CN113613630A - 地匹福林口腔崩解片剂制剂 - Google Patents
地匹福林口腔崩解片剂制剂 Download PDFInfo
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- CN113613630A CN113613630A CN202080023332.5A CN202080023332A CN113613630A CN 113613630 A CN113613630 A CN 113613630A CN 202080023332 A CN202080023332 A CN 202080023332A CN 113613630 A CN113613630 A CN 113613630A
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- Prior art keywords
- odt
- dipivefrin
- hydrochloride
- epinephrine
- tablet
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Abstract
本公开提供口腔崩解地匹福林片剂(ODT)制剂,其包括含有L‑地匹福林盐酸盐的ODT制剂。本公开的ODT制剂包括10%‑70%的粘合剂(wt%)、5%‑50%的基质形成剂(wt%)和1%‑20%的掩味剂(wt%)。本公开的ODT制剂在给药时迅速向患者提供肾上腺素。本公开还提供了一种通过向患者给药口腔崩解地匹福林片剂制剂而治疗患有肾上腺素反应性病症如心脏事件、哮喘、哮吼、癌症、微生物感染、艾迪生病或过敏性反应,尤其是过敏反应的患者的方法。
Description
相关申请的交叉引证
本申请要求享有2019年3月1日提交的美国临时申请第62/812,540号的优先权,以及根据35 U.S.C.§119(b)之下由其增加的所有受益,其内容通过引用以其整体结合于本文中。
技术领域
本公开提供了口腔崩解型地匹福林片剂制剂。本公开还提供了一种通过向患者给药口腔崩解性地匹福林片剂制剂而治疗患有肾上腺素反应性病症如心脏事件、哮喘、哮吼、癌症、微生物感染、艾迪生(Addison)病或过敏性反应,尤其是过敏反应的患者的方法。
背景技术
地匹福林(Dipivefrin)是肾上腺素的二戊酰酯前药。地匹福林的亲脂性比肾上腺素高100-600倍,因此,进入兔眼的地匹福林比肾上腺素高8-10倍。在人眼中,地匹福林的眼部渗透率比肾上腺素高17倍。地匹福林在角膜和前房中迅速水解为肾上腺素。当以0.5%的溶液滴入人眼时,80%的地匹福林会在30分钟内转化为肾上腺素。地匹福林盐酸盐已被批准作为0.1%滴眼液而用于眼部,被指作为控制慢性开角型青光眼眼内压的初始疗法。口服地匹福林在血液中吸收良好并迅速水解而将肾上腺素输送到体循环中,因此能够用于治疗对肾上腺素反应性病症。
肾上腺素用于治疗多种疾病,包括过敏反应、心脏骤停、浅表出血、哮喘和哮吼。注射型肾上腺素也已被证明能有效预防和治疗癌症。美国专利第5,925,682号公开了向哺乳动物注射有效量的肾上腺素会导致肿瘤生长显著减少。肾上腺素也可以有效治疗微生物感染。肾上腺素通过肌内或皮下注射给药,是紧急治疗过敏反应的可选药物。它可以通过自动注射器或预充式注射器以可注射形式市售获得。在美国,肾上腺素注射液有0.5毫克(mg)、0.3毫克、0.15毫克和0.1毫克的剂量强度,用于过敏反应的紧急治疗。美国专利US 10,039,710 B2公开了能够通过舌下或鼻内途径给药而用于过敏反应的肾上腺素喷雾制剂。对于能够快速将肾上腺素输送到患者血液中的有效、经济且易于使用的制剂,仍存需要。本公开提供了一种有效、方便、易于使用的制剂,其能够将治疗水平的肾上腺素快速递送至患者的血流中并提供额外的优点。
发明内容
本公开内容涉及地匹福林口腔崩解片剂(ODT),其包含地匹福林盐酸盐、粘合剂、崩解剂和/或基质形成剂以及掩味剂。在某些实施方式中,所述ODT包含约0.01mg-约60mgL-地匹福林盐酸盐或0.5mg、1.0mg、2.5mg或5mg L-地匹福林盐酸盐。本公开的地匹福林ODT能够具有小于100mg的总片剂重量。本公开的地匹福林ODT能够包含10%-70%的粘合剂重量百分比(wt%)、5%-50%的基质形成剂和/或崩解剂(wt%)和1%-20%的掩味剂(wt%)。在某些实施方式中,本公开的ODT能够包含5%-15%地匹福林盐酸盐、25%-40%基质形成剂、35%-50%粘合剂和10%-20%甜味剂,其中所有百分比均为重量百分比。在某些实施方式中,本公开的ODT能够包含5%-15%的地匹福林盐酸盐、25%-35%的基质形成剂、35%-45%的粘合剂和10%-20%的甜味剂,其中所有百分比均为重量百分比。在某些实施方式中,本公开的ODT能够包含5%-15%的地匹福林盐酸盐、20%-40%的基质形成剂、19%-73%的粘合剂和5%-10%的甜味剂,其中所有百分比均为重量百分比。在某些实施方式中,该ODP包含0.4%-51%的L-地匹福林盐酸盐、9.94%-53.05%的明胶(wt%)、20.98%-39.75%的甘氨酸(wt%)、10.49%-19.87%的PVP K30(wt%)、5.25%-9.94%的柠檬酸(wt%)和5.25%-9.94%糖精钠(wt%)。在某些实施方式中,该ODP包含L-地匹福林盐酸盐、9%-53%的明胶(wt%)、20%-40%的甘氨酸(wt%)、10%-20%的PVP K30(wt%)、5%-10%的柠檬酸(wt%)和5%-10%的糖精钠(wt%)。
粘合剂能够包括明胶和/或聚维酮。该基质形成剂能够是甘氨酸或甘露醇。掩味剂能够包括柠檬酸和/或甜味剂如三氯蔗糖和糖精钠。该地匹福林ODT组合物能够可选地包含螯合剂。该地匹福林ODT组合物能够可选地包含抗氧化剂。该地匹福林ODT组合物能够可选地包含渗透促进剂。该地匹福林ODT组合物能够可选地包含调味剂。该地匹福林ODT组合物能够可选地包含着色剂。本公开的地匹福林ODT组合物能够可选地包含pH调节剂。
本公开的地匹福林ODT适用于治疗受试者的病症如受试者的体循环中迫切需要肾上腺素的过敏反应。因此,本公开包括当给药于受试者时能够提供从向受试者给药后小于60分钟或在某些实施方式中小于45分钟的肾上腺素Tmax和0.1-50纳克/毫升(ng/mL)的肾上腺素血浆Cmax的地匹福林ODT。
在某些实施方式中,地匹福林ODT包含不超过10mg的地匹福林盐酸盐并且在给药后20分钟能够提供等于或高于由美国FDA批准的可注射肾上腺素剂型提供的血浆肾上腺素水平的血浆肾上腺素水平。美国FDA批准的注射型肾上腺素剂型能够是用于肌肉注射的0.5mg、0.3mg、0.15mg或0.1mg肾上腺素剂型。美国FDA批准的可注射肾上腺素剂型能够是用于皮下给药的0.5mg、0.3mg、0.15mg或0.1mg肾上腺素剂型。
本公开包括一种通过给药本公开的地匹福林ODT而治疗患有肾上腺素反应性病症的受试者的方法。肾上腺素反应性病症能够是呼吸困难,如呼吸困难与过敏反应、哮喘、支气管炎、肺气肿、哮吼或呼吸道感染有关。在某些实施方式中,肾上腺素反应性病症是过敏反应。
本公开包括一种降低受试者的过敏性反应或过敏反应的严重程度或抑制过敏性反应或过敏反应的发作的方法,其包括在受试者暴露于过敏原之后向受试者给药本公开的地匹福林ODT。本公开的地匹福林ODT能够是给药于受试者的唯一活性剂或能够与另一种活性剂如抗组胺剂,例如,苯海拉明(diphenhydramine)一起给药。
本公开包括一种用于治疗受试者中肾上腺素反应性病症的方法,其中受试者患有肾上腺素缺乏症。这种缺乏能够是短期的或慢性的。此类病症包括艾迪生(Addison)病、肾上腺增生、低血糖或慢性活动性肝炎。
附图说明
图1.比格犬(交叉设计,N=3)中单次口服地匹福林盐酸盐口腔崩解片剂5mg(是指地匹福林盐酸盐的重量)和单次标准肾上腺素肌内(IM)注射0.3mg后的平均血浆肾上腺素浓度相对于时间的曲线图。
图2.比格犬(交叉设计,N=3)中单次口服地匹福林盐酸盐口腔崩解片剂5mg和63.5mg(是指地匹福林盐酸盐的重量)后平均血浆肾上腺素浓度相对于时间的曲线图。
图3.比格犬(交叉设计,N=6)中单次口服地匹福林盐酸盐口腔崩解片1.0mg、2.5mg(是指地匹福林盐酸盐的重量)和单次标准肾上腺素肌内注射0.3mg后的平均血浆肾上腺素浓度相对于时间的曲线图。
具体实施方式
术语
此处使用的术语仅用于描述具体实施方式的目的,而非旨在是限制性的。正如本文所用,单数形式“一种”、“一个”和“该”旨在包括复数形式,包括“至少一个”,除非内容另有明确指示。“或”是指“和/或”。正如本文所用,术语“和/或”包括一个或多个相关联的所列项目的任何和所有组合。应该进一步理解的是,当在本说明书中使用时,术语“包含”和/或“含有”,或“包括”和/或“囊括”,指定所述特征、区域、整数、步骤、操作、元件和/或组件的存在,但不排除一个或多个其他特征、区域、整数、步骤、操作、元件、组件和/或其组群的存在或添加。
除非另有定义,本文使用的所有术语(包括技术和科学术语)与本公开所属领域的普通技术人员通常理解的含义相同。还应当理解的是,术语,如在常用词典中定义的那些,应当解释为具有与其在相关领域和本公开的上下文中的含义一致的含义,并且不会以理想化或过于正式的意义进行解释,除非在此明确定义。
正如本文所用,术语“地匹福林口腔崩解片剂”或“地匹福林口腔溶解片剂”或“地匹福林ODT”是指包含地匹福林(游离碱)或其药用盐、地匹福林的溶剂化物或多晶型物的口腔崩解片剂。优选的地匹福林ODT包含地匹福林盐酸盐或L-地匹福林盐酸盐。
地匹福林和L-地匹福林的结构如下:
地匹福林的IUPAC名称是4-(1-羟基-2-(甲基氨基)乙基)-1,2-亚苯基双(2,2-二甲基丙酸酯)。地匹福林的同义词是[±]-3,4-二羟基-α-[(甲基氨基)甲基]苯甲醇3,4-二新戊酸酯、1-(3',4'-二新戊酰氧基苯基)-2-甲基氨基-1-乙醇、4-[1-羟基-2-(甲基氨基)乙基]-O-亚苯基二新戊酸酯、双特戊酰肾上腺素(Dipivalyl Epinephrine)、和[2-(2,2-二甲基丙酰氧基)-4-[1-羟基-2-(甲基氨基)乙基]苯基]2,2-二甲基丙酸酯。地匹福林具有化学文摘服务社登记号(CAS登记号)52365-63-6,地匹福林盐酸盐具有CAS登记号64019-93-8。L-地匹福林具有CAS登记号56298-24-9和L-地匹福林盐酸盐具有CAS登记号79071-01-5。
正如本文所用,术语“药用盐”是由,例如,地匹福林组合物的酸和碱性基团形成的盐。示例性的盐包括,但不限于,硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、酰氯、溴化物、碘化物、硝酸盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐(tannate)、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、苯磺酸盐、龙胆香茅酸盐(gentisinante)、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和巴莫酸盐(例如,1,1′-亚甲基-二-(2-羟基-3-萘甲酸))盐。在一个实施方式中,地匹福林的盐是盐酸盐。除非上下文明显矛盾,“地匹福林”包括地匹福林的药用盐。
术语“药用盐”还是指由具有酸性官能团如羧酸官能团和药用无机或有机碱的组合物制备的盐,也指由具有碱性官能团,例如氨基官能团和药用无机或有机酸的组合物制备的盐。
“活性剂”是指当单独或与另一种化合物、成分或混合物组合给药于受试者时会直接或间接赋予对受试者的生理影响的一种化合物(包括,例如,地匹福林)、成分或混合物。间接生理效应可以通过代谢物或其他间接机制发生。
术语“施用”、“正给药”、“给药的”或“给药”是指向受试者或患者提供活性剂(例如,地匹福林或其药用盐)的任何方式。给药途径能够通过本领域技术人员已知的任何方式完成。此类方式包括口服、口腔、静脉内、皮下、肌肉内、经皮和吸入、舌下、鼻内。口服给药是地匹福林给药的优选途径。
术语“口服”和“口服给药”是指通过嘴经由胃肠道(消化道、消化系统、GI道、GIT、肠胃或消化管道)向受试者或患者提供活性剂的方式并且可以互换使用。胃肠道是人类和其他动物体内摄取食物,消化食物以提取和吸收能量和营养,并将剩余的废物作为粪便排出的一个器官系统。口腔、食道、胃和肠是胃肠道的部分。
“剂型”是指活性剂的给药单位。在本公开中,剂型是口腔崩解片剂。
“口腔崩解(或溶解)片剂”是一种固体剂型,当放入口中时,通常会在几秒钟内迅速崩解或溶解。口腔崩解剂型设计为在与唾液接触时迅速崩解或溶解,从而消除了咀嚼、吞咽或用水服用固体制剂之需。口腔崩解剂能够促进活性成分通过口腔、舌下、口咽和食道膜的胃前吸收。因此,与常规固体剂型相比,口腔溶解剂能够提供更快的起效和更高的生物利用度。
“药用赋形剂”是指适用于制备通常安全、无毒且在生物学上或其他方面均无不良反应的药物组合物的赋形剂,并且包括可接受用于兽医用途以及人类药物用途的赋形剂。本申请中使用的“药用赋形剂”包括一种和多种这样的赋形剂。
“受试者”是人类或非人类哺乳动物,如伴侣动物,例如,猫或犬。受试者可以是需要医学治疗的人类或非人患者。
“治疗有效量”或“有效量”是达到药理作用的药剂的量。术语“治疗有效量”包括,例如,预防有效量,即有效显著降低患疾病风险的患者发生疾病的可能性的量。地匹福林的“有效量”是在没有不适当的不良副作用的情况下实现所需的药理作用或治疗改善所需的量。本领域技术人员将根据具体患者和所治疗病症的类型能够选择地匹福林的有效量。应该理解的是,“有效量”或“治疗有效量”能够因受试者的一般状况、所治疗的病症、所治疗的病症的严重程度以及处方医师的判断的变化而有所不同。当讨论治疗癌组织的方法时,有效量包括有效地对患者的癌症增殖率随时间推移或对癌症生物标志物水平具有统计学显著性和有利影响的量。
术语“治疗”和“治疗处理”是指以旨在减轻症状的严重程度或频率、消除症状或根本原因、预防症状或其根本原因的发生或对由于病症或疾病造成的损害进行改善或补救而实施的疗法。在某些实施方式中,“治疗”包括预防性治疗,其包括给药一定量的地匹福林,以有效地显著减少癌组织的增殖,减少患者被微生物病原体感染的机会。在某些实施方式中,治疗包括抑制暴露于过敏原的受试者的过敏反应的发作或降低过敏症状的严重性。
口腔崩解片剂
口腔崩解片或口腔溶解片剂(ODT)是一种药物剂型,可用于有限范围的非处方(OTC)和处方药。ODT与传统片剂的不同之处在于,它们被设计成在舌头上溶解而不是整个吞咽。ODT可作为吞咽困难症(吞咽困难)患者或依从性已知是个问题的且需要更易于吞咽的剂型才能确保服药的患者的替代剂型。吞咽困难在所有年龄组中都很常见。在约20%的普通人群、33%的住院患者和高达40%的长期护理机构患者中会观察到这种情况。ODT剂型也是年龄太小而无法吞咽药丸的儿科患者的一种选择。由于胃前吸收(随着唾液向下进入胃时从口腔、咽部和食道的吸收),ODTs也比片剂或胶囊起效更快,并且能够方便地在没有水的情况下服用。
据记载,由于患者害怕注射、携带肾上腺素自动注射器(必须保持于20-25℃的温度)以及高成本肾上腺素自动注射器的不便,过敏性协会中肾上腺素自动注射器的使用率明显不足。ODT特别适用于过敏反应紧急治疗的肾上腺素递送,因为它们具有独特的优势,即患者友好且方便的药物剂型,任何人都能够随时随地服用,无需喝水,无需吞服整片药片。本领域众所周知的是,当口服时肾上腺素不会被吸收,从而排除了用于过敏反应的肾上腺素ODT的开发。本发明人开发了新型口腔崩解地匹福林片剂,适用于商业用途。本公开的ODT在低于0-至少60℃的温度下是稳定的,而因此提供优于肾上腺素自动注射器的显著优势,因为它们不需要储存于狭窄的温度范围内。本公开的地匹福林ODT的稳定性能够通过在其制造和储存期间排除水分和氧气而进一步增强。
本公开的地匹福林ODT包含约0.01-约60mg地匹福林或地匹福林盐如地匹福林盐酸盐。本公开包括含有0.1mg、0.5mg、1.0mg、2.0mg、3.0mg、4.0mg、5.0mg、7.0mg、7.5mg、10mg、12mg、15mg或20mg地匹福林盐酸盐的ODT。
本公开的地匹福林ODT可以包含粘合剂。合适粘合剂的非限制性实例包括水溶性、醇溶性或丙酮/水溶性粘合剂,例如,明胶、葡聚糖、藻酸盐、阿拉伯树胶、改性淀粉、包括PVPK30(Cas登记号9003-39-8,K值是指聚维酮平均分子量,PVP K30的平均分子量为40,000)的聚乙烯吡咯烷酮(PVP,也称为Povidone、Plasdone、Polyvidone)、玉米淀粉、聚环氧乙烷、聚乙二醇、羟丙基甲基纤维素(HPMC)、甲基纤维素和羟丙基纤维素(HPC)及其组合。地匹福林ODT中粘合剂的用量范围为10%~70%(wt%),包括20%~70%、25%~65%、30%~60%、35%~60%、40%~60%、45%-60%和30%-35%(wt%)。
本公开的地匹福林ODT可选地包含崩解剂。当ODT通过直接压制制备时,通常存在崩解剂。崩解剂可以是任何适用于口腔崩解片剂的崩解剂,例如,该崩解剂可以是糖醇,如山梨糖醇、甘露醇、木糖醇、异麦芽酮糖醇和氢化淀粉水解物,或氨基酸如甘氨酸,该崩解剂也可以是交联聚维酮(交联PVP)、羟基乙酸淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素或任何上述物质的混合物。在某些实施方式中,该崩解剂是甘露醇、甘氨酸或其组合。ODT中崩解剂的量能够为1%-50%(wt%)、10%-50%、15%-50%、20%-50%、20%-40%、25%-40%或30%-40%(wt%)。
本公开的地匹福林ODT可选地包含基质形成物。本公开通过冻干制备的地匹福林ODT包含基质形成剂并且可选地包含崩解剂。基质形成物优选是在冻干时保持结晶但易于溶解于唾液中的结晶材料。基质形成剂包括甘氨酸、结晶糖如甘露醇(包括D-甘露醇)、赤藓糖醇和木糖醇、微晶纤维素、麦芽糖糊精和结晶纤维素。
本公开的地匹福林ODT可以包括掩味剂。合适的掩味剂包括,但不限于,人造和天然调味剂、柠檬酸和甜味剂,包括人造甜味剂、营养性甜味剂和糖醇。用作掩味剂的甜味剂的实例包括糖精、阿斯巴甜、乙酰舒泛K、纽甜、糖精钠、三氯蔗糖、海藻糖、塔格糖、甘露糖醇、山梨糖醇、木糖醇、赤藓糖醇、麦芽糖醇、蔗糖、果糖和葡萄糖。合适的调味剂包括,但不限于,薄荷油、薄荷醇、留兰香油、柑橘油、肉桂油、草莓香精、樱桃香精、覆盆子香精、橙油和任何前述的组合。
本公开的地匹福林ODT中掩味剂的量能够为0.1%-25%(wt%)、0.5%-25%、1%-25%、2%-25%、5%-25%、10%-25%、1%-20%、2%-20%、5%-20%、10%-20%、0.5%-10%、1%-10%或5%-10%(wt%)。在某些实施方式中,掩味剂是柠檬酸、三氯蔗糖或糖精,或其组合。
地匹福林ODT组合物能够可选地包含螯合剂。用于本公开的地匹福林ODT的合适螯合剂包括,但不限于,乙二胺四乙酸(EDTA)、EDTA盐、去铁胺B、去铁胺、二硫卡钠(dithiocarb sodium)、青霉胺、喷替酸钙、喷替酸钠盐、琥巯酸(succimer)、曲恩汀(trientine)、次氮基三乙酸(nitrilotriacetic acid)、反式二氨基环己烷四乙酸(DCTA)、二亚乙基三胺五乙酸、双(氨基乙基)乙二醇醚-N,N,N',N'-四乙酸、亚氨基二乙酸、柠檬酸、酒石酸、富马酸或其盐。本公开的地匹福林ODT中螯合剂的量可以为0.1%-25%(wt%)、0.5%-25%、1%-25%、2%-25%、5%-25%、10%-25%、1%-20%、2%-20%、5%-20%、10%-20%、0.5%-10%、1%-10%或5%-10%(wt%)。
地匹福林ODT组合物能够可选地包含抗氧化剂。适用于本公开的地匹福林ODT的抗氧化剂包括,但不限于,丁基化羟基茴香醚(BHA)、丁基化羟甲苯(BHT)、抗坏血酸、甲硫氨酸、抗坏血酸钠、硫代硫酸钠、亚硫酸氢钠、焦亚硫酸钠、抗坏血酸棕榈酸酯、硫代甘油、α生育酚(维生素E)、半胱氨酸盐酸盐及其组合。
本公开的地匹福林ODT组合物能够可选地包含渗透促进剂。适用于本公开的渗透促进剂包括,但不限于,辛酸、油酸、聚山梨醇酯80(聚乙二醇脱水山梨糖醇单油酸酯,CAS登记号9005-65-6)、薄荷醇、EDTA、依地酸钠、氯化十六烷基吡啶鎓、十二烷基硫酸钠、柠檬酸、脱氧胆酸钠、脱氧乙醇酸钠、油酸甘油酯、L-赖氨酸及其组合。
本公开的地匹福林ODT组合物能够可选地包含pH调节剂。适用于本发明的pH调节剂包括,但不限于,盐酸、柠檬酸、富马酸、乳酸、氢氧化钠、磷酸一钠或磷酸氢二钠、氨基酸、柠檬酸钠、碳酸氢钠、碳酸钠、碳酸铵以及任何前述的组合。通常而言,当溶解于去离子水中时,本公开的地匹福林ODT组合物具有pH 1-7,在一些实施方式中,pH为1-5,并且在一些实施方式中,pH为2.5-3.5。
地匹福林ODT能够可选地包含药用着色剂。本公开的地匹福林ODT能够可选地包含包衣,如速释包衣。
在某些实施方式中,地匹福林ODT可以是冻干片剂,其可以含有粘合剂、可选的崩解剂、至少一种基质形成试剂(也称为基质形成剂)和至少一种掩味剂。掩味剂可以包括甜味剂。冻干地匹福林ODT的典型包装可以包括铝泡罩包装。泡罩包装包括多层(例如,5层)层压泡罩膜和盖箔。封盖箔是可剥离的,而使每个片剂上的封盖箔可以被移除而到达所述片剂。
地匹福林ODT能够通过本领域已知的用于制备ODT的任何制造方法制成。例如,本公开的地匹福林ODT能够使用常规压片工艺方法如直接压制而制造。地匹福林ODT也能够通过湿法造粒,然后将颗粒干燥并将颗粒压制成片剂而制造。本公开的地匹福林ODT能够通过使用水溶性赋形剂如糖类的片剂成型工艺方法制造。本公开的直接压制片剂通常包含崩解剂。
在某些实施方式中,ODT的总重量小于100mg、小于70mg、小于50mg、小于40mg、小于30mg、小于20mg或小于10mg。
在某些实施方式中,地匹福林口腔崩解片剂在37℃下在不到30秒、或小于10秒或小于5秒内完全溶解于模拟唾液中。
在某些实施方式中,地匹福林口腔崩解片剂在环境温度下在不到30秒或小于10秒或小于5秒内完全溶解于水中。
治疗方法
本公开包括通过向受试者给药本公开的地匹福林ODT而治疗受试者肾上腺素反应性病症的方法。
肾上腺素反应性病症包括呼吸困难,包括与过敏反应、哮喘、支气管炎、肺气肿、哮吼或呼吸道感染相关的呼吸困难。
肾上腺素反应性病症还包括过敏发作、严重过敏症状和过敏反应。治疗方法包括向患有过敏性发作、严重过敏或过敏反应的受试者给药本公开的地匹福林ODT。本公开的治疗方法还包括在受试者暴露于已知过敏原之后向受试者给药本公开的地匹福林ODT,从而降低过敏发作、严重过敏或过敏反应的风险或减轻来自过敏发作、严重过敏或过敏反应的严重度。地匹福林ODT能够作为唯一的活性剂进行给药,或能够可选地与另一种活性剂如抗组胺药或类固醇一起进行给药。抗组胺药的实例包括苯海拉明、溴苯那敏、西替利嗪、氯苯那敏、氯马斯汀、非索非那定和氯雷他定。
治疗方法包括向肾上腺素不足的受试者给药本公开的地匹福林ODT。这种病症能够是慢性病症或急性病症。实例包括艾迪生病、肾上腺增生、低血糖和慢性活动性肝炎。
肾上腺素反应性病症能够是癌症。癌症能够是皮肤癌、脑癌、神经胶质瘤、肉瘤、乳腺癌、肺癌、非小细胞肺癌、间皮瘤、阑尾癌、泌尿生殖系统癌、肾细胞癌、前列腺癌、膀胱癌、睾丸癌、阴茎癌、宫颈癌、卵巢癌、范希佩尔-林道(von Hippel Lindau)病、头颈癌、胃肠道癌、肝细胞癌、胆囊癌、食道癌、胃癌、结直肠癌、胰腺癌、神经内分泌肿瘤、甲状腺肿瘤、垂体肿瘤、肾上腺肿瘤、血液系统恶性肿瘤、淋巴瘤、白血病或其组合。该病症能够是皮肤癌,而皮肤癌是黑色素瘤。地匹福林或其药用盐能够是辅助抗癌治疗,并且该方法包括向受试者给药至少一种额外的抗癌治疗。
肾上腺素反应性病症能够是微生物感染。微生物感染可以是细菌、病毒、真菌或寄生虫感染。微生物感染能够是病毒感染,如流感感染。微生物感染能够是细菌感染,如耐甲氧西林金黄色葡萄球菌(MRSA)感染。地匹福林或其药用盐能够是辅助抗微生物剂并且该方法还包括使用至少一种另外的抗微生物剂治疗受试者的感染。额外的抗微生物剂能够是抗生素。该额外的抗微生物剂能够是抗病毒剂。
肾上腺素反应性病症能够是自身免疫性疾病。自身免疫性疾病能够是类风湿性关节炎、系统性红斑狼疮(狼疮)、多发性硬化症(MS)、1型糖尿病、格林-巴利(Guillain-Barre)综合征、慢性炎性脱髓鞘性多发性神经病、银屑病、格雷夫斯(Graves)病、桥本(Hashimoto)甲状腺炎、重症肌无力(Myasthenia gravis)、脉管炎(vasculitis)和炎症性肠病(IBD)。溃疡性结肠炎和克罗恩(Crohn)病是IBD的两种主要形式。地匹福林或其药用盐能够是辅助剂并且该方法还包括使用至少一种另外的活性剂治疗受试者的自身免疫疾病。另外的活性剂能够包括类固醇、免疫抑制药物、吡啶斯的明(pyrdostigmine)、胰岛素或合成甲状腺激素。
肾上腺素反应性病症的实例包括哮吼、浅表出血、心脏骤停和低血压。
实施例
通用方法
模拟唾液组成
表A提供了模拟唾液的组成,用于体外评价地匹福林ODT。1当量(N)HCl用于将模拟唾液pH值调节为6.8。
q.s.:补足量
体外溶解试验方法
准确称量溶解后获得1mg/mL地匹福林盐酸盐浓度所需的合适体积的模拟唾液,置于玻璃小瓶中并在37℃下加热。将一种地匹福林盐酸盐ODT滴入溶液中并轻轻旋转直至片剂完全溶解。记录溶解时间。
地匹福林盐酸盐ODT的HPLC分析
HPLC(高效液相色谱)样品制备:对于5.0mg地匹福林盐酸盐ODT(是指地匹福林盐酸盐HCl的重量),准确称取5.00克(g)模拟唾液至20毫升(mL)玻璃闪烁(scintillation)瓶中。对于2.5mg地匹福林盐酸盐ODT,使用2.50g模拟唾液。将小瓶置于37℃的油浴中5分钟。将一片片剂放入合适的小瓶中,用手轻轻摇动直至完全溶解。记录溶解时间。溶解样品立即通过HPLC分析纯度并进行测试。
HPLC法:
色谱柱:Phenomenex Gemini C18,100×4.6毫米(mm),3.0微米(μm)
流速:1.0毫升/分钟
检测:254纳米(nm)
温度:30℃
进样量:10微升(μL)
流动相:A:0.1%三氟乙酸(TFA)水溶液
B:0.1%TFA乙腈溶液
梯度:
时间(分钟) | 溶剂A(%) | 溶剂B(%) |
0 | 90 | 10 |
4 | 50 | 50 |
6 | 35 | 65 |
8 | 90 | 10 |
12 | 90 | 10 |
实施例1.地匹福林盐酸盐ODT的制备
本实施例公开了各种强度的地匹福林盐酸盐ODT的制备。除非另有说明,本专利申请中的片剂强度是指每片片剂中所含地匹福林盐酸盐的重量。根据表1.1制备稀释溶液(预冻干(lyo)溶液-地匹福林盐酸盐)。为了制备所需强度的地匹福林盐酸盐ODT,将所需量的地匹福林盐酸盐溶解于适量的稀释剂中而获得地匹福林盐酸盐lyo溶液。然后将一试样的lyo溶液分散到泡罩包装袋中。然后将所填充的泡罩包装在干冰上冷冻至少一小时并冷冻干燥而获得地匹福林盐酸盐ODT。
为了制备稀释剂,首先将明胶溶解于约40℃的去离子水中,而获得澄清溶液。然后加入表1.1中所列出的其余赋形剂并在搅拌下溶解以获得pH3.43的稀释剂溶液。
地匹福林盐酸盐ODT 0.5mg
将地匹福林盐酸盐(5mg)溶解于5.30g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(535μL)分散到直径为13毫米、深度为3毫米的泡罩包装的每个口袋中,导致每片剂量为0.5毫克。然后将片剂泡罩包装放在干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24小时(h),冷凝器温度为-90℃,压力为50毫托(mTorr)。冻干的片剂呈白色、光滑、精致并且具有足够的强度以供手工处理。片剂重量:29.87mg±0.29mg(SD,N=9)。37℃模拟唾液中的体外溶解:2.30秒;体内溶解时间:5.03秒;通过HPLC进行地匹福林盐酸盐测定:96.3%。
地匹福林盐酸盐ODT 1.0毫克
将地匹福林盐酸盐(10mg)溶解于4.46g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(446μL)分散到直径为13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂的剂量为1.0毫克。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24h,冷凝器温度为-90℃,压力为50mTorr。冻干片剂为白色,光滑,精致,并且具有足够的强度以供手工处理。片剂重量:25.02mg±0.33mg(SD,N=10)。37℃模拟唾液中的体外溶解:3.82秒;通过HPLC进行地匹福林盐酸盐测定:98.1%。
地匹福林盐酸盐ODT 2.5毫克
将地匹福林盐酸盐(25mg)溶解于5.30g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(535μL)分散到直径为13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂的剂量为2.5毫克。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24h,冷凝器温度为-90℃,压力为50mTorr。冻干片剂为白色,光滑,精致,并且具有足够的强度以供手工处理。片剂重量:32.04mg±0.42mg(SD,N=9)。37℃模拟唾液中的体外溶解:3.86秒;通过HPLC进行地匹福林盐酸盐测定:98.8%。
地匹福林盐酸盐ODT 5.0毫克
将地匹福林盐酸盐(50mg)溶解于5.30g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(535μL)分散到直径为13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂的剂量为2.5毫克。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24h,冷凝器温度为-90℃,压力为50mTorr。冻干片剂为白色,光滑,精致,并且具有足够的强度以供手工处理。片剂重量:34.48mg±0.51mg(SD,N=9)。37℃模拟唾液中的体外溶解:4.03秒;通过HPLC进行地匹福林盐酸盐测定:96.7%。
实施例2.含有糖精钠和三氯蔗糖作为甜味剂的地匹福林盐酸盐ODT的比较
本实施例举例说明了甜味剂对地匹福林盐酸盐ODT干燥(最终片剂重量)的影响。稀释剂组成列于表2.1中。
使用含糖精钠的稀释剂(SS-稀释剂)和含三氯蔗糖的稀释剂(SU-稀释剂)以与实施例1中所述相同的方式同时制备2.5mg和5.0mg地匹福林盐酸盐ODT片剂。将片剂从泡罩包装中取出,各自称重并储存于封闭玻璃小瓶中。在37℃下,以1.0毫克/毫升(mg/mL)的标称药物浓度测试每组中的一片片剂在模拟唾液中的溶解。来自溶解试验的澄清溶液通过HPLC进行纯度评价和地匹福林盐酸盐分析测定。结果总结于下表2.2中。据观察,在相同的地匹福林强度下,含三氯蔗糖的地匹福林盐酸盐ODT比含糖精钠的那些具有显著更高的重量(对于5mg强度,p<0.05,对于2.5mg强度,p<0.01,双尾T-检验)。这些结果表明,含糖精钠的地匹福林盐酸盐lyo溶液比含三氯蔗糖作为甜味剂的溶液能更有效地干燥。
将含有糖精钠和三氯蔗糖的5毫克片剂从泡罩包装中取出,并在60℃密闭玻璃小瓶中进行平行稳定性研究。稳定性数据总结于表2.3和2.4中。主要的降解物是一对单新戊酰肾上腺素异构体,这由液相色谱-质谱法(LCMS)证实,其由地匹福林的部分酯水解而形成。与其高片剂重量一致,含有三氯蔗糖的地匹福林盐酸盐ODT在5周后60℃下似乎遭受更严重水解降解。
实施例3.不含D-甘露醇的地匹福林盐酸盐ODT制剂的制备和稳定性
本实施例报告了不含D-甘露醇作为基质形成剂的地匹福林盐酸盐ODT的制备及其体外溶解性能和稳定性。稀释剂组成如下表3.1中所示,其提供了pH 2.99的澄清溶液。
地匹福林盐酸盐ODT 5.0毫克
将地匹福林盐酸盐(60.24mg)溶解于6.36g稀释剂溶液中,而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24小时,冷凝器温度为-90℃,压力为50mTorr。冻干的片剂呈白色,光滑,精致,具有足够强度适合手工操作。片剂重量:35.92mg±0.59mg(SD,N=11)。37℃模拟唾液中的体外溶解:2.55秒。通过HPLC进行地匹福林盐酸盐测定:102.1%。
地匹福林盐酸盐ODT 2.5毫克
将地匹福林盐酸盐(30.00mg)溶解于6.36g稀释剂溶液中,而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24小时,冷凝器温度为-90℃,压力为50mTorr。冻干的片剂呈白色,光滑,精致,具有足够强度适合手工操作。片剂重量:33.73mg±0.48mg(SD,N=11)。37℃模拟唾液中的体外溶解:1.92秒。通过HPLC进行地匹福林盐酸盐测定:102.1%。
地匹福林盐酸盐ODT 1.0毫克
将地匹福林盐酸盐(13.20mg)溶解于7.00g稀释剂溶液中,而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24小时,冷凝器温度为-90℃,压力为50mTorr。冻干的片剂呈白色,光滑,精致,具有足够强度适合手工操作。片剂重量:31.30mg±0.62mg(SD,N=11)。37℃模拟唾液中的体外溶解:2.28秒。通过HPLC进行地匹福林盐酸盐测定:100.1%。
地匹福林盐酸盐ODT 0.5毫克
将地匹福林盐酸盐(6.60mg)溶解于7.00g稀释剂溶液中,而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片剂5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机将冷冻片剂冷冻干燥24小时,冷凝器温度为-90℃,压力为50mTorr。冻干的片剂呈白色,光滑,精致,具有足够强度适合手工操作。片剂重量:32.24mg±0.95mg(SD,N=11)。37℃模拟唾液中的体外溶解:2.02秒。通过HPLC进行地匹福林盐酸盐测定:99.6%。
将5毫克和2.5毫克片剂都从泡罩包装中取出,并在60℃密闭玻璃小瓶中测定稳定性。表3.2和3.3总结了60℃下2周稳定性数据。
实施例4.含有EDTA的地匹福林盐酸盐ODT制剂的制备和稳定性试验
稀释剂组成显示于下表4.1中,其给出pH 3.02的澄清溶液。
地匹福林盐酸盐ODT 5.0毫克
将地匹福林盐酸盐(66.4mg)溶解于7.00g稀释剂溶液中而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个口袋中,导致每片5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机,冷凝器温度为-90℃,压力为50mTorr,在环境温度下将冻干片剂冷冻干燥24小时且在60℃下冷冻干燥20小时(h)。冻干的片剂呈白色,光滑,精致,具有足够的强度适合手工操作。将片剂从泡罩包装中取出,各自称重并储存于封闭玻璃小瓶中。片剂重量:28.76mg±0.42mg(SD,N=9)。37℃模拟唾液中的体外溶解:1.56秒。通过HPLC进行地匹福林盐酸盐测定:100.1%。
地匹福林盐酸盐ODT 2.5毫克
将地匹福林盐酸盐(33.0mg)溶解于7.00g稀释剂溶液中而获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个袋中,导致每片5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。使用VirTis Sentry 2.0(SPScientific)冷冻干燥机,冷凝器温度为-90℃,压力为50mTorr,在环境温度下将冻干的片剂冷冻干燥24小时且在60℃下冷冻干燥20小时(h)。冻干的片剂呈白色,光滑,精致,具有足够的强度适合手工操作。将片剂从泡罩包装中取出,各自称重并储存于封闭玻璃小瓶中。片剂重量:24.23mg±0.53mg(SD,N=9)。37℃模拟唾液中的体外溶解:1.52秒。通过HPLC进行地匹福林盐酸盐测定:93.0%。
将片剂从泡罩包装中取出,并在60℃密闭玻璃瓶中评价稳定性。稳定性数据总结于表4.2和4.3中。
实施例5.采用硅胶袋的泡罩包装储存的地匹福林盐酸盐ODT制剂
本实施例表明,在制备、包装和处理期间保持地匹福林盐酸盐ODT片剂不受潮对其长期稳定性至关重要。稀释剂组成与实施例3的表3.1中所示相同。
地匹福林盐酸盐ODT 5.0毫克
将地匹福林盐酸盐(66.4mg)溶解于7.00g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个袋中,导致每片5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。冷冻片剂在环境温度下冷冻干燥24小时。从泡罩包装中取出一片剂并测试其体外溶解、HPLC纯度和HPLC分析测试(T0)。然后将泡罩包装转移到与冷冻干燥机相连的真空烘箱中,并在60℃和86mTorr压力下干燥1周。取出一片剂并测试外观、体外溶解、HPLC纯度和HPLC分析测试(T 1周,60℃)。剩余片剂保存于装有旨在保护91.5立方英寸的区域免受潮的10克硅胶袋的密封塑料袋中的泡罩包装中。袋子在室温和60℃下储存,进行长期稳定性试验。
地匹福林盐酸盐ODT 2.5mg
将地匹福林盐酸盐(33.2mg)溶解于7.00g稀释剂溶液中以获得lyo溶液。然后将lyo溶液(535μL)分散到直径13毫米、深度3毫米的泡罩包装的每个袋中,导致每片5.0毫克的剂量。然后将片剂泡罩包装放置于干冰顶部上一小时。冷冻片剂在环境温度下冷冻干燥24小时。从泡罩包装中取出一片剂并测试其体外溶解、HPLC纯度和HPLC分析测试(T0)。然后将泡罩包装转移到与冷冻干燥机相连的真空烘箱中,并在60℃和86mTorr压力下干燥1周。取出一片剂并测试外观、体外溶解、HPLC纯度和HPLC分析测试(T 1周,60℃)。剩余片剂保存于装有旨在保护91.5立方英寸的区域免受潮的10克硅胶袋的密封塑料袋中的泡罩包装中。袋子在室温和60℃下储存,进行长期稳定性试验。
稳定性数据总结于表5.1和5.2中。正如数据所示,在60℃和高真空下,5mg和2.5mg强度地匹福林盐酸盐ODT在1周后的外观、体外溶解、HPLC纯度和分析测定结果均无变化。由于地匹福林的主要降解途径是部分酯水解,则不希望受理论的束缚,地匹福林ODT在60℃下的非凡稳定性是由于在高真空下不存在水分。然而,由于冻干片剂的高度多孔性,地匹福林盐酸盐ODT在从真空烘箱中取出时能够迅速从空气中吸收一些水分。这与第2周观察到的加速水解降解以及第2-4周之间明显减缓的现象一致,这可能是由于第2周后水含量的减少所致。
实施例6.在37℃下新鲜人唾液中地匹福林盐酸盐ODT的孵育
本实施例表明,配制为口腔崩解片剂的地匹福林盐酸盐在口腔崩解片剂给药的典型短时间内不会在口腔中发生明显水解。
将具有下表6.1中所列组成的地匹福林盐酸盐lyo溶液在泡罩包装(0.560mL/袋)中冻干以获得如实施例3中所述的地匹福林盐酸盐ODT25mg强度。片剂为精致的,具有用于人工处理的良好强度,在37℃模拟唾液中的体外溶解时间为26秒。
约四分之一的片剂溶解并37℃下11分钟孵育于1mL新鲜人唾液中。用去离子水稀释等分试样,通过0.2微米(μm)尼龙注射器过滤器过滤并注入HPLC。分析表明在唾液中孵育后存在约13%的肾上腺素。在一项独立实验中,约四分之一的相同片剂在1mL新鲜人唾液中37℃下孵育3min,并且HPLC表明孵育后未检测到肾上腺素。
实施例7.用于犬药代动力学研究的地匹福林盐酸盐ODT 63.5mg的制备
正如实施例1所述,将具有下表7.1中所列组成的地匹福林盐酸盐lyo溶液在泡罩包装(0.594mL/袋)中冻干而获得地匹福林盐酸盐ODT 63.5mg。片剂重量为90.95±1.88mg(SD,N=9)。
实施例8.用于犬药代动力学研究的地匹福林盐酸盐ODT 5.0mg的制备
正如实施例1所述,将具有下表8.1中所列组成的地匹福林盐酸盐lyo溶液冻干于泡罩包装(0.535mL/袋)中而获得地匹福林盐酸盐ODT 5.0mg。片剂为白色并且具有精致的外观,令人愉快的味道。重量:34.97±0.42mg(SD,N=9)。在37℃的模拟唾液中的体外溶解时间:4.90秒。
实施例9.地匹福林盐酸盐ODT在犬(N=3)单次口服给药后的药代动力学研究
根据下表9.3,以三腿交叉设计(three leg cross-over design)在犬中评价地匹福林盐酸盐的药代动力学。在研究开始前四天,从四只(n=4)年龄1.5-6.5岁、体重9.8-10.8公斤的非幼稚雄性比格犬收集1mL全血于4个含有K2EDTA(EDTA二钾)的冷冻管中。将血液加工成血浆,并根据Ellman方法使用碘化乙酰硫代胆碱作为底物(Ellman,G.L.et al.,Biochemical Pharmacology,1961,volume 7,page 88-95)分析测定血浆胆碱酯酶活性。分析测定结果总结于表9.1中。根据血浆胆碱酯酶活性分析测定结果,选择具有最高血浆胆碱酯酶活性的前三只犬进行PK研究。
U/L:微摩尔/分钟/升(μmol/min/L)
每笼子关着一只犬,并通过耳标和笼标签进行识别。在研究开始时,动物是健康的。主围栏由美国农业部动物福利法(USDA Animal Welfare Act)(9CFR,parts 1,2and 3)指定,并如《实验室动物护理和使用指南(Guide for Care and Use of LaboratoryAnimals)》(ILAR出版物,2011,美国国家科学院出版社(National Academy Press))中所述。计量给药前动物禁食最少12小时,计量给药后4小时返回;向动物随意供应水。
根据研究设计表(表9.3),在适当日期的0小时进行计量给药。第一条腿的肾上腺素IM 0.3mg(组成见表9.2)是过敏反应的标准治疗,作为对照。通过25号针头和注射器将肌肉注射量施用到左或右大腿的外侧。在给药前将给药部位剪去毛发并用酒精清洁。口腔崩解片剂通过将一片片剂放于犬的舌头上进行计量给药。将口鼻轻轻闭合1-2分钟。在这段时间之后,张开嘴观察到片剂已完全溶解。
在适当的时间点通过直接静脉穿刺从犬颈静脉中收集全血样本(~0.5-1mL),并放入K2EDTA管中作为抗凝剂。血液样品在4℃温度下以3000g离心5分钟。所有样品在整个加工过程中都保持冷藏。血浆样品(250μL)一式多样分装到eppendorf管中的50μL 6wt%焦亚硫酸钠溶液中,并置于设置为保持~-70℃的冰箱中,直到用干冰运送到KeystoneBioanalytical进行血浆肾上腺素浓度分析。
犬中的地匹福林盐酸盐的PK分析结果总结如下(表9.4)。使用单向方差分析(ANOVA)随后是Turkey多重比较检验进行统计分析。所有统计分析均使用Prism 7.0(GraphPad Software,San Diego,CA)进行。
Cmax:最大血浆浓度(各犬的Cmax值的平均值±SEM);Tmax:达到最大血浆肾上腺素浓度的时间(各犬的Tmax值的平均值±SEM);AUC0-last:血浆浓度相对于时间的曲线之下的面积(各犬的AUC值的平均值±SEM)。Tmax是在每只个体犬中出现最高峰值肾上腺素浓度的时间。Tmax受实验设计的限制,因为它是一个基于血液采样定义时间的离散变量。
向比格犬给药地匹福林盐酸盐口腔崩解片剂后,血浆肾上腺素浓度迅速升高。与具有可比较的Tmax的肾上腺素标准IM 0.3mg注射液相比,地匹福林盐酸盐5mg口腔崩解片剂剂量提供了2倍的Cmax和AUClast。与5mg地匹福林盐酸盐口腔崩解片剂(对于Cmax,p<0.05,而对于AUC,p<0.01)或标准肾上腺素IM0.3 mg(对于Cmax和AUC,p<0.01)相比,地匹福林盐酸盐63.6mg产生了显著更高水平的肾上腺素。平均血浆肾上腺素相对于时间的曲线如图1和图2中所示。所有治疗组之中的Tmax没有显著差异(p>0.6)。本实施例表明,地匹福林盐酸盐ODT能够在犬体内产生与标准肾上腺素IM 0.3mg(一种用于过敏反应紧急治疗的可选药物)统计学上相等的肾上腺素水平。
实施例10.地匹福林盐酸盐ODT在犬(N=6)单次口服给药后的药代动力学研究
根据下表10.3,以三腿交叉设计在六只犬中评价了地匹福林盐酸盐的药代动力学。在研究开始前4天,从7只(n=7)年龄1.5-6.5岁、体重10.6-13.75公斤的非幼稚雄性比格犬中采集1mL全血于7个装有K2EDTA的冷冻管中。将血液加工成血浆,并根据Ellman方法使用碘化乙酰硫代胆碱作为底物(Ellman,G.L.et al Biochemical Pharmacology,1961,volume7,page 88-95)测定血浆胆碱酯酶活性。分析测试结果总结于表10.1中。根据血浆胆碱酯酶活性测定结果,选择具有最高血浆胆碱酯酶活性的前六只犬进行药代动力学(PK)研究。
每笼子关着一只犬,并通过耳标和笼标签进行识别。在研究开始时,动物是健康的。主围栏由美国农业部动物福利法(USDA Animal Welfare Act)(9CFR,Parts 1,2and 3)指定,并如《实验室动物护理和使用指南(Guide for Care and Use of LaboratoryAnimals)》(ILAR出版物,2011,美国国家科学院出版社(National Academy Press))中所述。计量给药前动物禁食最少12小时,计量给药后4小时返回;向动物随意供应水。
根据研究设计表(表10.2),在适当日期的0小时进行计量给药。第一条腿的肾上腺素IM 0.3mg(组成见表9.2)是过敏反应的标准治疗,作为对照。通过25号针头和注射器将肌肉剂量注射到左或右大腿的外侧。在给药前将给药部位剪去毛发并用酒精清洁。口腔崩解片剂(组成示于表10.2)通过将一片片剂放于犬的舌头上进行计量给药。将口鼻轻轻闭合1-2分钟。在这段时间之后,张开嘴观察到片剂已完全溶解。
在合适的时间点通过直接静脉穿刺从犬颈静脉中收集全血样本(~0.5-1mL)并置入K2EDTA管中作为抗凝剂。血液样品在4℃温度下以3000g离心5分钟。所有样品在整个加工过程中都保持冷藏。血浆样品(250μL)被一式多样分装于eppendorf管中的50μL 6wt%焦亚硫酸钠溶液中,并放置于设置为保持~-70℃的冰箱中,直到用干冰运送到KeystoneBioanalytical进行血浆肾上腺素浓度分析。
地匹福林盐酸盐的犬中PK分析结果总结如下(表10.4)。使用单向ANOVA随后是Turkey多重比较检验进行统计分析。所有统计分析均使用Prism 7.0(GraphPad Software,San Diego,CA)进行。
Cmax:最大血浆浓度(各犬的Cmax值的平均值±SEM);Tmax:达到最大血浆肾上腺素浓度的时间(各犬的Tmax值的平均值±SEM);AUC0-last:血浆浓度相对于时间的曲线之下的面积(各犬的AUC值的平均值±SEM)。Tmax是在每只个体犬中出现最高峰值肾上腺素浓度的时间。Tmax受实验设计的限制,因为它是一个基于血液采样定义时间的离散变量。
平均血浆肾上腺素相对于时间的曲线如图3中所示。本实施例证实,地匹福林盐酸盐ODT能够在犬体内产生与标准肾上腺素IM 0.3mg(一种用于紧急治疗过敏反应的可选药物)相似水平的肾上腺素。
实施例11.灵活片剂尺寸的地匹福林盐酸盐ODT制剂的制备
本实施例的目的是举例说明本发明在相同强度下关于片剂尺寸的灵活性。例如,通过简单地增加活性药物成分(API)的量,而同时在冻干之前保持溶液混合物中非活性成分的量相同,能够很方便地制备更小的片剂;冷冻干燥后,API含量越高,要求每个泡罩袋的剂量重量越小,从而生产的片剂就越小。每种非活性成分的量也能够容易调节(表11.1)。
Claims (27)
1.一种地匹福林口腔崩解片剂(ODT),包含地匹福林、其药用盐、粘合剂、基质形成剂和掩味剂。
2.根据权利要求1所述的ODT,包含0.01mg-20mg地匹福林盐酸盐。
3.根据权利要求1所述的ODT,包含0.5mg、1.0mg、2.5mg或5mg地匹福林盐酸盐。
4.根据权利要求1-3中任一项所述的ODT,其中所述片剂的总重量小于50mg。
5.根据权利要求1-4中任一项所述的ODT,包含10%-70%的粘合剂(wt%)、5%-50%的基质形成剂(wt%)和1%-20%的掩味剂(wt%)。
6.根据权利要求1-5中任一项所述的ODT,其中所述基质形成剂包含甘露醇或甘氨酸。
7.根据权利要求1-6中任一项所述的ODT,其中所述掩味剂包括甜味剂。
8.根据权利要求1-7中任一项所述的ODT,其中所述粘合剂包括明胶和聚维酮。
9.根据权利要求1-8中任一项所述的ODT,还包含乙二胺四乙酸(EDTA)。
10.根据权利要求1-9中任一项所述的ODT,其中当给予人时,所述ODT提供小于45分钟的肾上腺素Tmax。
11.根据权利要求1-10中任一项所述的ODT,其中当给予人时,所述ODT提供0.1-50ng/mL的肾上腺素血浆Cmax。
12.根据权利要求1-9中任一项所述的ODT,其中所述ODT包含不超过10mg的地匹福林盐酸盐,并且在给药后20分钟提供的血浆肾上腺素水平等于或大于由美国FDA批准的注射用肾上腺素剂型所提供的血浆肾上腺素水平。
13.根据权利要求12所述的ODT,其中美国FDA批准的所述剂型包含用于肌内给药的0.5mg、0.3mg、0.15mg或0.1mg肾上腺素剂型。
14.根据权利要求12所述的ODT,其中美国FDA批准的所述剂型包含用于皮下给药的0.5mg、0.3mg、0.15mg或0.1mg肾上腺素剂型。
15.根据权利要求1-12中任一项所述的ODT,其中所述地匹福林是L-地匹福林盐酸盐。
16.根据权利要求1-4中任一项所述的ODT,包含L-地匹福林盐酸盐和9%-53%的明胶(wt%)、20%-40%的甘氨酸(wt%)、10%-20%的PVPK30(wt%)、5%-10%的柠檬酸(wt%)和5%-10%的糖精钠(wt%)。
17.一种治疗患有肾上腺素反应性病症的受试者的方法,包括向所述受试者给予权利要求1-16中任一项所述的ODT。
18.根据权利要求17所述的方法,其中所述肾上腺素反应性病症是呼吸困难。
19.根据权利要求17所述的方法,其中呼吸困难与过敏反应、哮喘、支气管炎、肺气肿、哮吼或呼吸道感染有关。
20.根据权利要求17所述的方法,其中所述病症是过敏反应。
21.一种降低受试者的过敏性反应或过敏反应的严重度或抑制过敏性反应或过敏反应的发作的方法,包括在受试者暴露于过敏原之后向所述受试者给予权利要求1-16中任一项所述的ODT。
22.根据权利要求17-21中任一项所述的方法,还包括向所述受试者给予抗组胺。
23.根据权利要求22所述的方法,其中所述抗组胺是苯海拉明。
24.根据权利要求17所述的方法,其中所述病症是艾迪生病、肾上腺增生、低血糖或慢性活动性肝炎。
25.根据权利要求17所述的方法,其中所述病症是癌症。
26.根据权利要求17所述的方法,其中所述病症是自身免疫性疾病。
27.根据权利要求17所述的方法,其中所述病症是微生物感染。
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