調配物為兒科調配物。
在一些實施例中,粒子足夠小以致其可噴灑至食品上且容易吞咽。在一些實施例中,可吞咽該等粒子而不引起砂礫感。在一些實施例中,該等粒子不會使患者有咀嚼該等粒子之衝動。
在一些實施例中,各粒子包含核及圍繞核之塗層。各粒子之核可為集結粒、顆粒、微型錠劑、珠粒、微粒或微球體。活性醫藥成分可在核中或在塗層中。在一些實施例中,各粒子之塗層包含活性醫藥成分,而各粒子之核不包含活性醫藥成分。
核可為經口可分散的且包含可溶性成分,諸如糖(例如蔗糖)或可溶性聚合物(例如羥丙基甲基纖維素),或可為非經口可分散的且包含不可溶性成分,諸如不可溶性聚合物(例如微晶纖維素)。在一些實施例中,核為微晶纖維素球體。
塗層可進一步包含成膜聚合物,諸如基於纖維素之聚合物、基於多醣之聚合物、基於N
-乙烯吡咯啶酮之聚合物、丙烯酸酯、丙烯醯胺,或其共聚物。適合成膜聚合物之實例包括聚乙烯醇(PVA)、聚乙酸乙烯鄰苯二甲酸酯(PVAP)、聚乙二醇(PEG)、聚乙烯吡咯啶酮(PVP)、甲基丙烯酸共聚物、澱粉、羥丙基澱粉、聚葡萄胺糖、蟲膠、甲基纖維素、羥丙基纖維素(HPC)、低取代羥丙基纖維素、羥丙基甲基纖維素(HPMC;或羥丙甲纖維素)、乙酸羥丙基甲基纖維素丁二酸酯(HPMCAS)、鄰苯二甲酸羥丙基甲基纖維素(HPMCP)、乙酸纖維素鄰苯二甲酸酯(CAP)、乙酸纖維素苯偏三酸酯(CAT)以及其組合,諸如甲基纖維素及羥丙基甲基纖維素(羥丙甲纖維素)之混合物。在一些實施例中,塗層包含選自由以下組成之群的成膜聚合物:羥丙基甲基纖維素、聚乙烯醇(PVA)、聚乙二醇(PEG)、澱粉、羥丙基澱粉及羥丙基纖維素(HPC)。
塗層可視情況包含一或多種額外成份,諸如塑化劑(例如,聚乙二醇、三乙酸甘油酯或檸檬酸三乙酯)、抗黏著劑(例如,滑石或硬脂酸鎂)或染色劑(例如,二氧化鈦、氧化鐵、核黃素或薑黃)。
治療性或預防性治療所需之劑量將視以下而定:投與途徑、疾病嚴重程度、患者之年齡及體重以及在確定適合於特定患者之個別方案及劑量水準時主治醫師通常考慮之其他因素。
定義
術語「結晶修飾物」係指有機化合物之結晶固相。結晶修飾物可為溶劑合物或非溶劑合物。
術語「溶劑合物」係指有機化合物之結晶固相,其具有併入其結晶結構中之溶劑(亦即溶劑分子)。「水合物」是溶劑為水的溶劑合物。
術語「倍半水合物」係指含有每莫耳有機化合物約1.5莫耳與結晶相關聯之水(亦即,1.5水合物)。如本文所用,倍半水合物包括約1.2至約1.8,更佳約1.3至約1.7,更佳約1.4至約1.6,且甚至更佳約1.45至約1.55莫耳與結晶中之每莫耳奧德維希百相關聯之水。本文所計算之水量不包括吸附至結晶表面之水。
術語「混合溶劑合物」係指結晶結構中併入兩種或更多種不同溶劑分子的有機化合物之結晶固相。至少兩種溶劑分子中之一者可為水。
術語「同構溶劑合物」係指結晶固相可在結晶結構無變形之情況下容納不同溶劑的有機化合物之結晶固相。
術語「漿液」係指在飽和溶液中添加過量固體,由此形成的固體與飽和溶液之混合物。
如本文所用,術語「空隙體積」係指結晶結構中之通道、層或其他或多或少隔離之空隙。
如本文所用,術語「治療(treatment)」、「治療(treat)」及「治療(treating)」係指逆轉、緩解、延遲如本文所述之疾病或病症或其一或多種症狀的發作或抑制該疾病或病症或其一或多種症狀之進展。在一些實施例中,治療可在已出現一或多種症狀之後投與。在其他實施例中,治療可無症狀存在之情況下投與。舉例而言,治療可在症狀發作之前向易感個體投與(例如根據症狀病史及/或根據遺傳性或其他易感性因素)。亦可在症狀已消退之後繼續治療,例如以預防或延遲其復發。
如本文所用,術語「醫藥學上可接受之」係指適用於人類醫藥用途且通常安全、無毒且在生物學上或其他方面沒有不合需要的彼等化合物、材料、組合物及/或劑型。
如本文所使用,術語「約」係指包括(及描述)針對本文之值或參數本身之實施例的值或參數。舉例而言,涉及「約20」之描述包括「20」之描述。數值範圍包括定義該範圍之數值。一般而言,術語「約」係指變數之指定值及在指定值之實驗誤差內(例如,在平均值之95%信賴區間內)或在指定值之10%內之變數之所有值,以較大值為準。
可例如藉由X射線粉末繞射(XRPD)方法或藉由差示掃描熱量測定(DSC)方法,諸如實驗章節中所揭示之方法來量測奧德維希百之結晶樣品之結晶度。當在本文中提及結晶化合物時,較佳地如藉由DSC方法所量測之結晶度大於約70%,諸如大於約80%,特定言之大於約90%,更特定言之大於約95%。在一些實施例中,如藉由DSC方法所量測之結晶度大於約98%。在一些實施例中,如藉由DSC方法所量測之結晶度大於約99%。結晶度%係指結晶之總樣品質量之重量百分比。
較佳地,根據本發明之結晶修飾物實質上不含化合物之其他結晶修飾物。較佳地,所描述之奧德維希百之結晶修飾物包括小於(例如)約20重量%、約15重量%、約10重量%、約5重量%、約3重量%或尤其小於約1重量%之奧德維希百之其他結晶修飾物。因此,較佳地,所描述的奧德維希百之結晶修飾物的固相純度大於約80%、大於約85%、大於約90%、大於約95%、大於約97%或尤其大於約99%。
現將藉由以下實例描述本發明,該等實例在任何態樣不限制本發明。本文中所提及之所有文獻及參考文獻均以全文引用之方式併入。
縮寫
DMF 二甲基甲醯胺
DMSO 二甲亞碸
EtOH 乙醇
MeOH 甲醇
RH 相對濕度
2-PrOH 2-丙醇
實驗方法X 射線粉末繞射 (XRPD) 分析
在22℃下在裝備有Cu長細焦X射線管與PIXcel偵測器之PANalytical X´Pert Pro繞射儀上進行分析。自動發散及防散射縫隙與0.02弧度Soller縫隙及Ni-過濾器一起使用。將乾燥樣品塗至切割Silicon Zero Background Holders (ZBH)上,且在2θ 2-40°之間分析,分析時間為17分鐘。所有漿液樣品在回火多孔氧化鋁過濾器基板上滴落且在乾燥時分析兩次,首先用一分鐘16秒掃描(2-30° 2θ)且隨後用7分鐘掃描(2-30° 2θ)。當樣品已乾燥數小時時,進行最終17分鐘掃描。
在分析期間旋轉樣品以便增加樣品之隨機性。使用以下實驗設定:
管張力及電流:40 kV,50 mA
波長α1 (CuKα1):1.5406 Å
波長α2 (CuKα2):1.5444 Å
波長α1及α2意謂(CuKα):1.5418 Å
此項技術中已知,可獲得視量測條件(諸如設備、樣品製備或所用機器)而定具有一或多個量測誤差之X射線粉末繞射圖。特定言之,一般已知XRPD圖中之強度可視量測條件及樣品製備而變動。舉例而言,熟習XRPD技術者將意識到峰值之相對強度可根據受測樣品之定向及所用儀器之類型及設定而變化。熟習此項技術者亦將認識到,反射之位置可受樣品位於繞射儀中之精確高度及繞射儀之零校準影響。樣品之表面平坦度亦可具有少許效果。因此,熟習此項技術者應瞭解,不應將本文中呈現之繞射圖理解為提供與本文中所揭示之繞射圖實質上相同之粉末繞射圖的絕對及任何結晶形式屬於本發明之範疇內(進一步的資訊參見R. Jenkins及R.L. Snyder, 「Introduction to X-ray powder diffractometry」, John Wiley & Sons, 1996)。
熱解重量分析 (TGA)
在配備有Julabo FP40冷卻器之Mettler TGA/SDTA 851e上進行分析。將1-10 mg樣品稱取至100 µL Al蓋中且在分析期間用乾燥氮氣沖洗。使用兩種不同方法:在「標準掃描(standard scan)」中,以10℃/分鐘之掃描速率自25℃至200℃掃描樣品,且在「謹慎掃描(careful scan)」中,將樣品保持在25℃下30分鐘且隨後以10℃/分鐘之掃描速率自25℃至100℃掃描樣品。
動態氣相吸附 (DVS)
使用來自ProUmid (以前為「Projekt Messtechnik」), August-Nagel-Str. 23, 89079 Ulm (德國)之SPS11-100n 「Sorptions Prüfsystem」進行DVS量測。使用約20 mg樣品。使用每小時5%之濕度變化速率。將樣品置放於微天平頂部之鋁或鉑固持器上,且使其在0% RH下平衡,隨後開始預定義濕度程式:
(1) 在0% RH下5 h
(2) 0 → 95% RH (5%/h);在95% RH下5 h
(3) 95 → 0% RH (5%/h);在0% RH下5 h
(4) 0 → 95% RH (5%/h);在95% RH下5 h
(5) 95 → 0% RH (5%/h); 在0% RH下5 h
高效液相層析 (HPLC)
在配備有Agilent 1260 Infinity脫氣器之Agilent, Series 1100上進行分析。管柱:Waters XSelcet CHS C18 (150 x 3 mm, 3.5 µm);移動相A:含0.1%甲酸之水,移動相B:含0.1%甲酸之乙腈;梯度45%至90% B;流動速率0.425 mL/min;採集時間35分鐘;操作時間42分鐘;波長:283 nm;管柱溫度20℃。使用Chromeleon Version 6.8軟體。
差示掃描熱量測定 (DSC)
使用TA Instruments Q2000差示掃描式熱量計進行實驗。所使用之DCS坩堝為在蓋中具有針孔(直徑≥0.2 mm)之TZero鋁盤。 在整個量測中在DSC單元中以50 mL/min之恆定流動速率維持乾燥氮氣吹掃。
實例實例 1 製備結晶修飾物 1
在氮氣氛圍下在攪拌下將絕對酒精(100.42 kg)及粗奧德維希百(18.16 kg)裝入250-L GLR中。添加純化水(12.71 kg)且在25±5℃下在氮氣氛圍下攪拌反應物質15分鐘。在25±5℃下繼續攪拌3至60分鐘,直至形成澄清溶液。溶液經5.0 µ SS濾筒過濾,隨後經0.2 µ PP濾筒過濾,且隨後轉移至清潔反應器中。在25±5℃下經2至3小時之時間段緩慢添加純化水(63.56 kg),且溶液用奧德維希百之結晶修飾物1接種。在25±5℃下攪拌溶液12小時。在此期間,溶液變渾濁。經離心過濾所沈澱之固體且將材料旋轉乾燥30分鐘。此後在Nutsche過濾器中將材料真空乾燥12小時。材料隨後在真空(550 mm Hg)下在25±5℃下在真空盤乾燥器中乾燥10小時且隨後在真空(550 mm Hg)下在30±5℃下乾燥16小時。分離呈灰白色結晶固體狀之材料。 將經分離之結晶材料研磨且儲存於LDPE袋中。
用XRPD分析濕潤(未乾燥)樣品且繞射圖顯示於圖2中。在真空中在50℃下乾燥另一樣品且其後用XRPD分析。乾燥樣品之繞射圖顯示於圖1中。
圖3及4分別顯示在2θ範圍5-13°及18-25°內的乾燥樣品的繞射圖(底部為濕潤樣品及頂部為乾燥樣品)。
實例 2 自乙醇及水製備結晶修飾物 2A
將105.9 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及1.0 mL乙醇:水70:30 %v/v混合物且用卷邊蓋封閉容器。隨後將所得漿液在25℃下攪拌1週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖6中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 3 自丙酮及水製備結晶修飾物 2A
將27.0 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及0.5 mL丙酮:水50:50 %v/v混合物且用卷邊蓋封閉容器。隨後將所得漿液在3℃下攪拌2週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖7中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 4 自 2- 丙醇及水製備結晶修飾物 2A
將27.4 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及0.5 mL 2-丙醇:水50:50 %v/v混合物且用卷邊蓋封閉容器。 隨後將所得漿液在3℃下攪拌2週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖8中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 5 自 1,4- 二噁烷及水製備結晶修飾物 2A
將31.6 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及0.5 mL 1,4-二噁烷:水50:50 %v/v混合物且用卷邊蓋封閉容器。隨後將所得漿液在3℃下攪拌2週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖9中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 6 自甲醇製備結晶修飾物 2B
將103.9 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及0.9 mL甲醇且用卷邊蓋封閉容器。隨後將所得漿液在22℃下攪拌1週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖9中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 7 自乙腈及水製備結晶修飾物 2B
將20.2 mg奧德維希百溶解於1.5 mL乙腈中。向攪拌溶液中添加2.5 mL水作為奧德維希百。在20-30分鐘內,漿液已沈澱。
用XRPD分析濕潤樣品,且繞射圖顯示於圖10中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 8 自 DMSO 及水製備結晶修飾物 2C
將29.8 mg奧德維希百稱取至1 mL Chromacol容器中。添加磁性攪拌棒及0.5 mL DMSO:水50:50 %v/v混合物且用卷邊蓋封閉容器。隨後將所得漿液在3℃下攪拌2週。
用XRPD分析濕潤樣品,且繞射圖顯示於圖12中。在乾燥樣品後,將其轉化成結晶修飾物1。
實例 9 對結晶修飾物 1 及 2 之水及溶劑含量之分析
修飾物1之結晶之Karl-Fischer分析顯示3.4% w/w之含水量。相同材料之熱解重量分析(TGA)顯示3.5%之總質量損失(參見圖13)。此等類似發現指示結晶修飾物1含有每莫耳奧德維希百1.5莫耳之水,對應於1.5水合物。
藉由使用自奧德維希百之漿液製備之樣品在乙醇:水(60:40 %v/v)中分析結晶修飾物2中之水及溶劑含量,該漿液允許在3天期間平衡。根據XRPD形成形式2。漿液樣品自漿液取出至多孔盤且隨後與乙醇:水(60:40 %v/v)一起儲存於乾燥器中且平衡至少隔夜。將盤取出且在空氣中乾燥特定時間(5-30分鐘),且隨後在XRPD上快速掃描(1 min 16 s)分析以驗證結晶形式。一些樣品含有結晶修飾物2且仍非常濕,而結晶修飾物1已開始出現在較乾燥樣品中。對結晶修飾物2之乾燥樣品的Karl-Fischer分析指示略微超過4% w/w之含水量。結晶修飾物2之極濕樣品之熱解重量分析顯示此等樣品最初損失大量質量。其後觀測到乾燥速率之變化,其可能指示開始自修飾物2轉化成修飾物1。在進行若干次實驗之後,可測定修飾物2轉化為修飾物1之質量損失為大約12% w/w。由於乾燥修飾物1為倍半水合物(參見圖13),結晶修飾物2轉化為結晶修飾物1之大約12% (w/w)之總質量損失將對應於兩莫耳乙醇及0.5莫耳水之損失。
在另一實驗中,將結晶修飾物1之樣品保持在乾燥器中且在室溫下暴露於乙醇及水之60:40 (% v/v)混合物之氣相持續4天。樣品之熱解重量分析顯示約18.7%之質量損失(參見圖14)。質量損失容易在實驗開始時開始。藉由1H-NMR進一步檢測樣品表明乙醇含量對應於約2.7當量且含水量對應於約1.9當量。
實例 10 結晶修飾物 1 之動態蒸汽吸附分析
使用動態蒸氣吸附(DVS)量測結晶修飾物1之水吸收。該等量測表明,含水量可逆地取決於在95% RH下最大吸收約5.0% (w/w)之環境濕度,如圖15所示。
在0% RH下乾燥樣品且增加相對濕度之後,將大部分水重新吸收至約25% RH。 此對應於約3.5%之含水量。當濕度增加至95% RH時,接著吸收額外1.5%水。吸收/解吸過程顯示最小遲滯。XRPD分析已顯示水合物結構在20% RH下幾乎完全復原且在30% RH下完全復原。結晶修飾物1因此似乎需要約3.5%之水,其對應於倍半水合物。較高相對濕度下之其他水分吸收並不進一步改變結構。 結晶修飾物1因此可能為在30-95% RH範圍內之高相對濕度下可吸收額外1.5%水之略微吸濕性倍半水合物。
實例 11 穩定性檢驗
在空氣下在80℃下將非晶形奧德維希百之樣品(純度~91%)及奧德維希百之
結晶修飾物1 (純度>99%;結晶度100%)儲存於密閉容器中。在實驗開始時藉由HPLC測定樣品中之奧德維希百之
量,且在第1週、第2週及第4週之後再次測定。 結果顯示於下表中。 在儲存4週之後,非晶形樣品顯示0.3%分解,而結晶樣品之純度未改變。
實例 12 藉由差示掃描熱量測定來測定結晶分率
此方法定量部分結晶樣品中奧德維希百藥物物質之結晶分率。定量係基於部分結晶樣品為結晶水合物與A4250之非晶形相的二元混合物的假設。結晶分率係基於無水形式之熔融焓定量。此無水形式為脫水水合物,其藉由在高溫下乾燥水合物自發地且可再現地形成。
將5-6 mg奧德維希百之結晶樣品或部分結晶樣品精確稱取至DSC坩堝中,隨後使用適合壓力用多孔蓋將其密閉。標記DSC坩堝之總重量(盤+蓋+樣品),且在DSC檢驗之後再次測定坩堝之總重量。DSC檢驗期間之重量損失必須不大於5%。
DSC檢驗由三個循環組成:
循環1:溫度以5℃/min之掃描速率自20℃升高至120℃;
循環2:溫度以10℃/min之掃描速率自120℃降低至80℃;及
循環3:溫度以10℃/min之掃描速率自80℃升高至200℃。
第一掃描循環乾燥樣品且從而將水合物形式轉化成脫水的水合物(無水形式)。在第二掃描循環中,將樣品冷卻以在後續加熱中獲得穩定基線以用於信號積分。在第三掃描循環中測定熔融焓,其中藉由熔融無水形式來加熱樣品。
熔融引起之吸熱事件在140-165℃之溫度範圍內出現。必須使用TA通用分析軟體之Sig Tangent
積分功能將峰積分於S形切線基線上。視實際基線而定,積分應在130℃與140℃之間的溫度下開始,且在165℃與175℃之間的溫度下結束。視實際非晶形分率而定,非晶形部分之玻璃轉變可在120-130℃之溫度範圍內出現(例如參見圖16)。若不規則基線不允許積分,則應評估樣品之乾燥是否不完全。
熔融焓之評估藉由使用樣品之乾重進行,該乾重藉由自檢驗之前坩堝之總重量減去在DSC檢驗之後的DSC坩堝之總重量(盤+蓋+樣品)獲得。DSC掃描期間之重量損失百分比(即初始重量與乾重之間的差值除以初始重量)必須不大於5%,否則無法計算樣品之結晶含量。
實例 13 乾燥對結晶修飾物 1 之結晶度之影響
在此等實驗中,將結晶修飾物1在乙醇/水之6:4混合物中漿化之後,獲得結晶修飾物2;隨後將所獲得之濕潤材料在乙醇/水(6:4)蒸氣下在乾燥器中儲存兩個月。
隨後使用不同乾燥技術乾燥結晶修飾物2之樣品,以便觀察乾燥對結晶修飾物1之結晶度的影響。使用XRPD分析乾燥樣品(樣品在環境空氣氛圍中製備)且結果顯示於下表中。結果表明藉由將脫水形式復水獲得結晶修飾物1,該脫水形式藉由在真空下或在氮氣流下乾燥結晶修飾物2來獲得。當結晶修飾物2儲存於環境條件中時,乙醇-水交換似乎極低。
實例 14 溶劑對結晶修飾物 2 之結晶度之影響
在室溫下將結晶修飾物1懸浮於乙醇及水之30:70 (% v/v)混合物中(樣品A)或懸浮於乙醇及水之70:30 (% v/v)混合物中(樣品B)。在攪拌隔夜之後,進行過濾且使回收之濕樣品進行XRPD (透射)。兩個樣品之XRPD圖基本上對應於結晶修飾物2,但在兩種樣品之間觀測到一些輕微峰位移,可能歸因於兩個樣品之乙醇含量的差異。
隨後在室溫下對兩種樣品進行空氣乾燥且藉由XRPD再檢驗。在兩種情況下,獲得結晶修飾物1,但基於XRPD圖中之峰分辨率,自乙醇及水之70:30 (% v/v)混合物獲得之樣品呈現顯著更多的結晶。
對空氣乾燥之樣品進行DSC量測。發現自含有30%乙醇之混合物獲得之樣品A比自含有70%乙醇之混合物獲得之樣品B結晶少。發現樣品A之25.7 J/g之熔化焓對應於95%結晶度。對於樣品B,發現28.9 J/g之焓,其對應於超過100%結晶度。
圖1顯示脫水結晶修飾物1之X射線粉末繞射圖。
圖2顯示結晶修飾物1之過度水合樣品之X射線粉末繞射圖。
圖3顯示對結晶修飾物1之乾燥,X射線粉末繞射圖中底部處為結晶修飾物1之過度水合樣品且頂部處為乾燥樣品(2θ範圍5-13°)。
圖4顯示對結晶修飾物1之乾燥,X射線粉末繞射圖中底部處為結晶修飾物1之過度水合樣品且頂部處為乾燥樣品(2θ範圍18-25°)。
圖5顯示自結晶修飾物2 (底部)經結晶修飾物12 (中間)至結晶修飾物1 (頂部)之轉化,其中結晶修飾物2自乙醇(60-80 %v/v)及水(20-40 %v/v)之混合物獲得。
圖6顯示自乙醇及水之混合物(70:30 %v/v)獲得之結晶修飾物2A之X射線粉末繞射圖。
圖7顯示自丙酮及水之混合物(50:50 %v/v)獲得之結晶修飾物2A之X射線粉末繞射圖。
圖8顯示自2-丙醇及水之混合物(50:50 %v/v)獲得之結晶修飾物2A之X射線粉末繞射圖。
圖9顯示自1,4-二噁烷及水之混合物(50:50 %v/v)獲得之結晶修飾物2A之X射線粉末繞射圖。
圖10顯示自甲醇獲得之結晶修飾物2B之X射線粉末繞射圖。由於甲醇的吸濕性,因此由空氣獲得形式2結晶所需之水。
圖11顯示自乙腈及水之混合物(40:60 %v/v)獲得之結晶修飾物2B之X射線粉末繞射圖。
圖12顯示自DMSO及水之混合物(50:50 %v/v)獲得之結晶修飾物2C之X射線粉末繞射圖。
圖13顯示用於結晶修飾物1之熱解重量分析(thermogravimetric analysis,TGA)質量變化曲線。
圖14顯示藉由將結晶修飾物1暴露於乙醇及水之混合物之氣相所產生之結晶修飾物2的熱解重量分析(TGA)質量變化曲線。
圖15顯示用於結晶修飾物1之動態蒸氣吸附(dynamic vapour sorption,DVS)質量變化曲線。
圖16顯示具有約50%結晶分率之奧德維希百之樣品(在預加熱及冷卻之後)之DSC跡線。
Claims (31)
- 一種奧德維希百(odevixibat)之結晶水合物。
- 如請求項1之水合物,其為通道水合物。
- 如請求項1或2之水合物,其包含每莫耳奧德維希百約0至約2莫耳水與該結晶結合。
- 如請求項1至3中任一項之水合物,其為倍半水合物。
- 一種奧德維希百之結晶修飾物1,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置5.6±0.2、6.7±0.2及/或12.1±0.2。
- 如請求項5之結晶修飾物,其具有用CuKα1-輻射獲得之XRPD圖具有特定峰在°2θ位置5.6±0.2、6.7±0.2及12.1±0.2及一或多個以下特徵峰:4.1±0.2、4.6±0.2、9.3±0.2、9.4±0.2及10.7±0.2。
- 如請求項5之奧德維希百之結晶修飾物1,其具有用CuKα1-輻射獲得之XRPD圖如圖1所示。
- 如請求項5至7中任一項之奧德維希百之結晶修飾物1,其具有大於約99%之結晶度。
- 一種奧德維希百之混合溶劑合物,其含有每莫耳奧德維希百約兩莫耳水。
- 如請求項9之混合溶劑合物,其中該有機溶劑為甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF或DMSO。
- 如請求項9或10之混合溶劑合物,其中該有機溶劑為乙醇。
- 一種奧德維希百之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置5.0±0.2、5.1±0.2及/或11.8±0.2。
- 如請求項12之結晶修飾物,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置5.0±0.2、5.1±0.2、6.4±0.2、6.6±0.2、9.5±0.2及11.8±0.2。
- 如請求項12之奧德維希百之結晶修飾物2A,其具有用CuKα1-輻射獲得之XRPD圖如圖6至9中任一者所示。
- 一種奧德維希百之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置4.8±0.2、5.1±0.2及/或11.6±0.2。
- 如請求項15之結晶修飾物,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置4.8±0.2、5.1±0.2、6.2±0.2、6.67±0.2、9.5±0.2、11.6±0.2及20.3±0。
- 如請求項15之奧德維希百之結晶修飾物2B,其具有用CuKα1-輻射獲得之XRPD圖如圖10或11所示。
- 一種奧德維希百之結晶修飾物2C,其具有使用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置5.0±0.2、6.2±0.2、9.4±0.2及/或23.9±0.2。
- 如請求項18之結晶修飾物,其具有用CuKα1-輻射獲得之XRPD圖具有峰在°2θ位置5.0±0.2、6.2±0.2、9.4±0.2及23.9±0.2以及一或多個以下特徵峰:11.5±0.2、19.5±0.2及20.2±0.2。
- 如請求項18之奧德維希百之結晶修飾物2C,其具有用CuKα1-輻射獲得之XRPD圖如圖12所示。
- 一種如請求項12至20中任一項之奧德維希百之結晶修飾物2之用途,其用於製備奧德維希百之結晶修飾物1之方法中。
- 一種製備奧德維希百之結晶修飾物1之方法,其包含自奧德維希百於包含水及選自由以下組成之群的有機溶劑:甲醇、乙醇、2-丙醇、丙酮、乙腈、1,4-二噁烷、DMF及DMSO之溶劑混合物中之溶液分離奧德維希百之結晶修飾物2。
- 如請求項22之方法,其中該奧德維希百之結晶修飾物2為奧德維希百之結晶修飾物2A。
- 如請求項22或23之方法,其中奧德維希百之結晶修飾物2A自水與乙醇之混合物獲得。
- 如請求項24之方法,其中該溶劑混合物中之乙醇含量為約55至約75% (v/v)。
- 一種醫藥組合物,其包含如請求項5至8中任一項之奧德維希百之結晶修飾物1以及醫藥學上可接受之稀釋劑或載劑。
- 如請求項5至8中任一項之奧德維希百之結晶修飾物1,其用於療法。
- 如請求項5至8中任一項之奧德維希百之結晶修飾物1,其用於治療或預防心血管疾病或脂肪酸代謝障礙或葡萄糖利用障礙,諸如高膽固醇血症;脂肪酸代謝障礙;1型及2型糖尿病;糖尿病併發症,包括白內障、微血管及大血管疾病、視網膜病變、神經病變、腎病變及傷口癒合延遲,組織局部缺血、糖尿病足、動脈硬化、心肌梗塞、急性冠狀動脈症候群、不穩定型心絞痛、穩定型心絞痛、中風、周邊動脈阻塞性疾病、心肌病變、心臟衰竭、心律異常及血管再狹窄;糖尿病相關疾病,諸如胰島素抗性(葡萄糖穩態受損)、高血糖症、高胰島素血症、脂肪酸或甘油之血液含量升高、肥胖、血脂異常、包括高三酸甘油酯血症之高脂質血症、代謝症候群(症候群X)、動脈粥樣硬化及高血壓;及用於提高高密度脂蛋白含量。
- 如請求項5至8中任一項之奧德維希百之結晶修飾物1,其用於治療或預防胃腸疾病或病症,諸如便秘(包括慢性便秘、功能性便秘、慢性特發性便秘(CIC)、間歇性/偶發性便秘、繼發於糖尿病之便秘、繼發於中風之便秘、繼發於慢性腎病之便秘、繼發於多發性硬化症之便秘、繼發於帕金森病(Parkinson's disease)之便秘、繼發於全身性硬化症之便秘、藥物誘發之便秘、伴隨便秘之大腸急躁症(IBS-C)、混合型大腸急躁症(IBS-M)、小兒功能性便秘及類鴉片誘發之便秘);克羅恩氏病(Crohn's disease);原發性膽汁酸吸收障礙;大腸急躁症(IBS);發炎性腸病(IBD);迴腸發炎;及逆流病及其併發症,諸如巴雷特食道炎(Barrett's esophagus)、膽汁逆流性食道炎及膽汁逆流性胃炎。
- 如請求項5至8中任一項之奧德維希百之結晶修飾物1,其用於治療或預防肝臟疾病或病症,諸如肝臟之遺傳性代謝障礙;膽汁酸合成之先天性缺陷;先天性膽管異常;膽管閉鎖;葛西手術後膽管閉鎖(post-Kasai biliary atresia);肝移植後膽管閉鎖;新生兒肝炎;新生兒膽汁鬱積;遺傳形式之膽汁鬱積;腦腱性黃瘤病(cerebrotendinous xanthomatosis);BA合成之繼發性缺陷;齊威格氏症候群(Zellweger’s syndrome);囊性纖維化相關之肝病;α1-抗胰蛋白酶缺乏症;阿拉吉歐症候群(Alagilles syndrome,ALGS);拜勒症候群(Byler syndrome);膽汁酸(BA)合成之原發性缺陷;漸進性家族性肝內膽汁鬱積(PFIC),包括PFIC-1、PFIC-2、PFIC-3及非特定PFIC、膽汁分流後(post-biliary diversion) PFIC及肝移植後PFIC;良性復發性肝內膽汁鬱積(BRIC),包括BRIC1、BRIC2及非特定BRIC、膽汁分流後BRIC及肝移植後BRIC;自體免疫性肝炎;原發性膽汁性肝硬化(PBC);肝纖維化;非酒精性脂肪肝病(NAFLD);非酒精性脂肪變性肝炎(NASH);門靜脈高血壓;膽汁鬱積; 唐氏症候群膽汁鬱積(Down syndrome cholestasis);藥物誘發之膽汁鬱積;妊娠肝內膽汁鬱積(懷孕期間之黃疸);肝內膽汁鬱積;肝外膽汁鬱積;非經腸營養相關之膽汁鬱積(PNAC);低磷脂相關之膽汁鬱積;淋巴水腫膽汁鬱積症候群1 (LSC1);原發性硬化性膽管炎(PSC);免疫球蛋白G4相關之膽管炎;原發性膽汁性膽管炎;膽石症(膽結石);膽管結石(biliary lithiasis);輸膽管結石;膽石性(gallstone)胰臟炎;卡羅利病(Caroli disease);膽管惡性腫瘤;引起膽管樹(biliary tree)阻塞之惡性腫瘤;膽管狹窄;AIDS膽管病變;缺血性膽管病變;由膽汁鬱積或黃疸引起之搔癢病;胰臟炎;引起漸進性膽汁鬱積之慢性自體免疫肝病;肝脂肪變性;酒精性肝炎;急性脂肪肝;妊娠之脂肪肝;藥物誘發之肝炎;鐵超負荷病症;先天性膽汁酸合成缺陷1型(BAS 1型);藥物誘發之肝臟損傷(DILI);肝纖維化;先天性肝纖維化;肝硬化;蘭格漢氏(Langerhans)細胞組織細胞增多症(LCH);新生兒魚鱗癬硬化性膽管炎(NISCH);促紅血球形成性原紫質症(EPP);特發性成人期膽管缺失(ductopenia)(IAD);特發性新生兒肝炎(INH);非綜合症性小葉間膽管缺乏(NS PILBD);北美印第安兒童肝硬化(NAIC);肝類肉瘤病;澱粉樣變性;壞死性小腸結腸炎;血清膽汁酸引起之毒性,包括在異常血清膽汁酸概況中的心律不整障礙(例如心房纖維顫動)、與肝硬化相關之心肌病變(「膽心(cholecardia)」),及與膽汁鬱積性肝病相關之骨骼肌萎縮;病毒性肝炎(包括A型肝炎、B型肝炎、C型肝炎、D型肝炎及E型肝炎);肝細胞癌(肝癌);膽管癌;膽汁酸相關之胃腸癌;及由肝、膽管及胰臟之腫瘤及贅瘤引起之膽汁鬱積。
- 如請求項5至8中任一項之奧德維希百之結晶修飾物1,其用於治療或預防吸收過多症候群(包括無β脂蛋白血症、家族性低β脂蛋白血症(FHBL)、乳糜微粒滯留疾病(CRD)及豆固醇血症(sitosterolemia));維生素過多症及骨質石化病;高血壓;腎小球超微過濾;及腎衰竭之搔癢病。
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Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS57778B1 (sr) | 2010-11-08 | 2018-12-31 | Albireo Ab | Inhibitori crevnog transportera žučne kiseline (ibat) za lečenje bolesti jetre |
KR102560954B1 (ko) | 2014-06-25 | 2023-07-31 | 이에이 파마 가부시키가이샤 | 고형 제제 및 그의 착색 방지 또는 착색 감소 방법 |
US10441605B2 (en) | 2016-02-09 | 2019-10-15 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US10786529B2 (en) | 2016-02-09 | 2020-09-29 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US10441604B2 (en) | 2016-02-09 | 2019-10-15 | Albireo Ab | Cholestyramine pellets and methods for preparation thereof |
TW202015699A (zh) | 2018-06-05 | 2020-05-01 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽汁酸調節劑之用途 |
US10793534B2 (en) | 2018-06-05 | 2020-10-06 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
US11801226B2 (en) | 2018-06-20 | 2023-10-31 | Albireo Ab | Pharmaceutical formulation of odevixibat |
WO2019245449A1 (en) | 2018-06-20 | 2019-12-26 | Albireo Ab | Pharmaceutical formulation of odevixibat |
US10722457B2 (en) | 2018-08-09 | 2020-07-28 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US11007142B2 (en) | 2018-08-09 | 2021-05-18 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US11549878B2 (en) | 2018-08-09 | 2023-01-10 | Albireo Ab | In vitro method for determining the adsorbing capacity of an insoluble adsorbant |
US10941127B2 (en) | 2019-02-06 | 2021-03-09 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
US10975045B2 (en) | 2019-02-06 | 2021-04-13 | Aibireo AB | Benzothiazepine compounds and their use as bile acid modulators |
EP4069359B1 (en) | 2019-12-04 | 2024-01-03 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
CR20220315A (es) | 2019-12-04 | 2022-10-26 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como moduladores del ácido biliar |
US11014898B1 (en) | 2020-12-04 | 2021-05-25 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
ES2973355T3 (es) | 2019-12-04 | 2024-06-19 | Albireo Ab | Compuestos de benzotia(di)azepina y su uso como moduladores del ácido biliar |
EP4069247A1 (en) | 2019-12-04 | 2022-10-12 | Albireo AB | Benzothiadiazepine compounds and their use as bile acid modulators |
EP4188541A1 (en) | 2020-08-03 | 2023-06-07 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
WO2022101379A1 (en) | 2020-11-12 | 2022-05-19 | Albireo Ab | Odevixibat for treating progressive familial intrahepatic cholestasis (pfic) |
KR20230106651A (ko) | 2020-11-12 | 2023-07-13 | 알비레오 에이비 | 진행성 가족성 간내 담즙정체증(pfic)을 치료하기 위한 오데빅시바트 |
AU2021390172A1 (en) | 2020-12-04 | 2023-06-22 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
WO2022166680A1 (zh) * | 2021-06-25 | 2022-08-11 | 苏州科睿思制药有限公司 | 奥德昔巴特的晶型及其制备方法和用途 |
CN113913436B (zh) * | 2021-11-18 | 2023-09-29 | 天津市肿瘤医院(天津医科大学肿瘤医院) | 逆转录转座基因l1-atp8b1及其作为肺鳞癌标志物的用途和治疗肺鳞癌的药物 |
WO2023174937A1 (en) | 2022-03-16 | 2023-09-21 | Sandoz Ag | Particles comprising non-crystalline odevixibat |
US20240173333A1 (en) | 2022-11-03 | 2024-05-30 | Albireo Ab | Treating Alagille Syndrome (ALGS) |
WO2024121431A1 (en) | 2022-12-09 | 2024-06-13 | Albireo Ab | Cocrystals of odevixibat |
WO2024184924A1 (en) * | 2023-03-06 | 2024-09-12 | Rk Pharma Inc | "an improved process for the preparation of odevixibat and its crystalline forms" |
Family Cites Families (203)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3539380A (en) | 1968-01-08 | 1970-11-10 | Upjohn Co | Methylcellulose and polyalkylene glycol coating of solid medicinal dosage forms |
GB1566609A (en) | 1977-03-10 | 1980-05-08 | Reckitt & Colmann Prod Ltd | Pharmaceutical compositions containing cholestyramine and alginic acid |
GB1573487A (en) | 1977-05-23 | 1980-08-28 | Bristol Myers Co | Bile acid binding composition |
EP0019115B1 (de) | 1979-04-30 | 1983-01-12 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Pankreozymin-Cholezystokinin aktive Peptide, Verfahren zu ihrer Herstellung und sie enthaltende Arzneimittel |
CA1313135C (en) | 1987-02-09 | 1993-01-26 | The Dow Chemical Company | Cholestyramine composition and process for its preparation |
US5167965A (en) | 1987-02-09 | 1992-12-01 | The Dow Chemical Company | Palatable cholestyramine granules, tablets and methods for preparation thereof |
US4900757A (en) | 1988-12-08 | 1990-02-13 | Merrell Dow Pharmaceuticals Inc. | Hypocholesterolemic and antiatherosclerotic uses of bix(3,5-di-tertiary-butyl-4-hydroxyphenylthio)methane |
JP2800242B2 (ja) | 1989-03-30 | 1998-09-21 | 大正製薬株式会社 | 粒剤の製造方法 |
IL95574A (en) | 1989-09-09 | 1994-11-11 | Knoll Ag | Colstiramine preparation |
DE3930168A1 (de) | 1989-09-09 | 1991-03-14 | Knoll Ag | Verbesserte verabreichungsform fuer colestyramin |
GB8926639D0 (en) | 1989-11-24 | 1990-01-17 | Agricultural & Food Res | Delayed release formulations |
JP2542122B2 (ja) * | 1990-04-18 | 1996-10-09 | 旭化成工業株式会社 | 球状核、球形顆粒およびその製造方法 |
US5250524A (en) | 1990-12-06 | 1993-10-05 | Hoechst Aktiengesellschaft | Bile acid derivatives, process for their preparation and use of these compounds as pharmaceuticals |
DE59205695D1 (de) | 1991-12-20 | 1996-04-18 | Hoechst Ag | Polymere und Oligomere von Gallensäurederivaten, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
JPH05186357A (ja) | 1991-12-31 | 1993-07-27 | Shigeo Ochi | 飲食物消化分解産物吸収抑制手段 |
GB9203347D0 (en) | 1992-02-17 | 1992-04-01 | Wellcome Found | Hypolipidaemic compounds |
IT1257793B (it) | 1992-05-18 | 1996-02-13 | Composizione farmaceutica a base di acidi biliari in microgranuli a rilascio controllato | |
EP0650353B1 (en) | 1992-06-04 | 2002-05-22 | Smithkline Beecham Corporation | Palatable pharmaceutical compositions |
EP0573848B1 (de) | 1992-06-12 | 1997-12-03 | Hoechst Aktiengesellschaft | Gallensäurederivate, Verfahren zu ihrer Herstellung und Verwendung dieser Verbindungen als Arzneimittel |
US5350584A (en) | 1992-06-26 | 1994-09-27 | Merck & Co., Inc. | Spheronization process using charged resins |
JP3349535B2 (ja) * | 1993-01-12 | 2002-11-25 | フロイント産業株式会社 | 球形顆粒の製造方法 |
ZA941003B (en) | 1993-02-15 | 1995-08-14 | Wellcome Found | Hypolipidaemic compounds |
IL108634A0 (en) | 1993-02-15 | 1994-05-30 | Wellcome Found | Hypolipidaemic heterocyclic compounds, their prepatation and pharmaceutical compositions containing them |
ES2149250T3 (es) | 1993-04-23 | 2000-11-01 | Novartis Ag | Dispositivo para la administracion de medicamentos con liberacion controlada. |
EP0624593A3 (de) | 1993-05-08 | 1995-06-07 | Hoechst Ag | Gallensäurederivate, Verfahren zu ihrer Herstellung und Verwendung dieser Verbindungen als Arzneimittel. |
TW289757B (zh) | 1993-05-08 | 1996-11-01 | Hoechst Ag | |
TW289020B (zh) | 1993-05-08 | 1996-10-21 | Hoechst Sktiengesellschaft | |
TW289021B (zh) | 1993-05-08 | 1996-10-21 | Hoechst Ag | |
ZA956647B (en) | 1994-08-10 | 1997-02-10 | Wellcome Found | Hypolipidaemic compounds. |
US6262277B1 (en) | 1994-09-13 | 2001-07-17 | G.D. Searle And Company | Intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
PT781278E (pt) | 1994-09-13 | 2001-08-30 | Monsanto Co | Novas benzotiepinas com actividade inibidora do transporte de acido biliar ileal e da remocao do taurocolato |
US6642268B2 (en) | 1994-09-13 | 2003-11-04 | G.D. Searle & Co. | Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors |
US5994391A (en) | 1994-09-13 | 1999-11-30 | G.D. Searle And Company | Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
GB9423172D0 (en) | 1994-11-17 | 1995-01-04 | Wellcom Foundation The Limited | Hypolipidemic benzothiazepines |
US5811388A (en) | 1995-06-07 | 1998-09-22 | Cibus Pharmaceutical, Inc. | Delivery of drugs to the lower GI tract |
CA2242991C (en) | 1996-01-16 | 2007-07-24 | University Technology Corporation | Use of antioxidant agents to treat cholestatic liver disease |
DE19608592A1 (de) | 1996-03-06 | 1997-09-11 | Hoechst Ag | Antikörper zur selektiven immunologischen Bestimmung von Gallensäuren in biologischen Matrices |
DE69734100D1 (de) | 1996-03-11 | 2005-10-06 | G D Searle Llc St Louis | Benzothiepinen mit wirkung als inhibitoren des ileumgallensäuretransports und der taurocholate-aufnahme |
ES2306459T3 (es) | 1996-05-23 | 2008-11-01 | Novartis Ag | Prevencion y tratamiento de adenoma colonico o microadenoma colonico mediante acido 6-fluoroursodesoxicolico (6-fudca). |
AU3940897A (en) | 1996-07-24 | 1998-02-10 | Zumtobel Staff Gmbh | Adapter for a retaining means used to secure a built-in lamp in a mounting hole,or retaining means or built-in lamp provided with such an adapter |
DE19633268A1 (de) | 1996-08-19 | 1998-02-26 | Hoechst Ag | Polymere Gallensäure-Resorptionsinhibitoren mit gleichzeitiger Gallensäure-Adsorberwirkung |
GB9704208D0 (en) | 1997-02-28 | 1997-04-16 | Glaxo Group Ltd | Chemical compounds |
HUP0002395A3 (en) | 1997-03-11 | 2002-12-28 | G D Searle & Co Chicago | Combined pharmaceutical compositions containing ileal bile acid transport inhibiting benzothiepines and hmg co-a reductase inhibitors |
PT864582E (pt) | 1997-03-14 | 2003-10-31 | Aventis Pharma Gmbh | 1,4-benzotiazepina-1,1-dioxidos hipolipidemicos |
US6635280B2 (en) | 1997-06-06 | 2003-10-21 | Depomed, Inc. | Extending the duration of drug release within the stomach during the fed mode |
CA2290624C (en) | 1997-06-06 | 2006-12-05 | John W. Shell | Gastric-retentive oral drug dosage forms for controlled release of highly soluble drugs |
AU7552198A (en) | 1997-06-11 | 1998-12-30 | Sankyo Company Limited | Benzylamine derivatives |
AUPO763197A0 (en) | 1997-06-30 | 1997-07-24 | Sigma Pharmaceuticals Pty Ltd | Health supplement |
US5900233A (en) | 1997-10-16 | 1999-05-04 | Day; Charles E. | Epichlorohydrin and 1-(3-aminopropyl) imidazole copolymer and its use in treating irritable bowel syndrome |
US20030153541A1 (en) | 1997-10-31 | 2003-08-14 | Robert Dudley | Novel anticholesterol compositions and method for using same |
RU2236406C2 (ru) | 1997-12-19 | 2004-09-20 | Г.Д. Серл Энд Ко. | Способ получения энантиомерно-обогащенных тетрагидробензотиепиноксидов |
GB9800428D0 (en) | 1998-01-10 | 1998-03-04 | Glaxo Group Ltd | Chemical compounds |
JP2002513013A (ja) | 1998-04-24 | 2002-05-08 | 藤沢薬品工業株式会社 | グアニジン誘導体 |
DE19825804C2 (de) | 1998-06-10 | 2000-08-24 | Aventis Pharma Gmbh | 1,4-Benzothiepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
US6221897B1 (en) | 1998-06-10 | 2001-04-24 | Aventis Pharma Deutschland Gmbh | Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use |
EP1103552A4 (en) | 1998-08-07 | 2003-01-15 | Takeda Chemical Industries Ltd | BENZOTHIEPINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR USE |
ES2189529T3 (es) | 1998-12-23 | 2003-07-01 | Searle Llc | Combinaciones de inhiidores para el transporte de acidos biliares en el ileon y agentes complejantes para indicaciones cardiovasculares. |
PL348580A1 (en) | 1998-12-23 | 2002-06-03 | Searle Llc | Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications |
EP1342475A1 (en) | 1998-12-23 | 2003-09-10 | G.D. Searle LLC. | Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications |
IL143944A0 (en) | 1998-12-23 | 2002-04-21 | Searle Llc | Combinations for cardiovascular indications |
HUP0104593A3 (en) | 1998-12-23 | 2004-10-28 | G D Searle Llc Chicago | Combinations of benzothiepine ileal bile acid transport inhibitor and nicotinic acid derivatives for cardiovascular indications |
AU3694600A (en) | 1999-02-12 | 2000-08-29 | G.D. Searle Llc | Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake |
DE19915420A1 (de) | 1999-04-06 | 2000-10-12 | Basf Ag | Stabilisierte Polyvinylpyrrolidon-Zubereitungen |
DE19916108C1 (de) | 1999-04-09 | 2001-01-11 | Aventis Pharma Gmbh | Mit Zuckerresten substituierte 1,4-Benzothiazepin-1,1-dioxidderivate, Verfahren zu deren Herstellung und deren Verwendung |
SE9901387D0 (sv) | 1999-04-19 | 1999-04-19 | Astra Ab | New pharmaceutical foromaulations |
US6287609B1 (en) | 1999-06-09 | 2001-09-11 | Wisconsin Alumni Research Foundation | Unfermented gel fraction from psyllium seed husks |
US20020054903A1 (en) | 1999-10-19 | 2002-05-09 | Joseph Tyler | Direct compression polymer tablet core |
WO2001034570A1 (fr) | 1999-11-08 | 2001-05-17 | Sankyo Company, Limited | Derives heterocycliques azotes |
GB9927088D0 (en) | 1999-11-17 | 2000-01-12 | Secr Defence | Use of poly(diallylamine) polymers |
WO2001060807A1 (en) | 2000-02-18 | 2001-08-23 | Merck & Co. Inc. | Aryloxyacetic acids for diabetes and lipid disorders |
SE0000772D0 (sv) | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | Chemical compounds |
US20020061888A1 (en) | 2000-03-10 | 2002-05-23 | Keller Bradley T. | Combination therapy for the prophylaxis and treatment of hyperlipidemic conditions and disorders |
US6794544B2 (en) | 2000-03-10 | 2004-09-21 | Pharmacia Corporation | Method for the preparation of tetrahydrobenzothiepines |
TWI241195B (en) | 2000-04-10 | 2005-10-11 | Shionogi & Co | Preventive agent for bile acidic diarrhea |
US6638498B2 (en) | 2000-06-30 | 2003-10-28 | Semorex Inc. | Molecularly imprinted polymers for the treatment and diagnosis of medical conditions |
US20020183307A1 (en) | 2000-07-26 | 2002-12-05 | Tremont Samuel J. | Novel 1,4-benzothiazephine and 1,5-benzothiazepine compounds as inhibitors of apical sodium co-dependent bile acid transport and taurocholate uptake |
IL154008A0 (en) | 2000-07-28 | 2003-07-31 | Hoffmann La Roche | New pharmaceutical composition |
FR2812886B1 (fr) | 2000-08-08 | 2002-11-08 | Assist Publ Hopitaux De Paris | Depistage d'un nouveau syndrome hepatique et ses applications |
SE0003766D0 (sv) | 2000-10-18 | 2000-10-18 | Astrazeneca Ab | Novel formulation |
EG26979A (en) | 2000-12-21 | 2015-03-01 | Astrazeneca Ab | Chemical compounds |
WO2002053548A1 (en) | 2000-12-27 | 2002-07-11 | Banyu Pharmaceutical Co.,Ltd. | Benzothiazepine derivatives |
US6506921B1 (en) | 2001-06-29 | 2003-01-14 | Virginia Tech Intellectual Properties, Inc. | Amine compounds and curable compositions derived therefrom |
US20040077625A1 (en) | 2001-07-25 | 2004-04-22 | Tremont Samuel J. | Novel 1,4-benzothiazepine and 1,5-benzothiazepine compounds as inhibitors of apical sodium codependent bile acid transport abd taurocholate uptake |
US20040038862A1 (en) | 2001-07-30 | 2004-02-26 | Goodwin Bryan James | Identification of new therapeutic targets for modulating bile acid synthesis |
GB0121337D0 (en) | 2001-09-04 | 2001-10-24 | Astrazeneca Ab | Chemical compounds |
GB0121622D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
GB0121621D0 (en) | 2001-09-07 | 2001-10-31 | Astrazeneca Ab | Chemical compounds |
EP1427423B9 (en) * | 2001-09-08 | 2017-12-20 | AstraZeneca AB | Benzothiazepine and benzothiadiazepine derivatives with ileal bile acid transport (ibat) inhibitory activity for the treatment hyperlipidaemia |
US20030199515A1 (en) | 2001-09-12 | 2003-10-23 | G.D. Searle, Llc | Method for the preparation of crystalline tetrahydrobenzothiepines |
JP2005518347A (ja) | 2001-11-02 | 2005-06-23 | ジー.ディー. サール エルエルシー | 頂端ナトリウム共依存性胆汁酸輸送(asbt)およびタウロコール酸塩取り込みの阻害剤としての新規一および二フッ化ベンゾチエピン化合物 |
TW200300349A (en) | 2001-11-19 | 2003-06-01 | Sankyo Co | A 4-oxoqinoline derivative |
GB0229931D0 (en) | 2002-12-21 | 2003-01-29 | Astrazeneca Ab | Therapeutic agents |
GB0314079D0 (en) | 2003-06-18 | 2003-07-23 | Astrazeneca Ab | Therapeutic agents |
SE0104334D0 (sv) | 2001-12-19 | 2001-12-19 | Astrazeneca Ab | Therapeutic agents |
EP1461069A2 (en) | 2001-12-29 | 2004-09-29 | Novo Nordisk A/S | Combined use of a glp-1 compound and another drug for treating dyslipidemia |
GB0201850D0 (en) | 2002-01-26 | 2002-03-13 | Astrazeneca Ab | Therapeutic treatment |
US20040014806A1 (en) | 2002-03-08 | 2004-01-22 | Pharmacia Corporation | Methods and compositions for lowering levels of blood lipids |
EP1490029A4 (en) | 2002-03-22 | 2006-02-22 | Ranbaxy Lab Ltd | DRUG DELIVERY SYSTEM WITH CONTROLLED RELEASE OF PRAVASTATIN |
GB0209467D0 (en) | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
GB0213669D0 (en) | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
GB0216321D0 (en) | 2002-07-13 | 2002-08-21 | Astrazeneca Ab | Therapeutic treatment |
CN100494185C (zh) | 2002-08-28 | 2009-06-03 | 旭化成制药株式会社 | 新型季铵化合物 |
US7312208B2 (en) | 2002-08-28 | 2007-12-25 | Asahi Kasei Pharma Corporation | Quaternary ammonium compounds |
GB0304194D0 (en) | 2003-02-25 | 2003-03-26 | Astrazeneca Ab | Chemical compounds |
EP1639108A2 (en) | 2003-02-28 | 2006-03-29 | McGILL UNIVERSITY | Cell and enzyme compositions for modulating bile acids, cholesterol and triglycerides |
WO2004108067A2 (en) | 2003-04-03 | 2004-12-16 | Sun Pharmaceutical Industries Limited | Programmed drug delivery system |
AU2008202120B2 (en) * | 2003-04-05 | 2009-12-17 | Albireo Ab | Use of an IBAT inhibitor for the treatment of prophylaxis of constipation |
GB0307918D0 (en) | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
CA2584188C (en) | 2003-10-16 | 2014-03-18 | Techcom Group, Llc | Reduced digestible carbohydrate food having reduced blood glucose response |
CN1930137B (zh) | 2004-02-27 | 2011-07-20 | 旭化成制药株式会社 | 苯并硫氮杂卓和苯并虑平化合物 |
TW200533336A (en) | 2004-03-02 | 2005-10-16 | Fujisawa Pharmaceutical Co | Concomitant drugs |
EP1593671A1 (en) | 2004-03-05 | 2005-11-09 | Graffinity Pharmaceuticals AG | DPP-IV inhibitors |
US20050215882A1 (en) | 2004-03-23 | 2005-09-29 | The Regents Of The University Of Michigan | Noninvasive method to determine fat content of tissues using MRI |
TWI415635B (zh) | 2004-05-28 | 2013-11-21 | 必治妥施貴寶公司 | 加衣錠片調製物及製備彼之方法 |
US20050287178A1 (en) | 2004-06-23 | 2005-12-29 | Steed Barrie L | Diagnosis and treatment of heavy gallbladder densities |
JP4896480B2 (ja) | 2004-10-01 | 2012-03-14 | 第一三共ヘルスケア株式会社 | 陰イオン交換樹脂の粒子状組成物 |
US9149439B2 (en) | 2005-03-21 | 2015-10-06 | Sandoz Ag | Multi-particulate, modified-release composition |
WO2006121861A2 (en) | 2005-05-05 | 2006-11-16 | Microbia, Inc. | Biphenylazetidinone cholesterol absorption inhibitors |
WO2006125074A1 (en) | 2005-05-17 | 2006-11-23 | Brown University Research Foundation | Drug delivery formulations for targeted delivery |
US20070237818A1 (en) | 2005-06-02 | 2007-10-11 | Malcolm Bruce A | Controlled-release formulation of HCV protease inhibitor and methods using the same |
DE102005033100B3 (de) | 2005-07-15 | 2007-01-25 | Sanofi-Aventis Deutschland Gmbh | Neues 1,4-Benzothiazepin-1,1-Dioxidderivat mit verbesserten Eigenschaften, diese Verbindung enthaltene Arzneimittel und Verfahren zu deren Herstellung |
DE102005033099A1 (de) | 2005-07-15 | 2007-01-18 | Sanofi-Aventis Deutschland Gmbh | Neues 1,4-Benzothiazepin-1,1-Dioxidderivat mit verbesserten Eigenschaften, Verfahren zu dessen Herstellung, diese Verbindung enthaltende Arzneimittel und dessen Verwendung |
EP1928499B1 (en) | 2005-09-20 | 2011-06-29 | Novartis AG | Use of a dpp-iv inhibitor to reduce hypoglycemic events |
EP2007395A1 (en) | 2006-04-10 | 2008-12-31 | Merck & Co., Inc. | Cgrp antagonist salt |
GB0607534D0 (en) | 2006-04-13 | 2006-05-24 | Univ London Pharmacy | Colonic drug delivery formulation |
US8048413B2 (en) | 2006-05-17 | 2011-11-01 | Helene Huguet | Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules |
DE102006053637B4 (de) | 2006-11-14 | 2011-06-30 | Sanofi-Aventis Deutschland GmbH, 65929 | Neue mit Fluor substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
DE102006053636B4 (de) | 2006-11-14 | 2008-09-18 | Sanofi-Aventis Deutschland Gmbh | Neue mit Cyclohexylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate und deren Verwendung |
DE102006053635B4 (de) | 2006-11-14 | 2011-06-30 | Sanofi-Aventis Deutschland GmbH, 65929 | Neue mit Benzylresten substituierte 1,4-Benzothiepin-1,1-Dioxidderivate, diese Verbindungen enthaltende Arzneimittel und deren Verwendung |
WO2008058631A1 (de) | 2006-11-14 | 2008-05-22 | Sanofi-Aventis Deutschland Gmbh | Neue 1,4-benzothiepin-1,1-dioxidderivate mit verbesserten eigenschaften, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
CA2676417C (en) | 2007-01-19 | 2016-06-28 | Intercept Pharmaceuticals, Inc. | Tgr5 modulators and methods of use thereof |
DE602008002073D1 (de) | 2007-03-02 | 2010-09-16 | Farnam Co Inc | Wachsähnliches material enthaltende tabletten mit verzögerter freisetzung |
PL2200588T3 (pl) | 2007-09-25 | 2019-09-30 | Solubest Ltd. | Kompozycje zawierające lipofilowe związki aktywne i sposób ich wytwarzania |
US9295677B2 (en) | 2008-02-26 | 2016-03-29 | Qing Bile Therapeutics Inc. | Polyhydroxylated bile acids for treatment of biliary disorders |
BRPI0918499A2 (pt) | 2008-09-02 | 2015-12-01 | Usv Ltd | polímeros reticulados |
CA2744817C (en) | 2008-11-26 | 2020-07-07 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of obesity and diabetes |
US20110152204A1 (en) | 2009-12-18 | 2011-06-23 | Satiogen Pharmaceuticals, Inc. | Treatment of Obesity or Diabetes with Bile Acid Sequestrants |
PL2538930T3 (pl) | 2010-02-23 | 2016-11-30 | Preparaty do doustnego dostarczania środków adsorbujących do jelita | |
JO3131B1 (ar) | 2010-04-27 | 2017-09-20 | Glaxosmithkline Llc | مركبات كيميائية |
EP2575821B1 (en) | 2010-05-26 | 2015-08-12 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions |
RS57778B1 (sr) | 2010-11-08 | 2018-12-31 | Albireo Ab | Inhibitori crevnog transportera žučne kiseline (ibat) za lečenje bolesti jetre |
CA2815698C (en) | 2010-11-08 | 2019-04-30 | Albireo Ab | A pharmaceutical combination comprising an ibat inhibitor and a bile acid binder |
MY176863A (en) | 2010-11-08 | 2020-08-24 | Albireo Ab | Ibat inhibitors for treatment of metabolic disorders and related conditions |
US20120114588A1 (en) | 2010-11-08 | 2012-05-10 | Albireo Ab | Ibat inhibitors for treatment of metabolic disorders and related conditions |
KR20190135545A (ko) | 2011-10-28 | 2019-12-06 | 루메나 파마수티컬즈, 인코포레이티드 | 고담혈증 및 담즙 정체성 간 질환 치료용 담즙산 재순환 억제제 |
MX369466B (es) | 2011-10-28 | 2019-11-08 | Lumena Pharmaceuticals Inc | Inhibidores de la recirculación de ácidos biliares para el tratamiento de enfermedades hepáticas colestásicas pediátricas. |
RU2602739C2 (ru) | 2012-05-07 | 2016-11-20 | Киссеи Фармасьютикал Ко., Лтд. | Производное пиразола и его применение в медицинских целях |
JP2016514684A (ja) | 2013-03-15 | 2016-05-23 | ルメナ ファーマシューティカルズ エルエルシー | 原発性硬化性胆管炎および炎症性腸疾患の処置のための胆汁酸再循環阻害剤 |
JO3301B1 (ar) | 2013-04-26 | 2018-09-16 | Albireo Ab | تعديلات بلورية على إيلوبيكسيبات |
KR20160119863A (ko) | 2014-02-27 | 2016-10-14 | 뉴서트 사이언시스, 인크. | 간 지방증의 감소 또는 예방을 위한 조성물 및 방법 |
US20170143743A1 (en) | 2014-06-16 | 2017-05-25 | Valpharma International S.P.A. | Formulation for oral administration containing mesalazine |
KR102560954B1 (ko) | 2014-06-25 | 2023-07-31 | 이에이 파마 가부시키가이샤 | 고형 제제 및 그의 착색 방지 또는 착색 감소 방법 |
WO2015199146A1 (ja) | 2014-06-25 | 2015-12-30 | 味の素株式会社 | 固形製剤及びその安定化方法 |
KR101674806B1 (ko) | 2014-10-20 | 2016-11-10 | 씨제이헬스케어 주식회사 | 신규한 아미노알킬벤조티아제핀 유도체 및 이의 용도 |
EP3012252A1 (en) | 2014-10-24 | 2016-04-27 | Ferring BV | Crystal modifications of elobixibat |
US9684018B2 (en) | 2014-11-19 | 2017-06-20 | Texas Instruments Incorporated | Current sense circuit that operates over a wide range of currents |
KR20160061492A (ko) | 2014-11-21 | 2016-06-01 | 삼성디스플레이 주식회사 | 휴대용 먼지 센서 및 이를 이용한 휴대전화 |
CN105985254B (zh) | 2015-02-17 | 2018-03-16 | 上海中科绿碳化工科技有限公司 | 一种制备甲酰胺类化合物的方法 |
US10786529B2 (en) | 2016-02-09 | 2020-09-29 | Albireo Ab | Oral cholestyramine formulation and use thereof |
ES2874669T3 (es) * | 2016-02-09 | 2021-11-05 | Albireo Ab | Formulación oral de colestiramina y uso de la misma |
CN108601745B (zh) | 2016-02-09 | 2021-12-07 | 阿尔比里奥公司 | 口服考来烯胺制剂及其用途 |
ES2784446T3 (es) | 2016-02-09 | 2020-09-25 | Albireo Ab | Microgránulos de colestiramina y métodos para la preparación de los mismos |
US10441605B2 (en) | 2016-02-09 | 2019-10-15 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US10441604B2 (en) | 2016-02-09 | 2019-10-15 | Albireo Ab | Cholestyramine pellets and methods for preparation thereof |
US11350844B2 (en) | 2016-11-23 | 2022-06-07 | Mayo Foundation For Medical Education And Research | System and method for generating nonalcoholic fatty liver disease activity score (NAS) using magnetic resonance elastography |
KR101844184B1 (ko) | 2017-07-21 | 2018-04-02 | 씨제이헬스케어 주식회사 | 아미노알킬벤조티아제핀 유도체의 용도 |
JP2020530448A (ja) | 2017-08-09 | 2020-10-22 | アルビレオ・アクチボラグ | コレスチラミン顆粒、経口コレスチラミン製剤、及びそれらの使用 |
EP3664782A1 (en) | 2017-08-09 | 2020-06-17 | Albireo AB | Cholestyramine pellets, oral cholestyramine formulations and use thereof |
US10428109B1 (en) | 2018-03-09 | 2019-10-01 | Elobix Ab | Process for the preparation of 1,5-benzothiazepine compounds |
CN111836804A (zh) | 2018-03-09 | 2020-10-27 | 埃洛比克斯股份公司 | 用于制备依洛昔巴特的方法 |
TW202015699A (zh) | 2018-06-05 | 2020-05-01 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽汁酸調節劑之用途 |
US10793534B2 (en) | 2018-06-05 | 2020-10-06 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
US11801226B2 (en) | 2018-06-20 | 2023-10-31 | Albireo Ab | Pharmaceutical formulation of odevixibat |
WO2019245449A1 (en) | 2018-06-20 | 2019-12-26 | Albireo Ab | Pharmaceutical formulation of odevixibat |
US10722457B2 (en) | 2018-08-09 | 2020-07-28 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US20200046758A1 (en) | 2018-08-09 | 2020-02-13 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US11007142B2 (en) | 2018-08-09 | 2021-05-18 | Albireo Ab | Oral cholestyramine formulation and use thereof |
US11549878B2 (en) | 2018-08-09 | 2023-01-10 | Albireo Ab | In vitro method for determining the adsorbing capacity of an insoluble adsorbant |
US20200046757A1 (en) | 2018-08-09 | 2020-02-13 | Albireo Ab | Cholestyramine pellets, oral cholestyramine formulations, and uses thereof |
BR112021005714A2 (pt) | 2018-09-27 | 2021-06-22 | Albireo Energy, Llc | sistema, dispositivos, e dispositivo vav híbrido com múltiplas serpentinas de aquecimento |
US10941127B2 (en) | 2019-02-06 | 2021-03-09 | Albireo Ab | Benzothiadiazepine compounds and their use as bile acid modulators |
FI3921028T3 (fi) | 2019-02-06 | 2023-01-31 | Bentsotiadiatsepiinin yhdisteet ja niiden käyttö sappihapon modulaattoreina | |
US10975045B2 (en) | 2019-02-06 | 2021-04-13 | Aibireo AB | Benzothiazepine compounds and their use as bile acid modulators |
EP3921027B1 (en) | 2019-02-06 | 2023-07-19 | Albireo AB | Benzothiazepine compounds and their use as bile acid modulators |
KR20210137046A (ko) | 2019-02-12 | 2021-11-17 | 미룸 파마슈티컬스, 인크. | 담즙정체의 치료 방법 |
US20220105218A1 (en) | 2019-02-15 | 2022-04-07 | The Board Of Trustees Of The Leland Standford Junior University | Methods and systems for reducing a pathogen population |
WO2021110887A1 (en) | 2019-12-04 | 2021-06-10 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
CR20220315A (es) | 2019-12-04 | 2022-10-26 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como moduladores del ácido biliar |
ES2973355T3 (es) | 2019-12-04 | 2024-06-19 | Albireo Ab | Compuestos de benzotia(di)azepina y su uso como moduladores del ácido biliar |
AR120682A1 (es) | 2019-12-04 | 2022-03-09 | Albireo Ab | Compuestos de benzotiadiazepina y su uso como moduladores del ácido biliar |
EP4069247A1 (en) | 2019-12-04 | 2022-10-12 | Albireo AB | Benzothiadiazepine compounds and their use as bile acid modulators |
AR120683A1 (es) | 2019-12-04 | 2022-03-09 | Albireo Ab | Compuestos de benzoti(di)azepina y su uso como ácido biliar |
EP4069359B1 (en) | 2019-12-04 | 2024-01-03 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
US11014898B1 (en) | 2020-12-04 | 2021-05-25 | Albireo Ab | Benzothiazepine compounds and their use as bile acid modulators |
TW202134220A (zh) | 2019-12-04 | 2021-09-16 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
EP4188541A1 (en) | 2020-08-03 | 2023-06-07 | Albireo AB | Benzothia(di)azepine compounds and their use as bile acid modulators |
WO2022029101A1 (en) | 2020-08-03 | 2022-02-10 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
KR20230106651A (ko) | 2020-11-12 | 2023-07-13 | 알비레오 에이비 | 진행성 가족성 간내 담즙정체증(pfic)을 치료하기 위한 오데빅시바트 |
AU2021390172A1 (en) | 2020-12-04 | 2023-06-22 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
TW202313579A (zh) | 2021-06-03 | 2023-04-01 | 瑞典商艾爾比瑞歐公司 | 苯并噻(二)氮呯(benzothia(di)azepine)化合物及其作為膽酸調節劑之用途 |
US20230338392A1 (en) | 2022-04-22 | 2023-10-26 | Albireo Ab | Subcutaneous administration of an asbt inhibitor |
US20230398125A1 (en) | 2022-06-09 | 2023-12-14 | Albireo Ab | Treating hepatitis |
US20240067617A1 (en) | 2022-07-05 | 2024-02-29 | Albireo Ab | Benzothia(di)azepine compounds and their use as bile acid modulators |
-
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