TW202337464A - 免疫不全病症的新治療 - Google Patents
免疫不全病症的新治療 Download PDFInfo
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- TW202337464A TW202337464A TW111129582A TW111129582A TW202337464A TW 202337464 A TW202337464 A TW 202337464A TW 111129582 A TW111129582 A TW 111129582A TW 111129582 A TW111129582 A TW 111129582A TW 202337464 A TW202337464 A TW 202337464A
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- montelukast
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Abstract
提供了孟魯司特或其藥學上可接受的鹽用於製造用以治療免疫不全病症以及用以治療患有或易患以免疫抑制為特徵的病症的患者的以炎症為特徵的病症的醫藥品的用途。能夠提及的特定病症包括因作為例如癌症治療的一部分的放射療法導致的那些,如放射性直腸炎。將孟魯司特及其鹽優選地外用和局部投予,例如肛門直腸投予。
Description
本發明涉及已知的藥物活性化合物的新用途,特別是,其在治療以免疫抑制為特徵的病症(如放射性直腸炎)中的用途。
免疫系統是身體對抗外來或危險侵入物如微生物(例如細菌、病毒和真菌)、寄生蟲(例如蠕蟲)和癌細胞的天然防禦。
免疫系統區分什麼屬於身體和什麼不屬於身體。免疫系統所識別的物質被稱為“抗原”。在於其他方面健康的個體中,抗原如果被認為是危險的則會刺激身體內的免疫反應。正常的事件序列由以下組成:識別潛在有害的抗原,然後活化身體的免疫反應以動員並中和所述抗原。
先天免疫系統是主導且初級的免疫系統反應。它通過如下方式來運作:通過產生化學介質(細胞介素)將免疫細胞募集到感染部位,活化補體級聯以鑑定細菌、活化細胞,以及鑑定和去除器官、組織、血液和淋巴中存在的外來物質。
損傷細胞對於感染或刺激作出反應而釋放的細胞介素往往導致炎症,這有助於建立對抗感染蔓延的物理屏障,並且在清除病原體後促進任何受損組織的痊癒。
急性炎症階段發生在感染或損傷開始時,並且由存在於組織中的細胞(例如巨噬細胞、樹突細胞等)引發。這些細胞通過其樣式辨識受體(PRR)之一經歷活化,並且識別病原體相關分子樣式(PAMP)以釋放炎症介質(例如組織胺、舒緩肽、血清素、白三烯和前列腺素),這敏化疼痛受體,引起局部血管舒張,並且吸引吞噬細胞(例如嗜中性球),從而通過釋放召喚另外的白血球和淋巴球的因子來觸發免疫系統的其他部分。
先天免疫系統還活化高等脊椎動物免疫系統的次級鏈,稱為適應性免疫系統。適應性免疫系統由消除病原體或阻止其生長的特化的全身性細胞和過程構成。
與先天免疫系統不同,適應性免疫系統對身體過去遇到的每種特定病原體具有專一性,並且在對特定病原體的初次反應後產生免疫記憶。這導致增強未來遇到該病原體時的反應。這是從病毒或細菌疾病中恢復的人此後(有時在他們的餘生持續)受到保護的過程,並且是疫苗接種過程的基礎。
適應性免疫反應中涉及的關鍵細胞是兩種不同類型的淋巴球,即B細胞和T細胞。在適應性免疫反應中,B細胞被活化以分泌抗體(免疫球蛋白),所述抗體與抗原結合並使它失活,因此它不會造成損害,而T細胞則有助於鑑定和破壞外來或異常細胞。
適應性免疫導致獲得病原體專一性受體,以為免疫系統應對未來的挑戰做準備。然而,在一些情況下,適應性免疫系統無法將有害與無害的異物(如花粉或食物分子)區分,從而導致過敏或過敏性病症(如氣喘和花粉症),或導致自體免疫性病症,其中免疫系統可能攻擊身體自身的組織,所述自體免疫性病症包括類風濕性關節炎和全身性紅斑狼瘡。
免疫系統的其他病症包括身體無法產生針對抗原的適當免疫反應的那些。這樣的病症通常被稱為“免疫不全”,其中患者是“免疫受損的(immunocompromised)”。
以免疫不全為特徵的病症或“免疫不全病症”損害免疫系統使身體防禦抗原的能力。結果,感染可能更容易發生,或者可能患上癌症,如淋巴瘤。許多患有免疫不全病症的人還患有自體免疫性病症。
原發性免疫不全病症(PIDD)通常是罕見的先天性病症,它們經常是遺傳的。此類病症通常但並非總是在兒童期表現出來,並且可以根據受影響(缺失、數量減少、異常和/或功能失常)的免疫系統部分來定性,所述免疫系統部分包括:B細胞(體液性免疫不全);T細胞(細胞性免疫不全);吞噬細胞(嗜中性球、單核球、巨噬細胞和嗜酸性球;吞噬細胞性免疫不全);和/或補體蛋白(補體缺陷)。體液性免疫不全病症是最常見的PIDD,占超過一半。
繼發性免疫不全病症(SIDD)更為常見,並且往往在生命後期發展。它們通常是其他原因的結果,所述其他原因包括年老、營養不良(特別是營養不足)、暴露於化學物質(包括藥物)、慢性疾病或病症(如糖尿病、HIV感染或癌症(包括白血病和淋巴瘤,其損害骨髓產生淋巴球的能力))或用於治療病症(如癌症)的化學療法和/或放射療法。
活性藥物成分有時被設計成具有免疫抑制作用,這取決於它們預期要治療的疾病。例子包括被給予以預防移植器官或組織排斥或被給予患有自體免疫性病症的患者的那些,以及通常用於抑制各種病症(如類風濕性關節炎)中由過度活躍的免疫系統引起的炎症的皮質類固醇。然而,誘導免疫抑制的明顯副作用是,它影響身體抵抗感染的先天能力,如上所述。
當前對免疫不全病症的治療有些受限。除了通過良好的衛生預防感染外,還經常給予疫苗、抗病毒藥和抗生素。另外,替代免疫系統的缺失部分有時是有效的,例如通過免疫球蛋白療法(即用從免疫系統正常的人的血液中獲得的抗體治療患者)。
嚴重受影響的患者通常終生需要強化且頻繁的治療,並且他們的病症通常只能通過幹細胞移植來矯正。基因療法和胸腺組織移植有時是有幫助的,但是這些都是昂貴的並且只留給最致命的免疫不全病症。
因此,對免疫不全病症的更有效和/或更容易獲得的治療有明顯的未滿足的臨床需求。
這裡特別受到關注的是放射療法,其通過經由電離輻射對DNA、脂質和蛋白質的直接作用來破壞(例如癌症)細胞而起作用。由於水構成了細胞的大部分,因此電離輻射導致產生氧自由基(OFR)。已知OFR的產生參與全身性炎症反應症候群的發展。OFR活化(除其他外)細胞介素的產生。細胞介素是參與全身性炎症反應進展的主要介質(Closa等人,
IUBMB Life,
56, 185 (2004))。
放射性直腸炎是由於給予骨盆輻射以治療癌症(如前列腺癌或宮頸癌)而對直腸造成持續損害而發生的直腸炎症。放射性直腸炎可以是急性的或慢性的,這取決於相對於放射療法的時機,但是本質上是輻射劑量導致正常組織失去其修復損傷或從損傷中恢復的能力的結果。病因尚不清楚,但是已經有人提出,輻射後的全身性麩胱甘肽缺乏導致氧化損傷增加(Do等人,
Gastroenterol. Res. Pract.(2011), doi: 10.1155/2011/917941)。
如上所述,炎症是正常免疫反應的關鍵部分,因為它導致局部水平的痊癒。另一方面,放射性直腸炎是這樣的病症,其以損傷、損害和傷口(wounding)為特徵,但是其中患者的免疫反應受到抑制,因此局部炎症反應不傾向導向正常的痊癒過程,並且可以持續延長的時間段。此外,局部抗炎藥(如皮質類固醇)具有通過進一步抑制免疫反應而使病情變得更糟的趨勢。
因此,對使用這樣的藥劑的有效放射性直腸炎治療有明顯的未滿足的臨床需求,所述藥劑直接能夠恢復全身性免疫反應;能夠治療放射性直腸炎的症狀,如下文所述,而不進一步損害患者的全身性免疫反應;或者能夠同時做到這兩件事,即減少那些症狀,同時以具有免疫恢復作用或至少不具有免疫抑制作用的方式起作用。
孟魯司特(montelukast)是口服活性非類固醇免疫調節化合物,其被經口投予至胃腸道,用於維持治療和預防季節性過敏症狀(參見例如Hon等人,
Drug Design, Development and Therapy,
8, 839 (2014))。它主要通過阻斷白三烯D4(以及白三烯C4和E4)對呼吸道中半胱胺醯白三烯受體CysLT1的作用而起作用。已知它以片劑形式以低劑量(每天4 mg至10 mg)治療慢性過敏性病症,如氣喘。
在這方面,以與類固醇類似的方式,孟魯司特通常以其治療過度活躍的免疫系統(其中個體的免疫系統對原本無害的過敏原做出反應)的結果的方式來投予。如Theron等人(
J. Immunol. Res., http://dx.doi.org/10.1155/2014/608930)的回顧文章所述,孟魯司特對CysLT的作用有助於降低作為先天免疫系統的一部分的炎症反應的嚴重程度。
在國際專利申請WO 2019/007356中,描述了如何意外地發現包含孟魯司特的外用組成物在直接施加至開放性傷口(wound)和燒傷時促進傷口的恢復。
如下文所述,我們已經驚奇地發現,孟魯司特在動物模型中能夠恢復輻射誘導的免疫反應抑制,因此具有意想不到的免疫恢復特性。這使得它有可能用於治療免疫抑制性病症和/或治療在免疫系統受損的患者中誘導的病症或其症狀,包括傷口,如放射性直腸炎的情況。
在這方面,並且根據本發明的方面,提供了孟魯司特或其藥學上可接受的鹽用於製造用以治療患者的以免疫抑制為特徵的病症的醫藥品的用途。
根據本發明的一個進一步的方面,提供了孟魯司特或其藥學上可接受的鹽用於製造用以治療免疫不全病症、用以治療免疫系統受損的患者以及用於恢復患者免疫系統的正常功能的醫藥品的用途。
孟魯司特可以以鹽的形式存在。可以提及的鹽包括藥學上可接受的鹽,如藥學上可接受的酸加成鹽和鹼加成鹽。此類鹽可以通過常規手段形成,例如通過如下方式形成:使孟魯司特與一個或多個當量的適當的酸或鹼視需要地在溶劑中或在不溶解鹽的介質中反應,接著使用標準技術(例如在真空中、通過冷凍乾燥或通過過濾)去除所述溶劑或所述介質。鹽還可以通過例如使用合適的離子交換樹脂將呈鹽形式的活性成分的相對離子與另一種相對離子交換來製備。
優選的鹽包括例如乙酸鹽、鹽酸鹽、硫酸氫鹽、馬來酸鹽、甲磺酸鹽、甲苯磺酸鹽、鹼土金屬鹽(如鈣鹽和鎂鹽)或鹼金屬鹽(如鉀鹽,特別是鈉鹽)。
以免疫抑制為特徵的病症(或免疫不全病症)包括PIDD,因此包括體液性免疫不全病症,如普通變異型免疫不全病、選擇性免疫球蛋白缺陷(例如IgA缺陷)、新生兒暫時性低γ球蛋白血症、X連鎖無γ球蛋白血症;細胞性免疫不全病症,如慢性黏膜皮膚念珠菌病、迪格奧爾格症候群(DiGeorge syndrome)、X連鎖淋巴組織增生症候群;體液性和細胞性聯合免疫不全病症,如共濟失調-毛細血管擴張症、高免疫球蛋白血症E症候群、重症聯合免疫不全、威斯科特-奧爾德里奇症候群(Wiskott-Aldrich syndrome);吞噬細胞性免疫不全,如白血球異常色素減退症候群(Chédiak-Higashi syndrome)、慢性肉芽腫病、週期性嗜中性球減少症、白血球黏附缺陷;以及補體缺陷,如補體成分1(C1)抑制劑缺乏症(或遺傳性血管性水腫)、C3缺乏症、C4缺乏症以及C5、C6、C7、C8和/或C9缺乏症。
然而,我們更傾向根據本發明治療的免疫不全病症是SIDD,即由繼發性因素引起的免疫不全病症,所述繼發性因素如年老、營養不良(例如營養不足)、慢性病症、一種或多種化學藥劑(例如藥物)和/或(例如電離)輻射。
可能引起患者免疫不全的病症包括癌症;血液病症,如再生不良性貧血、白血病、多發性骨髓瘤;鐮狀細胞病;唐氏症;感染,如病毒感染(包括水痘、巨細胞病毒、EB病毒、HIV、麻疹)和細菌感染;糖尿病;內臟器官疾病,如慢性腎病、腎病症候群、慢性肝炎、肝衰竭;全身性紅斑狼瘡;酒精中毒、慢性燒傷;以及手術,如脾臟切除。
可能引起患者免疫不全的藥物包括抗癲癇藥物,如拉莫三嗪(lamotrigine)、苯妥英(phenytoin)、丙戊酸;免疫抑制劑,如硫唑嘌呤(azathioprine)、環孢菌素(cyclosporine)、依維莫司(everolimus)、來氟米特(leflunomide)、黴酚酸酯(mycophenolate)、嗎乙酯(mofetil)、西羅莫司(sirolimus)、他克莫司(tacrolimus)、托法替尼(tofacitinib);生物製劑,如阿巴西普(abatacept)、阿達木單抗(adalimumab)、阿那白滯素(anakinra)、巴利昔單抗(basiliximab)、賽妥珠單抗(certolizumab)、達利珠單抗(daclizuma)、依那西普(etanercept)、戈利木單抗(golimumab)、英利昔單抗(infliximab)、依奇珠單抗(ixekizumab)、莫羅莫那(muromonab,OKT3)、那他珠單抗(natalizumab)、利妥昔單抗(rituximab)、蘇金單抗(secukinumab)、托珠單抗(tocilizumab)、優特克單抗(ustekinumab)、維多珠單抗(vedolizumab);特別是皮質類固醇,如天然存在的皮質類固醇,包括皮質醇(氫化可體松)、醛固酮、皮質酮、可體松、孕烯醇酮、孕酮;以及皮質類固醇生物合成中的天然存在的前體和中間體;以及天然存在的皮質類固醇的其他衍生物,如11-去氧皮質醇、21-去氧皮質醇、11-去氫皮質酮、11-去氧皮質酮、18-羥基-11-去氧皮質酮、18-羥基皮質酮、21-去氧可體松、11β-羥基孕烯醇酮、11β,17α,21-三羥基孕烯醇酮、17α,21-二羥基孕烯醇酮、17α-羥基孕烯醇酮、21-羥基孕烯醇酮、11-酮基孕酮、11β-羥基孕酮、17α-羥基孕酮和18-羥基孕酮;以及合成皮質類固醇,包括氫化可體松類型的那些(A組),如醋酸可體松、醋丙氫化可體松(hydrocortisone aceponate)、醋酸氫化可體松、丁丙酸氫化可體松(hydrocortisone buteprate)、丁酸氫化可體松、戊酸氫化可體松、替可體松(tixocortol)和新戊酸替可體松(tixocortol pivalate)、潑尼松龍(prednisolone)、甲潑尼松龍(methylprednisolone)、潑尼松(prednisone)、氯潑尼松(chloroprednisone)、氯潑尼醇(cloprednol)、二氟潑尼酯(difluprednate)、氟氫可體松(fludrocortisone)、氟洛皮質醇(fluocinolone)、氟培龍(fluperolone)、氟潑尼松龍(fluprednisolone)、氯替潑諾(loteprednol)、潑尼卡酯(prednicarbate)和曲安西龍(triamcinolone);縮丙酮化合物和相關物質(B組),如安西奈德(amcinonide)、布地奈德(budesonide)、地奈德(desonide)、縮丙酮氟洛皮質醇(fluocinolone cetonide)、醋酸氟洛皮質醇(fluocinonide)、氯氟舒松(halcinonide)、曲安縮松(triamcinolone acetonide)、環索奈德(ciclesonide)、地夫可特(deflazacort)、福莫可他(formocortal)、氟氫縮松(fludroxycortide)、氟尼縮松(flunisolide)和丙酮氟洛皮質醇(fluocinolone acetonide);(倍他)米松((beta)methasone)類型的那些(C組),如倍氯米松(beclomethasone)、倍他米松(betamethasone)、二丙酸倍他米松和戊酸倍他米松、地塞米松(dexamethasone)、氟可龍(fluocortolone)、鹵米松(halometasone)、莫米松(mometasone)和糠酸莫米松、阿氯米松(alclometasone )和二丙酸阿氯米松、氯倍他索(clobetasol)和丙酸氯倍他索、氯倍他松(clobetasone )和丁酸氯倍他松、氯可托龍(clocortolone)、去羥米松(desoximetasone)、二氟拉松(diflorasone)、二氟可龍(difluocortolone)、氟氯洛龍(fluclorolone)、氟米松(flumetasone)、氟可丁(fluocortin)、氟潑尼定(fluprednidene)和醋酸氟潑尼定(fluprednidene acetate)、氟替卡松(fluticasone)、糠酸氟替卡松和丙酸氟替卡松、甲潑尼松(meprednisone)、帕拉米松(paramethasone)、潑尼立定(prednylidene)、利美索龍(rimexolone)和烏倍他索(ulobetasol);孕酮類型的那些,如氟孕酮(flugestone)、氟米龍(fluorometholone)、甲羥松(medrysone)和醋酸普貝地龍(prebediolone acetate);和孕酮衍生物(孕激素),如醋酸氯地孕酮(chlormadinone acetate)、醋酸環丙孕酮(cyproterone acetate)、美屈孕酮(medrogestone)、醋酸甲羥孕酮(medroxyprogesterone acetate)、醋酸甲地孕酮(megestrol acetate)和醋酸烯諾孕酮(segesterone acetate);以及其他皮質類固醇,如可的伐唑(cortivazol)和6-甲基-11β,17β-二羥基-17α-(1-丙炔基)雄甾-1,4,6-三烯-3-酮。可以提及的特定皮質類固醇包括可體松、潑尼松、潑尼松龍、甲潑尼松龍和地塞米松。
然而,可以特別提及的可能引起患者免疫不全的藥物包括癌症的化療治療,如阿侖單抗(alemtuzumab)、白消安(busulfan)、環磷醯胺、美法侖(melphalan)。
可以提及的特定SIDD包括由用於治療諸如癌症等病症的放射療法(即輻射誘導的免疫抑制)引起的那些。
電離輻射不僅以上文所述的方式抑制免疫系統,而且還可以以其他方式改變被放射線照射之器官中免疫系統的功能。例如,炎症介質(如NF-κB和SMAD2/3)和細胞介素(如IL-1、IL-2、IL-6、IL-8、IL-33、腫瘤壞死因子(TNF-α)、轉形生長因子β(TGF-β)和干擾素γ(IFN-γ))的水平升高與前列腺素和自由基(包括活性含氧物(ROS)和一氧化氮(NO))的釋放相關。在事故暴露期間可能發生的暴露於高劑量輻射(例如由於核災難或放射災難)可能導致炎症反應和/或傷口,這可能在此後持續數年和/或破壞被放射線照射之器官的功能。
因此,儘管如本文所述,已經意外地發現孟魯司特能夠治療輻射誘導的免疫抑制本身,因為還已知它具有抗炎和傷口痊癒兩種特性,特別是當外用投予至炎症和/或傷口部位時,它的免疫恢復特性意味著它在治療免疫系統受損的患者的以炎症和/或傷口為特徵的病症中特別有用。此類患者包括患有一種或多種以免疫不全為特徵的上述病症的那些,特別是包括具有輻射誘導的炎症、傷口和/或免疫抑制的那些。
特別地,在此類輻射誘導的病症的治療中,孟魯司特及其鹽不僅可以用於提供免疫恢復作用,而且還同時促進傷口恢復和/或痊癒。這鑑於如下事實而特別有用:因為輻射誘導的免疫抑制作用和沒有正常的內源性炎症反應,與這樣的病症相關的傷口難以(如果不是不可能的話)恰當地治療。
此外,通過提供上述免疫恢復作用,這使得身體的免疫系統和局部炎症反應能夠變得更有效,並且在這方面,孟魯司特及其鹽還可以用於提供抗炎作用,同時促進傷口進一步痊癒,但是採取不進一步損害患者免疫系統的方式(即皮質類固醇在用於治療炎症時會採取的方式)。
根據本發明的一個進一步的方面,提供了孟魯司特或其藥學上可接受的鹽用於製造用以治療患有或易患以免疫抑制為特徵的病症的患者的炎症和/或以炎症或傷口為特徵的病症的醫藥品的用途,所述治療包括治療以炎症和/或傷口為特徵的輻射誘導的病症。
本身是輻射誘導的和/或可能由輻射誘導的免疫抑制引起的疾病(包括以炎症和/或傷口為特徵的那些)包括可能在事故暴露於輻射(通常稱為“輻射中毒”)後或在故意和/或靶向暴露於輻射(例如由於治療疾病(如癌症)的(例如電離)放射療法)後出現的那些。
放射療法是一類例如癌症治療,其使用外部強能量束殺死癌細胞。放射療法最常使用X射線,但是還可以使用質子或其他類型的能量。放射療法可以用作主要癌症治療,用於新輔助療法(在術前縮小癌性腫瘤)、輔助療法(在術後防止癌細胞增殖)中,以減輕由晚期癌症引起的症狀,或者上述兩種或更多種的組合。放射療法還可以與其他治療(如化學療法)組合使用。
可能由暴露於輻射引起的以黏膜和/或皮膚的炎症和/或傷口為特徵的病症通常與被靶向/放射線照射的身體部分相關。例如:
● 輻射誘導的皮炎和黏膜炎可能分別發生在皮膚或黏膜中的可能靠近被放射線照射的身體部分的位置。例如,輻射誘導的口腔黏膜炎可能在頭部或頸部的放射線照射後發生;
● 輻射誘導的腦炎也可能在頭部或頸部的放射線照射後發生;並且
● 放射性肺炎和/或放射性食道炎通常由用輻射對肺癌、乳腺癌、淋巴瘤、胸腺腫瘤或食道癌進行的放射治療引起。
針對腹部、骨盆或直腸的放射治療(例如治療宮頸癌、前列腺癌、膀胱癌或直腸癌)可能導致放射性腸病(或放射性腸炎,包括放射性結腸炎)、放射性肝炎、放射性脊髓炎、放射性陰道炎、特別是放射性直腸炎中的一種或多種。
特別地,放射性直腸炎或放射性直腸病是以在放射療法期間在暴露於輻射之後對直腸的損害為特徵的病症。炎症可以是急性的(急性放射性直腸炎以及相關的放射性結腸炎),或慢性的(例如輻射相關的血管擴張症(RAVE)和慢性放射性直腸病)。
急性放射性直腸炎的最初症狀包括骨盆痛、腹瀉和裡急後重,但是對直腸的放射性損害通常引起失禁和直腸出血,嚴重的病例導致傷口、狹窄和/或瘺管。
因此,在由用於例如癌症療法的放射線照射(更特別是下腹區的放射線照射)引起的病症(包括諸如如上所定義的放射性直腸炎、放射性結腸炎和輻射誘導的皮炎等病症)的治療中,孟魯司特及其鹽可以用於:
● 提供免疫恢復作用,同時治療與這樣的病症相關的傷口和/或促進所述傷口的恢復和/或痊癒;和/或
● 提供更直接的抗炎作用,而不進一步損害患者的免疫系統,同時可用於促進傷口進一步痊癒。
根據本發明的兩個進一步的方面,提供了:
● 治療輻射誘導的病症的方法,所述病症以 (i) 免疫抑制和 (ii) 炎症和/或傷口為特徵;以及
● 治療患者的與輻射誘導的免疫不全病症相關的炎症和/或傷口,同時恢復免疫系統的正常功能的方法,
所述方法包括向有需要的患者投予孟魯司特或其藥學上可接受的鹽。
當由用於例如癌症療法的放射線照射誘導的病症如上所述由下腹區的放射線照射引起時,本文所述的治療方法和用途是特別有用的。
根據本發明的一個仍進一步的方面,提供了一種降低患者的與以炎症和/或傷口為特徵的輻射(例如電離輻射)誘導的病症相關或可能與所述病症相關的發病和/或死亡的發生率的方法,所述方法包括向需要這樣的治療的患者投予孟魯司特或其藥學上可接受的鹽。
為避免疑義,在本發明的情況下,術語“治療”、“療法”和“治療方法”包括對有需要的患者進行的治療性或姑息性治療以及對易患上述病症或病症的患者進行的預防性治療和/或診斷。
通過客觀測量(例如生物標記,如在下文中描述的那些)或通過主觀測量(例如患者本身意見,更可能是合格的醫學從業者的意見),可以確定治療是否已恢復患者免疫系統的正常功能。這個術語也將理解為不僅包括患者的免疫反應完全恢復到正常水平,也包括其部分恢復,甚至是在免疫抑制和/或免疫不全病症的進程期間,例如與基線水平相比和/或根據正常/預期的惡化進展,沒有隨著時間的推移惡化到預期的程度。
“患者”包括爬蟲類患者、禽類患者和優選哺乳動物(特別是人)患者。在這方面,術語“藥學的”和“藥學上可接受的”包括“獸醫學的”和“獸醫學上可接受的”。
根據本發明,孟魯司特及其藥學上可接受的鹽可以局部或全身投予,例如口服、靜脈內或動脈內(包括通過血管內和其他血管周裝置/劑型(例如支架))、肌內、皮膚、皮下、經黏膜(例如舌下或頰)、黏膜內、直腸或直腸內、陰道內、皮內、經皮、鼻、肺(例如氣管或支氣管)、優選地外用、經由直接注射或通過任何其他腸胃外途徑,以呈一種或多種藥學上可接受的劑型的包含孟魯司特或其鹽的藥物製劑的形式。
全身直接投予可以通過以下方式來實現:通過正常的經口投予和經胃腸道吸收有效成分,或通過直接腸胃外投予,例如經皮或經黏膜(例如經由任何黏膜(包括直腸、陰道、鼻腔、口腔或胃腸道(包括下腸(lower intestine),如結腸和/或肛門直腸黏膜))吸收有效成分),或通過皮內和/或黏膜內注射到相同生物表面。
在替代方案中,孟魯司特或其鹽可以通過直接局部和或外用投予來投予。例如,注射可以是局部(例如皮內、黏膜內或皮下)至相關組織,如脊柱(硬膜外),或局部地,為了產生全身作用,例如通過直接注射在骨髓中。
局部、外用(特別是黏膜)投予孟魯司特不僅可能產生局部作用,還可能產生全身作用(如上所述,作為全身吸收的結果)。
無論是對於局部/外用投予還是全身投予,用於注射的藥學上可接受的調配物可以包含與藥學上可接受的佐劑、稀釋劑或載劑混合的孟魯司特或其藥學上可接受的鹽,可以適當考慮預期的直接腸胃外投予途徑和標準藥學實踐來選擇所述藥學上可接受的佐劑、稀釋劑或載劑。此類藥學上可接受的載劑可以是對活性化合物呈化學惰性的,並且在使用條件下可以無有害副作用或毒性。此類藥學上可接受的載劑還可以賦予孟魯司特或其藥學上可接受的鹽的立即釋放或調節釋放。
因此,用於注射的調配物可以呈水性調配物的形式,如懸浮液和/或更優選地溶液(例如(視需要)緩衝的水性調配物(例如溶液),如含生理鹽水的調配物(例如溶液)、含磷酸鹽的調配物(例如溶液)、含乙酸鹽的調配物(例如溶液)或含硼酸鹽的調配物(例如溶液),或者可以在使用(例如注射)前用媒劑(如水性媒劑)重構的凍乾粉末)。
用於注射的調配物可以包括本領域技術人員已知的其他合適的賦形劑,如溶劑(例如水)、助溶劑、增溶劑(例如環糊精)、潤濕劑、助懸劑、乳化劑、增稠劑、螯合劑、抗氧化劑、還原劑、抗微生物防腐劑、膨脹劑和/或保護劑。
用於注射的調配物被優選地使用如本文所述的緩衝液和/或pH調節劑通過標準技術緩衝至生理學上可接受的pH值(例如pH在約4.5與約9.5之間,例如約6與約9之間,如約6.5與約8.5之間),和/或可以進一步包含張力調節劑(如氯化鈉)。
另外,孟魯司特或其鹽可以以靶向方式來投予,其中遵循腸胃外(parenteral)或經口投予,採用已知的蓋倫(galenic)操作將組成物的遞送靶向患者的一個或多個內臟器官,如胃、腸、胰腺、肝臟、脾臟、膀胱、腎臟、肺、心血管系統(包括心臟和血管系統)、卵巢、前列腺、中樞神經系統、骨髓、眼睛、陰道、子宮頸等。
例如,可以借助本領域技術人員已知的標準延遲釋放或延長釋放包衣技術,通過腸胃外遞送、特別是通過經口遞送來實現通過靶向局部遞送投予至下胃腸道。特別地,可以靶向上腸或下腸的不同部分。例如,還可以借助最初經口或腸胃外投予的靶向結腸的藥物遞送手段來實現結腸投予。
外用投予還可以借助吸入(例如鼻內或肺)至肺來實現。外用調配物可以以這種方式通過產生包含孟魯司特或其鹽的噴霧劑來投予,例如通過使用粉末氣霧劑或使用適當的霧化技術或設備(如噴霧器)借助水性霧來投予。
孟魯司特或其藥學上可接受的鹽的局部遞送手段還包括在適合應用於皮膚和/或適當黏膜表面的適當的(例如藥學上可接受的和外用可接受的)媒劑中直接外用應用(例如至黏膜,包括口腔和/或鼻黏膜、肺、肛門直腸區和/或結腸,或至皮膚)。此類媒劑可以是可商購的,並且也可以適合於口服、靜脈內、皮膚或皮下、鼻、肌內、腹膜內或肺遞送。
包含孟魯司特或其藥學上可接受的鹽的外用調配物通常將以與(例如藥學上可接受的和/或外用可接受的)佐劑、稀釋劑或載劑混合的一種或多種藥物調配物的形式來投予,可以適當考慮預期的投予途徑(例如外用至相關黏膜(包括肺)或優選地皮膚)和標準藥學或其他(例如化妝)實踐來選擇所述佐劑、稀釋劑或載劑。此類藥學上可接受的載劑可以是對活性化合物呈化學惰性的,並且在使用條件下可以無有害副作用或毒性。此類藥學上可接受的載劑還可以賦予孟魯司特的立即釋放或調節釋放。
合適的藥物調配物可以是可商購的,或者根據文獻中描述的技術以其他方式來製備,所述文獻例如Remington
The Science and Practice of Pharmacy, 第22版, Pharmaceutical Press (2012)和
Martindale - The Complete Drug Reference,第38版, Pharmaceutical Press (2014)和其中提及的文件,將全部所述文件的相關公開內容通過引用特此併入。在其他方面,技術人員可以使用常規技術非創造性地實現包括孟魯司特及其鹽的合適調配物的製備。
可以將孟魯司特及其鹽進一步和/或在替代方案中與適當的賦形劑組合以製備:
● 凝膠調配物(對於所述凝膠調配物,合適的凝膠基質材料包括纖維素衍生物、卡波姆和海藻酸鹽、西黃蓍膠、明膠、果膠、角叉菜膠、結冷膠、澱粉、黃原膠、陽離子瓜爾膠、瓊脂、非纖維素多醣、醣類(如葡萄糖)、甘油、丙二醇、乙烯基聚合物、丙烯酸樹脂、聚乙烯醇、羧乙烯基聚合物、特別是透明質酸);
● 洗劑(對於所述洗劑,合適的基質材料包括纖維素衍生物、甘油、非纖維素多醣、不同分子量的聚乙二醇和丙二醇);
● 糊劑或軟膏(對於所述糊劑或軟膏,合適的糊劑基質材料包括甘油、凡士林、石蠟、不同分子量的聚乙二醇等);
● 乳膏或泡沫(對於所述乳膏或泡沫,合適的賦形劑(例如發泡劑)包括羥丙基甲基纖維素、明膠、不同分子量的聚乙二醇、十二烷基硫酸鈉、脂肪醇聚氧乙烯醚磺酸鈉、玉米麩質粉和丙烯醯胺);
● 粉末氣霧劑(對於所述粉末氣霧劑,合適的賦形劑包括甘露醇、甘胺酸、糊精、右旋糖、蔗糖、乳糖、山梨糖醇和聚山梨醇酯,例如乾粉吸入劑);
● 用於口服使用或用於吸入的液體,例如水(氣霧劑)噴霧劑(對於所述液體,合適的賦形劑包括黏度調節劑(如透明質酸)、醣類(如葡萄糖和乳糖)、乳化劑、緩衝劑、醇、水、防腐劑、甜味劑、調味劑等);和/或
● 可注射溶液或懸浮液(所述可注射溶液或懸浮液可以是水性的或其他形式的,並且對於所述可注射溶液或懸浮液,合適的賦形劑包括溶劑和助溶劑、增溶劑、潤濕劑、助懸劑、乳化劑、增稠劑、螯合劑、抗氧化劑、還原劑、抗微生物防腐劑、緩衝液和/或pH調節劑、膨脹劑、保護劑和張力調節劑),可以提及的特定可注射溶液或懸浮液包括真皮填充劑(即可注射填充劑或軟組織填充劑),特別是當孟魯司特/其鹽與透明質酸組合時。
視情況而定,此類調配物還可以包括保濕劑,如丙三醇、甘油、聚乙二醇、海藻糖、丙三醇、礦脂、石蠟油、矽油、透明質酸及其鹽(例如鈉鹽和鉀鹽)、辛酸(octanoic/caprylic)甘油三酯等;和/或抗氧化劑,如維生素和麩胱甘肽;和/或pH調節劑,如酸、鹼和pH緩衝液。此外,可以包括表面活性劑/乳化劑,如十六烷醇(鯨蠟醇)、脂肪酸(例如硬脂酸)、十二烷基硫酸鈉(月桂基硫酸鈉)、山梨糖醇酯(例如山梨糖醇硬脂酸酯、山梨糖醇油酸酯等)、單醯基甘油酯(如單硬脂酸甘油酯)、聚乙氧基化醇、聚乙烯醇、多元醇酯、聚氧乙烯烷基醚(例如聚氧乙烯山梨糖醇單油酸酯)、聚氧乙烯蓖麻油衍生物、乙氧基化脂肪酸酯、聚氧甘油酯(polyoxylglyceride)、月桂基二甲基氧化胺、膽鹽(例如去氧膽酸鈉、膽酸鈉)、脂質(例如脂肪酸、甘油脂質、甘油磷脂、鞘脂、固醇、異戊烯醇(prenol)、醣脂(saccharolipid)、聚酮化合物)、磷脂、N,N-二甲基十二烷基胺-N-氧化物、十六烷基三甲基溴化銨、泊洛沙姆、卵磷脂、固醇(例如膽固醇)、醣酯、聚山梨醇酯等;防腐劑,如苯氧乙醇、乙基己基甘油等;以及增稠劑,如丙烯醯基二甲基牛磺酸酯/VP共聚物。具體地,特別是在乳膏調配物中,可以包括硬脂酸、單硬脂酸甘油酯、十六烷醇、山梨糖醇硬脂酸酯、鯨蠟醇、辛酸/癸酸甘油酯等。
孟魯司特及其鹽以及包括它們的(例如藥物)調配物(例如如上所述的水性溶液、凝膠、乳膏、軟膏、洗劑、泡沫、糊劑和/或乾粉)可以進一步與適當的基質材料組合以製備用於應用在生物表面(如皮膚或黏膜表面)上的敷料或治療性貼劑。因此,此類調配物可以用於浸漬基質材料,如紗布、無紡布或絲質紙。可替代地,治療性貼劑可以是例如OK繃、面膜、眼膜、手膜、腳膜等。
可以採用凡士林用於將這樣的敷料施加於傷口,但是我們還已經發現,可以將基於PEG(例如PEG 400)的軟膏與基質材料組合以製備敷料,而無需使用凡士林。
孟魯司特及其鹽還可以與固體支持物(如鼻敷料(例如,以停止鼻出血)、真皮支架(例如,在傷口痊癒中)或人造骨(例如,在骨移植/植入的情況下)組合使用。
用於外用投予(例如至黏膜表面,如本文所述)的凝膠除水外,還可以包括賦形劑,如增溶劑(例如,糊精,如環糊精,包括羥丙基-β-環糊精)、增稠劑或懸浮劑(例如羥基丙基甲基纖維素、明膠、聚乙二醇等)、螯合劑(如依地酸鈉)、抗微生物防腐劑、緩衝液和/或pH調節劑。
孟魯司特及其鹽可以借助懸浮液、乾粉或溶液吸入投予。合適的吸入裝置包括加壓計量劑量吸入器(pMDI)(其可以是手動致動的或呼吸致動的,並且可以與或不與標準間隔器裝置一起使用)、乾粉吸入器(DPI)(其可以是單劑量的、多劑量的和動力輔助的)以及軟霧吸入器(SMI)或噴霧器(其中以比使用例如pMDI遞送的噴霧劑慢的速度遞送呈細霧形式的氣霧劑藥物)。
在pMDI中,孟魯司特及其鹽可以作為分佈在推進劑(例如與諸如甘露醇、乳糖、山梨糖醇等賦形劑一起的HFA)中的微粒化顆粒的加壓懸浮液或作為乙醇溶液來投予,以便每次致動遞送一個或多個在約20與約100 μL之間的計量劑量。可以通過手動(例如按壓)或通過吸入(呼吸致動)來實現致動,其中涉及由彈簧驅動的流量觸發系統。
在DPI中,孟魯司特及其鹽可以以膠囊內部的單獨的或與較大粒度無活性賦形劑(例如甘露醇)共混的微粉化藥物顆粒(尺寸在約1 μm與約5 μm之間)的形式投予,所述膠囊可以預裝載或手動裝載到裝置中。從DPI吸入可以使藥物顆粒解聚並且使其分散在呼吸道內。
在SMI中,孟魯司特及其鹽可以作為溶液儲存在裝載到裝置中的藥盒內部。彈簧可以將劑量釋放到微型泵中,使得當按壓按鈕時釋放所述劑量,從而釋放藥物溶液的噴射流。
各種噴霧器也可以用於投予呈氣霧化溶液的細霧的形式的孟魯司特及其鹽。噴霧器可以包括呼吸增強型噴射噴霧器(其中,在壓縮機的輔助下,氣流通過噴射器移動,從而使藥物溶液氣霧化);呼吸致動型噴射噴霧器(其中,在患者吸入之後,在壓縮機的輔助下,氣流通過管移動,從而使藥物溶液氣霧化);超聲噴霧器(其中,壓電晶體振動通過加熱引起氣霧化,從而引起霧化);振動篩網噴霧器(其中,壓電晶體振動網板引起氣霧化,以得到非常細小的液滴,而在霧化期間溶液的溫度沒有明顯變化)。
然而,當待治療的病症是放射性直腸炎時,外用肛門直腸投予是特別有用的,使用適當的遞送手段,如上文所述的一種或多種靶向/延遲釋放的組成物的間接外用投予,或通過待手動施加和/或作為灌腸劑(例如泡沫灌腸劑、凝膠灌腸劑或液體灌腸劑)施加的溶液、泡沫或凝膠的直接外用投予,通過直腸內注射,或借助栓劑。
根據本發明使用的包含孟魯司特的組成物在投予前可以是(或可優選地是)無菌或滅菌的,以滿足適當的管理標準。滅菌可以通過原位滅菌過程進行,如滅菌過濾和/或無菌處理,或通過終端滅菌過程,如通過熱,其包括乾熱滅菌和濕熱滅菌(例如在高壓釜中)。
根據本發明的一個進一步的方面,提供了一種用於上文提及的病症的(例如藥物)組成物,其包含孟魯司特或其藥學上可接受的鹽以及一種或多種藥學上可接受的賦形劑(如佐劑、稀釋劑或載劑)。
適合於、適用於和/或包裝並呈現用於外用投予(例如至黏膜,包括皮膚、口腔和/或鼻黏膜、肺、結腸和/或特別是肛門直腸區)的包含孟魯司特或其藥學上可接受的鹽的優選藥物組成物,其借助該調配物的直接外用投予(例如至皮膚,至黏膜,包括口腔和/或鼻黏膜、肺、結腸和/或特別是肛門直腸區)和/或通過皮內、皮下和/或黏膜內注射,用於治療免疫抑制性病症,或治療免疫系統受到抑制的患者的傷口、炎症或以炎症為特徵的病症,所述受到抑制的免疫系統可能因用於例如癌症的放射療法導致的。
為避免疑義,包含孟魯司特或其鹽的外用調配物可以用於本文所述的任何和全部病症,包括治療本文所述的任何免疫抑制性病症,或免疫系統受到抑制的患者的炎症,所述受到抑制的免疫系統可能例如因用於例如癌症的放射療法導致的,如上文所提及、定義或描述。類似地,可以提及的包含孟魯司特或其鹽的外用調配物包括本文提及、定義或描述的那些中的任何和全部。將本文相關公開文本的任何和全部通過引用與本發明的這個方面結合特此併入。
孟魯司特或其鹽的投予可以是連續的或間歇的。投予方式還可以通過投予的時機和頻率來確定,但是在治療性治療的情況下還取決於病症的嚴重程度。
取決於待治療的病症和患者以及投予途徑,可以以不同的治療有效劑量向有需要的患者投予孟魯司特或其鹽。
類似地,調配物中孟魯司特或其鹽的量將取決於待治療的病症的嚴重程度以及患者,但是可以由技術人員確定。
在任何情況下,醫療從業者或其他技術人員將能夠常規地確定根據病症的嚴重程度和投予途徑最適合於個別患者的實際劑量。本文提及的劑量是一般情況的例示;當然可能存在應使用較高或較低劑量範圍的個別情況,並且這樣的情況在本發明的範圍內。
劑量可以在每天一次與四次之間(例如三次)來投予。
在所有按游離孟魯司特計算的情況下,孟魯司特或其鹽在水性溶液產品中的適當濃度可以為約0.01(例如約0.1)至約15.0 mg/mL。
在所有按游離孟魯司特計算的情況下,孟魯司特或其鹽的適當外用(包括外用施加)劑量在約0.05至約50(例如約20) µg/cm
2治療面積的範圍內,如約0.1(例如約0.5)至約20(例如約5) µg/cm
2治療面積,包括約1至約10 µg/cm
2治療面積,如約5 µg/cm
2治療面積。
在任何情況下,在本發明的情況下,投予給哺乳動物、特別是人的劑量應當足以在合理的時間範圍內在哺乳動物中影響治療反應(如上文所述)。本領域技術人員應認識到,確切劑量和組成以及最適當的遞送方案的選擇還將尤其受以下影響:調配物的藥理特性,所治療病症的性質和嚴重程度,和接受者的身體狀況和精神敏度,以及待治療的患者的年齡、健康狀況、體重、性別和反應,和疾病的階段/嚴重程度,以及患者之間的遺傳差異。
孟魯司特或其鹽可以與眾多已知的藥物活性成分組合,用於治療免疫抑制性病症和/或治療免疫系統受損的患者的炎症或以炎症為特徵的病症,所述藥物活性成分包括任何治療劑或藥物,所述治療劑或藥物:
● 能夠在活的個體(特別包括哺乳動物,尤其人類個體(患者))中產生某種生理作用(呈針對特定疾病狀態或病症的治療性或預防性能力),並且所述治療劑或藥物將與孟魯司特或其鹽“協同”起作用,以治療待治療的病症;或者
● 已知或懷疑引起免疫抑制和/或炎症與免疫抑制的組合,這可以被孟魯司特的免疫恢復和/或抗炎特性抵消。
關於已知或懷疑引起免疫抑制和/或炎症與免疫抑制的組合的藥物活性劑/治療劑,這些包括上文所述的那些中的任何一種或多種,將其通過引用併入本發明的這個方面。
對孟魯司特的免疫恢復和/或抗炎特性可以具有累積性、相加性和/或協同性作用的藥物活性劑可以選自某些其他抗炎劑、抗生素、抗細菌劑和/或抗原生動物劑、抗病毒劑(例如蛋白酶抑制劑)。
可以根據本文所述的用途和治療方法使用的抗炎藥包括用於治療以下的那些:自體免疫性疾病,如關節炎(如克他服寧(cataflam)、倍他米松、萘普生(naproxen)、環孢菌素、軟骨素、塞來昔布(celecoxib)、依託度酸(etodolac)、甲氯芬那酸(meclofenamate)、雙水楊酯(salsalate)、甲潑尼松龍和吡羅昔康(piroxicam));和骨關節炎(如舒林酸(sulindac)、美洛昔康(meloxicam)、非諾洛芬(fenoprofen)、依託考昔(etoricoxib)和萘丁美酮(nabumetone))。
可以根據本文所述的用途和治療方法使用的抗細菌藥物的非限制性例子包括氯黴素(chloramphenicol)、氧氟沙星(ofloxacin)、左氧氟沙星(levofloxacin)、妥布黴素(tobramycin)、諾氟沙星(norfloxacin)、環丙沙星(ciprofloxacin)、洛美沙星(lomefloxacin)、林可黴素(lincomycin)、氟康唑(fluconazole)、依諾沙星(enoxacin)、呋喃唑酮(furazolidone)、呋喃西林(nitrofurazone)、利福平(rifampicin)、小諾黴素(micronomicin)、慶大黴素(gentamicin)、西吡銨(cetylpyridinium)、新黴素、羅紅黴素(roxithromycin)、磺胺嘧啶銀(sulfadiazine silver)、克拉黴素(clarithromycin)、克林黴素(clindamycin)、甲硝唑(metronidazole)、阿奇黴素(azithromycin)、磺胺米隆(mafenide)、磺胺甲噁唑(sulfamethoxazole)、乙醯胺酚(paracetamol)、氯黴素、擬麻黃鹼、莫匹羅星(mupirocin)、阿莫西林(amoxicillin)、阿莫西林/克拉維酸(clavulanic acid)、甲氧苄啶(trimethoprim)/磺胺甲噁唑、頭孢氨苄(cefalexin)、莫西沙星(moxifloxacin)、任何前述藥物的已知或可商購的藥學上可接受的鹽以及任何前述化合物和/或鹽的組合。
可以根據本文所述的用途和治療方法使用的抗病毒藥物的非限制性例子包括妥布黴素(tobramycin)、利巴韋林(ribavirin)、阿昔洛韋(acyclovir)、嗎啉胍(moroxydine)、膦甲酸(foscarnet)、更昔洛韋(ganciclovir)、碘苷、曲氟尿苷(trifluridine)、溴夫定(brivudine)、阿糖腺苷(vidarabine)、恩替卡韋(entecavir)、替比夫定(telbivudine)、膦甲酸(foscarnet)、齊多夫定(zidovudine)、去羥肌苷(didanosine)、紮西他濱(zalcitabine)、司他夫定(stavudine)、拉米夫定(lamivudine)、阿巴卡韋(abacavir)、恩曲他濱(emtricitabine)、奈韋拉平(nevirapine)、地拉韋定(delavirdine)、依非韋侖(efavirenz,)、依曲韋林(etravirine)、利匹韋林(rilpivirine)、沙奎那韋(saquinavir)、利托那韋(ritonavir)、茚地那韋(indinavir)、奈非那韋(nelfinavir)、安普那韋(amprenavir)、洛匹那韋(lopinavir)、利托那韋(ritonavir)、阿紮那韋(atazanavir)、福沙那韋(fosamprenavir)、替拉那韋(tipranavir)、地瑞那韋(darunavir)、特拉匹韋(telaprevir)、波普瑞韋(boceprevir)、司美匹韋(simeprevir)、阿孫普韋(asunaprevir)、雷特格韋(raltegravir)、埃替拉韋(elvitegravir)、度魯特韋(dolutegravir)、rsv-igiv、帕利珠單抗(palivizumab)、二十二烷醇(docosanol)、恩夫韋肽(enfuvirtide)、馬拉韋羅(maraviroc)、vzig、varizig、阿昔洛韋、更昔洛韋、泛昔洛韋(famciclovir)、伐昔洛韋(valacyclovir)、噴昔洛韋(penciclovir)、纈更昔洛韋(valganciclovir)、西多福韋(cidofovir)、富馬酸替諾福韋二吡呋酯(tenofovir disoproxil fumarate)、阿德福韋二吡呋酯(adefovir dipivoxil)、福米韋生(fomivirsen)、普達非洛(podofilox)、咪喹莫特(imiquimod)、賽兒茶素(sinecatechin)、干擾素-α 2b(重組型,人)、任何前述藥物的已知或可商購的藥學上可接受的鹽以及任何前述化合物和/或鹽的組合。
根據本文所述的用途和治療方法,孟魯司特及其鹽還可以與幹細胞(例如全潛能(全能)幹細胞、富潛能幹細胞(如胚胎或誘導性富潛能幹細胞)、多潛能幹細胞(如間充質幹細胞)、寡潛能幹細胞(如造血幹細胞)或單潛能幹細胞(如肌肉幹細胞))組合。
患者還可能(和/或可能已經)正在接受基於投予一種或多種上述其他已知的藥物活性成分的療法,例如以治療一種或多種本文所述的病症,這意味著在用孟魯司特或其鹽治療之前、之外和/或之後,接受規定劑量的一種或多種本文提及的活性成分。
此類其他藥物活性成分還可以以多種方式與孟魯司特或其鹽組合投予。
例如,孟魯司特及其鹽可以與其他藥物活性成分(或“治療劑”)“組合”,用於在同一(例如藥物)調配物中一起投予,或在不同(例如藥物)調配物中分開(同時或順序)投予。
因此,此類組合產品提供了孟魯司特或其鹽與另一種治療劑的聯合投予,並且因此可以呈現為分開的調配物,其中那些調配物中的至少一種包含孟魯司特/其鹽,並且至少一種包含另一種治療劑,或者可以呈現(即調配)為組合製劑(即呈現為包括孟魯司特/其鹽和另一種治療劑的單一調配物)。
因此,進一步提供了:
(1) 一種(例如藥物)調配物,其包括孟魯司特或其藥學上可接受的鹽;如上文所述的另一種藥物活性成分;以及藥學上可接受的無活性賦形劑(例如佐劑、稀釋劑或載劑),所述調配物在下文中被稱為“組合製劑”;以及
(2) 一種套組,其包括以下組分:
(A) 孟魯司特或其藥學上可接受的鹽,其呈與藥學上可接受的無活性賦形劑(例如佐劑、稀釋劑或載劑)混合的藥物調配物的形式;和
(B) 如上文所述的另一種藥物活性成分,其呈與藥學上可接受的佐劑、稀釋劑或載劑混合的藥物調配物的形式,
所述組分 (A) 和 (B) 各自以適合與彼此聯合投予的形式提供。
在本發明的一個進一步的方面,提供了一種用於製備如上文所定義的組合製劑 (1) 的方法,所述方法包括使孟魯司特/其鹽、另一種藥物活性成分和至少一種藥學上可接受的賦形劑聯合。
在本發明的一個進一步的方面,提供了一種用於製備如上文所定義的套組 (2) 的方法,所述方法包括使組分 (A) 和 (B) 聯合。如本文所用,提及使……聯合時將意指使兩種組分適合與彼此聯合投予。
因此,關於用於製備如上文所定義的套組的方法,使兩種組分彼此“聯合”包括所述套組的兩種組分可以:
(i) 作為分開的調配物(即彼此獨立)來提供,所述分開的調配物隨後被放在一起以用於在組合療法中彼此聯合使用;或者
(ii) 作為“組合包”的個別組分一起包裝和呈現,用於在組合療法中彼此聯合使用。
因此,進一步提供了一種套組,其包含:
(I) 如本文所定義的組分 (A) 和 (B) 之一;以及
(II) 將該組分與所述兩種組分中的另一種聯合使用的說明。
本文所述的套組可以包含多於一種適當量/劑量的孟魯司特/其鹽(例如包括它的調配物)和/或多於一種適當量/劑量的另一種藥物活性成分(例如包括它的調配物),以便提供重複給藥。如果存在多於一種包含一定量/劑量的任一種前述物質的調配物或多於一種一定量/劑量的任一種前述物質,則其在任一種化合物的劑量、一種或多種化學組成和/或一種或多種物理形式方面可以相同或者可以不同。
關於如本文所述的套組,“與……聯合投予”包括在相關病症的治療過程中順序、分開和/或同時投予相應組分。
因此,關於根據本發明的組合產品,術語“與……聯合投予”包括,組合產品的兩種組分(孟魯司特/其鹽和另一種藥物活性成分)一起或在時間上足夠接近地投予(視需要地重複投予),以使得在相關病症的治療過程中對患者的有益作用能夠大於在相同的治療過程中在不存在另一種組分時單獨投予(視需要地重複投予)孟魯司特/其鹽或另一種藥劑的情況。對組合關於特定病症以及在特定病症的治療過程中是否提供更大有益作用的確定將取決於待治療或預防的病症,但是可以由技術人員常規地實現。
此外,在根據本發明的套組的情況下,術語“與……聯合”包括,兩種組分中的一種或另一種可以在投予另一種組分之前、之後和/或與其同時投予(視需要地重複投予)。當在這種情況下使用時,術語“同時投予”和“與……同時投予”包括,個別量/劑量的孟魯司特/其鹽和另一種藥物活性成分在彼此的48小時(例如24小時)內投予。
另外,孟魯司特及其藥學上可接受的鹽可以以適合與放射療法聯合投予的形式來提供,即向正在接受、已經接受或將要接受放射線照射療法以治療疾病(如癌症)的患者投予孟魯司特/其鹽。
以此類推,“與放射療法聯合投予孟魯司特/鹽”包括,兩種組分(孟魯司特/其鹽和放射療法)一起或在時間上足夠接近地投予(視需要地重複投予),以使得在相關病症的治療過程中對患者的有益作用能夠大於在相同治療(放射療法)過程中沒有投予(視需要地重複投予)孟魯司特/其鹽的情況。對此組合關於治療以及在治療過程中是否提供更大有益作用的確定將取決於待治療或預防的病症,但是可以由技術人員常規地實現。
此外,在這種情況下,術語“與……聯合”包括,孟魯司特/其鹽在投予放射療法之前、之後和/或與其同時投予(視需要地重複投予)。當在這種情況下使用時,術語“同時投予”和“與……同時投予”包括,一定量/劑量的孟魯司特/其鹽和放射療法在彼此的至多約60天、或約21天、或約10天、或約7天、或48小時(例如24小時)內投予。
因此,根據本發明的一個進一步的方面,提供了孟魯司特或其藥學上可接受的鹽用於製造用以治療輻射誘導的炎症病症(如放射性直腸炎)的醫藥品的用途,所述方法包括向正在接受、已經接受或將要接受放射線照射療法以治療疾病(如癌症)的患者投予孟特魯司特或其藥學上可接受的鹽。
無論在本文何處(例如在活性成分的量(如時間週期、濃度和/或劑量)、粒度、體積和pH的情況下)使用詞語“約”時,應意識到,此類變量是近似值,並且因此可以相對於本文指定的數字變化± 10%,例如± 5%,且優選地± 2%(例如± 1%)。在這方面,術語“約10%”意指例如在數字10附近± 10%,即在9%與11%之間。
本文所述的用途和方法還可以具有如下優點,即在上文提及的病症的治療中,相比於現有技術已知的類似化合物或方法(治療),它們可以對於醫師和/或患者而言更方便,更有效,毒性更低,具有更廣泛的活性範圍,更強效,產生更少副作用,或者它/它們可以具有其他有用的藥理特性,無論是對於用於治療免疫抑制性病症和/或治療患有以免疫抑制為特徵的病症的患者的炎症,還是在其他方面。
實施例1
大鼠的放射性直腸炎
將40隻Sprague-Dawley大鼠分為4組,每組含有10隻大鼠。
使用醫用直線加速器對三組(共30隻)大鼠進行放射線照射,而“正常對照”組中的10隻大鼠未做處理。輻射源與皮膚之間的距離為100 cm。輻射場區為從大鼠肛門起2 cm × 5 cm並且輻射劑量為17.5 Gy。在放射線照射之後,將大鼠放回籠子。
通過將0.033 g孟魯司特鈉(中國浙江Tianyu Pharmaceutical Co.)溶解到42.167 g蒸餾水中來製備低劑量(0.33 mg/g)孟魯司特凝膠。將20.0 g羥基丙基-β-環糊精(HP-β-CD,Shandong Binzhou Zhiyuan Biotechnology Co., Ltd.)在連續攪拌下緩慢添加到所得溶液中,直至它完全溶解。然後,添加24 g羥基丙基甲基纖維素(HPMC,Rohm Haas Electronic Materials (Shanghai) Co., Ltd.;5%水性溶液),並且充分混合。將0.01 g氫氧化鈉(China Pharmaceutical Group Chemical Reagents Co., Ltd)和0.1 g EDTA-2Na(China Pharmaceutical Group Chemical Reagents Co., Ltd)分開溶解於16.69 g蒸餾水中,以製備pH為7.2-7.5的溶液。將兩種溶液在連續攪拌下混合在一起,並且放在一邊,直至全部氣泡消失。
通過將0.1 g孟魯司特鈉添加到大致等量蒸餾水中,然後以相同的順序添加上述賦形劑,採用基本上相同的程序來製備高劑量(1 mg/g)孟魯司特凝膠。
在放射線照射後將低劑量和高劑量孟魯司特凝膠投予至兩個分開的組(分別為“低劑量”組和“高劑量”組)的10隻大鼠中的每隻的直腸中。向正常對照組的大鼠和其餘10隻被放射線照射的大鼠(“模型”組)給予空白凝膠基質(與上述相同的凝膠,但不含孟魯司特)。
每隔一天從正常對照組、模型組和高劑量組採集血液樣品。確定總白血球、淋巴球和嗜中性球計數。
結果在圖1中示出。與正常對照組相比,在放射線照射之後總細胞計數顯著降低。然而,高劑量孟魯司特組的細胞計數在5天之後開始增加,這未見於模型組中。
在7天之後劃破大鼠。獲取5 cm的直腸組織並將其切成兩段,一部分送去進行組織病理學分析(圖2),並且將另一部分均質化以通過ELISA套組檢測細胞介素(IL-1β)(圖3)。
圖2中呈現的結果顯示,孟魯司特降低直腸中的損害程度(圖2(a))並促進上皮再生(圖2(b))。圖3中呈現的結果顯示,與對照組相比,模型組、低劑量組和高劑量組中的IL-1β濃度降低。然而,孟魯司特處理組中的IL-1β濃度高於模型組中的IL-1β濃度,呈劑量依賴性方式。
因此,在模型中顯示,在抑制大鼠免疫反應的輻射水平下,孟魯司特可以幫助恢復免疫反應,同時促進傷口痊癒且具有抗炎作用。
實施例2
通過經直腸和靜脈內投予孟魯司特凝膠來治療放射性直腸炎
從Zhejiang Vital River Laboratory Animal Technology Co., Ltd(中國浙江)獲得70隻稱重為180-220 g的雄性Wistar大鼠。將所有動物維持於標準籠中,給予標準的囓齒動物飼料和自來水,且光暗週期12小時交替。
通過腹膜內注射10%水合氯醛(3.3 mL/kg)麻醉大鼠。將大鼠通過尾和四肢以仰臥位束縛並用膠帶綁在硬紙板上。使用Elekta Synergy醫療線性加速器(Elekta limited,英國)給予放射線照射。除假手術組(“假處理組”)外,所有動物均接受單次連續骨盆放射線照射劑量。從動物到放射線照射源的距離是100 cm。輻射區域為2 cm × 5 cm,從肛門向上5 cm。輻射劑量為17.5 Gy,劑量速率為600 cGy/min。
放射線照射後,將動物放回籠中自然恢復。將假處理組中的動物在腹腔中進行麻醉而不進行放射線照射。測量大鼠的每日採食量和體重,並且每天進行總體觀察。
將第1天(D1)定義為藥物投予的第一日,即放射線照射後24小時。根據下表1給予大鼠不同藥物。給予在假處理組和模型組(“模型”)的那些大鼠空白凝膠(即按下文描述製備的凝膠基質,但不含孟魯司特)。
通過將羥基丙基甲基纖維素(24 mg)、羥基丙基-β-環糊精(400 mg)和依地酸二鈉(2 mg)混合並且在121ºC下通過蒸汽滅菌30分鐘來製備無菌的孟魯司特凝膠。將1 mg(Monte L)、3 mg(Monte M)或10 mg(Monte H)孟魯司特鈉溶解在水(1,564 mL)中並且經由0.2 μm過濾器過濾以將其滅菌。然後通過將兩部分混合在一起形成凝膠。
通過將450 mg孟魯司特鈉溶解在300 mL水中,然後將其經由0.2 μm過濾器過濾以獲得滅菌的1.5 mg/mL來製備靜脈(i.v.)注射用孟魯司特溶液(Monte IV)。
將美沙拉嗪栓劑(Dr Falk Pharma GmbH,德國)用作陽性對照(美沙拉嗪)。將栓劑在40ºC水浴中熔化,打開,並且將0.2 g美沙拉嗪注射至大鼠的直腸中。
將大鼠每天處理一次,並且連續進行21天(D1至D21)。
表1
組 | 治療 | 劑量 | 體積 | 濃度 | 途徑 |
對照 | 凝膠基質 | —— | 0.3 g/大鼠 | 0 mg/g | 直腸 |
模型 | 凝膠基質 | —— | 0.3 g/大鼠 | 0 mg/g | 直腸 |
美沙拉嗪 | 來自美沙拉嗪栓劑 | 45 mg/大鼠 | 0.2 g/大鼠 | 0.5 g/段 | 直腸 |
Monte L | 孟魯司特凝膠 | 0.1 mg/大鼠 | 0.3 g/大鼠 | 0.33 mg/g | 直腸 |
Monte M | 孟魯司特凝膠 | 0.3 mg/大鼠 | 0.3 g/大鼠 | 1 mg/g | 直腸 |
Monte H | 孟魯司特凝膠 | 0.9 mg/大鼠 | 0.3 g/大鼠 | 3 mg/g | 直腸 |
Monte IV | 孟魯司特溶液 | 3 mg/kg | 2 mL/kg | 1.5 mg/ml | 注射 |
為減少排便並且延長凝膠在直腸中的持續時間,每天在投予前對所有動物給予5%水合氯醛的6 mL/kg腹膜內注射。用灌胃針在直腸內部約3 cm處引入調配物,每隻大鼠的投予體積是0.3 mL。
每天觀察並且記錄整體狀態和糞便特徵。根據在下表2中描述的標準評估疾病活動指數(DAI)。在第22天(D22),將所有動物處死,獲取直腸進行評估。在投予之前使大鼠空腹至少12小時。
表2
整體觀察 | 得分 | 分級 | 症狀分類 | ||
腹部膨隆 (AD) | 糞便特徵 | 死亡 | |||
AD | 正常 | 0 | <0.1 | 無症狀 | |
AD | 非常柔軟,但成形 | 1 | <0.7 | 1級 | |
AD+ | 黏液狀 | 2 | <1.3 | 2級 | |
AD++ | 稀 | 3 | >2.0 | 3級 | |
AD+++ | 稀(+) | 4 | |||
稀(++ ) | 5 | ||||
稀(+++ )和/或出血 | 6 | ||||
死亡 | 7 |
通過腹膜內注射水合氯醛麻醉後,通過後頸動脈放血對大鼠劃痕。
在距肛周皮毛邊緣約0.3 cm處分離約7 cm的結直腸道。修剪樣本,並由同一人分別切除1 cm的近端和遠端結直腸樣品。然後,將腸管縱向解剖,拍照並且稱重。
根據下表3中的標準通過總體觀察評估結腸黏膜損害指數(CMDI)的得分。
表3
CMDI 標準 | 得分 |
正常,無損害 | 0 |
輕度充血、水腫、表面光滑、無糜爛 | 1 |
中度充血、水腫、粗糙的顆粒狀黏膜,伴有糜爛或腸黏連。 | 2 |
高度充血並且水腫,伴黏膜表面壞死和潰瘍,潰瘍最大縱徑小於1 cm,腸壁增厚或表面壞死和炎症。 | 3 |
基於3個得分,潰瘍的最大縱徑大於1 cm或全腸壁壞死。 | 4 |
將樣本在10%甲醛溶液中固定48小時,並且用HE染色,然後由病理學家(對研究不知情)用光學顯微鏡檢查。黏膜上皮變性/壞死/脫落,黏膜下水腫及炎性細胞浸潤分級如下:
0 = 正常或無法(確定地)歸因於輻射的微小變化;
1 = 輕微的輻射損害(輕微的炎症和/或輕微的隱窩改變);
2 = 輕微損害(更嚴重的炎症和/或隱窩損害);
3 = 中度損害(一定有明顯的上皮損失,炎症程度可變);以及
4 = 重度損害(潰瘍、壞死)。
通過DAI得分評估結腸直腸功能,DAI得分是結腸直腸功能的指標。結果在表4和圖4中示出,其中示出了每組中不同DAI等級的大鼠數量。
表4
組 | n | DAI 得分 | 症狀等級 |
對照 | 10 | 0.0 ± 0.03 | 無症狀 |
模型 | 10 | 1.3 ± 1.01 | 2級 |
美沙拉嗪栓劑 | 10 | 1.0 ± 0.75 | 2級 |
Monte L | 10 | 0.9 ± 1.01 | 2級 |
Monte M | 10 | 0.6 ± 0.21 | 1級 |
Monte H | 10 | 0.5 ± 0.26 | 1級 |
Monte IV | 10 | 0.6 ± 0.74 | 1級 |
與對照組相比,每個組都顯示不同程度的疾病,如腹瀉、軟便、稀便和/或黏液狀糞便,甚至死亡,發現直腸內和靜脈內投予孟魯司特均以劑量依賴性方式降低疾病的嚴重程度。靜脈內投予略優於Monte M直腸內投予劑量,但不如Monte H劑量有效。
通過CMDI得分評估結腸黏膜的總體形態學評估,其中得分越高表示病變程度越高。結果在下表5和圖5中示出,其中示出了每組的CMDI得分的百分比分佈。
表5
組 | N | 平均值 | SD |
對照 | 10 | 0.2 | 0.42 |
模型 | 10 | 3.8 | 0.46 |
美沙拉嗪 | 10 | 3.0 | 0.87 |
Monte L | 10 | 2.6 | 0.74 |
Monte M | 10 | 2.0 | 0.67 |
Monte H | 10 | 1.9 | 0.64 |
Monte IV | 10 | 2.1 | 0.60 |
結果顯示隨著孟魯司特劑量增加,病變程度降低。同樣,靜脈內投予略優於Monte M劑量,但不如直腸內投予的Monte H劑量有效。
組織病理學評估結果在圖6中示出,並且顯示了孟魯司特凝膠減少了由輻射引起的病變,並且上皮損害、黏膜下水腫和炎症細胞浸潤以劑量相關的方式得到減輕。在修復上皮方面,直腸內投予顯示出比靜脈內投予更好的功效。
無
[圖1]至[圖6]:通過以下實施例說明本發明,其中圖1至圖3示出了在放射線照射的大鼠中,孟魯司特隨時間推移對外周血中的免疫細胞計數(圖1)、組織病理學結果(圖2)以及直腸組織中的IL-1β濃度(圖3)的影響;並且圖4至7示出了在已經被誘導出放射性直腸炎的大鼠中,不同藥物對結腸-直腸功能(圖4)、結腸黏膜的總體形態學評估(圖5)和組織病理學結果(圖6)的影響。
Claims (28)
- 一種孟魯司特(montelukast)或其藥學上可接受的鹽的用途,其係用於製造用以治療免疫不全病症的醫藥品。
- 根據請求項1所述的用途,其中所述免疫不全病症是選自以下者之群的原發性免疫不全病症:體液性免疫不全病症、細胞性免疫不全病症、體液性和細胞性聯合免疫不全病症、吞噬細胞性免疫不全和/或補體缺陷。
- 根據請求項1所述的用途,其中所述免疫不全病症是繼發性免疫不全病症。
- 根據請求項3所述的用途,其中所述病症是由以下者之群中的一或多者所引起的:年老、營養不良、慢性病症、一種或多種藥物和/或輻射。
- 根據請求項4所述的用途,其中引起免疫抑制的所述慢性病症選自以下者之群:癌症和/或選自以下者之群的血液病症:再生不良性貧血、白血病、多發性骨髓瘤和鐮狀細胞病;唐氏症;病毒感染;細菌感染;糖尿病;慢性腎病;腎病症候群;慢性肝炎;肝衰竭;全身性紅斑狼瘡;酒精中毒;慢性燒傷和/或手術。
- 根據請求項4所述的用途,其中所述一種或多種藥物選自以下者之群:抗癲癇藥物、免疫抑制劑、生物製劑、化療藥物和/或皮質類固醇。
- 根據請求項4所述的用途,其中所述輻射是在治療病症期間投予的放射療法。
- 一種孟魯司特或其藥學上可接受的鹽的用途,其係用於製造用以治療免疫系統受到抑制或免疫系統易於受到抑制的患者中以炎症和/或傷口(wounding)為特徵的病症的醫藥品。
- 根據請求項8所述的用途,其中所述孟魯司特或其藥學上可接受的鹽提供免疫恢復作用,同時促進與所述病症相關的傷口(wound)的恢復和/或痊癒。
- 根據請求項8或請求項9所述的用途,其中所述孟魯司特或其藥學上可接受的鹽提供抗炎作用,而不損害所述患者的免疫系統。
- 根據請求項8至10中任一項所述的用途,其中所述免疫抑制是因在治療病症期間投予的放射療法導致的。
- 根據請求項7或請求項11所述的用途,其中通過所述放射療法治療的病症是癌症。
- 根據請求項7、11或12中任一項所述的用途,其中所述放射療法靶向下腹部。
- 根據請求項8至13中任一項所述的用途,其中以炎症為特徵的所述病症選自以下者之群:放射性腸炎、放射性結腸炎、放射性肝炎、放射性脊髓炎、放射性陰道炎和放射性直腸炎。
- 根據請求項14所述的用途,其中所述病症是放射性直腸炎和/或包括以下者之群中的一或多者:急性放射性直腸炎、放射性結腸炎、輻射相關的血管擴張症和/或慢性放射性直腸病。
- 根據前述請求項中任一項所述的用途,其中將所述孟魯司特或其藥學上可接受的鹽局部和外用施加。
- 根據請求項16所述的用途,其中將所述孟魯司特以凝膠的形式施加。
- 根據請求項16或請求項17所述的用途,其中所述局部、外用施加是肛門直腸的。
- 一種孟魯司特或其藥學上可接受的鹽,其係用於治療如請求項1至15中任一項所定義的病症的方法中。
- 一種治療如請求項1至15中任一項所定義的病症的方法,所述方法包括向需要此治療的患者投予孟魯司特或其藥學上可接受的鹽。
- 一種治療患者中以免疫抑制為特徵的病症的方法,所述方法包括向需要此治療的患者投予孟魯司特或其藥學上可接受的鹽。
- 根據請求項21所述的方法,其中所述病症是如請求項1至15中任一項所定義的病症。
- 一種治療免疫系統受損的患者的方法,所述方法包括向這樣的患者投予孟魯司特或其藥學上可接受的鹽。
- 一種用於恢復患者免疫系統的正常功能的方法,所述方法包括向這樣的患者投予孟魯司特或其藥學上可接受的鹽。
- 一種治療患者中以免疫抑制以及炎症和/或傷口為特徵的輻射誘導的病症的方法,所述方法包括向需要此治療的患者投予孟魯司特或其藥學上可接受的鹽。
- 一種治療患者之與輻射誘導的免疫不全病症相關的炎症和/或傷口,同時恢復免疫系統的正常功能的方法,所述方法包括向需要此治療的患者投予孟魯司特或其藥學上可接受的鹽。
- 根據請求項19所使用的化合物或根據請求項20至26中任一項所述的方法,其中所述方法包括以如請求項16至18中任一項所定義的方式投予孟魯司特或其藥學上可接受的鹽。
- 根據前述請求項中任一項所述的用途、所使用的化合物或方法,其中所述孟魯司特藥學上可接受的鹽是孟魯司特鈉。
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