TWI617307B - 包含抑制癌細胞之生長的醯胺衍生物及非金屬鹽潤滑劑之藥學組成物 - Google Patents
包含抑制癌細胞之生長的醯胺衍生物及非金屬鹽潤滑劑之藥學組成物 Download PDFInfo
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- TWI617307B TWI617307B TW101120270A TW101120270A TWI617307B TW I617307 B TWI617307 B TW I617307B TW 101120270 A TW101120270 A TW 101120270A TW 101120270 A TW101120270 A TW 101120270A TW I617307 B TWI617307 B TW I617307B
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- pharmaceutical composition
- glyceryl
- metal salt
- polyethylene glycol
- salt lubricant
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明揭示含一醯胺衍生物或其一藥學上可接受鹽與一非金屬鹽潤滑劑之藥學組成物,由於其增強的貯存安定性及經過一段時間後無品質變化現象,所以可作為有效的癌細胞生長抑制劑。
Description
本發明係有關於含一抑制癌細胞之生長的醯胺衍生物或其藥學上可接受鹽、及一非金屬鹽潤滑劑之藥學組成物。
已知表皮生長因子受體(EGFR)具有4種受體亞型,亦即EGFR/ErbB1、Her-2/ErbB2、Her-3/ErbB3、及Her-4/ErbB4。其等可在大部份實體腫瘤細胞內異常地過度表現。而且,藉配位基而活化該受體之作用可導致細胞傳訊路徑的活化,其會使腫瘤細胞生長、分化、血管生成、轉移、並產生抗藥性(A.Wells,Int.J.Biochem.Cell Biol.,1999,31,637-643)。因此,已預期藉該表皮生長因子受體而媒介之腫瘤細胞傳訊路徑的阻斷可產生抗腫瘤效用。所以,已進行用於研發可靶定該表皮生長因子受體之抗癌藥物的許多研究努力。
此等可靶定該表皮生長因子受體之抗癌藥物分成兩類:可靶定一細胞外的結構域之單株抗體以及可靶定一細胞內的酪胺酸激酶之小分子藥物。由於對於該等表皮生長因子受體之選擇性結合作用,所以該等單株抗體具有以下優點:良好的藥學功效且副作用小。然而,該等單株抗體的缺點為很昂貴且必需藉注射而投藥。同時,該可靶定一酪胺激酶的小分子藥物價格相當不昂貴且可口服,而且經
由選擇性或同時與該等受體亞型(例如EGFR、Her-2、Her-3及Her-4)反應,其等亦具有良好的藥效。
該等小分子藥物的實例包括EGFR之選擇性抑制劑,諸如Iressa®(Gefitinib,AstraZenaca)與Tarceva®(Erlotinib,Roche);及同時可阻斷EGFR及Her-2之雙重抑制劑,諸如Tykerb®(Lapatinib,GlaxoSmithKline)。這些藥物目前分別被用於治療肺癌及晚期的Her-2陽性乳癌。因此,亦進行臨床試驗以增加抗其它實體腫瘤的效力。
一項最近的研究已報告第二突變(亦即在對該EGFR酪胺酸激酶結構域之三磷酸腺苷(ATP)結合部位內之胺基酸位置790的蘇胺酸對甲硫胺酸之取代反應)可減少該藥物的結合能力,其會導致藥物反應速率的激烈地降低(C.H.Gow,等人,PLoS Med.,2005,2(9),e269)。因此,需要研發一具有抗EGFR抗性癌細胞之增強的抑制活性的藥物。
韓國專利早期公開案第2008-0107294號揭示一式(I)化合物,其可選擇性且有效性地抑制癌細胞的生長與藉該EGFR及其突變物誘發之抗藥性的形成且不會有副作用。然而,已發現該含作為活性成份之式(I)化合物及其藥學上可接受添加物之藥學調配物會在某些貯存條件下助長式(II)化合物(下文,稱為相關化合物IV)的形成,因此會減少該式(I)化合物的數量。
一活性成份的純度為用於製造安全且有效的藥學組成物之重要因素,因為藥物所含的某些雜質在治療期間會產生副作用。在該藥物的製造期間可移除該等雜質之一部份。但是由於在,諸如溫度、濕度及光的各種條件內之變化,所以藉該藥物之降解而產生的某些物質可呈雜質形式殘留。
本發明者已努力研究在一含式(I)化合物的藥學調配物之貯存期間可促進該相關化合物IV的形成之因素且已發現藥學上可接受添加物,尤其潤滑劑內所含的金屬鹽,可導致該相關化合物IV的形成。因此,本發明者已藉使用一非金屬鹽潤滑劑(其不含金屬鹽組份)而研發出一具有增強的安定性之藥學組成物。
本發明之一目標為提供含一醯胺衍生物或其一藥學上
可接受鹽之具有改良安定性的藥學組成物,其能有效地抑制癌細胞的生長。
根據本發明之一方面,係提供含一式(I)化合物或其一藥學上可接受鹽、及一非金屬鹽潤滑劑的藥學組成物:
可自以下本發明說明連同附圖瞭解本發明之上述及其它目標與特性,該等附圖分別表示:第1圖:表示於60℃下,將實例1至8及比較例1之藥學組成物加熱後所製成之相關化合物IV的數量之安定性結果;第2圖:表示於60℃下,將比較例1至4及實例1之藥學組成物加熱後所製成之相關化合物IV的數量之安定性試驗結果;第3圖:表示使實例1及2與比較例1及3之藥學組成物暴露在催促條件(40℃及75% RH)下後所製成之相關化合物IV的數量之催促安定性試驗結果;及第4圖:表示使實例1及2與比較例1及3之藥學組成物暴露在催促條件(40℃及75% RH)下後所製成之相關化合物IV的數量之在一HDPE瓶內的催促安定性試驗結果。
本發明提供含一式(I)化合物或其一藥學上可接受鹽、及一非金屬鹽潤滑劑之藥學組成物:
本發明藥學組成物之各成份詳述如下。
該根據本發明之藥學組成物包含一作為藥學上活性成份的式(I)化合物或其藥學上可接受鹽。
如韓國專利早期公開案第2008-0107294號內所揭示的該式(I)化合物(在下文係指代號名稱“HM781-36B”)可選擇性且有效性抑制癌細胞的生長與藉該EGRF及其突變物而誘發的抗藥性之形成,且不會導致副作用。
該式(I)化合物之藥學上可接受鹽包括,但不限於:一無機或有機酸的酸加成鹽。該無機酸加成鹽的實例可包括鹽酸鹽、硫酸鹽、二碳酸鹽、硝酸鹽、磷酸鹽、過氯酸鹽或溴酸鹽;該有機酸加成鹽的實例可包括甲酸鹽、乙酸鹽、丙酸鹽、草酸鹽、琥珀酸鹽、苯甲酸鹽、檸檬酸鹽、順丁烯二酸鹽、丙二酸鹽、蘋果酸鹽、酒石酸鹽、葡萄糖酸鹽、乳酸鹽、龍膽酸鹽、反丁烯二酸鹽、乳糖酸鹽、柳酸鹽、酞酸鹽、恩波酸(embonic acid)鹽、天冬胺酸鹽、麩胺酸鹽、
樟腦磺酸鹽、苯磺酸鹽或乙醯基柳酸(阿斯匹靈(aspirin))鹽。該藥學上可接受鹽亦可包括衍生自鹼金屬(諸如鈣、鈉、鎂、鍶、鉀等)之金屬鹽。
在本發明內,以該組成物的總重計,該式(I)化合物之使用量範圍為自0.1至5.0重量%、較佳自0.5至10重量%。該組成物內之該化合物含量範圍可以是每1劑量單位該組成物之自0.1毫克至100毫克、較佳自0.5至50毫克。
潤滑劑為用以改善顆粒之壓製方法所添加的成份,且其等被視為重要的賦形劑,其在固體壓製的組成物之製造中扮演重要的角色。使用潤滑劑的優點包括該等粉末或顆粒狀材料的改善流量,其可以使該等粉末或顆粒狀材料更容易裝填在模具內;該等粉末或顆粒狀材料之減少摩擦以及該等粉末或顆粒狀材料與該衝床或該模具間的摩擦減少;及錠劑之增強可壓縮性及排放量。潤滑劑可如表1內所示經分類。
該含一式(I)化合物之本發明藥學組成物的特徵為經由
一非金屬鹽潤滑劑之使用以防止該相關化合物IV的形成,若該組成物含有金屬鹽,則會形成該相關化合物IV。
根據本發明之該名詞“非金屬鹽潤滑劑”係指一不含金屬材料(例如如硬脂酸鈣、硬脂酸鎂、硬脂基反丁烯二酸鈉、硬脂酸鋅等之金屬鹽)之潤滑劑。該根據本發明之非金屬鹽潤滑劑的實例可包括脂肪酸酯、脂肪酸、脂肪醇、油、反丁烯二酸、聚乙二醇(PEG)、聚四氟乙烯、澱粉、滑石等。本發明藥學組成物的增強貯存安定性可藉使用此等非金屬鹽潤滑劑而獲得。
特定地,可用於本發明之該非金屬鹽潤滑劑的實例可包括,但不限於:脂肪酸酯(例如甘油蘿酸酯、甘油棕櫚硬脂酸酯、甘油單硬脂酸酯、甘油三肉豆蔻酸酯、甘油三硬脂酸酯、蔗糖脂肪酸酯等);脂肪酸及脂肪醇(例如棕櫚酸、棕櫚醯醇、硬脂酸、硬脂醇等);油(氫化蓖麻油、礦物油、氫化植物油等);反丁烯二酸;聚乙二醇(例如PEG 4000或PEG 6000);聚四氟乙烯;澱粉;及滑石。可單獨或呈其混合物形式使用該等非金屬鹽潤滑劑。
根據本發明之代表性非金屬鹽潤滑劑較佳可包括蔗糖脂肪酸酯、氫化植物油、硬脂酸、甘油蘿酸酯、甘油棕櫚硬脂酸酯、滑石、澱粉、及PEG 6000、更佳為蔗糖脂肪酸酯及氫化植物油。
在本發明內,以1重量份該式(I)化合物計,該非金屬鹽潤滑劑的使用量範圍可自0.1至100重量份、較佳為0.1至50重量份、更佳為0.25至10重量份。
若該非金屬鹽潤滑劑的使用量小於0.1重量份,在該錠劑形成法進行期間,所形成的錠劑不能輕易地自該鑄模脫模、或會黏住該鑄模。另一方面,若該使用量大於100重量份,則錠劑會發生,諸如覆蓋或脫層之問題。而且,由於潤滑劑通常具疏水性,所以若大量使用,其等會導致,諸如延遲分解及低溶解率的非預定問題。
本發明的藥學組成物可進一步包含藥學上可接受添加物且可經調製成各種投藥形式、較佳為口服形式。該用於口服的調配物之代表性實例可包括散劑、錠劑、丸劑、膠囊、液體、懸浮液、乳液、糖漿、及顆粒、較佳為錠劑及膠囊,但不限於其等。
在本發明內,該等藥學上可接受添加物可包括稀釋劑、結合劑、分解劑等。
該稀釋劑的實例可包括微結晶狀纖維素、乳糖、甘露糖、磷酸鈣等;該結合劑的實例可包括帕吡酮(povidone)、羥丙基纖維素(HPC)、羥丙基甲基纖維素(HPMC)、聚乙烯醇(PVA)、羧甲基纖維素鈉等;且該分解劑的實例可包括交聯之帕吡酮(crospovidone)、交聯之羧甲基纖維素鈉、澱粉甘酸酸鈉等。
以該組成物的總重計,該稀釋劑的使用量範圍可自20至95重量%,該結合劑的使用量範圍可自1至10重量%,且該分解劑的使用量範圍可自1至30重量%。
本發明該藥學組成物可經一披覆基質披覆以防止該組
成物直接接觸使用者的手或皮膚。
可用於本發明的該披覆基質可包括一快速釋放披覆基質、一腸衣基質或一緩釋披覆基質。該快速釋放披覆基質可選自以下所組成的群組:羥丙基纖維素、羥丙基甲基纖維素、聚乙烯醇、聚乙烯醇-聚乙二醇接枝聚合物(Kollocoat IR®,BASF)、及其等之混合物。該腸衣基質可選自以下所組成的群組(甲基)丙烯酸酯共聚物(Eudragit®,EVONIK)、羥丙基甲基纖維素酞酸酯、乙酸酞酸纖維素、及其等之混合物。該緩釋披覆基質可選自以下所組成的群組:乙酸纖維素、乙基纖維素、聚乙烯乙酸酯、及其等之混合物。
以100重量份該未經披覆核心計,可披覆在該組成物表面上的該披覆基質之數量範圍為自1至50重量份、較佳1至30重量份。
本發明亦提供一用於製造該含一式(I)化合物或其一藥學上可接受鹽及一非金屬鹽潤滑劑的藥學組成物之方法。
可藉以下方法而製造該含上述成份之藥學組成物的調配物,該方法包括以下步驟:(1)混合一式(I)化合物或其一藥學上可接受鹽與一,諸如稀釋劑及結合劑之藥學上可接受添加物,並粒化該混合物以獲得顆粒;(2)混合步驟(1)內所製成的顆粒與,一諸如稀釋劑及分解劑之藥學上可接受添加物,並添加一非金屬鹽潤滑劑於其內以獲得混合型顆粒;及(3)使步驟(2)內所製成的該等混合型顆粒進行調製步驟。
在本發明之一實施例中,可藉以下步驟而製成本發明藥學組成物:在帕吡酮之純水溶液內混合一式(I)化合物及甘露醇,使該所製成混合物進行濕式粒化,然後乾燥所形成顆粒。可藉混合該等所製成顆粒與甘露醇及交聯之帕吡酮,添加一非金屬鹽潤滑劑於其中,然後藉製片機而將該等混合型顆粒製成錠劑。
可根據本項技藝已知的習知技術而進行與本發明該藥學組成物之調製有關的各種步驟。此外,本發明該方法可進一步包括以下步驟:為了方便貯存及容易使用,使用上述披覆基質披覆步驟(3)內所製成的該調配物。
本發明該藥學組成物可有效地抑制癌細胞的生長,其係藉包含可選擇性且有效地抑制癌細胞的生長及藉該EGFR及其突變物所誘發的抗藥性之形成的該式(I)化合物。而且,本發明該藥學組成物可藉包含該非金屬鹽潤滑劑而在極端的條件(例如於60℃下保持在一不漏氣的HDPE容器內,費時4週)及催促的條件(例如於40℃/75% RH下保持在一不漏氣的HDPE容器內,費時6個月)下,使雜質(亦即該相關化合物IV)的形成數量小於0.5重量%。因此,本發明該藥學組成物可增強效力且可改良該式(I)化合物的安定性。
因此,本發明提供一安定含該式(I)化合物或其一藥學上可接受鹽的藥學組成物之方法,其包括添加該非金屬鹽潤滑劑至該藥學組成物。
以下實例有意進一步闡明本發明而非限制其範圍。
根據表2內所述的組成物及數量(單位:毫克),藉使用一式(I)化合物(下文稱為“HM781-36B”,Dongwoo Syntech Co.,Ltd.,Korea);甘露醇(Roquette);Povidone®(BASF);Crospovidone®(BASF);及作為非金屬鹽潤滑劑之蔗糖脂肪酸酯(Daiichi Kogyo Seiyaku,Japan)、氫化植物油(Lubritab®,JRS Pharma)、或硬脂酸(Emery Oleochemicals.)而製成實例1至3之藥學組成物。
特定地,係混合HM781-36B及甘露醇,並藉一習知方法,使用帕吡酮(Povidone)在純水中之結合劑溶液而使該混合物進行濕式粒化方法。將如此獲得的濕顆粒乾燥,經甘露醇及交聯之帕吡酮(Crospovidone)混合,且其後添加一先前已經由30網目篩篩選過的潤滑劑以製成一最終混合物。根據一習知方法,藉製片機(Sejong,Korea)而將如此製成的該最終混合物製成具有約5至10kp之硬度的錠劑。
根據表3內所述的組成物及數量(單位:毫克),藉如上述之相同方法,使用一式(I)化合物(HM781-36B,Dongwoo
Syntech Co.,Ltd.,Korea);甘露醇(Roquette);Povidone®(BASF);Crospovidone®(BASF);及作為非金屬鹽潤滑劑之甘油蘿酸酯(Compritol 888 ATO®,Gattefosse)、甘油棕櫚硬脂酸酯(Compritol HD5®,Gatefosse)、滑石(Nippon Talc Corp.,Japan)、澱粉(Roquette)、或PEG 6000(Sanyo Chemical,Japan)以製成實例4至8的藥學組成物。
根據表4內所述的組成物及數量(單位:毫克),藉與上述相同的方法,使用一式(I)化合物(HM781-36B,Dongwoo Syntech Co.,Ltd.,Korea);甘露醇(Roquette);Povidone®(BASF);Crospovidone®(BASF);及作為非金屬鹽潤滑劑之甘油單硬脂酸酯(Capmul GMS-50)、棕櫚醯醇(Landz International Company Ltd.,China)、硬脂醇(Lubrizol Advanced Materials,U.S.)、氫化蓖麻油(BASF)、礦物油(Alfa Aesar,U.S.)、反丁烯二酸(Merck)、或二氧化矽(Grace Davison,U.S.)以製成實例9至15的藥學組成物。
藉使用表5內所述的組成物及數量(單位:毫克),重複以上實例之程序以製造含金屬鹽潤滑劑之比較例1至4的藥學組成物。
為了評估實例1至8及比較例1至4內所製成的藥學組成
物之貯存安定性,在一HDPE瓶內以1克矽凝膠包裝該等藥學組成物並貯存在一室(60℃)內。分別經2及4週後,藉作為溶劑之60%乙腈而萃取該相關化合物IV(其係為HM781-36B之一主要降解產物),然後進行HPLC分析。實例1至8的結果示於表6及第1圖內,而比較例1至4的結果示於表7及第2圖內。
為了觀測根據實例1及2以及比較例1及3所製成的藥學組成物之安定性對溫度及濕度的變化,使該等藥學組成物暴露於40℃及75% RH下。分別經1及2週後,藉作為溶劑之60%乙腈而萃取該相關化合物IV(其係為HM780-36B之一主要降解產物),然後進行HPLC分析。結果示於表8及第3圖內。
為了觀測在催促條件下,根據實例1及2以及比較例1及3所製成的藥學組成物之安定性對溫度及濕度的變化,在密
封的HDPE容器內,使該等組成物暴露於40℃及75% RH下,費時1、3及6個月。藉作為溶劑之60%乙腈而萃取各組成物的相關化合物IV,然後進行HPLC分析。結果示於表9及第4圖內。
如表6至9及第1至4圖中所示,與該等含金屬鹽潤滑劑之藥學組成物比較,在該等含任一非金屬鹽潤滑劑之藥學組成物內,該相關化合物IV之形成減少約4至10倍或更高。因此,該等含作為活性成份之HM781-36B的藥學組成物之貯存安定性可藉添加任一非金屬鹽潤滑劑至該等藥學組成物而增強。
根據the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH)之準則,未知及已知雜質的限值分別被規定為0.2%及0.5%。於40℃下,在如該ICH準則中所述之催促安全性試驗中,根據本發明之實例1及2之藥學組成物顯示小於0.5%的令人滿意之結果。反之,含習知金屬鹽潤滑劑之比較例1及3的藥學組成物超過該ICH之預定限值。
雖然已參考上述具體實施例描述本發明,應瞭解可藉熟悉本項技藝者而進行本發明的各種修飾及改變,且其等亦屬於如藉附加申請專利範圍而定義的本發明範圍。
第1圖:表示於60℃下,將實例1至8及比較例1之藥學組成物加熱後所製成之相關化合物IV的數量之安定性結果;第2圖:表示於60℃下,將比較例1至4及實例1之藥學組成物加熱後所製成之相關化合物IV的數量之安定性試驗結果;第3圖:表示使實例1及2與比較例1及3之藥學組成物暴露在催促條件(40℃及75% RH)下後所製成之相關化合物IV的數量之催促安定性試驗結果;及第4圖:表示使實例1及2與比較例1及3之藥學組成物暴露在催促條件(40℃及75% RH)下後所製成之相關化合物IV的數量之在一HDPE瓶內的催促安定性試驗結果。
Claims (17)
- 一種藥學組成物,其包含一式(I)化合物或其一藥學上可接受鹽及一非金屬鹽潤滑劑,
- 如申請專利範圍第1項之藥學組成物,其中該非金屬鹽潤滑劑為蔗糖脂肪酸酯或氫化植物油。
- 如申請專利範圍第1項之藥學組成物,其中該式(I)化合物的含量範圍為每1劑量單位之該組成物自0.1毫克至100毫克。
- 如申請專利範圍第1項之藥學組成物,其中以該式(I)化合物之1重量份計,該非金屬鹽潤滑劑的含量範圍為自0.1至100重量份。
- 如申請專利範圍第1項之藥學組成物,其進一步包含一選自由稀釋劑、結合劑、分解劑、及其等之混合物組成 之群組的藥學上可接受添加物。
- 如申請專利範圍第5項之藥學組成物,其中以該組成物之總重計,該稀釋劑的含量範圍為自20至95重量%。
- 如申請專利範圍第5項之藥學組成物,其中以該組成物之總重計,該結合劑的含量範圍為自1至10重量%。
- 如申請專利範圍第5項之藥學組成物,其中以該組成物之總重計,該分解劑的含量範圍為自1至30重量%。
- 如申請專利範圍第1項之藥學組成物,其係經一選自由快速釋放披覆基質、腸衣基質、及持續釋放披覆基質組成之群組的披覆基質所披覆。
- 如申請專利範圍第9項之藥學組成物,其中該披覆基質係選自以下所組成的群組:羥丙基纖維素、羥丙基甲基纖維素、聚乙烯醇、聚乙烯醇-聚乙二醇接枝共聚物、(甲基)丙烯酸共聚物、酞酸羥丙基甲基纖維素、酞酸纖維素乙酸酯、乙酸纖維素、乙基纖維素、聚乙烯乙酸酯、及其等之混合物。
- 如申請專利範圍第1項之藥學組成物,其含有小於0.5重量%之式(II)化合物,且該化合物係於60℃下在極端的條件下保持在一不漏氣的HDPE容器內,費時4週,或於40℃及75% RH下,在催促條件下保持在一不漏氣的HDPE容器內,費時6個月,
- 一種用於製造如申請專利範圍第1項之藥學組成物之調配物的方法,其包括以下步驟:(1)混合一式(I)化合物或其一藥學上可接受鹽與一藥學上可接受添加物,並粒化該混合物以獲得顆粒,
- 如申請專利範圍第12項之方法,其進一步包括以一選自由快速釋放披覆基質、腸衣披覆基質、及持續釋放披覆基質組成之群組的披覆基質披覆該在步驟(3)內所製成之調配物的步驟。
- 一種用於安定化一含式(I)化合物或其一藥學上可接受鹽之藥學組成物的方法,其包括添加一非金屬鹽潤滑劑至該藥學組成物,
- 如申請專利範圍第1項之藥學組成物,其中該非金屬鹽潤滑劑係選自以下所組成的群組:甘油蘿酸酯、甘油棕櫚硬脂酸酯、甘油單硬脂酸酯、甘油三肉豆蔻酸酯、甘油三硬脂酸酯、蔗糖脂肪酸酯、棕櫚酸、棕櫚醯醇、硬脂酸、硬脂醇、反丁烯二酸、聚乙二醇4000、聚乙二醇 6000、聚四氟乙烯、澱粉及其等之混合物,且其中該藥學組成物不含金屬鹽潤滑劑。
- 如申請專利範圍第12項之方法,其中使在步驟(2)內所製成之混合型顆粒進行一壓製步驟,該非金屬鹽潤滑劑係選自以下所組成的群組:甘油蘿酸酯、甘油棕櫚硬脂酸酯、甘油單硬脂酸酯、甘油三肉豆蔻酸酯、甘油三硬脂酸酯、蔗糖脂肪酸酯、棕櫚酸、棕櫚醯醇、硬脂酸、硬脂醇、反丁烯二酸、聚乙二醇4000、聚乙二醇6000、聚四氟乙烯、澱粉及其等之混合物,且其中該藥學組成物不含金屬鹽潤滑劑。
- 如申請專利範圍第14項之方法,其中該非金屬鹽潤滑劑係選自以下所組成的群組:甘油蘿酸酯、甘油棕櫚硬脂酸酯、甘油單硬脂酸酯、甘油三肉豆蔻酸酯、甘油三硬脂酸酯、蔗糖脂肪酸酯、棕櫚酸、棕櫚醯醇、硬脂酸、硬脂醇、反丁烯二酸、聚乙二醇4000、聚乙二醇6000、聚四氟乙烯、澱粉及其等之混合物,且其中該藥學組成物不含金屬鹽潤滑劑。
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Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101317809B1 (ko) | 2011-06-07 | 2013-10-16 | 한미약품 주식회사 | 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물 |
KR20140096571A (ko) * | 2013-01-28 | 2014-08-06 | 한미약품 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법 |
EP2878453A1 (de) | 2013-11-28 | 2015-06-03 | Authentic Vision GmbH | Objektmarkierung zur optischen Authentifizierung und Verfahren zu deren Herstellung |
GB201400034D0 (en) | 2014-01-02 | 2014-02-19 | Astrazeneca Ab | Pharmaceutical Compositions comprising AZD9291 |
KR101669240B1 (ko) * | 2015-03-12 | 2016-10-25 | 아주대학교산학협력단 | 테노포비어 디소프록실 유리염기를 포함하는 정제 및 이의 제조방법 |
JP6585193B2 (ja) * | 2015-12-28 | 2019-10-02 | 沢井製薬株式会社 | ゲフィチニブ含有錠剤 |
CN108057036B (zh) * | 2016-11-07 | 2023-06-13 | 正大天晴药业集团股份有限公司 | 一种egfr抑制剂的固体药物组合物 |
MX2019005834A (es) | 2016-11-17 | 2019-10-14 | Univ Texas | Compuestos con actividad antitumoral contra células cancerosas que tienen mutaciones en el exón 20 de egfr o her2. |
JP7386174B2 (ja) * | 2018-03-27 | 2023-11-24 | ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム | Her2エクソン19変異を有するがん細胞に対する抗腫瘍活性を有する化合物 |
WO2019220369A2 (en) | 2018-05-16 | 2019-11-21 | Janssen Biotech, Inc. | Methods of treating cancers and enhancing efficacy of t cell redirecting therapeutics |
WO2020056156A1 (en) * | 2018-09-14 | 2020-03-19 | Spectrum Pharmaceuticals, Inc. | Kits and methods for treating cancers |
CA3132834A1 (en) * | 2019-03-29 | 2020-10-08 | Board Of Regents, The University Of Texas System | Compounds with anti-tumor activity against cancer cells bearing her2 exon 21 insertions |
KR102254307B1 (ko) * | 2019-04-03 | 2021-05-21 | 위더스제약주식회사 | 보관 안정성이 향상된 에페리손 약제학적 조성물 |
JP2022553744A (ja) * | 2019-10-24 | 2022-12-26 | ハンミ ファーマシューティカル カンパニー リミテッド | がん細胞の成長を阻害するアミド誘導体を含む医薬調製物およびそれを含有する医薬品 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150118A2 (en) * | 2007-06-05 | 2008-12-11 | Hanmi Pharm. Co., Ltd. | Novel amide derivative for inhibiting the growth of cancer cells |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02275891A (ja) * | 1988-12-29 | 1990-11-09 | Tsumura & Co | 新規な複核白金錯体および該錯体を有効成分とする抗腫瘍剤 |
RU2140782C1 (ru) | 1994-08-23 | 1999-11-10 | СмитКлайн Бичем ПЛК | Улучшенные фармацевтические препараты, содержащие ибупрофен и кодеин |
KR980008219A (ko) | 1996-07-16 | 1998-04-30 | 김상응 | 안정화된 주사제용 약제학적 조성물 |
KR980008219U (ko) | 1996-07-31 | 1998-04-30 | 배순훈 | 세탁기의 구동모터 냉각팬 |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
JP3687025B2 (ja) * | 1998-06-04 | 2005-08-24 | 東和薬品株式会社 | 安定なマレイン酸エナラプリル錠剤 |
ES2334879T3 (es) | 1999-09-21 | 2010-03-17 | Astrazeneca Ab | Derivados de quinazolina y su uso como productos farmaceuticos. |
DE10042061A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE10042058A1 (de) | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
NZ536114A (en) | 2002-03-30 | 2007-11-30 | Boehringer Ingelheim Pharma | 4-(N-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors |
US20070037837A1 (en) | 2003-09-19 | 2007-02-15 | Hennequin Laurent Francois A | Quinazoline derivatives |
GB0322409D0 (en) | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
US20070043010A1 (en) | 2003-09-25 | 2007-02-22 | Astrazeneca Uk Limited | Quinazoline derivatives |
DE10345875A1 (de) | 2003-09-30 | 2005-04-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Vewendung und Verfahren zu ihrer Herstellung |
JPWO2005090332A1 (ja) | 2004-03-23 | 2008-01-31 | 萬有製薬株式会社 | 置換キナゾリン又はピリドピリミジン誘導体 |
KR20050104152A (ko) * | 2004-04-28 | 2005-11-02 | 최승호 | 경구용 약물의 흡수를 증진하는 약제학적 조성물 |
US20100234371A1 (en) | 2005-08-22 | 2010-09-16 | Frank Himmelsbach | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof |
CA2631813A1 (en) | 2005-12-12 | 2007-06-21 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for the production thereof |
DK1847258T4 (da) | 2006-04-13 | 2013-04-15 | Acino Pharma Ag | Partialglycerider som smøremiddel til farmaceutiske sammensætninger indeholdende thieno[3,2-c]pyridin-derivater |
US8937181B2 (en) | 2006-04-13 | 2015-01-20 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
AU2008268630A1 (en) | 2007-06-22 | 2008-12-31 | Bristol-Myers Squibb Company | Tableted compositions containing atazanavir |
MY144136A (en) | 2009-04-20 | 2011-08-10 | Univ Sains Malaysia | Throttle and brake lock |
ES2627909T3 (es) * | 2009-07-15 | 2017-08-01 | Diatech Holdings, Inc. | Selección de fármacos para el tratamiento del cáncer gástrico usando matrices basadas en anticuercuerpos |
RU2558931C2 (ru) * | 2010-01-12 | 2015-08-10 | Нестек С.А. | Способы предсказания ответа трижды негативного рака молочной железы на терапию |
KR101217526B1 (ko) * | 2010-06-11 | 2013-01-02 | 한미사이언스 주식회사 | 아마이드 유도체 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물 |
KR101317809B1 (ko) | 2011-06-07 | 2013-10-16 | 한미약품 주식회사 | 암세포의 성장을 억제하는 아마이드 유도체 및 비금속염 활택제를 포함하는 약학 조성물 |
KR101272613B1 (ko) | 2011-10-05 | 2013-06-10 | 한미사이언스 주식회사 | 1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온 염산염의 제조 방법 및 이에 사용되는 중간체 |
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- 2012-06-07 AR ARP120102013A patent/AR086851A1/es not_active Application Discontinuation
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2017
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008150118A2 (en) * | 2007-06-05 | 2008-12-11 | Hanmi Pharm. Co., Ltd. | Novel amide derivative for inhibiting the growth of cancer cells |
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