CN1993108A - 红细胞生成素受体激动剂的稳定的混悬液制剂 - Google Patents
红细胞生成素受体激动剂的稳定的混悬液制剂 Download PDFInfo
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- CN1993108A CN1993108A CNA2005800263383A CN200580026338A CN1993108A CN 1993108 A CN1993108 A CN 1993108A CN A2005800263383 A CNA2005800263383 A CN A2005800263383A CN 200580026338 A CN200580026338 A CN 200580026338A CN 1993108 A CN1993108 A CN 1993108A
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Abstract
用于治疗用途的混悬液制剂,包含:显示出粘性流体特性的非水单相载体;和,包含分散在载体中的红细胞生成素受体激动剂的微粒制剂。
Description
发明背景
[0001]本发明通常涉及制剂的用于连续递送的药物制剂。
[0002]红细胞生成素(EPO)为多效的()糖蛋白激素,其主要由肾产生。EPO刺激骨髓产生红细胞,并在骨髓外发挥组织保护效应,例如神经保护作用。EPO通过结合细胞表面受体而发挥生物效应。EPO受体激动剂(ERAs)为一类可活化EPO受体的重组体分子。在ERA类中的重组体分子可能或不可能包含天然人EPO(hEPO)的同源性序列。在ERA类中包含天然hEPO同源性序列的产品的实施例显示在下面的表1中。
表1
产品名称 | 重组体分子 | 与人红细胞生成素的氨基酸序列的同源性 |
PROCRIT/EPOGEN | Epoetinα | 100% |
EPREX/ERYPO | Epoetinα | 100% |
NeoRecormon | Epoetinβ | 100% |
ARANESP | Darbepoetinα | 97% |
[0003]ERA产品已经表明可用于治疗慢性肾衰竭引起的贫血、与癌症化疗和外科手术有关的贫血,和AZT治疗ADDS继发的贫血。目前市售的ERA产品为通过皮下或肌肉注射给药患者,每周给药三次(EPREX、ERYPO和PROCRIT)或每周一次(ARANESP)。目前市售的某些ERA产品为液体,需要在2至8℃贮存,在室温和高温下不稳定。ERAs对聚集体敏感,其可导致药物的效能降低,并可引起不想要的副作用。与目前给药ERAs有关的不良副作用包括,但不限于血栓形成事件、感染、高血压、肌痛和头痛。
[0004]如果ERAs可以使用例如可植入递送装置,如渗透性的、机械性的或电动机械的泵植入管以低剂量连续递送,则与给药ERAs有关的治疗的效果可能会提高。可植入递送装置的使用通常确保了患者的顺应性,因为可植入装置不易受患者干预,其可设计在几周内、几月内或甚至几年内提供治疗量的药物而不需要患者加药。当与在相对短时期需要多次给药的注射相比,采用一次植入装置,而不是每隔几天的注射,存在如下优点:减少部位发炎、对患者和医师的职业危害较少、降低废物处理的危险、通过减少用于重复注射的设备费用而提高了成本效果和提高了功效。
[0005]为了在长期内以控制速率从可植入递送装置递送ERAs,ERAs必须被包含于在高温例如37℃或更高温度下,在所述装置的使用年限内,保持它们稳定性的制剂中,并且制剂必须是可流动的形式。
发明概述
[0006]在一个方面,本发明涉及一种混悬液制剂,其包含:显示出粘性流体特性的非水单相载体,和其包含分散在载体中的红细胞生成素受体激动剂的微粒制剂。
[0007]在另一个方面,本发明涉及刺激患者中红细胞生成的方法,其包含给药所述患者如上所述有效量的混悬液制剂。
[0008]在另一个方面,本发明涉及一种可植入递送装置,其包含含有足量的如上所述混悬液制剂的储库,所述足量未能在使用环境下,以治疗有效速度提供连续递送红细胞生成素受体激动剂的量。
[0009]根据下述说明书,本发明的其它特点和益处将变得显而易见。
附图简述
[0010]图1为包含根据本发明的一个实施方案的ERA制剂的渗透泵图。
[0011]图2A显示了包含根据本发明一个实施方案的ERA制剂的渗透泵的释放速率,其中渗透泵用于泵入释放速率介质。
[0012]图2B显示了包含根据本发明一个实施方案的ERA制剂的渗透泵的释放速率,其中渗透泵是用于泵入空气。
[0013]图3显示根据本发明一个实施方案的释放的制剂的生物活性。
发明详述
[0014]本发明现在将参考几个优选的实施方案进行详细阐述。在下述说明书中,列出许多特定的详述是为了使对本发明有彻底的理解。然而,对本领域技术人员显而易见的是,在没有某些或所有这些特定的详述下,也可以实施本发明。在其它的情况下,没有详细描述熟知的特征和/或制备方法是为了避免使本发明不明确的多余内容。参照附图和下述谈论,可更透彻地理解本发明的特征和优点。
[0015]本发明的实施方案提供了红细胞生成素受体激动剂(ERAs)的稳定的制剂,其为使用可植入递送装置在缓释期内以控制速率递送的。本发明在某种程度上是基于发现了将ERA微粒制剂混悬于非水单相载体而获得了ERA的混悬液制剂,该制剂在高温,例如37℃或更高温度下长期稳定,例如3个月至12个月。在悬浮于载体之前,ERA微粒制剂通常具有低水分含量,优选小于5%。ERA微粒制剂可以使用本领域用于制备蛋白质微粒的已知方法来制备,例如喷雾干燥和冷冻干燥。所述ERA微粒制剂可以全部是纯ERA或可以是纯ERA与一种或多种助剂或赋形剂制剂的。
[0016]术语″ERA″或″红细胞生成素受体激动剂″指一类可以活化EPO受体的分子。这些分子可包含或不包含与天然hEPO同源性的序列。根据本发明的一个实施方案的ERA可选自:具有重组体hEPO生物活性的多肽和蛋白质、EPO类似物、EPO同工型、EPO模拟物、EPO片段、杂种EPO蛋白质、融合蛋白质低聚体和上述多聚体、上述的同系物、上述的糖基化模式变异体(glycosylation pattern variants)、上述的突变蛋白和包含上述列举物小修饰体的EPO分子。根据本发明的ERAs将不会受到合成或制备方法的限制,包括由重组体(无论产生自cDNA还是基因组DNA)法、化学合成法、转基因法和基因活化法合成或制备的那些。
[0017]特别优选的ERAs为能刺激哺乳动物红细胞生成的那些。能刺激哺乳动物红细胞生成的ERAs的实例包括,但不限于,epoetin α(商品名EPREX、ERYPO、PROCRIT)、epoetinβ(商品名NEORECORMON)和darbepoetinα(商品名NESPTM、ARANESP)。darbepoetinα的一种形式描述于PCT公布WO95/05465(Amgen,Inc.)中,将其教导性内容引入本文作为参考。在WO95/05465公布中,darbepoetinα包括hEPO的类似物,其含有包括至少一个另外的位点或至少一个用于糖基化位点重排的氨基酸序列。糖基化位点位于N-连接的或O-连接的碳水化合物链。
[0018]表明能刺激哺乳动物红细胞生成的其它ERAs包括hEPO类似物,例如在PCT公布WO 99/66054(Genzyme Transgenics Corp)中描述的人血清白蛋白融合蛋白质,将其教导性内容引入本文作为参考,和EPO突变体,例如在PCT公布WO 99/38890(Beth IsraelDeaconess Medical Center)中描述的,将其教导性内容引入本文作为参考。在WO 99/38890公布中,EPO突变体包括分离的核酸编码的EPO,其中在非编码区域,核酸具有一个或多个突变,且EPO具有改变的生物活性。在一个实施方案中,突变位于非编码区域的51位。
[0019]表明能刺激哺乳动物红细胞生成的其它ERAs包括EPOω,其可产生自描述于U.S.专利No.5,688,679(Powell)中的hEPO基因的Apa I限制性片断,将其教导性内容引入本文作为参考,和改变的糖基化hEPO,例如描述于PCT公布WO 99/11781(Hoechst MarionRoussel Deutschland GMBH)中,将其内容引入本文作为参考。在WO99/11781公布中,改变的糖基化hEPO包括具有EPO的部分或所有主要结构构型的多肽,其为外原性DNA序列的真核表达产物。
[0020]证实能刺激哺乳动物红细胞生成的另一种ERA包括聚乙二醇(PEG)共轭的红细胞生成素类似物,其公开于例如PCT公布WO98/05363(Ortho Pharmaceutical Corporation)中,将其教导性内容引入本文作为参考,和WO 01/76640(Amgen,Inc.),将其教导性内容引入本文作为参考,和U.S.专利No.5,643,575(Martinez等.),将其内容引入本文作为参考。
[0021]其它的实例包括用于表达内源性人EPO的修饰的细胞系,如描述于PCT公布WO 99/05268(Boehringer Mannheim GMBH)中,将其教导性内容引入本文作为参考,和WO 94/12650(transkaryoticTherapies,Inc),将其教导性内容引入本文作为参考。ERAs的组织和细胞保护形式也包括在内。
[0022]根据本发明的ERAs也可包括长效形式的EPO。如本文使用的″长效EPO″包括具有循环半衰期增加的EPO,典型地通过修饰获得,例如降低免疫原性和清除率,和包囊在聚合物微球体中的EPO的缓释组合物和制剂。
[0023]长效EPO的一个实例公开于PCT公布WO 02/49673(F.Hoffman-La Roche AG)中,将其内容引入本文作为参考。WO02/49673公布描述了包含具有N-末端α-氨基的红细胞生成素糖蛋白的共轭物,选自hEPO或其类似物,该类似物具有通过通过添加1-6糖基化位点或糖基化位点重排来修饰的hEPO序列,其中糖蛋白共价连接至PEG基。
[0024]长效EPO的其它实例包括,但不限于公开于PCT公布WO02/32957(Chugal Seiyaku Kabushiki Kaisha,Japan)中的PEG-修饰的EPO,描述于PCT公开WO 94/28024(Enzon,Inc.)中的具有红细胞生成活性和具有至少一个与非抗原性聚合物共价连接的氧化的碳水化物部分的糖蛋白共轭物,及使用琥珀酰亚胺基羧甲基化PEG(SCM-PEG)、琥珀酰亚胺基丙酸酯PEG(SPA-PEG)和SBA-PEG制备的其它PEG-EPO。
[0025]在本发明的一个实施方案中,在悬浮于非水单相载体之前,在37℃或更高温度下,ERA可稳定地防止聚集。在一个实施方案中,含有稳定剂和缓冲剂的ERA稳定地防止聚集。在一个实施方案中,稳定剂包括糖。糖在ERA微粒制剂中的含量可以为0.1至99.9%重量。可包括在微粒制剂中的糖的实例包括,但不限于,蔗糖、海藻糖、葡萄糖、乳糖、麦芽糖和果糖。在一个实施方案中,在微粒制剂中使用的缓冲剂的含量为0.1至99.8%重量。优选地,缓冲剂具有的pH值为5.0至8.0,更优选地为5.5至7.5。在一个实施方案中,缓冲剂在溶液中的浓度为5mM至50mM。缓冲剂的实例包括,但不限于柠檬酸盐、组氨酸、磷酸盐、琥珀酸盐、马来酸盐、三羟甲基氨基甲烷、醋酸盐、碳酸盐和甘氨酸-甘氨酸(gly-gly)。在这些实例中,柠檬酸盐and组氨酸缓冲剂是最优选的。稳定剂与ERA的比率可以改变。使用柠檬酸盐缓冲剂时,稳定剂和ERA的比率优选为大于2.0。
[0026]在本发明的其它实施方案中,在ERA微粒制剂中使用的稳定剂可进一步包括一种或多种选自下述的组分:氨基酸、多元醇和聚合物。微粒制剂可包括0至99.9%重量的氨基酸,0至99.9%重量的多元醇,和0至99.9%重量的聚合物。可加入到微粒制剂中的氨基酸的实例包括,但不限于组氨酸、甘氨酸、丙氨酸、L-亮氨酸、谷氨酸、异亮氨酸、甲硫氨酸、L-苏氨酸、2-苯胺和精氨酸。可加入到微粒制剂中的多元醇的实例包括,但不限于脱水山梨醇和甘露醇。可加入到微粒制剂中的聚合物的实例包括,但不限于聚乙烯吡咯烷酮(PVP)、葡聚糖和丙二醇。
[0027]微粒制剂可包括其它的赋形剂,选自例如表面活性剂、填充剂和盐。微粒制剂可包括0至10wt%,优选0至5wt%的表面活性剂,0至99.9wt%,优选0至70wt%的填充剂和0至99.9wt%,优选0至70wt%的盐。包括在微粒制剂中的表面活性剂可以是离子型的或非离子型的。表面活性剂的实例包括,但不限于聚氧乙烯(20)脱水山梨醇单月桂酸酯(商品名TWEEN20)、聚氧乙烯山梨聚糖单油酸酯(商品名TWEEN80)、聚氧乙烯-聚氧丙二醇(商品名PLURONICF68)和十二烷基硫酸钠(SDS)。填充剂的实例包括,但不限于,甘露醇和甘氨酸。盐的实例包括,但不限于氯化钠、氯化钙和氯化镁。
[0028]下述表2列举了稳定地防止聚集的冻干Epoetinα(EPO)组合物,以及当将该组合物储存在37℃下三个月时,它们的总可溶性聚集体,其通过尺寸排阻色谱法(SEC)测定。
表2
制剂 | 蔗糖∶EPO比率 | EPO装载量(wt%) | TWEEN20(wt%) | 冷冻干燥前溶液中的柠檬酸盐,mM | 全部可溶性聚集体(%) |
A | 2.5 | 17.8 | 1 | 25 | 0.95 |
B | 2.5 | 18.0 | 0 | 25 | 0.90 |
C | 13.5 | 6.0 | 1 | 25 | 0.07 |
D | 13.5 | 6.0 | 0 | 25 | 0.08 |
E | 2.5 | 25.6 | 0 | 5 | 0.32 |
F | 13.5 | 6.6 | 1 | 5 | 0.20 |
G | 8 | 9.7 | 0.5 | 15 | 0.08 |
H | 13.5 | 6.7 | 0 | 5 | 0.00 |
I | 2.5 | 24.6 | 1 | 5 | 0.24 |
J | 4.2 | 16.5 | 0.5 | 10 | 0.18 |
[0029]适用于本发明的非水单相载体可以是任意混合溶剂、聚合物(液体和非液体)、非聚合物(液体和非液体)和表面活性剂。选择载体的组分以使载体能与水相混溶,尽管载体的每种组分易于与水混溶并不是必要的。选择并混合物载体的组分以使得到的载体为均匀系统,即在物理上和化学上都是均匀的。所述载体为可生物降解的,其中其在对生物环境的应答期内崩解或分解。载体在生物环境中的崩解可通过一种或多种物理或化学方法来进行,例如酶促作用、氧化作用、还原作用、水解作用(例如蛋白水解作用)、移位(displacement)或增溶作用的溶解、乳化作用或胶束形成。
[0030]选择本发明载体的组分,以使载体具有的粘性为大约1,000至10,000,000泊(poise),优选10,000至250,000泊。为了在高温,例如37℃或更高下保持一段时间的稳定性,选择载体的组分以使载体不会与ERA反应。当载体的组分包括聚合物和溶剂时,载体优选地包含几乎不会从溶剂中相分离的聚合物,当在给药期间载体与水混合时,例如可减少递送装置部分或完全堵塞事件。选择载体的组分,以使载体对选择的ERA几乎没有可溶性,从而保持选择的ERA为无水微粒,从而获得了选择的ERA的稳定性。
[0031]在一个实施方案中,载体包括至少一种聚合物。所述聚合物优选为生物相容的,且可以是可生物降解的或非生物降解的。在形成载体中有用的聚合物的实例包括,但不限于吡咯烷酮例如聚乙烯吡咯烷酮(具有的分子量为2,000至1,000,000)、聚(丙交酯)、聚(乙交酯)、聚(丙交酯乙交酯)、聚乳酸乙醇酸(PLGA)、聚(乳酸)、聚(乙醇酸)、聚氧乙烯-聚氧丙烯嵌段共聚物(在37℃显示出高粘度),例如PLURONIC105,和不饱和醇的酯或醚例如醋酸乙烯酯。载体也可包括能与聚合物混合获得载体的任意可药用溶剂,所述载体为非水的、单相的、生物相容的,且能与水混溶。在形成载体中有用的溶剂的实例包括,但不限于苯甲酸苄酯(BB)、苯甲醇(BA)、月桂基乳酸酯(LL)、月桂醇(LA)、聚乙二醇、四氢呋喃聚乙二醇醚(glycofural)(GF)、维生素E。
[0032]载体可包括多于一种不同的聚合物或不同等级的单一聚合物。载体可同时包括多于一种与聚合物混合的溶剂。特别地,需要两种或多种溶剂来提供都能在水混中溶,且能促进制备稳定的ERA制剂的载体。包括在载体中的聚合物和溶剂的含量可改变,以提供具有预期性能特性的载体。通常,载体包括大约40至80wt%的聚合物和大约20至60wt%的溶剂。
[0033]除了聚合物和溶剂,载体也可包括其它的赋形剂,例如一种或多种表面活性剂或防腐剂。可在载体中使用的表面活性剂包括,但不限于聚山梨酯例如以商品名TWEEN出售的,乙烯氧化物-丙烯氧化物共聚物例如以商品名PLURONIC出售的,脱水山梨醇的脂肪酸酯例如以商品名SPAN出售的,甘油基辛酸酯,PEG-8辛酸癸酸甘油酯,聚甘油基-6油酸酯,二辛基钠,磺基丁二酸酯和维生素E TPGS。表面活性剂可包括在载体中,以便当将制剂递送到使用环境中时能促进ERA从载体释放,或当将ERA悬浮在载体中时能保持ERA的稳定性。当包括表面活性剂时,其典型地占载体的量为小于20wt%,优选地小于10wt%,更优选地小于5wt%。可在载体中使用的防腐剂包括,例如抗氧剂和抗微生物剂。可用作抗氧剂的可能的实例包括,但不限于生育酚(维生素E)、抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁基化的羟基甲苯和没食子酸丙酯。当将一种或多种防腐剂加入载体中时,其用量可根据应用、使用的防腐剂和想要的结果而改变。通常,防腐剂的量为仅足够获得想要的防腐效果的量。
[0034]然而,所述载体不限于包括聚合物和溶剂的那些。作为进一步的实例,载体可以包括非聚合物。非聚合物质的实例包括疏水性糖类物质、有机凝胶或起单相载体作用的类脂物质。示范性糖类物质包括,但不限于在室温或生理学温度下以流体存在的蔗糖酯,例如蔗糖乙酸异丁酸酯(SAIB)。SAIB为一种液体非聚合物。某些非聚合物质如SAEB可被用作″neat″,即不加入其他溶剂。包括非聚合材料的载体可同时包括一种或多种溶剂。包括非聚合材料的载体可同时包括一种或多种表面活性剂,其中的某些实例已在上述给出。包括非聚合材料的载体可同时包括防腐剂,其中的某些实例已在上述给出。
[0035]非水单相载体可以载有各种量的ERA微粒制剂以提供混悬液制剂,其能在选择的时期内以想要的比率给药ERA。混悬液制剂可包括0.1至40wt%,优选0.1至20wt%的ERA。混悬液制剂使其能以想要的流速从可植入递送装置中分散。可制剂混悬液制剂以在几个月至一年内递送1ng/天至600μg/天的ERA。当ERA从设计提供低流率的渗透泵植入物中递送时,优选地将混悬液制剂制成用于递送0.5至5μg/天的形式,流量为大约1.5μl/天,特别优选1.0μl/天。应当注意,所述混悬液制剂不限于可植入递送装置例如泵植入物,但也可能被用作贮存注射液(depot injection)。
[0036]根据本发明的实施方案,本发明也包括再由ERA混悬液制剂的可植入递送装置。可植入递送装置可包含具有下述特性的任意输送系统装置:在植入患者后,其能在缓释期内,以控释速率递送可流动制剂。根据本发明的可植入递送装置可包括,例如渗透泵植入物,例如以商品名DUROS出售的,调节剂类型的泵植入物,例如售自如Codman of Raynham,Massachusetts,Medtronic of MinneapolisMinnesota和Tricumed Medinzintechnik GmbH of Germany,或其它非渗透泵植入物。
[0037]研究旨在评价EPO(epoetinα)在非水单相载体中的微粒制剂的稳定性。微粒制剂的稳定性使用尺寸排阻色谱法(SEC)来评价。根据EPO负载量和总可溶性聚集体来评价稳定性。EPO负载量为总的可溶性EPO在包括单体、二聚物、及其它较高分子量产品的微粒制剂中的百分比。EPO负载量提供有关在存贮或递送期间是否形成大量不溶性EPO的某些信息。总可溶性聚集体为比单体大且可溶于水的EPO有关化合物的百分数。
[0038]下述实施例是用于阐述的目的,而不意味着以与本文描述的不同方式限制本发明。
实施例1
[0039]如下制备EPO微粒制剂:获得呈冷冻溶液的EPO的本体溶液,具有的浓度为约3.1mg/ml。用10mM组氨酸缓冲溶液渗析EPO溶液。按想要的比率的EPO与蔗糖与表面活性剂,将蔗糖(稳定剂)和TWEEN20(表面活性剂)加入到渗析的EPO溶液。将缓冲溶液喷雾干燥成含有EPO∶蔗糖∶Tween20∶10mM组氨酸的比率等于1∶4.53∶0.03∶0.50,pH为6.9,且EPO负载量为16.5%。
实施例2
[0040]评价在高温下贮存的EPO微粒制剂的稳定性。将如在实施例1中制备的EPO三个微粒制剂样品贮存在40℃下3个月。在初始时、1个月、2个月和3个月使用SEC分析样品。在初始时间点,EPO微粒制剂具有的平均粒度为约4.5μm,玻璃化转变温度为54.9±5.6℃,含水量为1.16±0.01%。下述表3显示稳定性结果。当将其贮存在40℃下3个月时,结果显示出EPO微粒稳定地防止聚集。
表3
EPO负载量(%) | 单体(%) | 二聚体(%) | 总可溶性聚集体(%) | |
初始时 | 15.8 | 100.0 | 0.00 | 0.00 |
16.0 | 100.0 | 0.04 | 0.04 | |
16.0 | 100.0 | 0.00 | 0.00 | |
在40℃一个月 | 15.6 | 99.9 | 0.091 | 0.09 |
15.7 | 99.9 | 0.081 | 0.08 | |
16.0 | 99.9 | 0.079 | 0.08 | |
在40℃两个月 | 15.8 | 99.9 | 0.13 | 0.13 |
16.0 | 99.9 | 0.13 | 0.13 | |
15.9 | 99.9 | 0.13 | 0.13 | |
在40℃三个月 | 14.9 | 99.8 | 0.16 | 0.16 |
15.2 | 99.9 | 0.13 | 0.13 | |
15.6 | 99.8 | 0.15 | 0.15 |
实施例3
[0041]如下制备混悬液制剂:如在实施例1中的描述,将EPO微粒制剂悬浮于Ceraphyl31/PVP载体中,靶微粒负荷为大约10%(w/w)。
实施例4
[0042]在40℃下,将如在实施例3中制备的三个混悬液样品贮存在玻璃容器中3个月。在初始时、1个月、2个月和3个月使用SEC分析样品。下述表4显示了稳定性结果。在3个月观察到混悬液的总可溶性聚集体为大约1.57%,与之比较,在3个月,EPO粉末的为0.1%。结果表明,当在40℃下贮存3个月时,悬浮在Ceraphyl31/PVP载体中的EPO为稳定的。
表4
EPO负载量(%) | 单体(%) | 二聚体(%) | 总可溶性聚集体(%) | |
初始时 | 1.55 | 99.9 | 0.08 | 0.08 |
1.58 | 99.9 | 0.09 | 0.09 | |
1.58 | 99.9 | 0.08 | 0.08 | |
在40℃下一个月 | 1.53 | 99.4 | 0.46 | 0.63 |
1.53 | 99.5 | 0.40 | 0.48 | |
1.54 | 99.5 | 0.41 | 0.49 | |
在40℃下两个月 | 1.57 | 98.7 | 1.02 | 1.34 |
1.57 | 98.8 | 1.05 | 1.22 | |
1.57 | 98.6 | 1.20 | 1.43 | |
在40℃下三个月 | 1.48 | 98.3 | 1.42 | 1.70 |
1.48 | 98.3 | 1.04 | 1.67 | |
1.47 | 98.7 | 1.02 | 1.35 |
[0043]研究旨在评价使用可植入递送装置例如渗透泵植入物时,悬浮于非水单相载体中的EPO微粒制剂的释放速率。图1显示了在研究中使用的渗透泵植入物100的示意图。渗透泵植入物100包括圆柱状体102,由钛制成,具有开口端104、106。扩散缓和器(diffusionmoderator)108封固在圆柱状体102的端口106。扩散缓和器108具有导管110,其允许液体从圆柱状体102的内部输送到外部。由扩散缓和器108提供的导出管110为直形的。然而,也可预期除了直形外的其它结构的扩散缓和器,其也包括在本发明内。在该研究中,使用直形递送导管的扩散缓和器,该导管的直径为0.25mm至0.5mm,长度为1.5mm。将半透膜114插入到圆柱状体102的端口104,形成圆柱状体102的外部和内部之间的流体可渗透屏障。将柱塞116和渗透剂122置于圆柱状体102中。药物储库120定义为圆柱状体102的内部。
[0044]下述实施例是用于阐述的目的,而不意味着以与发本文描述的不同方式限制本发明。
实施例5
[0045]将在实施例3中制备的大约150μl(大约150mg)的混悬液装入渗透泵植入物100的药物储库120中,如在124(图1)所示。靶剂量为3000IU/天(24μg/天)。
实施例6
[0046]如在实施例5中所述制备几个渗透泵。将每个渗透泵的薄膜端置入装有3mL磷酸盐缓冲液(PBS)的堵塞式(stoppered)Vacutainer中,将渗透泵的扩散缓和器端置入干燥的Vacutainer中。将系统置入封端的试管中,扩散缓和器朝下,并部分浸入37℃水浴中。7天后,从水浴中取出系统的部分,将系统的扩散缓和器端的干燥的Vacutainers用装有2.5mL释放速率介质(20mM柠檬酸盐和50mg/mL蔗糖,pH为6.9)的vacutainers替换,将系统放回水浴。因此,给系统的部分泵入释放速率介质(泵入释放速率介质),同时其它部分泵入空容器(泵入空气)。
[0047]在特定的时间点,为了给系统泵入释放速率介质,将扩散缓和器端的vacutainers用新的装有2.5ml入上述的释放速率介质的vacutainers替换。使用高效液相色谱(HPLC)分析从除去扩散缓和器端的vacutainers中收集的样品。在特定的时间点,为了给系统泵入空气,将系统从水浴中移出,将扩散缓和器端的vacutainers替换为新的干的vacutainers,再将系统放回水浴。称重从除去扩散缓和器端的vacutainers中收集的样品,然后使用HPLC分析。为了积累足够的物质用于分析,收集在3至4天内释放的制剂。
[0048]将在37℃下于3个月内每天的释放速率绘制在图2A和2B中。图2A显示给泵入释放速率介质的系统的释放速率。图2B显示了泵入空气的系统的释放速率。结果表明,在37℃下,于3个月内,系统以常数递送EPO,大约为靶向速率(23.5μg)(零级速率递送)。在2.5个月的时间点,使用细胞增殖法评价释放的样品的生物活性。结果显示在图3中。结果显示出在37℃下,于2.5个月内,与本体溶液相比,释放的EPO的生物活性没有明显降低。在37℃,于2.5个月内,释放的EPO包含大于99%的单体。
[0049]虽然本发明参照有限的实施方案进行了描述,从本发明公开的内容受益的本领域技术人员应当理解,可以设计其它的实施方案,而不会背离如本文公开的本发明的范围。下面概述了本发明的示范性实施方案。
Claims (20)
1.用于治疗用途的混悬液制剂,包含:
显示出粘性流体特性的非水单相载体;和,
包含分散在载体中的红细胞生成素受体激动剂的微粒制剂。
2.权利要求1的混悬液制剂,其在40℃下稳定至少3个月。
3.权利要求1的混悬液制剂,其在40℃下稳定达12个月。
4.权利要求1的混悬液制剂,其中在分散于载体中之前,微粒的含水量小于5wt%。
5.权利要求1的混悬液制剂,其中微粒制剂进一步包含缓冲剂和选自下述的稳定剂:糖、氨基酸、多元醇、聚合物及其组合。
6.权利要求5的混悬液制剂,其中所述缓冲剂选自组氨酸和柠檬酸盐缓冲剂。
7.权利要求5的混悬液制剂,其中糖为蔗糖。
8.权利要求5的混悬液制剂,其中缓冲剂为柠檬酸盐缓冲剂,且稳定剂与红细胞生成素受体激动剂的比率为大于2.0。
9.权利要求5的混悬液制剂,其中微粒制剂进一步包含表面活性剂、填充剂和盐中的至少一种。
10.权利要求1的混悬液制剂,其中载体包含选自溶剂、聚合物、非聚合物和表面活性剂中的一种或多种组分。
11.权利要求1的混悬液制剂,其中在混悬液制剂中,红细胞生成素受体激动剂的含量为大约0.1至40wt%。
12.权利要求1的混悬液制剂,其中红细胞生成素受体激动剂选自epoetinα、epoetinβ、和darbepoetinα。
13.权利要求1的混悬液制剂,其使用可植入递送装置递送。
14.权利要求1的混悬液制剂,其在使用环境中,能以靶剂量连续释放红细胞生成素受体激动剂达12个月。
15.刺激患者中红细胞生成的方法,包括:
给药患者有效量的混悬液制剂,该制剂包含显示出粘性流体特性的非水单相载体;和包含分散在载体中的红细胞生成素受体激动剂的微粒制剂。
16.权利要求15的方法,其中给药患者经由可植入递送装置递送。
17.权利要求15的方法,其中给药患者为长期连续给药。
18.可植入递送装置,包含:
储库,其包含在使用环境中能提供以有效速率连续递送红细胞生成素受体激动剂的足量混悬液制剂,所述混悬液制剂包含显示出粘性流体特性的非水单相载体,和包含分散在载体中的红细胞生成素受体激动剂的微粒制剂。
19.权利要求18的可植入递送装置,其提供连续递送红细胞生成素受体激动剂达3个月。
20.权利要求18的可植入递送装置,其提供连续递送红细胞生成素受体激动剂达12个月。
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US (1) | US7772182B2 (zh) |
EP (1) | EP1778184A1 (zh) |
JP (1) | JP2008509160A (zh) |
KR (1) | KR20070042195A (zh) |
CN (1) | CN1993108A (zh) |
AR (1) | AR050285A1 (zh) |
CA (1) | CA2573810A1 (zh) |
TW (1) | TW200613008A (zh) |
WO (1) | WO2006017772A1 (zh) |
ZA (1) | ZA200701876B (zh) |
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-
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- 2005-08-01 US US11/194,850 patent/US7772182B2/en not_active Expired - Fee Related
- 2005-08-04 AR ARP050103259A patent/AR050285A1/es not_active Application Discontinuation
- 2005-08-04 WO PCT/US2005/027965 patent/WO2006017772A1/en active Application Filing
- 2005-08-04 JP JP2007525044A patent/JP2008509160A/ja active Pending
- 2005-08-04 TW TW094126458A patent/TW200613008A/zh unknown
- 2005-08-04 CN CNA2005800263383A patent/CN1993108A/zh active Pending
- 2005-08-04 EP EP05783338A patent/EP1778184A1/en active Pending
- 2005-08-04 CA CA002573810A patent/CA2573810A1/en not_active Abandoned
- 2005-08-04 KR KR1020077005259A patent/KR20070042195A/ko not_active Application Discontinuation
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AR050285A1 (es) | 2006-10-11 |
WO2006017772A1 (en) | 2006-02-16 |
EP1778184A1 (en) | 2007-05-02 |
ZA200701876B (en) | 2009-02-25 |
TW200613008A (en) | 2006-05-01 |
US20060030526A1 (en) | 2006-02-09 |
JP2008509160A (ja) | 2008-03-27 |
US7772182B2 (en) | 2010-08-10 |
CA2573810A1 (en) | 2006-02-16 |
KR20070042195A (ko) | 2007-04-20 |
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