TWI498128B - 經安定化培美曲塞調配劑 - Google Patents
經安定化培美曲塞調配劑 Download PDFInfo
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- TWI498128B TWI498128B TW102143402A TW102143402A TWI498128B TW I498128 B TWI498128 B TW I498128B TW 102143402 A TW102143402 A TW 102143402A TW 102143402 A TW102143402 A TW 102143402A TW I498128 B TWI498128 B TW I498128B
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- formulation
- pemetrexed
- acid
- citrate
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Description
本發明乃有關經安定化培美曲塞(pemetrexed)調配劑，更具體而言係有關包含乙醯半胱胺酸作為抗氧化劑與檸檬酸鹽作為緩衝劑之經安定化培美曲塞調配劑。
已知具抗葉酸活性之特定化合物以用於癌症治療之化學治療劑而聞名。美國專利案第5,344,932號揭示用於製備包括培美曲塞之某些經取代之吡咯并[2,3-d]嘧啶系抗葉酸衍生物之方法；歐洲專利公開案第0434426號揭示一系列4-羥基吡咯并[2,3-d]嘧啶-L-麩胺酸衍生物。
培美曲塞，5-經取代之吡咯并[2,3-d]嘧啶，係藉由抑制涉及葉酸代謝之代謝物的活性而展現對包括非小細胞肺癌之各種癌症的抗癌作用之多標靶抗葉酸。
一般已知，培美曲塞經由主要葉酸運輸系統之還原型葉酸載體(RFC)進入細胞，然後被葉醯聚麩胺酸合成酶(FPGS)活化，形成靶向胸腺嘧啶核苷酸合成酶(TS)與二氫葉酸還原酶(DHFR)之聚麩胺酸衍生物。
目前，培美曲塞以愛寧達(Alimta)商品名在
市場上銷售，且係用於作為惡性肋膜間質細胞瘤(malignant pleural mesothelioma)與非小細胞肺癌之治療劑[參見Physicians’Desk Reference,60th
ed.,pp.1722-1728(2006)]。愛寧達呈凍乾調配劑販售，給藥前必須重組。具體而言，愛寧達呈凍乾粉末調配劑(100mg或500mg)販售，於投予病患前，必須以0.9%氯化鈉溶液重組，且最後以0.9%氯化鈉溶液稀釋至最終濃度為0.25mg/ml。
凍乾粉末調配劑之製備複雜，且製備彼等調配劑之方法非常昂貴。此外，凍乾調配劑於再組成時具有遭微生物污染之風險；參與包含彼等調配劑之藥物製備之藥劑師、醫生、護士等極可能暴露於破壞細胞之物質中。因此，於例如培美曲塞之細胞毒性抗癌劑之情況下，需要開發可長時間貯存之隨時可用之液態調配劑，而非開發凍乾調配劑。
許多情況下，液態調配劑之問題在於貯存期間之不安定性。由於此不安定性，大量可注射調配劑係使用注射前立即溶解之凍乾調配劑的形式。甚至在近來已提供凍乾調配劑形式之培美曲塞或其醫藥上可接受之鹽之情況下，呈水溶液調配劑之製劑於室溫下長時間貯存時會引起未知雜質增加之問題。亦即，此水溶液調配劑遭遇安定性問題。由於此安定性問題，於臨床應用上，培美曲塞或其醫藥上可接受之鹽目前係使用凍乾成形之形式。
為了克服上述缺點，已有若干調配劑被提出。舉例而言，美國專利案第6,686,365號(相當於韓國專
利公開案第2002-0081293號)揭示穩定之培美曲塞之液態調配劑，其包含有效治療量之培美曲塞、有效量之抗氧化劑與醫藥上可接受之賦形劑，其中抗氧化劑係選自由硫代甘油(monothioglycerol)、L-半胱胺酸與硫代乙醇酸所組成之群組。
然而，有關上述專利案中所揭示之調配劑問題，據報導，當調配劑於25℃下長期貯存時發生沈澱，表示該調配劑於所欲期間之長期安定性無法獲得保證(PCT國際專利公開案WO 2012/015810號)。迄今，尚無可長期安定貯存之液態培美曲塞調配劑於實驗或商業上被實現。事實上，本發明人等使用上述抗氧化劑的L-半胱胺酸製備含培美曲塞之液態調配劑，並針對所製備之調配劑進行安定性試驗，於逆境試驗(stress test)條件下2週後，惟觀察到包括例如褪色之外觀變化、雜質增加、與pH下降之數個問題。此外，本發明人等使用包括抗壞血酸、硫代硫酸鈉、丁基化之羥基苯甲醚、沒食子酸丙酯、EDTA、L-甲硫胺酸、與乙醯半胱胺酸等約60種安定劑製備含培美曲塞之液態調配劑，惟彼等調配劑均具不充足之安定性。
針對此背景，本發明人等進行精深研究以克服液態培美曲塞調配劑之安定性問題，結果發現，當一起使用乙醯半胱胺酸作為抗氧化劑與檸檬酸鹽作為緩衝劑時，具高安定性之安定培美曲塞調配劑於貯存期間維持無
沈澱之透明溶液狀態，其中培美曲塞異構物雜質與未知雜質之形成被有效調控或抑制，從而完成本發明。
本發明之目的在於提供一種經安定化培美曲塞調配劑。
本發明可提供一種容易以商業方式製備、可防止於冷凍乾燥與重組期間所可能發生之微生物污染、且具改善之便利性與安定性之培美曲塞調配劑。此外，不同於習知之含培美曲塞之可注射液態調配劑，本發明可提供含有乙醯半胱胺酸作為抗氧化劑以及檸檬酸鈉作為緩衝劑，從而展現沒有例如褪色或沈澱等異常外觀，並符合接受標準(acceptance criteria)之經安定化培美曲塞調配劑。
第1圖顯示於4週逆境安定性試驗(60℃與80%)後，習知之含培美曲塞可注射液態調配劑(比較例1、12與14)與本發明之含培美曲塞之可注射液態調配劑(實施例11)間之外觀比較。WFI(注射用水)之外觀亦顯示於第1圖中，以供比較。
於一態樣中，本發明提供一種培美曲塞調配劑，其包含：作為活性成分之培美曲塞或其醫藥上可接
受之鹽；N-乙醯基-L-半胱胺酸；及檸檬酸鹽。
於本發明中，培美曲塞或其醫藥上可接受之鹽、N-乙醯基-L-半胱胺酸與檸檬酸鹽可以1至30：0.15至2.0：1.0至15.0之濃度比例呈現。
較佳為，培美曲塞或其醫藥上可接受之鹽、N-乙醯基-L-半胱胺酸與檸檬酸鹽可以1至30：1.5：1.0至15.0之濃度比例呈現。
於本發明中，該調配劑可為可呈溶液狀態貯存之液態調配劑。
於本發明中，該調配劑可為包含於密封容器中，以便隨時可用之可注射液態調配劑。
然而，本發明之範圍不必侷限於可注射之液態調配劑，而包括根據該發明所屬技術領域中具有通常知識者之常識或根據相關技術領域中之常用方法所製備之其他液態調配劑及非液態調配劑。
下文中，將詳細說明本發明。
通常，使用廣泛之各種抗氧化劑以達安定調配劑之目的，其具體實例包括對羥苯甲酸酯衍生物、醇類、酚衍生物、乙汞硫柳酸鈉(thimerosal)、乙酸酐、羧酸鈉、月桂基硫酸鹽、抗氧化劑、硫化物、亞硫酸鹽、胱胺酸、半胱胺酸、半胱胺、胺基酸、有機酸例如抗壞血酸、視網醇、生育酚、丁基化之羥基苯甲醚等。
此外，韓國專利註冊案第10-0774366號揭示為作為紫杉醇之抗氧化劑之N-乙醯胺基酸；及韓國專利
公開案第10-2007-0028331號揭示作為待克菲那(diclofenac)組成物之抗氧化劑之硫代甘油與乙二胺四乙酸。
本發明人等於可注射之培美曲塞調配劑中測試上述抗氧化劑，惟特別是於可注射之調配劑中，以此類常用物質作為賦形劑(抗氧化劑)，而非原料藥(API)使用時，其日劑量受到限制。此外，單只有抗氧化劑無法改善調配劑之安定性。再者，於使用習知之可注射之調配劑中常用之抗壞血酸、乳酸等時，彼等可注射之調配劑會部分褪色及/或產生沈澱，表示彼等調配劑具酸不穩定性(實驗例1與2)。
然而，本發明人等意外發現，當包含作為活性成分之培美曲塞或其醫藥上可接受之鹽之組成物與乙醯半胱胺酸及檸檬酸鈉一起使用時，於逆境試驗條件(60℃及80%)下之4週安定性試驗期間，該活性成分未被大幅修飾，且未發生褪色或沈澱，表示該組成物具有符合所要求之接受標準之安定性(實驗例1與2)。乙醯半胱胺酸與檸檬酸鈉均為一般常用之物質，且由於價格低廉，於商業條件下亦有利。
本發明之培美曲塞調配劑包含作為活性成分之培美曲塞或其醫藥上可接受之鹽。本發明之該培美曲塞包含具醫藥活性之藥物或經由體內化學或酵素加工而成為具藥理活性之藥物。具體而言，用於本發明之培美曲塞可為培美曲塞藥物本身或其醫藥上可接受之鹽。
本文所用之“培美曲塞”一詞係指名為5-
經取代之吡咯并[2,3-d]嘧啶之化合物。具體而言，該術語係指下式1所示並對包括非小細胞肺癌與惡性肋膜間質細胞瘤之各種癌症展現抗癌作用之多標靶抗葉酸：
培美曲塞藉由抑制涉及葉酸代謝之代謝物的活性而展現對包括非小細胞肺癌與惡性肋膜間質細胞瘤之各種癌症之抗癌作用。
本文所用之“醫藥上可接受之鹽”一詞係指本領域中已知之傳統方法所製備之鹽。此製備方法為該發明所屬技術領域中具有通常知識者已知者。醫藥上可接受之鹽之具體實例包括，惟不限於，衍生自藥理學上或生理學上可接受之如下述之無機酸、有機酸與鹼之鹽。適當酸之實例包括鹽酸、溴酸、氫溴酸、硫酸、硝酸、過氯酸、反丁烯二酸、順丁烯二酸、磷酸、乙醇酸、乳酸、水楊酸、琥珀酸、對甲苯磺酸、酒石酸、乙酸、檸檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸等。衍生自適當鹼之鹽之實例包括，惟不限於，例如鈉與鉀等鹼金屬之鹽，及例如鎂之鹼土金屬之鹽。
本文所用之“乙醯半胱胺酸”一詞係指名
為N-乙醯基-L-半胱胺酸(NAC，C5
H9
NO3
S，CAS登錄號616-91-1)之化合物，於本發明之培美曲塞調配劑中用於作為抗氧化劑。本發明中，“乙醯半胱胺酸”與“N-乙醯基-L-半胱胺酸”係彼此互換使用。
作為抗氧化劑之乙醯半胱胺酸見述於美國藥典(參見U.S.Pharmacopeia 35-National Formulary 10,p 2069)。乙醯半胱胺酸為食物中所含胺基酸L-半胱胺酸之前驅物。半胱胺酸容易經氧化而變化為不溶性物質，而乙醯半胱胺酸則穩定且不易變化，從而可口服或經靜脈內投予。
本文所用之“檸檬酸鹽”一詞係指檸檬酸之鹽及意指於本發明之培美曲塞調配劑中用於作為緩衝劑之化合物。檸檬酸鹽可為檸檬酸鈉。
根據本發明，經由使用乙醯半胱胺酸作為抗氧化劑以及檸檬酸鈉作為緩衝劑，可提供能使培美曲塞於1至30℃之溫度下，以安定方式於醫藥上貯存長時間之培美曲塞調配劑。
於本發明之培美曲塞調配劑中，培美曲塞或其醫藥上可接受之鹽：N-乙醯基-L-半胱胺酸：檸檬酸鹽之濃度比例較佳為1至30：0.15至2.0：1.0至15.0，更佳為1至30：1.5：1.0至15.0。本文中，各個濃度可以單位mg/mL表示。可觀察到，於上述濃度比例範圍之外的濃度比例之培美曲塞調配劑的情況下，隨著貯存時間之推移，雜質之產生增加至超出接受標準(實驗例1)。
於本發明中，培美曲塞調配劑可包含醫藥
上可接受之載劑及pH調整劑。
於本發明中，培美曲塞調配劑較佳為可呈溶液狀態貯存之液態調配劑，且更佳為包含於密封容器中，以便隨時可用之可注射液態調配劑。
當本發明之培美曲塞調配劑為可注射液態調配劑時，醫藥上可接受之載劑為WFI(注射用水)。
於本發明中，培美曲塞之可注射液態調配劑之pH較佳為約6.0至8.0，更佳為約7.2至7.8。液態調配劑之pH可使用酸例如鹽酸，或鹼例如氫氧化鈉調整。
本發明之培美曲塞調配劑除了乙醯半胱胺酸與檸檬酸鹽之外，雖然可能不含其他添加劑，惟其可進一步包含醫藥上可接受之賦形劑。醫藥上可接受賦形劑之實例包括已知添加劑，例如乳糖、右旋葡萄糖、環糊精及其衍生物、蔗糖、甘油、碳酸鈉。較佳之賦形劑可為氯化鈉與甘露糖醇。
於製備本發明之調配劑之方法中，進行以例如氮或氬之惰性氣體之驅氣(purge)以維持低氧條件，隨後進行滅菌及過濾。
此外，本發明之經安定化培美曲塞調配劑可裝填於本領域中已知之適當容器中。舉例而言，該容器可為玻璃小瓶、玻璃瓶、藥匣(cartridge)、預充式注射器等。較佳地，該容器係玻璃小瓶。
本發明之培美曲塞可注射液態調配劑係分配於已先行洗滌及滅菌之容器中，且該容器以其表面不與
液態調配劑反應之鐵氟龍塞子密封。若有需要，則於該可注射液態調配劑與塞子間之空間填充惰性氣體。使用雷管夾(crimper)裝上塞子，然後，若有需要，則將裝填可注射之液態調配劑之該小瓶加熱及滅菌。
下文中，將參照實施例更詳細地說明本發明；然而，欲被瞭解的是彼等實施例僅供說明用途，而不並非意欲對本發明範圍構成侷限。
實施例1至14：含有不同量乙醯半胱胺酸作為抗氧化劑與檸檬酸鈉作為緩衝劑之含培美曲塞可注射液之製備
使2.5g D-甘露糖醇溶於100ml WFI(注射用水)中，然後於其內依序添加下表1中所示濃度之乙醯半胱胺酸與檸檬酸鈉，使之於其中完全溶解。緩緩添加2.5g培美曲塞至溶液中(實施例14中為緩緩添加3.0g培美曲塞)，攪拌該溶液至成為清澈透明。然後，使用鹽酸或氫氧化鈉水溶液調整該溶液至表1中所示pH。於無塵室中，通過經滅菌之0.22-μm膜濾器，使溶液進行無菌過濾。將所得溶液裝填於經洗滌/殺菌之已先行以氮驅氣之可密封容器中。
所製得之含培美曲塞之可注射液之成分與pH顯示於下表1。
實施例15與16：具不同pH之含培美曲塞之可注射液之製備
使2.5g D-甘露糖醇溶於100ml WFI(注射用水)中，然後於其內依序添加下表2中所示濃度之乙醯半胱胺酸與檸檬酸鈉，使之於其中完全溶解。緩緩添加2.5g培美曲塞至溶液中，攪拌該溶液直至成為清澈透明。然後，使用鹽酸或氫氧化鈉水溶液調整溶液至表2中所示pH。於無塵室中，通過經滅菌之0.22-μm膜濾器，使溶液進行無菌過
濾，將所得溶液裝填於經洗滌/殺菌之已先行以氮驅氣之可密封容器中。
所製得之含培美曲塞之可注射液之成分與pH示於下表2。
比較例1至8：使用不同種類抗氧化劑之含培美曲塞之可注射液之製備
根據下表3中所示成分及含量，以如實施例1中敘述之相同方法製備含培美曲塞之溶液。比較例1中，係製備無抗氧化劑而只含WFI(注射用水)作為載劑之溶液。
比較例9至14：含有不同種類抗氧化劑與含或不含緩衝劑之含培美曲塞之可注射液之製備
根據下表4中所示成分及含量，以如實施例1中敘述之相同方法製備含培美曲塞之溶液。
比較例15至17：含有不同種類緩衝劑之含培美曲塞之可注射液之製備
根據下表5中所示成分及含量，以如實施例1中敘述之相同方法製備含培美曲塞之溶液。
實驗例：安定性試驗
測試實施例1至16及比較例1至17所製備之組成物於為時4週之逆境試驗條件下(60℃與80%)之安定性。於彼等組成物中，亦測試實施例11及比較例1、12與14之組成物於為時4個月之加速條件(accelerated conditions)(40℃與70%)下之安定性。使用高效液相層析法，於下表6中所示條件下，測定水溶液中培美曲塞與雜質之含量以進行安定性評估。
實驗例1：逆境安定性試驗(60℃/80%，4週評估)
如上文所述，進行逆境安定性試驗，試驗結果示於下表7至11中。
又，第1圖顯示在逆境試驗條件(60℃與80%)下之4週安定性試驗期間，本發明之含培美曲塞之可注射液態調配劑(實施例11)與本領域中之含培美曲塞之可注射液態調配劑(比較例1、12與14)間之外觀比較。WFI(注射用水)之外觀亦顯示於第1圖中，以供比較。
從表7之結果可看出，4週逆境試驗條件期間，含1.5mg/mL乙醯半胱胺酸作為抗氧化劑及1至15
mg/mL檸檬酸鈉作為緩衝劑之調配劑顯示0.2%以下之個別雜質含量及1.0%以下之總雜質含量，表示彼等調配劑具優異之安定性(實施例9至12)。
此外，含1.0至1.5mg/mL之乙醯半胱胺酸及2.0mg/mL檸檬酸鈉作為緩衝劑之調配劑顯示0.2%以下之個別雜質含量及1.0%以下之總雜質含量，表示彼等調配劑具優異之安定性(實施例8與10)。然而，觀察到當乙醯半胱胺酸濃度低於1.0至1.5mg/mL時，雖然雜質含量符合接受標準，惟發生外觀之變化(褪色)(實施例1至2)。
此外，當乙醯半胱胺酸濃度為2.0mg/mL及檸檬酸鈉濃度為5.0mg/mL時，雜質含量符合接受標準，惟發生外觀之變化(褪色)(實施例13)。
再者，當乙醯半胱胺酸濃度為0.5mg/mL及檸檬酸鈉濃度為1.0至5.0mg/mL時，雜質含量符合接受標準，惟發生外觀之變化(褪色)(實施例3至7)。
從上表8之結果可看出，逆境條件下之4週安定性試驗期間，儘管有pH上之變化，含作為抗氧化劑之乙醯半胱胺酸及作為緩衝劑之檸檬酸鈉之調配劑顯示0.2%以下之個別雜質含量及1.0%以下之總雜質含量，表示彼等調配劑具優異之安定性。
從上表9之結果可看出，含有本領域中常用之抗氧化劑之調配劑中，逆境條件下之安定性試驗期間，發生外觀之變化(沈澱或褪色)，或個別雜質含量增加至高於0.2%及總雜質含量增加至高於1.0%。此顯示含有本領域中常用之抗氧化劑之含培美曲塞的可注射液，就雜質或外觀變化而言，未提供足夠之安定性。
從上表10之結果可看出，逆境條件下之4週安定性試驗期間，當調配劑含乙醯半胱胺酸作為抗氧化劑以及檸檬酸鈉作為緩衝劑時，較佳為於乙醯半胱胺酸濃度1.5mg/mL及檸檬酸鈉濃度5.0mg/mL時，該調配劑顯示0.2%以下之個別雜質含量及1.0%以下之總雜質含量，表示此調配劑具優異之安定性(實施例11)。
然而，於調配劑溶液中只含檸檬酸鈉作為緩衝劑之情況下，清楚觀察到，逆境條件下2週後，該溶液的顏色開始變成深黃色(比較例9與10)。此外，於調配劑含L-半胱胺酸或乙醯半胱胺酸作為抗氧化劑之情況下，清楚觀察到，逆境條件下2週後，該溶液的顏色開始變成淡黃色，及於逆境條件下4週試驗期間，pH顯著下降(比較例11與12至14)。換言之，可看出，不同於單獨使用乙醯半胱胺酸或檸檬酸鈉，結合使用乙醯半胱胺酸與檸檬酸鈉顯著改善雜質之安定性。
此外，於比較例13與14之只含L-半胱胺酸之調配劑溶液中，顯示嚴苛條件下2週後，開始出現似腐蛋之異味，惟於本發明調配劑中，不產生此異味。
從上表11之結果可看出，對含作為抗氧化劑之乙醯半胱胺酸及各種常用緩衝劑之調配劑之安定性進行比較，發現當使用檸檬酸鈉以外之緩衝劑時，於開始階段出現外觀之變化(褪色)，或個別雜質含量增加至高於0.2%及總雜質含量增加至高於1.0%。
因此證實，只有含乙醯半胱胺酸作為抗氧化劑以及檸檬酸鈉作為緩衝劑之含培美曲塞之可注射液顯示最佳安定性。
實驗例2：加速之安定性試驗(40℃/70%，4個月評估)
如上所述，進行加速之安定性試驗，試驗結果示於下表12。
從上表12之結果可看出，只使用WFI(注射用水)作為載劑而不添加抗氧化劑所製備之比較例1調配劑中，在加速條件下2個月後，溶液外觀變成黃色，4個月時，該溶液顯示0.2%以上之個別雜質含量及1%之總
雜質含量，表示該調配劑安定性不充足。同時，含乙醯半胱胺酸作為抗氧化劑以及檸檬酸鈉作為緩衝劑之實施例11之調配劑中，加速條件下6個月試驗期間，顯示0.2%以下之個別雜質含量及1%以下之總雜質含量，表示該調配劑具優異之安定性。
相反地，發現只含乙醯半胱胺酸作為抗氧化劑之調配劑中，在加速條件下4個月後，溶液顏色變成黃色，且個別雜質含量大於0.2%，表示該調配劑安定性不充足(比較例12)。
此外，於只含L-半胱胺酸之比較例14之調配劑之情況下，雜質含量符合接受標準，惟逆境安定性試驗結果出現似腐蛋之異味。然而，此異味不會出現於本發明調配劑，亦即實施例11之調配劑中。
由於本案的圖為含培美曲塞可注射液態調配劑外觀比較，並非本案的代表圖。故本案無指定代表圖。
Claims (6)
- 一種培美曲塞(pemetrexed)調配劑，其包含：作為活性成分之培美曲塞或其醫藥上可接受之鹽；N-乙醯基-L-半胱胺酸；與檸檬酸鹽。
- 如申請專利範圍第1項所述之培美曲塞調配劑，其中該培美曲塞或其醫藥上可接受之鹽：N-乙醯基-L-半胱胺酸：檸檬酸鹽之濃度比例為1至30：0.15至2.0：1.0至15.0。
- 如申請專利範圍第2項所述之培美曲塞調配劑，其中該培美曲塞或其醫藥上可接受之鹽：N-乙醯基-L-半胱胺酸：檸檬酸鹽之濃度比例為1至30：1.5：1.0至15.0。
- 如申請專利範圍第1項所述之培美曲塞調配劑，其中該檸檬酸鹽為檸檬酸鈉。
- 如申請專利範圍第1項所述之培美曲塞調配劑，其中該調配劑係可呈溶液狀態貯存之液態調配劑。
- 如申請專利範圍第1項所述之培美曲塞調配劑，其中該調配劑係包含於密封容器中，以便隨時可用之可注射之液態調配劑。
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| DE102012010774A1 (de) | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmazeutische Pemetrexed-Lösung |
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| KR101919436B1 (ko) | 2015-05-28 | 2018-11-16 | 주식회사 삼양바이오팜 | 안정화된 약학 조성물 및 그의 제조방법 |
| KR101693675B1 (ko) | 2015-12-14 | 2017-01-06 | 주식회사 종근당 | 페메트렉시드 또는 그의 약제학적으로 허용가능한 염을 함유하는 안정화된 약학조성물 |
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| CA2032695A1 (en) | 1989-12-20 | 1991-06-21 | Hiroshi Akimoto | Condensed heterocyclic compounds, their production and use |
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| US6686365B2 (en) * | 2000-02-04 | 2004-02-03 | Eli Lilly And Company | Pharmaceutical composition |
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| CH697021A5 (de) * | 2003-06-26 | 2008-03-31 | Merck Eprova Ag | Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat. |
| US20050238674A1 (en) | 2004-03-10 | 2005-10-27 | Shimoda Biotech (Pty) Ltd. | Stable injectable compositions |
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| EP2072518A1 (en) * | 2007-12-23 | 2009-06-24 | Sun Pharma Advanced Research Company Limited | Stable Amorphous Form of Pemextred Disodium |
| KR101069128B1 (ko) * | 2011-03-10 | 2011-09-30 | 건일제약 주식회사 | 페메트렉시드 또는 그의 염을 포함하는 항산화제-비함유 주사용 용액 형태의 약학적 제제의 제조방법 |
| DE102012010774A1 (de) * | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmazeutische Pemetrexed-Lösung |
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| WO2012015810A2 (en) * | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
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| US20150297724A1 (en) | 2015-10-22 |
| JOP20130342B1 (ar) | 2021-08-17 |
| HK1212224A1 (zh) | 2016-06-10 |
| BR112015012460B1 (pt) | 2022-04-05 |
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| PH12015500900A1 (en) | 2015-07-06 |
| CL2015001461A1 (es) | 2015-10-23 |
| BR112015012460A2 (zh) | 2017-08-22 |
| EP2925325A1 (en) | 2015-10-07 |
| WO2014084651A1 (en) | 2014-06-05 |
| US9265832B2 (en) | 2016-02-23 |
| KR101260636B1 (ko) | 2013-05-13 |
| TW201434493A (zh) | 2014-09-16 |
| JP5934448B2 (ja) | 2016-06-15 |
| RU2015122023A (ru) | 2017-01-10 |
| EP2925325A4 (en) | 2016-07-13 |
| MX355461B (es) | 2018-04-19 |
| PH12015500900B1 (en) | 2015-07-06 |
| CN104812392A (zh) | 2015-07-29 |
| AR093645A1 (es) | 2015-06-17 |
| RU2620341C2 (ru) | 2017-05-24 |
| CN104812392B (zh) | 2017-05-17 |
| EP2925325B1 (en) | 2017-11-01 |
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