TWI424995B - 含有醯胺衍生物或其藥學上可接受之鹽類的藥學組成物 - Google Patents
含有醯胺衍生物或其藥學上可接受之鹽類的藥學組成物 Download PDFInfo
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Description
本發明係有關於具有改良貯存穩定性之包含一醯胺衍生物或一其藥學上可接受鹽類之一藥學組成物。
細胞內有許多訊息傳遞系統,其等於功能上係彼此連接以控制細胞之增殖、生長,及死亡(Kaelin,Nature Reviews Cancer,2005,5:689)。藉由基因或環境因子分解細胞內之控制系統造成訊息傳遞之異常放大或破壞,導致腫瘤細胞產生(Hanahan及Weinberg,Cell,2000,100:57)。
蛋白質酪胺酸激酶於此間胞內訊息傳遞扮演重要角色(Melnikova及Golden,Nature Reviews Drug Discovery,2004,3:993),且其異常表現或突變於癌細胞經常觀察到。蛋白質酪胺酸激酶係一種催化磷酸鹽基團自ATP輸送至蛋白質基質上之酪胺酸之酶。許多生長因子受體蛋白質作為運送細胞訊息之酪胺酸激酶。生長因子與其受體間之交互作用對於細胞生長之正常控制係重要,但藉由此等受體之突變或過度表現造成之異常訊息傳遞通常誘發腫瘤細胞及癌症。
蛋白質酪胺酸激酶係依據其生長因子類型分類成許多家族,且特別地,上皮細胞生長因子(EGF)及其EGF受體(EGFR)酪胺酸激酶已被認真地研究(Hynes及Lane,Nature Reviews Cancer,2005,5:341)。EGFR酪胺酸激酶,一種透膜蛋白質,係由一受體及一酪胺酸激酶所組成,且經由細胞膜將細胞外之訊息遞送至細胞核。各種EGFR酪胺酸激酶係以其結構特徵為基準分類成EGFR(Erb-B1)、Erb-B2、Erb-B3及Erb-B4,每一者可與其它亞型一起形成一同型二聚物或異型二聚物-訊息遞送錯合物。已報導二或更多種之此等異型二聚物於惡性疾病之過度表現會造成增加之轉變。此等過度表現通常於惡性腫瘤觀察到。
吉非替尼(Gefitinib)或爾諾替尼(Erlotinib),發展作為用於抑制EGFR酪胺酸激酶之小分子,選擇性且可逆地抑制EGFR(Erb-B1),EGFR之亞型,且已作為非小細胞性肺癌(NSCLC)之治療劑。拉帕替尼(Lapatinib),美國食品及藥物管理局(FDA)於2008年核准作為乳癌之治療劑,可逆地抑制EGFR亞型中之Erb-B1及Erb-B2。
再者,數種用於抑制EGFR酪胺酸激酶之藥物,例如,不可逆性之抑制劑,諸如,卡那替尼(Canertinib)、HKI-272、BIBW-2992及PF00299804,及可逆性抑制劑,諸如,AEE-788、CP24714、ARRY334543及AV-412,現今係於臨床試驗。此等抑制劑係發展成選擇性抑制Erb-B2,同時抑制二或更多種EGFR亞型,包括Erb-B1,或EGFR及其它受體。
由治療NSCLC之臨床試驗結果,與傳統之可逆性抑制劑相比,此等不可逆性之抑制劑顯示改良之藥物活性。但是,此等藥物對於遭受抗藥性癌症之患者未能提供顯著治療效果。
因此,持續需要發展一種新穎藥物,其與傳統不可逆性抑制劑相比有效治療此抗藥性癌症,同時不會造成不利副作用。依據此需要,如韓國專利早期公開第2008-0107294號案所揭露,本案發明人發展出一種新穎化合物,其選擇性且有效地抑制癌細胞生長及藉由EGFR及EGFR突變種誘發之抗藥性發展且無副作用。
本案發明人亦發展出各種型式之配製物,其包含於韓國專利早期公開第2008-0107294號案中所揭露之化學式(I)之1-(4-(4-(3,4-二氯-2-氟苯基胺基)-7-甲氧基喹唑啉-6-基氧)哌啶-1-基)丙-2-烯-1-酮作為一活性成份。但是,藉由使用傳統藥學上可接受添加劑製備之配製物造成較低量之此化合物且於貯存期間容易形成化學式(II)之化合物(雜質E)。
活性成份之純度係用以製備一安全且有效之藥學組成物之一重要因素。特別地,施加至具有極弱免疫系統之遭受癌症之患者之抗癌性藥物需包含具有最大純度之活性成份。除能於活性成份之製備方法移除雜質外,藥物之雜質,諸如,藉由各種環境因素(諸如,溫度、濕度,及光線)誘發之自最終藥物產物降解之產物,可能會對正被治療之患者造成副作用。
因此,本案發明人努力藉由抑制任何雜質形成而改良化學式(I)之化合物之穩定性,且發現酸添加劑能有效改良本發明活性成份之穩定性。
本發明之一目的係提供具有改良穩定性之一藥學組成物,其包含一醯胺衍生物或一其藥學上可接受鹽類。
依據本發明之一方面,提供一種藥學組成物,其包含一化學式(I)之化合物或一其藥學上可接受鹽類,及一酸添加劑:
本發明之如上及其它之目的及特徵由與附圖結合時之下列本發明之說明會變明顯,此等附圖係個別顯示:第1圖:依據實施例1至7及比較例1製備之配製物於60℃之穩定性;第2圖;依據酸添加劑之量之配製物之穩定性;第3圖:依據實施例1及比較例2至5製備之配製物於60℃之穩定性;且第4圖:依據實施例11及12與比較例6製備之配製物於60℃之穩定性。
本發明提供一種藥學組成物,包含一化學式(I)之化合物或一其藥學上可接受鹽類,及一酸添加劑:
依據本發明之藥學組成物可藉由使用一酸添加劑及抑制雜質形成而改良活性成份之穩定性。包含化學式(I)之化合物作為活性成份之藥學組成物由於貯存期間形成之雜質而顯示低穩定性。但是,與藉由於製備方法中降低水含量,或添加一特定賦形劑或穩定劑而製備之一藥學組成物相比,藉由使用一酸添加劑而製備之本發明藥學組成物可更有效地抑制雜質形成。
本發明藥學組成物之每一成份係於下詳細說明。
(1)活性成份
用於本發明藥學組成物之活性成份係化學式(I)之1-(4-(4-(3,4-二氯-2-氟苯基胺基)-7-甲氧基喹唑啉-6-基氧)哌啶-1-基)丙-2-烯-1-酮,或一其藥學上可接受鹽類。
化學式(I)之化合物已被揭露為一新穎化合物,其可選擇性且有效地抑制癌細胞生長及藉由EGFR及EGFR突變體誘發之抗藥性發展,同時未造成不利副作用(見韓國專利早期公開第2008-0107294號案)。
於本發明,藥學上可接受鹽類不受限地包括無機酸或有機酸之酸加成鹽類,或金屬鹽類。較佳地,無機酸加成鹽類之例子可包括氫氯酸、磷酸、硫酸,或焦硫酸之鹽類;有機酸鹽類之例子可包括蘋果酸、馬來酸、檸檬酸、福馬酸、苯磺酸、樟樹磺酸,或乙二磺酸之鹽類;且金屬鹽類之例子可包括鈣鹽類、鈉鹽類、鎂鹽類、鍶鹽類,或鉀鹽類。
組成物中每1配製單位可包含範圍從0.1毫克至1,000毫克之本發明活性成份。
(2)酸添加劑
用於本發明藥學組成物中之酸添加劑可為選自由下列所構成族群之至少一者:(1)具有一COOH或SO3
H基團之一C2-20
有機酸或脂肪酸;(2)選自由磷酸、硫酸、硼酸,及一其等之混合物所構成族群之一無機酸;以及(3)作為一藥學上可接受賦形劑之當以1至5%(w/v)之濃度溶解或分散於水中顯示pH 1至6之任何材料。
特別地,具有一COOH基團之酸添加劑之例子可不受限地包括乙酸、己二酸、檸檬酸、抗壞血酸、異抗壞血酸、乳酸、丙酸、酒石酸、福馬酸、甲酸、草酸、樟腦磺酸、蘋果酸、馬來酸、乙烷二磺酸、棕櫚酸,或硬脂酸。
以1至5%(w/v)之濃度溶解或分散於水中時顯示pH 1至6之材料的例子可不受限地包括藻朊酸或SiO2
。
於本發明之藥學組成物中,以1重量份之化學式(I)之化合物為基準,酸添加劑可以範圍從0.1至100之重量份,較佳係0.25至50重量份之量使用。
酸添加劑可於化學式(I)之化合物及一藥學上可接受賦形劑(例如,一崩解劑、一潤滑劑、一稀釋劑等)之濕式或乾式顆粒化處理期間或於顆粒化處理之後添加。再者,可添加化學式(I)之化合物及一藥學上可接受賦形劑之一混合物以供直接壓縮或填充一膠囊。
(3)其它成份
本發明之藥學組成物可進一步包含選自一稀釋劑、一結合劑、一崩解劑,及一潤滑劑之至少一賦形劑。稀釋劑之例子可包括微結晶纖維素、乳糖、甘露醇、磷酸鈣等;結合劑之例子可包括聚維酮、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯基醇、羧甲基纖纖維素鈉等;崩解劑之例子可包括六聚維酮、交聯甲羧纖維素鈉、澱粉乙醇酸鈉等;且潤滑劑之例子可包括硬脂酸鎂、硬脂酸鈣、硬脂基福馬酸鈉等。
較佳地,以組成物總重量為基準,稀釋劑可以範圍從20至80重量%之量使用,結合劑可以範圍從1至10重量%之量使用,崩解劑可以範圍從1至30重量%之量使用,且潤滑劑可以範圍從0.5至5重量%之量使用。
本發明之藥學組成物可配製成用於口服投藥。用於口服投藥之配製物之代表性例子可包括粉末、錠劑、膠囊、顆粒,或糖漿,較佳係錠劑或膠囊,但不限於此。
本發明之藥學組成物可以一塗覆基材塗覆,以避免組成物與使用者之手或皮膚接觸。用於本發明之塗覆基材可包括一快速釋放之塗覆基材,諸如,羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯基醇、聚乙烯基醇-聚乙二醇接枝聚合物(Kollocoat IR,BASF)等;腸道塗覆基材,諸如,(甲基)丙烯酸酯共聚物(Eudragit,EVONIK)、羥基丙基甲基纖維素酞酸酯、纖維素乙酸酯酞酸酯等;及一持續釋放之塗覆基材,諸如,纖維素乙酸酯、乙基纖維素、聚乙酸乙烯酯等。以未經塗覆之芯材為基準,塗覆基材可以範圍從1至50重量%,較佳係1至30重量%之量使用。
實施例
下列實施例係用以進一步例示說明本發明,且非限制其範圍。
實施例1至7:製備包含酸添加劑之一錠劑
依據第1表中所述之組成物,具有化學式(I)之化合物之一錠劑係藉由使用化學式(I)之化合物(韓國Hanmi Pharm. Co.,Ltd.)、甘露醇、聚維酮(德國BASF)、交聚維酮(德國BASF)、硬脂酸鎂,及一或多種酸添加劑,諸如,檸檬酸、異抗壞血酸、磷酸、藻朊酸、硬脂酸,及二氧化矽而製備。添加至一濕顆粒組成物之酸添加劑(檸檬酸及磷酸)係溶解或分散於水,結合溶劑。當於顆粒化後添加或添加至一直接壓縮混合物時,酸添加劑經由一30篩網篩選。實施例1至7之錠劑之每一者係藉由使用一錠劑機器製備成具有6至12 kp之硬度之一錠劑。
依據第2表中所述之組成物,實施例8至10之錠劑之每一者係以實施例1之程序為基礎但使用不同量之檸檬酸作為一酸添加劑而製備。
依據第3表中之組成物,比較例1之一錠劑係以實施例1之程序為基礎未使用任何酸添加劑而製備。再者,依據第3表中所述之組成物,比較例2至5之錠劑之每一者係以實施例1之程序為基礎,但替代使用一酸添加劑,丁基化羥基甲苯(BHT)或生育醇作為一非酸抗氧化劑,或碳酸鈣(CaCO3
)或葡甲胺作為一鹼穩定劑而製備。
依據第4表中所述之組成物,化學式(I)之化合物及賦形劑係經由一30篩網篩選,然後混合。含有8毫克之化學式(I)之化合物之一混合物被注至尺寸編號0之一膠囊內以製備實施例11及12之每一膠囊。比較例6之膠囊係以實施例11之程序為基礎於未添加任何酸添加劑而製備。
為評估依據實施例1至12及比較例1至6製備之含有化學式(I)之化合物之配製物之貯存穩定性,作為一主要降解產物之化學式(II)之化合物(雜質E)之量被測量。配製物每一者係以1克之矽石凝膠封裝於一HDPE瓶內,且貯存於一腔室(60℃),且雜質E之量於其後之4週及8週測量。結果係顯示於第5至7表及第1至4圖。
如第5至7表及第1至4圖所示,雜質E之產生降低約4至10倍或更多,因此,含有化學式(I)之化合物之配製物之貯存安定性係藉由添加一或多種酸添加劑至此等配製備而改良。依據International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH)之準則,未知雜質及已知雜質之限制個別規定係0.2%及0.5%。就此而言,添加一或多種酸添加劑可改良含有化學式(I)之化合物之錠劑及膠囊之穩定性,因此,優異貯存穩定性可被預期。
但是,通常作為藥學穩定劑之非酸抗氧化劑(BHT或生育醇)或鹼穩定劑(碳酸鈣(CaCO3
)或葡甲胺)未改良穩定性,或對穩定性具有非所欲作用。
雖然本發明已關於如上特別實施例作說明,但需瞭解亦落於藉由所附申請專利範圍界定之本發明範圍內之各種修改及變化可由熟習此項技藝者對本發明為之。
第1圖:依據實施例1至7及比較例1製備之配製物於60℃之穩定性;
第2圖;依據酸添加劑之量之配製物之穩定性;
第3圖:依據實施例1及比較例2至5製備之配製物於60℃之穩定性;且
第4圖:依據實施例11及12與比較例6製備之配製物於60℃之穩定性。
Claims (16)
- 一種藥學組成物,包含一化學式(I)之化合物或一其藥學上可接受鹽類;以及一酸添加劑:
- 如申請專利範圍第1項之藥學組成物,其中,該藥學上可接受鹽類係一無機酸鹽類、一有機酸鹽類,或一金屬鹽類。
- 如申請專利範圍第2項之藥學組成物,其中,該無機酸鹽類係氫氯酸、磷酸、硫酸,或焦硫酸之一鹽類;該有機酸鹽類係蘋果酸、馬來酸、檸檬酸、福馬酸、苯磺酸、樟樹磺酸,或乙二磺酸之一鹽類;且該金屬鹽類係一鈣鹽類、鈉鹽類、鎂鹽類、鍶鹽類,或鉀鹽類。
- 如申請專利範圍第1項之藥學組成物,其中,該酸添加劑係選自由下列所組成之群組:具有一COOH或SO3 H基團之一C2-20 有機酸或脂肪酸;選自磷酸、硫酸及硼酸之一無機酸;以及一其等之混合物。
- 如申請專利範圍第4項之藥學組成物,其中,該酸添加劑係選自由下列所組成之群組:乙酸、己二酸、檸檬酸、抗壞血酸、異抗壞血酸、乳酸、丙酸、酒石酸、福馬酸、甲酸、草酸、樟腦磺酸、蘋果酸、馬來酸、乙烷二磺酸、棕櫚酸,硬脂酸,及一其等之混合物。
- 如申請專利範圍第1項之藥學組成物,其中,該酸添加劑係一藥學上可接受之賦形劑,其當以1至5%(w/v)之濃度溶解或分散於水中時顯示pH 1至6。
- 如申請專利範圍第6項之藥學組成物,其中,該酸添加劑係藻朊酸或SiO2 。
- 如申請專利範圍第1項之藥學組成物,其中,該化學式(I)之化合物係以每1單位之該組成物從0.1毫克至1,000毫克之量的範圍被包含。
- 如申請專利範圍第1項之藥學組成物,其中,以1重量份之該化學式(I)之化合物為基準,該酸添加劑係以範圍從0.1至100重量份之量被包含。
- 如申請專利範圍第9項之藥學組成物,其中,以1重量份之該化學式(I)之化合物為基準,該酸添加劑係以範圍從0.25至50重量份之量被包含。
- 如申請專利範圍第1項之藥學組成物,其中,該組成物係以一膠囊或錠劑之型式配製。
- 如申請專利範圍第1項之藥學組成物,其進一步包含一賦形劑,其係選自由下列所組成之群組:一稀釋劑、一結合劑、一崩解劑、一潤滑劑,或一其等之混合物。
- 如申請專利範圍第12項之藥學組成物,其中,以該組成物之總重量為基準,該稀釋劑係以範圍從20至80重量%之量被包含,該結合劑係以1至10重量%之量被包含,該崩解劑係以範圍從1至30重量%之量被包含,或該潤滑劑係以範圍從0.5至5重量%之量被包含。
- 如申請專利範圍第1項之藥學組成物,其係以一快速釋放之塗覆基材、一腸道塗覆基材、一持續釋放之塗覆基材,及一其等之混合物塗覆。
- 如申請專利範圍第14項之藥學組成物,其中,該快速釋放之塗覆基材係羥基丙基纖維素、羥基丙基甲基纖維素、聚乙烯基醇、聚乙烯基醇-聚乙二醇接枝聚合物,或一其等之混合物;該腸道塗覆基材係(甲基)丙烯酸酯共聚物、羥基丙基甲基纖維素酞酸酯、纖維素乙酸酯酞酸酯,或一其等之混合物;且該持續釋放之塗覆基材係纖維素乙酸酯、乙基纖維素、聚乙酸乙烯酯,或一其等之混合物。
- 如申請專利範圍第14項之藥學組成物,其中,以該未經塗覆之芯材總重量為基準,該塗覆基材係以範圍從1至50重量%之量使用。
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