TWI386386B - N-(5-氯柳醯基)-8-胺基辛酸之二鈉鹽的晶形 - Google Patents
N-(5-氯柳醯基)-8-胺基辛酸之二鈉鹽的晶形 Download PDFInfo
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- TWI386386B TWI386386B TW095134448A TW95134448A TWI386386B TW I386386 B TWI386386 B TW I386386B TW 095134448 A TW095134448 A TW 095134448A TW 95134448 A TW95134448 A TW 95134448A TW I386386 B TWI386386 B TW I386386B
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- Prior art keywords
- chloroindolyl
- disodium salt
- aminooctanoic acid
- acid disodium
- cnac
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Description
本發明是有關於N-(5-氯柳醯基)-8-胺基辛酸(以下稱為“5-CNAC”)的二鈉鹽的晶形、含有此等的藥學組成物、製備此等的方法,以及利用此等來促進活性劑的輸送的方法。
美國專利第5,773,647號揭示193種輸送劑化合物(delivery agent compounds),包含N-(5-氯柳醯基)-8-胺基辛酸(“5-CNAC”)。這些輸送劑化合物增加了一廣範圍的生物活性劑(biologically active agents)(特別是典型地不適用於口服投藥的生物活性劑)的生物可利用性(bioavailability)。美國公開申請案案號(U.S.Published Application Nos.)2006/0078622以及2006/0078623揭示輸送劑化合物(包括5-CNAC)的微粒子(microparticles)或奈米粒子(nanoparticles)。美國公開專利申請案案號(U.S.Published Patent Application No.)2005/0054557揭示包含有副甲狀腺激素(parathyroid hormone)、降鈣素(calcitonin)與5-CNAC的藥學組成物。國際公開案案號(International Publication No.)WO 00/59863揭示N-(5-氯柳醯基)-8-胺基辛酸的二鈉鹽。
國際公開申請案案號WO 2005/01403揭示使用降鈣素與5-CNAC來治療骨關節炎(osteoarthritis)。美國公開申請案案號2006/0106110揭示一種用以抑制一哺乳動物的血小板凝集的方法,其包括投藥一經修飾的胺基酸(modified amino acid)(包含5-CNAC)。國際公開申請案案號(International Published Application No.)03/015822揭示使用5-CNAC作為一種用於副甲狀腺激素片段(parathyroid hormone fragments)的口服輸送劑(oral delivery agent)。國際公開申請案案號WO 02/45754揭示包含有藥理活性劑、交聯聚維酮(crospovidone)或聚維酮(povidone)以及一輸送劑(例如,5-CNAC)的藥學組成物。
本發明是有關於N-(5-氯柳醯基)-8-胺基辛酸(“5-CNAC”)的二鈉鹽的四種晶形(以下稱為形式I至IV)[包含一種5-CNAC的八水合物(octahydrate)]。
本發明之一具體例是一種藥學組成物,其包含(A)5-CNAC的形式I至IV之一或多者,以及(B)一活性劑(active agent),諸如,降鈣素(例如,鮭魚降鈣素)或人類生長激素(human growth homone)(例如,重組型人類生長激素)。依據一較佳具體例,該藥學組成物包含有,根據5-CNAC在該藥學組成物中的100%總重量,至少大約20、30、40、50、60、70、80、90、95、96、97、98、99、99.1、99.2、99.3、99.4、99.5、99.6、99.7、99.8或99.9%重量計之5-CNAC的形式I至IV之一或多者。依據另一個較佳具體例,該藥學組成物包含有,根據結晶5-CNAC在該藥學組成物中的100%總重量,至少大約20、30、40、50、60、70、80、90、95、96、97、98、99、99.1、99.2、99.3、99.4、99.5、99.6、99.7、99.8或99.9%重量計之5-CNAC的形式I至IV之一者。
另一個具體例是一種藥學組成物(諸如一錠劑),其包含有5-CNAC的形式I至IV之至少一者,以及至少一種活性劑和/或藥學上可接受的添加劑(pharmaceutically acceptable additive)(諸如那些被描述於下面者)。一較佳的活性劑是降鈣素。又另一較佳的活性劑是一含降鈣素與副甲狀腺激素(諸如PTH[1-34])的治療混合物(therapeutic mixture)。又另一較佳的活性劑是胰島素(insulin)。又另一較佳的活性劑是生長激素(諸如重組型人類生長激素)。
本發明的又另一個具體例是一種藉由投予本發明的藥學組成物來投藥或促進一活性劑輸送至一動物(諸如人類)的方法。
又另一個具體例是一種用於治療一有需要治療的哺乳動物(諸如人類)之佩吉特氏病(Paget’s disease)或高血鈣症(hypercalcemia)或治療或預防骨質疏鬆症(osteoporosis)的方法,其係藉由口服地投藥一有效數量之本發明的藥學組成物[例如,一藥學組成物包含有形式I、II、III和/或IV的5-CNAC以及(i)降鈣素(例如,鮭魚降鈣素)或(ii)一由降鈣素與副甲狀腺激素或其一片段(諸如PTH[1-34])所構成的組合]。其他可被治療的疾病或病狀(conditions),或藉由口服地投藥一有效數量之本發明的藥學組成物[例如,一藥學組成物包含有形式I、II、III和/或IV的5-CNAC以及(i)降鈣素(例如,鮭魚降鈣素)或(ii)一由降鈣素與副甲狀腺激素或其一片段(諸如PTH[1-34])所構成的組合]而被達到的生理效用(physiological affects)包含:骨骼的疾病(diseases of bones)、骨疼痛(包含與骨質疏鬆症或癌症有關的疼痛)、骨關節炎、軟骨下骨(sub-chondral bone)的不正常再吸收(resportion)與轉換(turnover)、保存和/或刺激軟骨(cartilage)、抑制磷脂酶(phosholipase A2)和/或膠原酶(collagenase)活性、刺激糖胺聚多糖(glycosaminoglycan)和/或蛋白多糖(proteoglycan)合成、刺激新骨形成、對軟骨下骨之密度或勁度(stiffness)的不均勻性(inhomogeneity)產生作用、對發炎過程產生作用、導致運動上的疼痛以及相關症狀的減弱、減低病人的關節內之退化性變化(degenerative change)。
又另一個具體例是一種用於製備形式I之5-CNAC的方法,其包括藉由:(a)將一種5-CNAC的單乙醇溶劑化物(monoethanol solvate)溶解於一含乙腈(acetonitrile)與水的混合物中,以及(b)將步驟(a)中所製得的溶液冷卻至一有效溫度(例如,從大約5℃至大約15℃),俾以產生形式I的5-CNAC。
又另一個具體例是一種用以製備形式I的5-CNAC的方法,其係藉由:(a)將一種5-CNAC的水性溶液加熱(例如,從大約40℃至大約70℃),以及(b)從該溶液中移除水[例如,以一旋轉式蒸發器(rotary evaporator)和/或真空烘箱],俾以產生形式I的5-CNAC。
又另一個具體例是一種用以製備一種5-CNAC的單乙醇溶劑化物(monoethanol solvate)(諸如形式II)的方法,其係藉由:(a)將氫氧化鈉加入至一含N-(5-氯柳醯基)-8-胺基辛酸與乙醇的溶液中,以及(b)將形式II的5-CNAC從該溶液中沉澱出來。較佳地,氫氧化鈉與N-(5-氯柳醯基)-8-胺基辛酸的莫耳數比(molar ratio)是大約2:1。
又另一個具體例是一種用以製備一種5-CNAC的八水合物(octahydrate)(諸如形式III)的方法,其係藉由將(i)一種5-CNAC的單水合物(monohydrate)(諸如形式I、IV或它們的一個混合物)、(ii)一種5-CNAC的單乙醇溶劑化物(monoethanol solvate)(諸如形式II)或(iii)此等之一混合物維持在一為至少大約75%的相對溼度(relative humidity)下歷時一充分時間,俾以形成該八水合物。依據一具體例,該八水合物在環境溫度(ambient temperature)或一範圍落在大約22℃至大約40℃或大約50℃的溫度下被製備出。
又另一個具體例是一種用以製備形式IV的5-CNAC的方法,其係藉由:(a)在一升高的溫度(例如,從大約30℃至大約70℃)下,將5-CNAC溶解於丁酮(methyl ethyl ketone)中,以及(b)將步驟(a)的丁酮溶液冷卻,俾以產生形式IV的5-CNAC。
又另一個具體例是一種用以製備一含形式I與IV的5-CNAC之混合物的方法,其係藉由將一種具有5-CNAC與丙酮的溶液冷卻歷時一充分時間,俾以產生該含形式I與IV的混合物。選擇性地,該溶液亦可以含有水。
藉由上述處理程序中的任一者所製得的結晶(crystals)可以藉由本技藝中已知的任何方法來回收。
第1、3、4與5圖分別是如實施例1至4所製得的形式I至IV的5-CNAC(第3圖的上方光譜是形式II的光譜)的X射線粉末繞射圖(X-ray powder diffractograms,XRPDs);以及第2與6圖分別是如在實施例1與4中所製得的形式I與IV的5-CNAC的微差掃描熱量法(DSC)分析[differential scanning calorimetry(DSC)analyses]。
術語“多形物(polymorph)”意指一物質之結晶學上的不同形式(crystallographically distinct forms)。
如此處所用的,術語“水合物(hydrate)”包含,但不限於:一種包含有一或多種呈一明確比例的水分子作為一含有自由水(free water)的結晶材料(crystalline material)的結晶或一結晶物質(crystalline substance)之一組成部分(integral part)。
如此處所用的,術語“5-CNAC”意指N-(5-氯柳醯基)-8-胺基辛酸的二鈉鹽。除非另有指明,如此處所用的,術語“5-CNAC”意指5-CNAC的所有多形物(polymorphs)。
如此處所用的,術語“5-CNAC單水合物”意指5-CNAC的一種晶形,其中1個分子的水與5-CNAC的各個分子締合。
如此處所用的,術語“5-CNAC八水合物”意指5-CNAC的一種晶形,其中8個分子的水與5-CNAC的各個分子締合。
如此處所用的,術語“溶劑化物(solvate)”包含,但不限於:一溶劑的分子或離子與5-CNAC的分子或離子之一分子性或離子性錯合物。如此處所用的,術語“共-溶劑化物(co-solvate)”包含,但不限於:二或多種溶劑的分子或離子與5-CNAC的分子或離子之一分子性或離子性錯合物。
如此處所用的,術語“輸送劑”意指5-CNAC(包含它的晶形)。
一“有效數量的藥物”是一數量的活性劑(例如,肝素、降鈣素、副甲狀腺激素或重組型人類生長激素),它在被投藥至一活生物體經過某段時間期間能有效治療或預防該生物體之一病狀,例如,在一所欲的給藥間隔(dosing interval)期間提供一治療效果(therapeutic effect)。如熟習此技藝者所認知的,有效劑量會視下列而變化:投藥的途徑,存在的賦形劑,以及該活性劑是否是一使用其他用於治療一病狀的藥劑之共同療法(co-therapy)的一部分。
術語“治療(treat)”、“治療(treating)”或“被治療(treated)”意指投藥一活性劑以達到下列目的:治癒(cure)、癒合(heal)、減輕(alleviate)、緩和(reIieve)、改變(alter)、矯治(remedy)、改良(ameIiorate)、改善(improve)或影響一病狀(例如,一疾病)、該病狀的症狀(symptom)或朝向該病狀的罹病傾向(predisposition)。
一“有效數量的輸送劑”是一數量的輸送劑,其促進一所欲數量之活性劑經由任何投藥途徑[諸如那些被討論於本申請案中的,包含,但不限於:口服的(例如,穿越胃腸道內之一生物膜)、經鼻的、肺的、皮膚的、陰道的和/或眼睛的途徑]的吸收。
如此處所用的,術語“降鈣素”意指所有形式的降鈣素,包含,但不限於:人類、鮭魚、豬以及鰻魚降鈣素(包含它們的天然的、合成的或重組的來源),以及降鈣素衍生物(諸如1,7-Asu-鰻魚降鈣素)。一較佳的降鈣素是合成的鮭魚降鈣素。
術語“副甲狀腺激素”意指所有形式的副甲狀腺激素(天然的與合成的)、它的片段以及同效劑(agonists)。例如,它可以包含,但不限於:人類副甲狀腺激素[1-36]與人類副甲狀腺激素[1-34]。
術語“胰島素”意指所有形式的胰島素(天然的與合成的),包含,但不限於:重組型人類胰島素。
術語“生長激素”意指所有形式的生長激素(天然的與合成的),包含,但不限於:人類生長激素(例如,重組型人類生長激素)。
如此處所用的,活性劑的“片段”此術語意指活性劑之截短形式(truncated form),當投藥至一個體,它提供一有如未截短的活性劑之類似生理效用。如此處所用的,活性劑的“類似物(analogs)”此術語意指活性劑之經些微修飾的形式(slightly modified forms),當投藥至一個體,它提供一有如該類似物以之為基礎的活性劑之類似生理效用。據知,活性劑的類似物(例如,被揭示於美國專利第5,474,978號中的胰島素類似物)與活性劑的片段(例如,被揭示於此處的PTH片段)可以與形式I至IV的5-CNAC被投藥而具有有如投藥該活性劑(例如,胰島素與PTH)本身與形式I至IV的5-CNAC之類似效力。
如此處所用的,術語“大約”意指落在一給定數值(a given value)之10%範圍內,較佳為落在5%範圍內,以及更較佳為落在一給定數值之1%範圍內。另擇地,術語“大約”意指一數值可以落在一就該數值的類型而言是科學上可接受的誤差範圍(scientifically acceptable error range)內,這係視如何從可利用的工具來得到一定性的量測而定。
形式I的5-CNAC是一種單水合物。在室溫下,形式I是形式I至IV當中最安定的。依據微差掃描熱量法(differential scanning calorimetry,DSC),形式I具有一個第一吸熱轉移(endothermic transition)[具有一為大約69℃(69.3℃)的起始溫度並在大約76℃(75.2℃)達到高峰],繼而為一個第二廣泛吸熱現象(broad endothermic event)[具有一為大約98℃的起始溫度並在大約140℃(141.2℃)達到高峰](參見第2圖)。形式I的5-CNAC具有一個XRPD圖樣實質上是相同於那個被顯示於第1圖中的。例如,形式I展現一個特性波峰(characteristic peak)位在15.5° 2 θ±0.2或0.1° 2 θ處。有關形式I的特性XRPD波峰位置[被表示為2 θ±0.2、0.1、0.05或0.01° 2 θ(角度)]與晶格間距(d-spacing)被提供於下面表1中。
形式I可以藉由在上面與在下面的實施例1中所描述的處理程序而被製備出來。
本發明亦提供一種含有形式I的5-CNAC的藥學組成物,其中小於90、80、70或60%的5-CNAC是結晶狀(crystalline)(以5-CNAC之100%總重量為基礎)。
本發明亦提供一種藥學組成物(諸如一錠劑),其包含有一含形式I的5-CNAC以及至少一活性劑和/或藥學上可接受的添加劑(諸如那些被描述於下面的)之經研磨的(milled)[例如,球磨的(ball milled)]或直接壓製(directly compressed)的混合物。較佳地,該藥學組成物(或經研磨的或直接壓製的混合物)包含,根據5-CNAC在該藥學組成物(或經研磨的或直接壓製的混合物)中的總重量,至少50、60、70、80、90、95、96、97、98或99%重量計的形式I。
形式II是一種5-CNAC的單乙醇溶劑化物。形式II的5-CNAC具有一個XRPD圖樣實質上是相同於那個被顯示於第3圖中的。例如,形式II展現一個特性波峰位在16.5° 2 θ±0.2或0.1° 2 θ處。有關形式II的特性XRPD波峰位置[被表示為2 θ±0.2、0.1、0.05或0.01° 2 θ(角度)]與晶格間距被提供於下面表2中。
形式II的5-CNAC可以如上述以及於實施例2中所述的來製備。
形式III是一種5-CNAC的八水合物。形式III在一低於大約50%的相對溼度(relative humidity)下是不安定的。形式III的5-CNAC具有一個XRPD圖樣實質上是相同於那個被顯示於第4圖中的。例如,形式III展現一特性波峰位在4.8° 2 θ±0.2或0.1° 2 θ處。有關形式III的特性XRPD波峰位置[被表示為2 θ±0.2、0.1、0.05或0.01° 2 θ(角度)]與晶格間距被提供於下面表3中。
形式III可以如上述以及於實施例3中所述的來製備。例如,形式III可以藉由將二鈉5-CNAC(諸如它的乙醇溶劑化物)貯存在75%(或更高)的相對溼度下歷時至少6天而被製造出。
本發明亦提供一種藥學組成物(諸如一錠劑),其包含有一含形式III的5-CNAC以及至少一活性劑和/或藥學上可接受的添加劑(諸如那些被描述於下面的)之直接壓製的混合物。較佳地,該藥學組成物(或直接壓製的混合物)包含,根據5-CNAC在該藥學組成物(或直接壓製的混合物)中的總重量,至少50、60、70、80、90、95、96、97、98或99%重量計的形式III。
形式IV的5-CNAC是一種單水合物。形式IV的5-CNAC具有一個XRPD圖樣實質上是相同於那個被顯示於第5圖中的。例如,形式IV展現一個特性波峰位在7.2°和/或18.2° 2 θ±0.2或0.1° 2 θ處。有關形式IV的特性XRPD波峰位置[被表示為2 θ±0.2、0.1、0.05或0.01° 2 θ(角度)]與晶格間距被提供於下面表4中。
形式IV可以如上述以及於實施例4中所述的來製備。
本發明亦提供一種含有形式IV的5-CNAC的藥學組成物,其中至少50、60、70、80或90%(以5-CNAC的100%重量為基礎)的5-CNAC是結晶狀。
形式I與IV的5-CNAC是單水合物。有關該混合物的特性XRPD波峰位置[被表示為2 θ±0.2、0.1、0.05或0.01° 2 θ(角度)]與晶格間距被提供於下面表5中。
該混合物可以如上述以及於實施例5中所述的來製備。
藉由上述處理程序的任一者所製得的結晶可以經由本技藝中已知的任一種方法來回收。
適合供用於本發明的活性劑包含生物活性劑與化學活性劑,包含,但不限於:殺蟲劑(pesticides)、藥劑(pharmacological agents)以及治療劑(therapeutic agents)。適合的活性劑包含那些於胃腸道內透過酸水解(acid hydrolysis)、酵素(enzymes)以及類似之物而被弄成效用較低的、無效的或被破壞者。亦被包含作為適合的活性劑的是那些巨分子藥劑(macromolecular agents),當被口服地給藥時,它們的生理化學特性(諸如,大小、結構或電荷)會阻止或妨礙吸收。
例如,適合供用於本發明的生物或化學活性劑包含,但不限於:蛋白質;多肽;胜肽;激素;多醣,以及特別是含黏多醣的混合物;碳水化合物;脂質;小型極性有機分子(亦即,具有一為500道爾頓或更低的分子量之極性有機分子);其他的有機化合物;以及,特別地,本身不會通過(或其僅通過被投予的劑量之一小部分)胃腸黏膜和/或容易為胃腸道中的酸與酵素而化學分解(chemical cleavage)的化合物;或此等的任一組合。
進一步的實例包含,但不限於下列(包含此等之合成的、天然的或重組的來源):生長激素,包含人類生長激素(hGH)、重組型人類生長激素(rhGH)、牛生長激素以及豬生長激素;生長激素釋放激素;生長激素釋放因子、干擾素,包括α[例如,干擾素alfacon-1(可以Infergen而從InterMune,Inc.of Brisbane,CA得到)]、β以及γ;介白素-1;介白素-2;胰島素,包含豬的、牛的、人類的以及人類重組的,選擇性地具有相對離子(counter ions)(包含鋅、鈉、鈣以及銨);類胰島素生長因子(insulin-like growth factor),包含IGF-1;肝素,包含未分餾的(unfractionated)肝素、類肝素(heparinoid)、皮膚素(dermatan)、軟骨素(chondroitin)、低分子量肝素、極低分子量肝素以及超低分子量肝素;降鈣素,包含鮭魚的、鰻魚的、豬的以及人類的;紅血球生成素;心房利尿鈉因子(atrial natriuretic factor);抗原;單株抗體;體抑素(somatostatin);蛋白酶抑制劑(protease inhibitor);皮質促激素(adrenocorticotropin)、激性腺素釋放素(gonadotropin releasing hormone);催產素(oxytocin);促黃體素釋放激素(leutinizing-hormone-releasing-hormone);促濾泡素(follicle stimulating hormone);葡糖腦苷脂酶(glucocerebrosidase);血小板生成素(thrombopoietin);惠爾血添(filgrastim);前列腺素(prostaglandins);環孢靈(cyclosporin);升壓素(vasopressin);果莫林鈉(cromolyn sodium)(色甘酸鈉或二鈉)(sodium or disodium chromoglycate);萬古黴素(vancomycin);去鐵胺(desferrioxamine,DFO);雙膦酸鹽類(bisphosphonates),包含阿侖膦酸鹽(alendronate)、替魯膦酸鹽(tiludronate)、益迪膦酸鹽(etidronate)、氯膦酸鹽(clodronate)、帕米膦酸鹽(pamidronate)、奧帕膦酸鹽(olpadronate)以及因卡膦酸鹽(incadronate);副甲狀腺激素(PTH),包含它的片段;抗偏頭痛劑(anti-migraine agent),諸如BIBN-4096BS以及其他與降鈣素基因有關的蛋白質拮抗劑(proteins antagonist);類升糖素胜肽1(glucagon-like peptide 1,GLP-1);阿加曲班(Argatroban);抗微生物劑(antimicrobial),包含抗生素、抗細菌劑以及抗真菌劑;維生素;這些化合物的類似物、片段、模擬物(mimetics)或經聚乙二醇(PEG)修飾的衍生物;或此等之任一組合。抗生素的非限制性實例包含革蘭氏陽性作用的(gram-positive acting)、殺細菌的(bacteriocidal)、脂胜肽類(lipopeptidal)以及環胜肽類(cyclic peptidal)的抗生素[諸如達托黴素(daptomycin)及其類似物]。
依據一具體例,該活性劑是一種有藥理活性的胜肽,諸如一骨骼活性劑(bone active agent)(例如,降鈣素)。骨骼活性劑包含在動物體內展現出活體內藥理活性[諸如骨骼的安定化(stabilization)、癒合(healing)或生長;骨骼轉變(bone turnover)的減緩(deceleration)或抑制;骨骼再吸收(bone resorption)的減緩或抑制;蝕骨細胞活性(osteoclast activity)的抑制;以及造骨細胞(osteoblast)活性的刺激]的藥劑種類。這些藥劑之中的某些可以是胜肽類(peptidic),例如,降鈣素、副甲狀腺激素(PTH)、PTH片段(例如,PTH[1-34])、轉形生長因子(Transforming Growth Factors,TGFs),以及上面任一者的類似物與片段。骨骼活性劑亦可以是小分子的非胜肽類結構,它們顯示出如在這個段落的前面所描述的活體內藥理骨骼活性。
此等藥理活性劑的一已知種類,降鈣素,具有多樣化的藥學效用並且一般地被使用於治療,例如,佩吉特氏病、高血鈣症以及骨質疏鬆症(包含,但不限於:停經後骨質疏鬆症)。各種不同的降鈣素(包含鮭魚、豬以及鰻魚降鈣素)是商業上可得的,並且一般地被使用於治療,例如,佩吉特氏病、惡性高血鈣症(hypercalcemia of malignancy)以及骨質疏鬆症。降鈣素可以是任何降鈣素(例如,人類、鮭魚、豬或鰻魚),包含此等之天然的、合成的或重組的來源,以及降鈣素衍生物(諸如1,7-Asu-鰻魚降鈣素)。該組成物可以包含有一種單一的降鈣素或二或多種降鈣素之任何組合。較佳的降鈣素是合成的鮭魚降鈣素。
該等降鈣素是商業上可得到的,或可藉由已知的方法來合成。
當該藥理活性劑是鮭魚降鈣素時,適當的劑量當然地將依據,例如,要被治療的宿主以及病狀的性質與嚴重性,而變化。適合的劑量數量被提供於國際公開案案號WO 2004/012772、WO 2005/004900以及WO 2005/014031中,它們全部在此被併入本案以作為參考資料。當組合以一口服輸送劑(例如,5-CNAC)被投藥時,鮭魚降鈣素之一口服人類劑量典型地是落在大約0.05 mg至5 mg的範圍內,較佳為大約0.1 mg至2.5 mg。依據一具體例,從大約0.4 mg至大約2.5 mg的鮭魚降鈣素被每日投藥給一病人[例如,一人類(諸如一為大約70 kg的普通人類)]中。更佳地,從大約0.8至大約1.2 mg(例如,大約1 mg)被每日投藥。又較佳的是低於1 mg,但高於0.4 mg的劑量。
適合的副甲狀腺激素之劑量數量被提供於國際公開案案號WO 2005/002549、WO 03/015822以及WO 02/098453中,它們全部在此被併入本案以作為參考資料。要被投藥的副甲狀腺激素之數量是一能有效達到所欲的生理狀況的數量。在一具體例中,副甲狀腺組份(component)(例如,PTH、PTH[1-28]-PTH[1-41])的數量是會使得它會提供一個PTH組份的每日投藥劑量是從大約0.001 μg/kg至大約10 mg/kg的動物體重,或從大約1 μg/kg至大約6 μg/kg的動物體重。單位劑量形式(unit dosage forms)可以含有,例如,800 μg的PTH組份。用於特殊應用的特定PTH數量將依據要被治療的個體的年齡、大小、性別以及病狀而變化,並且可為熟習此技藝之人士來決定。
HGH或HGH組份的數量亦可為熟習此技藝之人士來決定。在一具體例中,HGH[例如,191個胺基酸的天然種類(somatropin)]或HGH組份[例如,192個胺基酸的N-端甲硫胺酸(met)種類(somatrem)]的數量是會使得它會於一單位劑量形式內提供從大約10 mg至大約300 mg的HGH或HGH組份(例如,100 mg的HGH或HGH組份)。用於特殊應用的特定HGH數量將依據要被治療的個體的年齡、大小、性別以及病狀而變化,並且可為熟習此技藝之人士來決定。
藥理活性劑通常包含有,相對於整個藥學組成物的總重量,從大約0.05百分比至大約70百分比(以重量計),較佳為一從大約0.01百分比至大約50百分比(以重量計)的數量,更較佳為相對於整個藥學組成物的總重量是大約0.3百分比至大約30百分比(以重量計)。
該藥學組成物較佳地是呈固體形式並且可以呈一劑量形式之形式(例如,一固體劑量形式,諸如一固體口服劑量形式)。該固體劑量形式可以是一膠囊(capsule)、錠劑(tablet)或粒子(particle)[諸如一粉末或小藥囊(sachet)]。粉末可以呈一被混合以一液體而被投藥的小藥囊之形式。又,粉末亦可被包裝至膠囊中或被壓製成錠劑,或者粉末可以直接被投藥給個體。
另擇地,該固體劑量形式可以是一局部輸送系統(topical delivery system),諸如一軟膏(ointment)、乳霜(cream)或半固體(semi-solid)。例如,粉末可以被加入至局部賦形劑(例如,聚乙二醇)並且有如一軟膏而被投藥。
該藥學組成物可以包含一持續釋放或控制釋放系統(sustained release or controlled release system)。較佳地,該固體劑量形式是供用於口服投藥。
輸送劑(delivery agent)在該固體劑量形式中的數量是一輸送有效數量,並且可就任何特定的化合物或生物或化學活性劑而藉由熟習本技藝者所知的方法來決定。
在投藥之後,該劑量單位形式中的活性劑被吸收到循環中。該活性劑的生物可利用性可藉由測量血液之一已知的藥理活性而被容易地評估,例如,由肝素所引起的血液凝固時間(blood clotting time)之一增加,或由降鈣素所引起的循環鈣位準(circulating calcium levels)之一降低。另擇地,該活性劑本身的循環位準可以被直接地測量。
該固體劑量形式可以包含藥學上可接受的添加劑,諸如:賦形劑(excipients)、載劑(carriers)、稀釋劑(diluents)、安定劑(stabilizers)、塑化劑(plasticizers)、黏合劑(binders)、滑動劑(glidants)、崩解劑(disintegrants)、增容劑(bulking agents)、潤滑劑(lubricants)、塑化劑、著色劑(colorants)、薄膜形成劑(film formers)、調味劑(flavoring agents)、防腐劑(preservatives)、劑量載劑(dosing vehicles)、介面活性劑(surfactants),以及上述之中任一者的任何組合。較佳地,這些添加劑是藥學上可接受的添加劑,諸如那些被描述於Remington's,The Science and Practice of Pharmacy
(Gennaro,A.R.,ed.,19th edition,1995,Mack Pub.Co.)中的,該文獻在此被併入本案以作為參考資料。
適合的黏合劑包含,但不限於:澱粉、明膠(gelatine)、糖類[諸如蔗糖、糖蜜(molasses)與乳糖]、磷酸二氫鈣二水合物(dibasic calcium phosphate dihydrate)、天然的與合成的樹膠[諸如阿拉伯樹膠(acacia)]、藻酸鈉(sodium alginate)、羧甲基纖維素(carboxymethyl cellulose)、甲基纖維素(methyl cellulose)、聚乙烯吡咯酮(polyvinylpyrrolidone)、聚乙二醇、乙基纖維素以及蠟(waxes)。
適合的滑動劑包含,但不限於:滑石(talc)以及二氧化矽(矽石)[例如,燻矽(fumed silica)與膠體二氧化矽(colloidal silicon dioxide)]。
適合的崩解劑包含,但不限於:澱粉、澱粉甘醇酸鈉(sodium starch glycolate)、交聯甲基纖維素鈉(croscarmellose sodium)、交聯聚維酮(crospovidone)、黏土(clays)、纖維素(諸如純化的纖維素、甲基纖維素、羧甲基纖維素鈉)、藻酸鹽、預糊化玉米澱粉(pregelatinized corn starches)以及樹膠[諸如瓊脂(agar)、瓜耳豆(guar)、刺槐豆(locust bean)、刺梧桐(karaya)、果膠(pectin)以及黃蓍膠(tragacanth gums)]。一較佳的崩解劑是澱粉甘醇酸鈉。
適合的增容劑包含,但不限於:澱粉(諸如米澱粉)、微晶纖維素、乳糖(例如,乳糖單水合物)、蔗糖、右旋糖(dextrose)、甘露醇(mannitol)、硫酸鈣、硫酸二鈣以及硫酸三鈣。
適合的潤滑劑包含,但不限於:硬脂酸、硬脂酸鹽(諸如硬脂酸鈣與硬脂酸鎂)、滑石、硼酸、苯甲酸鈉、乙酸鈉、延胡索酸鈉(sodium fumarate)、氯化鈉、聚乙二醇、氫化棉籽(hydrogenated cottonseed)與蓖麻油(castor oils)。
適合的介面活性劑包含,但不限於:月桂基硫酸鈉(sodium lauryl sulfate)、羥基化大豆卵磷脂(hydroxylated soy lecithin)、聚山梨醇酯(polysorbates)以及環氧丙烷(propylene oxide)與環氧乙烷(ethylene oxide)的嵌段共聚物(block copolymers)。
該等藥學上可接受的非活性賦形劑可以包含聚合物與非活性化合物,它們,例如,輔助本發明所預期的固體口服劑量形式之配方處理或製造,或者它們可以輔助該固體口服組成物在胃腸環境中的釋放。
在本發明之一額外的具體例中,該藥學上可接受的非活性賦形劑可以是聚合物交聯聚維酮(crospovidone)或聚維酮(povidone)之中的一者或這兩者。
於上所指的該等藥學上非活性成分,例如,選擇性地包含交聯聚維酮與聚維酮,它們可以是任一種交聯聚維酮與聚維酮。交聯聚維酮是N-乙烯基-2-吡咯酮[亦被稱為1-乙烯基-2-吡咯啶酮(1-ethenyl-2-pyrrolidinone)]之一合成的交聯均聚物,具有一為1,000,000或更高的分子量。商業上可獲得的交聯聚維酮包含Polyplasdone XL、Polyplasdone XL-10、Polyplasdone INF-10(可得自於ISP)、Kollidon CL(可得自於BASF Corporation)。較佳的交聯聚維酮是Polyplasdone XL。
聚維酮是一由線性1-乙烯基-2-吡咯啶酮基團所構成之合成的聚合物,具有一通常是介於2,500與3,000,000之間的分子量。商業上可獲得的聚維酮包含Kollidon K-30、Kollidon K-90F(可得自於BASF Corporation)以及Plasdone K-30與Plasdone K-29/32(可得自於ISP)。
如在上面所提到的,該交聯聚維酮與聚維酮是商業上可獲得的。另擇地,它們可藉由已知的方法來合成。
交聯聚維酮、聚維酮或它們的組合通常是,相對於整個藥學組成物的總重量,呈一從大約0.5百分比至50百分比重量計的數量而存在於該組成物中,較佳為一從2百分比至25百分比,更佳為5百分比至20百分比重量計的數量(相對於該藥學組成物的總重量)。
被使用於本發明之一藥學組成物中的活性劑之數量是一能有效的達到該特定的活性劑用於目標指徵(target indication)之目的的數量。該活性劑在該組成物中的數量典型地是一種藥理學上、生物學上、治療上或化學上有效的數量。但是,當該組成物是呈一劑量單位形式被使用時,該數量可以低於那個數量,因為該劑量單位形式可以含有數個輸送劑化合物/活性劑組成物,或可含有一經區分的藥理學上、生物學上、治療上或化學上有效的數量。總有效數量(total effective amount)於是可呈累計單位(cumulative units)(總計含有一有效數量的該活性劑)而被投藥。
要被使用的活性劑之總數量可以藉由熟習此技藝者所知的方法來決定。但是,因為本發明的組成物可比其他組成物或含有該活性劑本身的組成物更有效地輸送該活性劑,要比習知劑量單位形式或輸送系統(prior dosage unit forms or delivery systems)中所用的那些為低之生物或化學活性劑的數量可以被投藥給個體,而仍能達到相同的血液位準和/或治療效用。
一般而言,輸送劑(例如,5-CNAC)相對於活性劑(例如,HGH或HGH組份,PTH或PTH片段)的重量比是落在從大約0.1:1至大約300:1或1000:1的範圍內。在一具體例中,輸送劑(例如,5-CNAC)相對於活性劑(例如,HGH或HGH組份,PTH或PTH片段)的重量比是落在從大約50:1或40:1至大約0.5:或0.2:1的範圍內。在一具體例中,輸送劑(例如,5-CNAC)相對於活性劑(例如,HGH或HGH組成,PTH或PTH片段)的重量比是落在從大約10:1至大約0.5:1(例如,2:1)的範圍內。輸送劑(例如,5-CNAC)的重量比是根據該輸送劑的自由酸形式來計算。重量比將依據該活性劑以及有關於該活性劑被投藥的特殊指示而變化。
現在所揭示的輸送劑促助生物與化學活性劑的輸送,特別是在口服的、舌下的、頰內的、十二指腸內的、結腸內的、直腸的、陰道的、黏膜的、肺的、鼻內的以及眼睛的系統中。
本發明的化合物與組成物可應用於將生物或化學活性劑投藥給任一種動物,包含,但不限於:鳥類,諸如雞;哺乳動物,諸如齧齒類、牛、豬、狗、貓、靈長類,以及特別是人類;以及昆蟲。
該等化合物與組成物特別地有利於輸送化學或生物活性劑,否則在到達它們的目標區域(target zone)(亦即,該輸送組成物的活性劑要被釋出的區域)之前以及在它們被投藥的動物之體內,該等活性劑將會為所遭遇到的狀況予以破壞或被弄成較低效用的。特別地,本發明的化合物與組成物在口服投藥活性劑上是有效的,特別是那些通常為不可口服地輸送的,或那些被欲求能有改善的輸送的。
相較於無該輸送劑的該活性劑之投藥,包含有該等化合物與活性劑的組成物在輸送活性劑至被選擇的生物系統上以及在該活性劑之一增高的或改善的生物可利用性上具有實用性。輸送可被改善,藉由輸送更多活性劑歷時一段時間,或在一特定的時間期間內輸送活性劑(俾以能完成更快的或被延遲的輸送)或輸送活性劑歷時一段時間(諸如持續釋放輸送)。
本發明的另一個具體例是一種藉由投藥本發明的組成物來治療或預防一動物之一疾病或達到一所欲的生理效用(physiological effect)(諸如被列舉於下面表格中的那些)的方法。關於活性劑的特殊指徵可被發現於Physicians’ Desk Reference(59t h
Ed.,2005,Medical Economics Company,Inc.,Montvale,NJ),該文獻在此被併入本案以作為參考資料。在下面表格中的活性劑包含它們的類似物、片段、模擬物以及經聚乙二醇修飾的衍生物。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應降鈣素的作用而反應的障礙[諸如佩吉特氏病、高血鈣症或骨質疏鬆症之方法(例如,治療停經後超過5年且相較於健康的停經前女性具有較低的骨質(bone mass)的女性之骨質疏鬆症),其係藉由口服地投藥本發明之一藥學組成物(包含有形式I、II、III和/或IV的5-CNAC以及降鈣素)。較佳地,該藥學組成物是在沒有食物之下被投藥,有利地是在消耗食物之前的一個短間隔(例如,在一餐之前的一個短間隔),俾以提高降鈣素的口服生物可利用性。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應人類生長激素的作用而反應的障礙[諸如生長障礙(例如,身材矮小)]的方法,其係藉由口服地投藥本發明之一藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及人類生長激素)。可被本發明的藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及人類生長激素)所治療的病狀或被達到的效用之其他實例包括:長期治療由於內生性生長激素的不充分分泌所引起的生長不足之幼兒病患、長期治療由於普拉德-威利症候群(Prader-Willi syndrome,PWS)所引起的生長不足之幼兒病患、他們的骨骺(epiphyses)沒有被閉合的病人之與透納氏症候群(Turner syndrome)有關聯的身材矮小(short stature)、原發性身材矮小(idiopathic short stature)、患有具幼年時期或成人發病病因學(adult-onset etiology)的生長激素缺乏(GHD)[例如,由於腦垂體疾病、下視丘疾病(hypothalamic disease)、手術、放射治療(radiation therapy)、慢性腎臟功能不全或創傷所造成的生長激素缺乏]之成人的長期替代治療(replacement therapy),以及因為妊娠期(gestational age)不足而出生體型小且至兩歲也無法展現出適齡成長(catch-up growth)的孩童之生長不足的長期治療。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應副甲狀腺激素的作用而反應的障礙[諸如骨質疏鬆症(例如,具有骨質疏鬆症的停經後女性,她有骨折的高危險性)]的方法,其係藉由口服地投藥本發明之一藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及副甲狀腺激素)。可被本發明的藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及人類生長激素)所治療的病狀或被達到的效用之其他實例包括:帶有原發性或性腺低能性(hypogonadal)骨質疏鬆症的男性(他有骨折的高危險性)之骨質(bone mass)的增加。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應Imitinab的作用而反應的障礙(諸如慢性骨髓性白血病與胃腸道基質瘤)的方法,其係藉由口服地投藥本發明之一藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及Imitinab)。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應流行性感冒病毒疫苗的作用而反應的障礙(諸如流行性感冒感染)的方法,其係藉由口服地投藥本發明之一藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及流行性感冒病毒疫苗)。
另一個具體例是一種用於治療一有需要治療的哺乳動物(例如,一人類)之一因應ranibizumab的作用而反應的障礙[諸如黃斑點退化(例如,濕性黃斑點退化以及年齡相關的黃斑點退化)]的方法,其係藉由口服地投藥本發明之一藥學組成物(包含形式I、II、III和/或IV的5-CNAC以及ranibizumab)。
本發明將藉由下列實施例來作闡述而不受之所限制。除非有另外指明,所有的百分比是以重量計。
被引用的熔點(melting point)是藉由微差掃描熱量法(DSC)來決定。被引用的數值是使用一種Perkin Elmer微差掃描熱卡計(Differential Scanning Calorimeter)DSC-7而被獲得。DSC曲線是使用一為20 K/min的加熱速度與一為1至3 mg的樣品質量(sample mass)而被記錄。
粉末X射線繞射分析(Powder X-Ray diffraction analysis)是使用一種Scintag X1繞射儀(diffractometer)以及銅Kα1
放射(radiation)而被完成。
形式I的5-CNAC被製備如下。一為200加侖之玻璃襯裡的反應器(glass-lined reactor)被建立以供用於常壓蒸餾(atmospheric distillation)。冷卻被施加到冷凝器(condenser)與接受器(receiver)上。該反應器以氮予以淨化(purged)。該反應器被充填以565 L的乙腈(acetonitrile)。攪拌器被設定在100 rpm。該反應器被充填以13.7 kg的純水(purified water)與43.25 kg的5-CNAC單乙醇溶劑化物。該反應器內容物(content)被加熱至迴流而致使餾出物(distillate)開始收集至該接受器中。常壓蒸餾被持續直至大約102 L的餾出物被收集。該反應器夾套(jacket)的加熱被停止,並且一具有102 L的新鮮乙腈與2.5 kg的純水之混合物被充填至該反應器中。該反應器內容物被冷卻至介於5與15℃之間,並且被攪拌歷時介於1與2小時之間。所形成的濃漿藉由離心而被分離。濕性餅(wet cake)沒有被清洗。該濕性餅在一完全真空、介於75與85℃之間的真空烘箱內被乾燥歷時48小時。二鈉5-CNAC單水合物的產率大約是40 kg(達到一為大約99.9%的產率)。
有關如上面所製備的形式I的XRPD與DSC光譜分別被顯示在第1與2圖中。
形式I的5-CNAC亦可如下被製備。一為22L、Pyrex玻璃製、五頸、圓底燒瓶被配備以一高架的攪拌器(overhead stirrer)、溫度讀出的熱電偶(thermocouple temperature read out)以及加熱罩(heating mantle)。該燒瓶被充填以2602.3 g的5-CNAC與4000 mL的水。一種具有660 g之氫氧化鈉被溶解在2000 mL之水中的溶液被添加至此被攪拌的濃漿中。該混合物被加熱至55℃並且大部分的固體被溶解。輕微模糊(slightly hazy)的溶液經由Whatman #1過濾紙(filter paper)而被熱過濾,俾以移除不可溶的微粒物質。過濾物被轉移到一大的實驗室旋轉式蒸發器的罐熔燒瓶(pot flask)中。該旋轉式蒸發器以一為60℃的浴溫(bath temperature)與一為60 mmHg的壓力而被操作。水從二鈉鹽溶液中被移除,直至一固體團塊(solid mass)在該旋轉式蒸發器的罐熔燒瓶中被獲得。真空被釋放,並且從該旋轉式蒸發器中移除該罐熔燒瓶。該固體從該罐熔燒瓶被刮落至盤子(tray)中。這些盤子接而被放置在一真空烘箱中,而該固體在60℃且完全真空下被乾燥歷時48小時。該經乾燥的固體被穿經一實驗室研磨機(laboratory mill)直至所有的固體通經一個35篩目的篩網。經研磨與過篩的二鈉5-CNAC單水合物被放進盤子中並且被放回至乾燥烘箱(drying oven)中。乾燥在45℃並且完全真空下被持續而產生2957.1 g之所欲的產物(有如一乾燥的粉末)。
形式II的5-CNAC是如下被製備。對一為200加侖的不鏽鋼反應器(stainless steel reactor)充填以132 L的乙醇與11.6 kg的氫氧化鈉顆粒。該反應器被加熱至大約55℃並被保持在此溫度直至氫氧化鈉被溶解。該氫氧化鈉/乙醇溶液被冷卻並被維持在一至少25℃的溫度下。該氫氧化鈉/乙醇溶液被取樣以供用於藉由滴定的鹼分析(base assay)。對一第二個200加侖之玻璃襯裡的反應器充填以135 L的乙醇與44.69 kg的5-CNAC。濃漿被加熱攪拌至55℃。此溫度與攪拌被維持直至該固體被溶解。2莫耳當量(當以滴定分析來測定時)的乙醇/氫氧化鈉溶液被添加至該被攪拌的乙醇/5-CNAC溶液中。當該氫氧化鈉溶液被加入時,二鈉5-CNAC乙醇溶劑化物開始沉澱。此添加步驟是放熱的並且必須被控制以避免過度迴流。該反應器被建立供作為常壓蒸餾,而大約146 L的乙醇被蒸餾出來。該批次被冷卻至小於10℃並且被保持在此溫度歷時大約4小時。固體產物經由離心過濾而被回收。過濾餅(filter cake)被放置在一乾燥烘箱中並且在45℃與完全真空下被乾燥歷時介於大約16與24小時之間。乾燥的二鈉5-CNAC單乙醇溶劑化物的產率係大約43.25 kg。
有關形式II的XRPD光譜被顯示在第3圖中。
形式III是如下被製備。一薄層的二鈉5-CNAC單乙醇溶劑化物被塗佈在一玻璃盤子中。該包含有材料的盤子被放置在一個40℃之被設定在75%RH的溼度室(humidity chamber)中。在該玻璃盤子中的固體被定期地攪拌與秤重。該材料被留在該溼度室中直至該樣品不再改變重量或含有乙醇(當以氣相層析來測定時)。這需要大約6天。
有關形式III的XRPD光譜被顯示在第4圖中。
形式IV是如下被製備。一配備有一底部排水管(bottom drain)之1公升的反應器被充填以375 mL的2-丁酮、125 mL的水,以及125 g的二鈉5-CNAC單水合物。該反應器內容物被攪拌並加熱至50℃。固體被溶解而形成一雙相溶液(biphasic solution)。攪拌被停止,並且該溶液允許分開成為兩個不相溶的液體層。該反應器上的底部排水管被用來移除並且丟棄較低的層(lower layer)。剩餘的溶液被冷卻至環境溫度(ambient temperature)。在此冷卻循環的期間,產物開始結晶(crystallize)。250 mL之額外的2-丁酮被添加至所生成的濃漿中。固體產物藉由經過一燒結玻璃漏斗(sintered glass funnel)的真空過濾而被回收。濕性餅在一為55℃之完全真空的真空烘箱中被乾燥過夜。乾燥的二鈉5-CNAC單水合物具有一為54.35 g的重量。產率是43%。
有關形式IV的XRPD與DSC光譜分別被顯示在第5與6圖中。
形式I與IV的5-CNAC的混合物被製備如下。一乾淨的200加侖之玻璃襯裡的反應器被充填以525的丙酮。該反應器以氮予以清洗。攪拌被開啟。35 kg的5-CNAC被充填至該攪拌的反應器內容物中。該反應器內容物被加熱至介於50與60℃之間,並且被保持在此溫度下歷時至少大約20分鐘。在此時間期間,大多數的固體被溶解。該反應器內容物經由一壓力過濾器(pressure filter)而被唧打(pumped)至一鄰接的200加侖之玻璃襯裡的反應器中。該最初的反應器與該壓力過濾器以20 L的新鮮丙酮而被沖洗至該第二個反應器中。一水性的氫氧化鈉溶液藉由將8.92 kg的氫氧化鈉溶解在44.6 L的純水中而被製備於一獨立槽(separate tank)中。此水性的鹼性溶液(aqueous bases olution)被唧打至含有丙酮/5-CNAC過濾物的反應器中。此水性鹼添加引起該反應器內容物迴流。該水性鹼槽(aqueous base tank)以8.9 L的新鮮水而被沖洗至該迴流的反應器中。加熱或冷卻沒有被施加至該反應器容器上,而該反應器內容物被允許緩慢地冷卻至環境溫度。冷卻被施加至該反應器的夾套(jacket)上,而該反應內容物進一步被冷卻至介於0℃與5℃之間。整個冷卻循環耗費介於16與24小時之間。在該反應混合物中已經形成的沉澱物(precipitate)藉由離心過濾而被回收。過濾餅被放置於一乾燥烘箱中,並且在60℃與完全真空下被乾燥歷時至少16小時。經乾燥的二鈉5-CNAC單水合物的產率係大約39.9 kg。此5-CNAC單水合物被發現是一種形式I與IV的混合物。在貯存該材料的期間,形式IV被發現到會轉變成形式I。
在上面所提到的所有專利案、申請案、文獻、公開案與測試方法在此被併入本案以作為參考資料。
第1、3、4與5圖分別是如實施例1至4所製得的形式I至IV的5-CNAC(第3圖的上方光譜是形式II的光譜)的X射線粉末繞射圖(X-ray powder diffractograms,XRPDs);以及第2與6圖分別是如在實施例1與4中所製得的形式I與IV的5-CNAC的微差掃描熱量法(DSC)分析[differential scanning calorimetry(DSC)analyses]。
Claims (16)
- 一種N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的結晶形式,其係N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的結晶乙醇溶劑化物,其展現一X射線粉末繞射圖樣具有位於7.5、14.1、16.5、18.5、25以及26° 2 θ±0.2° 2 θ之特徵性波峰。
- 一種N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的結晶形式,其係N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的八水合物,其展現一X射線粉末繞射圖樣具有位於4.8、10.4、11.7以及14.6° 2 θ±0.2° 2 θ之特徵性波峰。
- 一種N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的結晶形式,其係N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的結晶單水合物,其展現一X射線粉末繞射圖樣具有位於7.2、18.2以及24.7° 2 θ±0.2° 2 θ之特徵性波峰。
- 一種藥學組成物,其包含有如申請專利範圍第1至3項中任一項的結晶形式以及一生物活性劑。
- 如申請專利範圍第4項的藥學組成物,其中該生物活性劑是降鈣素。
- 如申請專利範圍第5項的藥學組成物,其進一步包含副甲狀腺激素。
- 如申請專利範圍第4項的藥學組成物,其中該生物活性劑是胰島素。
- 如申請專利範圍第4項的藥學組成物,其中該生物活性劑是一生長激素。
- 一種用於製備如申請專利範圍第1項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之單乙醇溶劑化物的方法,其包含下面步驟:(a)將氫氧化鈉加入至一含N-(5-氯柳醯基)-8-胺基辛酸與乙醇的溶液中;以及(b)從該溶液中沉澱出如申請專利範圍第1項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之單乙醇溶劑化物。
- 一種用於製備如申請專利範圍第2項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之八水合物的方法,其包含將種N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽的單水合物維持在一為至少75%的相對溼度下歷時一充分時間,俾以形成如申請專利範圍第2項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之八水合物。
- 一種用於製備如申請專利範圍第3項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之單水合物的方法,其包括下面步驟:(a)在一升高的溫度下,將N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之單水合物溶解於丁酮中;以及(b)冷卻步驟(a)的丁酮溶液,俾以產生如申請專利範圍第3項之N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之單水合物。
- 一種用於製備一種含形式I與IV的N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之混合物的方法,其包括將一含N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽與丙酮的溶液冷卻歷時一充 分時間之步驟,俾以產生該含形式I與IV的混合物,其中形式I的N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽係結晶單水合物,其展現一X射線粉末繞射圖樣具有位於15.5、24.5以及24.8° 2 θ±0.2° 2 θ之特徵性波峰;以及形式IV的N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽係結晶單水合物,其展現一X射線粉末繞射圖樣具有位於7.2、18.2以及24.7° 2 θ±0.2° 2 θ之特徵性波峰。
- 一種藥學組成物,其包含:(a)N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之結晶單水合物,其展現一X射線粉末繞射圖樣具有位於7.5、10.4、14.2、15.0、15.5、16.1、18.4、20.8、23.6、24.1、24.5、24.8、25.4、26.6、27.2、27.5、29.6以及31.5° 2 θ±0.2° 2 θ之特徵性波峰;(b)N-(5-氯柳醯基)-8-胺基辛酸二鈉鹽之結晶單水合物,其展現一X射線粉末繞射圖樣具有位於7.2、18.2以及24.7° 2 θ±0.2° 2 θ之特徵性波峰;以及(c)生物活性劑。
- 如申請專利範圍第13項的藥學組成物,其中該生物活性劑是降鈣素。
- 如申請專利範圍第13項的藥學組成物,其中該生物活性劑是人類生長激素。
- 如申請專利範圍第13項的藥學組成物,其中該生物活性劑是副甲狀腺激素。
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