CN102089051A - 作为形态学改变剂的两亲性蛋白质 - Google Patents
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Abstract
本发明公开了用于改变有机物质的形态学和/或多晶型的方法,所述方法包括用一种或多种两亲性蛋白质处理固体物质或其溶液或分散体。
Description
技术领域
本发明涉及用两亲性蛋白质改变固态有机化合物的形态学和/或多晶型(polymorphism),例如晶体的大小、习性(habit)和转变(modification)的方法,两亲性蛋白质的相应用途和由本发明方法可得的改性固体。
背景技术
固化、尤其结晶化在大多数药物、食品和特殊化学品(例如色素)工艺中是关键的分离和纯化单元,并且对总体工艺的效率和收益性具有重要的影响。大多数药品含有以结晶形式产生的活性成分。因此,结晶化对工业具有深远的重要性。为了有效率的下游操作(例如过滤、干燥、压片)和产品效力(例如生物利用度、片剂稳定性),控制晶体纯度、粒度分布和形状可能是极其重要的。
通常,药用级结晶产品需要狭窄的粒度分布,这意味着主要生产工艺必须精心设计且严格控制在最适条件下。控制晶体的大小和形状将允许优化溶解速度,而这可以使利益最大化而使副作用最小化。很多药物可形成呈现多种形态学形状和习性的晶体,所述形态学形状和习性对产品的配制和最终的使用性能是至关重要的。
技术背景
图9示例了典型结晶工艺,包括下列步骤:
(a)有机分子通过扩散过程形成随机定向的分子簇。
(b)这些簇可再次分解成单分子或开始形成称作晶胚的不稳定晶格结构。
(c)这些晶胚可再次分解成簇或充分地生长以形成稳定的晶核从溶液中沉淀出来(成核)。该临界尺寸由操作条件(温度、过饱和等)规定。
(d)然后这些核生长成较大的微晶,其可继续生长成单晶或聚在一起形成微晶聚集体。
(e)这些聚集体可以是可容易分解成初始微晶的软聚集体(softaggregate)至仅可通过侵入性工艺(例如研磨)分解的硬聚集体(hardaggregate)。
过饱和是结晶化的驱动力,因此成核和生长的速率由溶液中存在的过饱和驱动。过饱和被定义为在给定的温度条件下超过饱和浓度的溶质浓度。一旦失去过饱和,固-液系统就达到平衡且结晶过程停止。
当存在过饱和时,成核和生长继续同时发生。
某些溶剂、杂质或添加剂的存在、和与进行结晶的化合物具有类似化学类型的化合物可通过改变结晶过程的过饱和性质而极大影响其成核和晶体生长阶段。
取决于条件,成核或生长可以一者比另一者占优势,因此,获得具有不同大小、不同粒度分布和习性(形状)的晶体。
晶体习性可以是,例如立方、四方、正交、六方、单斜、三斜和三方的。
还可通过结晶过程中的变化产生不同的多晶型物。
多晶型物被定义为在晶格中具有不同的分子的排列和/或构象的晶相。这些晶形具有不同的堆积(packing)、热力学、光谱、动力学、表面和力学性质。
尽管多晶型物具有相同的元素组成,但是多晶型物显示不同的物化性质和物理技术性质,例如自由能、熵、热容量、熔点、升华温度、溶解性、稳定性、溶出速率、生物利用度、硬度、相容性、流动性、抗张强度和可压缩性等。为此,多晶型在结晶产品的工业生产中是非常重要的。
结晶过程的性质决定于热力学和动力学两因素,其可能使得结晶过程的性质高度可变且难以控制。因素例如杂质水平、混合方案、容器设计和降温曲线对所产生晶体的大小、数量和形状具有很大的影响。
晶体大小和性状的控制不当还可导致长得令人难以接受的过滤或干燥时间,或导致额外的加工步骤(例如重结晶或研磨),并且可影响产物的纯度,该纯度在消费晶体的食品和药物工业中尤其重要。
已知,可通过结晶过程中所用的溶剂影响生物活性物质的形态学和大小。例如单斜晶系对乙酰氨基酚通过从乙醇中结晶而形成,但是稳定性较差的多晶型物-正交晶系对乙酰氨基酚仅在阻止多重成核时通过从热水中缓慢结晶而形成。然而,由于毒性的原因,结晶溶剂的选择被严重限制。
许多添加剂已用于影响生长期或成核期,导致多晶型物或晶体习性的改变。在某些情况下,对乙酰氨基酚在本文用作模型物质。
合成的(共)聚合物和表面活性剂已被证实可以改变生物活性物质的形态学,但是再次由于毒性的原因,这具有有限的商业价值。
WO03/033462提出了用于启动晶体多晶型物生长的聚合物文库,并描述了使用某些聚合物以改变对乙酰氨基酚的结晶:通过冷却对乙酰氨基酚(paracetamol)在热水中的溶液而生长晶体。在缺少聚合物下,预计这些条件可收获单斜晶系对乙酰氨基酚。当在存在尼龙或卤代聚合物下进行结晶时,明显偏向于产生正交晶系对乙酰氨基酚。Rodríguez-Hornedo等人,JPharm Sci.(2004)93(2),449-60描述了使用表面活性剂十二烷基硫酸钠和牛磺胆酸钠用于氨甲酰苯(carbamazepine)二水合物的结晶。
Garekani等人,Int.J.of Pharmaceutics 208(2000)87及其中所引用的文献报导了某些通过在存在添加剂下结晶而改变对乙酰氢基酚晶体习性的方法。
WO 05/115344要求保护在存在结晶改变剂下重结晶后所得的对乙酰氨基酚的速溶形式,所述结晶改变剂可以是聚合物或蛋白质,例如白蛋白、木瓜蛋白酶、胃蛋白酶。
发明内容
现已发现,可通过两亲性蛋白质(尤其是疏水蛋白)诱导溶液中的有机物质的快速成核,甚至是在升高的温度下。也已发现,此类蛋白质在结晶过程期间改变有机物质的晶体生长行为,产生预料不到的晶体习性和晶体粒度分布。两亲性蛋白质如疏水蛋白可用作添加剂用于结晶期间或之后,例如以便控制有机化合物(例如生物活性物质,如用于化妆品、生物农药、药学或医学应用(例如化妆品活性成分、活性药物成分[API]、动物护理产品、农业化学品、生物农药、色素、染料))的形态学(亚稳态多晶型物的稳定)和粒度分布,或以便稳定某些多晶型物。本发明因此涉及用于改变有机物质的形态学和/或多晶型的方法,所述方法包括用一种或多种两亲性蛋白质处理固体物质或其溶液或分散体。
该方法有利地使用有机物质的溶液或分散体和/或蛋白质的溶液或分散体而进行。溶液通常是在极性溶剂、往往是水性溶剂例如水、低级醇(例如甲醇、乙醇、丙醇、异丙醇、丁醇、异丁醇)或水和低级醇的混合物、尤其是水中的溶液。
本发明的一个最重要方面是通过在结晶过程期间采用两亲性蛋白质而改变生物活性物质的晶体性质。
发现大多数生物活性物质难溶于水,并且已知形成微细颗粒(微米和微米以下)可提高其生物利用度或溶出速率(由于其表面积增加)。
因此,本发明还涉及包含有机生物活性物质和两亲性蛋白质、尤其是疏水蛋白的组合物,例如在本发明方法中可得的组合物。本发明的组合物含有有机生物活性物质,优选地以细粒的形式,其平均粒度取决于所需的最终用途,范围为例如0.1-1000微米,或在其它情况下可通过动态光散射检测,为例如5-5000nm,尤其为20-2000nm。此类颗粒可为自由流动的,分散在液体中、或尤其是聚集的或压紧的(compacted)。两亲性蛋白质在组合物中、例如在固体颗粒组合物中的量,可覆盖一个宽范围,取决于最终用途和所需效应,范围为例如约0.0001至约10%、通常为0.001至约2%、尤其为0.01至约1%,所有均按最终组合物的重量计。
因此,本发明方法的一方面涉及包括降低微晶大小的改变。
本发明方法的另一方面涉及包括改变晶体习性的改变。
本发明方法的又一方面涉及包括改变晶体形态学的改变。
本发明还涉及改变有机固体,其包括下述晶体性质中的两种或两种以上的组合:
(a)降低微晶大小;(b)改变晶体习性和(c)改变晶体形态学。
两亲性蛋白质兼具疏水和亲水性质,可以被称为“天然表面活性剂”。两亲性的同义词是“双亲的(amphipathic)”。
两亲性蛋白质可以物理地吸附在固体物质的表面上,形成依据所处理表面的润湿性而定向的兼有疏水性和亲水性的表面。
如果表面是疏水性的,那么该覆盖层的疏水侧与被覆盖的该疏水性表面接触,而该覆盖层的外表面是亲水性的,由此增加被覆盖的表面的水可润湿性。
基质上蛋白质的表面活性性质可通过界面张力测量、水包油乳液的表征、和与水的接触角来评价。用于本发明的两亲性蛋白质的特征在于,极大降低疏水表面(例如聚烯烃表面或表面)上水的接触角(WCA)。特别地,用于本发明的两亲性蛋白质的1%b.w.水溶液或分散体通常显示,聚丙烯表面(尤其是:PP均聚物类型HC115MO,Borealis,熔体流动速率=4.0g/10min[230℃/2.16kg])上的接触角,比就纯水所观察到的接触角,低20度或更多,优选30度或更多,更优选40度或更多,最优选45度或更多,且在某些特定情况下,低50度或更多(参见图8;所有WCA根据静止座滴法(static sessile drop method)测量)。
于1991发现的疏水蛋白是一类小的、分泌型、富含半胱氨酸的两亲性蛋白质,其存在于真菌中且在真菌生长和发育中行使着广谱功能。疏水蛋白属于最具表面活性的分子,并可以在任何亲水-疏水界面自组装成两亲性膜(Biochimica et Biophysica Acta-Reviews on Biomembranes-1469卷,第2期,2000年9月18日,第79-86页)。
疏水蛋白通常易溶于水中。疏水蛋白的自发自组装导致两亲性层的形成,所述两亲性层显著降低水的表面张力。可以在J.Biol.Chem.,282卷,第39期,28733-28739,2007年9月28日中找到提议的疏水蛋白的功能机制:单体多聚化成二聚体,两个二聚体形成四聚体。四聚体可分裂成两个新二聚体,其中疏水表面区域对齐(aligned)。这些两亲性二聚体先于在疏水-亲水界面上的两亲性单层的形成。在高浓度下,过量疏水蛋白形成原纤维结构。
基于亲水模式和生物物理学性质的差异,疏水蛋白被分成两种类型:I类和II类。
I类疏水蛋白的例子:
来自糙皮侧耳(Pleurotus ostreatus)的POH3(PO)
来自嗜热篮状菌(Talaromyces thermophilus)的TT1(TT)
来自裂褶菌(Schizophyllum commune)的SC3(SC)
II类疏水蛋白的例子:
来自里氏木霉(Trichoderma reesei)的HFBI&HFBII(TR)
来自黄枝孢(Cladosporium fulvum)的HCf-6
CU(Cerato-ulmin)
疏水蛋白的纯化和分离在下列参考文献中描述:
WO-A-96/41882描述了来自食用菌的疏水蛋白。
WO-A-00/58342涉及通过相萃取纯化含疏水蛋白的融合蛋白。
WO-A-01/57066描述了由于亚硫酸盐处理而对疏水蛋白的稳定、增溶和与此相关的改良应用。
WO-A-01/57076描述了通过吸附到特氟隆珠上和借助于洗涤剂例如吐温在低温下洗脱而纯化疏水蛋白。
美国专利7,147,912陈述到疏水蛋白属于最具表面活性的分子。在50微克/ml具有从72mJm-2至24mJm-2的水表面张力的最大降低,SC3(裂褶菌)被视为是已知的最具有表面活性的蛋白质。SC3是1类疏水蛋白。
可以用于本发明的另外的疏水蛋白及其来源和性质尤其述于WO96/41882(参见第1页第14行至第7页第20行的段落,和实施例1至5);WO 03/10331(参见第1页第4行至第5页第20行的段落);或WO06/103230(参见第3页第6段至第12页倒数第3行的段落);所提及的具体段落由此并入作为参考。
令人惊讶的是,已发现两亲性蛋白质、尤其是疏水蛋白也影响有机物质的形态学性质,并且常比使用溶剂、聚合物或合成的表面活性剂时给出更有利的组合物。
本发明方法往往通过下述来进行:
i)将蛋白质在极性溶剂中的溶液或分散体与有机物质在可与所述蛋白质的溶剂混溶的极性溶剂中的溶液或分散体混合,或
ii)将有机物质在极性溶剂中的溶液或分散体与用所述蛋白质浸渍的表面接触。
一个实施方案包括:
(a)将两亲性蛋白质溶解或分散于溶剂中;
(b)将有机物质溶解于可与所述蛋白质的溶剂混溶的溶剂中;
(c)将(a)和(b)混合;
(d)调节混合物的物理环境以允许有机物质在两亲性蛋白质存在下发生沉淀/结晶。
第二实施方案包括:
(a)将两亲性蛋白质溶解或分散于溶剂中;
(b)将(a)加到待于其中通过化学反应形成有机物质的反应容器中;
(c)允许化学反应在两亲性蛋白质的存在下发生;
(d)调节混合物的物理环境以允许有机物质在两亲性蛋白质存在下发生沉淀/结晶。
第三实施方案包括:
(a)将两亲性蛋白质溶解或分散于溶剂中;
(b)将有机物质溶解于可与所述蛋白质的溶剂混溶的溶剂中;
(c)将(a)和(b)混合;
(d)在两亲性蛋白质的存在下对有机物质进行湿磨。
第四实施方案包括:
在添加两亲性蛋白质的溶液/分散体之前或之后,将有机物质的“晶种”(稳定晶核)加到有机物质的溶液中。
第五实施方案包括:
将两亲性蛋白质与其它添加剂、尤其是也可影响有机物质的结晶过程的那些添加剂组合。此类其它的添加剂的例子是盐(例如氯化钠、铵盐)或另外的聚合物(尤其是可溶性聚合物,包括合成聚合物例如聚乙烯吡咯烷酮和天然聚合物例如明胶)。在此定义内包括少量溶剂。
此外,本发明包括下列实施方案,每个所述实施方案可彼此组合:
·用于改变有机物质的形态学和/或多晶型的方法,所述方法包括用一种或多种两亲性蛋白质处理固体物质或其溶液或分散体。
·所述方法,其中所用两亲性蛋白质的1%b.w.水溶液或分散体的特征在于,聚丙烯表面上的接触角比就纯水可观察到的接触角低20度或更多。
·所述方法,其包括有机物质的沉淀、结晶或固-固相转变。
·所述方法,其包括将蛋白质在极性溶剂中的溶液或分散体与有机物质在可与所述蛋白质的溶剂混溶的极性溶剂中的溶液或分散体混合;或将有机物质在极性溶剂中的溶液或分散体与用所述蛋白质浸渍的表面接触。
·所述方法,其包括在两亲性蛋白质的存在下对有机物质进行湿磨。
·所述方法,其包括在添加两亲性蛋白质之前或之后将有机物质的晶种加到有机物质的溶液中。
·所述方法,其中所述溶液含有另外的添加剂,例如盐和/或聚合物。
·所述方法,其中所述有机物质是有机化合物,所述有机化合物在0℃为固体并且溶于、部分溶于或可分散于极性溶剂中,例如以胶体形式。
·所述方法,其中所述有机物质是分子量80-1000g/mol、尤其是100-500g/mol的有机化合物,其优选选自生物活性化合物,例如药物、药用和化妆品用成分、农药和杀真菌剂。
·所述方法,其用于降低微晶大小、增加无定形部分、改变晶体习性和/或改变晶体多晶型(polymorphy)。
·所述方法,其中所述蛋白质为疏水蛋白,例如II类疏水蛋白或尤其是I类疏水蛋白。
·所述方法,其中有机物质的沉淀或结晶通过将其溶液或分散体与两亲性蛋白质的溶液或分散体组合而诱导。
·两亲性蛋白质、尤其是如任何上述实施方案中所表征的两亲性蛋白质,用于改变有机物质的形态学和/或多晶型的用途。
·组合物,其包括固体有机物质,尤其是如上所定义或如下所列出的那些有机物质,和两亲性蛋白质,尤其是如任何上述实施方案所表征的两亲性蛋白质。
·所述组合物,其包括细颗粒形式的固体有机物质,例如平均粒度为0.1-1000微米,或为5-5000nm。
因此,本发明包括:
·用于改变有机物质的形态学和/或多晶型的方法,所述方法包括用一种或多种两亲性蛋白质处理固体物质或其溶液或分散体;
·所述方法,其中所用两亲性蛋白质的1%b.w.水溶液或分散体的特征在于,聚丙烯表面上的接触角比就纯水可以观察到的接触角低20度或更多;
·任何所述方法,其包括有机物质的沉淀、结晶或固-固相转变;尤其是用于降低微晶大小,增加无定形部分,改变晶体习性和/或改变晶体多晶型;
·任何所述方法,其包括i)将蛋白质在极性溶剂中的溶液或分散体与有机物质在可与所述蛋白质的溶剂混溶的极性溶剂中的溶液或分散体混合,或ii)将有机物质在极性溶剂中的溶液或分散体与用所述蛋白质浸渍的表面接触;
·任何所述方法,其包括在两亲性蛋白质的存在下对有机物质进行湿磨;
·任何所述方法,其包括在添加两亲性蛋白质之前或之后将有机物质的晶种加到有机物质的溶液中;
·任何所述方法,其中溶液含有另外的添加剂,例如盐和/或聚合物;
·任何所述方法,其中所述有机物质是有机化合物,在0℃为固体并且可溶于、部分可溶于或可分散于极性溶剂中,例如以胶体形式;
·任何所述方法,其中所述有机物质是分子量80-1000g/mol、尤其为100-500g/mol的有机化合物,其优选选自生物活性化合物,例如药物、药用和化妆品用成分、农药和杀真菌剂;
·任何所述方法,其中所述蛋白质为疏水蛋白,例如II类疏水蛋白或尤其是I类疏水蛋白;
·任何所述方法,其中有机物质的沉淀或结晶通过将其溶液或分散体与两亲性蛋白质的溶液或分散体组合而诱导。
本发明还包括两亲性蛋白质、尤其是如上所述特征在于降低接触角的两亲性蛋白质、尤其是如上所述的疏水蛋白,用于改变有机物质的形态学和/或多晶型的用途;以及组合物,其包括固体有机物质、尤其是在0℃为固体并且可溶、部分可溶或可分散于极性溶剂中(例如以胶体形式)的有机化合物、和/或分子量80-1000g/mol、尤其为100-500g/mol、优选选自生物活性化合物例如药物、药用和化妆品用成分、农药和杀真菌剂的有机化合物,以及两亲性蛋白质。所述组合物优选包括细颗粒形式的固体有机物质。
固体形式可通过本发明方法被改变的生物活性有机物质的例子包括下列有机物质:
药用成分(API):阿卡波糖、乙酰水杨酸、阿夫唑嗪、阿利吉仑(aliskiren)、安贝生坦(ambrisentan)、氨氯地平、阿莫西林、阿那曲唑(Anastrozole)、阿哌沙班(apixaban)、阿瑞吡坦(aprepitant)、阿立哌唑(aripiprazole)、阿扎那韦(atazanavir)、阿替洛尔(atenolol)、阿托西汀(atomoxetine)、阿托伐他汀(atorvastatin)、阿奇霉素(azithromycin),巴多昔芬(bazedoxifene),贝那普利(benazepril),bicalutamide,比沙可啶(bisacodyl),布地奈德(budesonide),丁基茛菪胺(butylscopolamine),坎地沙坦(candesartan),卡培他滨(capecitabine),氨甲酰苯(carbamazepine),carisbamate,卡维地洛(carvedilol),casopitant,塞来考昔(celecoxib),西替利嗪(cetirizine),氯喹(chloroquine),西那卡塞(cinacalcet),环丙沙星(ciprofloxacin),克拉维酸(clavulanic acid),氯屈膦酸盐(clodronate),可乐定(clonidine),氯吡格雷(clopidogrel),醋酸环丙孕酮(cyproterone acetate),达泊西汀(dapoxetine),达如那韦(darunavir),达沙替尼(dasatinib),地拉罗司(deferasirox),右美沙芬(dextromethorphan),双氯芬酸(diclofenac),地诺孕素(dienogest),双嘧达莫(dipyridamole),多西紫杉醇(docetaxel),多奈哌齐(donepezil),屈螺酮(drospirenone),度洛西汀(duloxetine),依法韦仑(efavirenz),依来曲普坦(eletriptan),依那普利(enalapril),恩他卡朋(entacapone),恩替卡韦(entecavir),enzastaurin,埃罗替尼(erlotinib),埃索美拉唑(esomeprazole),艾司佐匹克隆(eszopiclone),炔雌醇(ethinylestradiol),艾托考昔(etoricoxib),etravirine,依维莫司(everolismus),依西美坦(exemestane),非索非那定(fexofenadine),非那雄胺(finasteride),氟西汀(fluoxetine),氟替卡松(fluticasone),丙酸氟替卡松(fluticasone propionate),氟伐他汀(fluvastatin),福莫特罗(formoterol),更昔洛韦(ganciclovir),吉非替尼(gefitinib),格列美脲(glimepiride),氢可酮(hydrocodone),伊班膦酸(ibandronic acid),布洛芬(ibuprofen),茚地那韦(indinavir),异丙托铵(ipratropium),厄贝沙坦(irbesartan),拉莫三嗪(lamotrigine),兰索拉唑(lansoprazole),拉帕替尼(lapatinib),来曲唑(letrozole),左炔诺孕酮(levonorgestrel),利奈唑胺(linezolid),赖诺普利(lisinopril),氯沙坦(losartan),maraviroc,美洛昔康(meloxicam),二甲双胍(metformin),哌醋甲酯(methylphenidate),美托洛尔(metoprolol),莫昔克丁(moxidectin),麦考酚酸(mycophenolic acid),萘普生(naproxen),那格列胺(nateglinide),奈韦拉平(nevirapine),尼可地尔(nicorandil),硝苯地平(nifedipine),尼洛替尼(nilotinib),奥氮平(olanzapine),奥美拉唑(omeprazole),奥利司他(orlistat),奥司他韦(oseltamivir),奥沙利铂(oxaliplatin),奥卡西平(oxcarbazepine),帕潘立酮(paliperidone),泮托拉唑(pantoprazole),对乙酰氨基酚(paracetamol),帕罗西汀(paroxetine),吡格列酮(pioglitazone),普拉克索(pramipexole),普伐他汀(pravastatin),普瑞巴林(pregabalin),喹硫平(quetiapine),雷贝拉唑(rabeprazole),雷洛昔芬(raloxifene),雷米普利(ramipril),瑞波西汀(reboxetine),利塞膦酸钠(risedronate sodium),利伐沙班(rivaroxaban),利斯的明(rivastigmine),利扎曲普坦(rizatriptan),罗格列酮(rosiglitazone),ruboxistaurin,沙美特罗(salmeterol),枸橼酸西地那非(sildenafil citrate),辛伐他汀(simvastatin),西罗莫司(sirolimus),sitagliptin,索拉非尼(sorafenib),舒马普坦(sumatriptan),舒尼替尼(sunitinib),surinabant,他达拉非(tadalafil),坦洛新(tamsulosin),他喷他多(tapentadol),telbivudine,替米沙坦(telmisartan),盐酸特比萘芬(terbinafine hydrochloride),特立氟胺(teriflunomide),噻托溴铵(tiotropium),托特罗定(tolterodine),托吡酯(topiramate),盐酸戊卡色林(vabicaserin hydrochloride),伐昔洛韦(valaciclovir),缬更昔洛韦(valganciclovir),缬沙坦(valsartan),凡德他尼(vandetanib),伐地那非(vardenafil),伐仑克林(varenicline),文拉法辛(venlafaxine),维达列汀(vildagliptin),伏立康唑(voriconazole),华法林(warfarin),齐拉西酮(ziprasidone),佐米曲普坦(zolmitriptan),唑吡坦(zolpidem)。
另外的药物:乙酰丙嗪(acepromazine)、阿莫西林(amoxicillin)、氨苄西林(ampicillin)、安普霉素(apramycin)、贝那普利(benazepril)、倍他米松(betamethasone)、丁溴东茛菪碱(buscopan)、卡洛芬(carprofen)、头孢匹林(cefapirin)、克仑特罗(clenbuterol)、克林霉素(clindamycin)、氯唑西林(cloxacillin)、环孢霉素A(cyclosporine A)、环丙马秦(cyromazine)、地拉考昔(deracoxib)、dichlorvos、dicyclanil、二氟沙星(difloxacin)、恩氟沙星(enrofloxacin)、依托度酸(etodolac)、芬苯达唑(fenbendazole)、framycetin、呋塞米(furosemide)、griseofulvin、海他西林(hetacillin)、潮霉素(hygromycin)、imidacloprid、左旋咪唑(levamisole)、左甲状腺素(levothyroxine)、氯芬奴隆(lufenuron)、美洛昔康(meloxicam)、美贝霉素肟(milbemycin oxime)、莫能星(monensin)、莫昔克丁(moxidectin)、narasin、尼卡巴辛(nicarbazin)、尼藤吡蓝(nitenpyram)、竹桃霉素(oleandomycin)、奥芬达唑(oxfendazole)、羟氯扎胺(oxyclozanide)、paramectin、巴龙霉素(paromomycin)、扑灭司林(permethrin)、苯甲丁氮酮(phenylbutazone)、吡喹酮(praziquantel)、普鲁卡因苄青霉素(procaine benzylpenicillin)、普鲁卡因青霉素(procaine penicillin)、双羟萘酸噻嘧啶(pyrantel pamoate)、spinosad、sulphadiazine、噻虫嗪(thiamethoxam)、硫姆林(tiamulin)、曲安西龙(triamcinolone)、三氯苯达唑(triclabendazole)、甲氧苄啶(trimethoprim)、泰洛星(tylosin)。
农业化学品例如农药和杀真菌剂:阿巴克丁(abamectin)、溴鼠灵(brodifacoum)、环丙马秦(cyromazine)、依马菌素(emamectin)、苯氧威(fenoxycarb)、抗蚜威(pirimicarb)、吡蚜酮(pymetrozine)、噻虫嗪(thiamethoxam)。
化妆品成分例如:
UV过滤物质(例如(+/-)-1,7,7-三甲基-3-[(4-甲基苯基)亚甲基]二环[2.2.1]庚-2-酮;1,7,7-三甲基-3-(苯基亚甲基)二环[2.2.1]庚-2-酮;(2-羟基-4-甲氧基苯基)(4-甲基苯基)甲酮;2,4-二羟基二苯甲酮;2,2′,4,4′-四羟基二苯甲酮;2-羟基-4-甲氧基二苯甲酮;2-羟基-4-甲氧基二苯甲酮-5-磺酸;2,2′-二羟基-4,4′-二甲氧基二苯甲酮;2,2′-二羟基-4-甲氧基二苯甲酮;α-(2-氧代龙脑-3-亚基)甲苯-4-磺酸及其盐;1-[4-(1,1-二甲基乙基)苯基]-3-(4-甲氧基苯基)丙-1,3-二酮;N,N,N-三甲基-4-[(4,7,7-三甲基-3-氧代二环[2,2,1]庚-2-亚基)甲基]苯胺硫酸甲酯;3,3,5-三甲基环己基-2-羟基苯甲酸酯;对甲氧基肉桂酸异戊酯;o-氨基苯甲酸薄荷酯;水杨酸薄荷酯;2-氰基-3,3-二苯基丙烯酸2-乙基己酯;4-(二甲基氨基)苯甲酸2-乙基己酯;4-甲氧基肉桂酸2-乙基己酯;水杨酸2-乙基己酯;苯甲酸,4,4′,4″-(1,3,5-三嗪-2,4,6-三基三亚氨基)三-,三(2-乙基己基)酯;2,4,6-三苯胺基-(对碳-2′-乙基己基-1′-氧代)-1,3,5-三嗪;4-氨基苯甲酸;苯甲酸,4-氨基-,乙酯,与环氧乙烷的聚合物;2-苯基-1H-苯并咪唑-5-磺酸;2-丙烯酰胺,N-[[4-[(4,7,7-三甲基-3-氧代二环[2.2.1]庚-2-亚基)甲基]苯基]甲基]-,均聚物;三乙醇胺水杨酸酯;3,3′-(1,4-亚苯基二亚甲基)二[7,7-二甲基-2-氧代-二环[2.2.1]庚烷-1-甲磺酸];2,2′-亚甲基-二-[6-(2H-苯并三唑-2-基)-4-(1,1,3,3-四甲基丁基)-苯酚];2,4-二{[4-(2-乙基己基氧基)-2-羟基]-苯基}-6-(4-甲氧基苯基)-(1,3,5)-三嗪;1H-苯并咪唑-4,6-二磺酸,2,2′-(1,4-亚苯基)二-,二钠盐;苯甲酸,4,4′-[[6-[[4-[[(1,1-二甲基乙基)氨基]羰基]苯基]氨基]1,3,5-三嗪-2,4-二基]二亚氨基]二-,二(2-乙基己基)酯;苯酚,2-(2H-苯并三唑-2-基)-4-甲基-6-[2-甲基-3-[1,3,3,3-四甲基-1-[(三甲基甲硅烷基)氧基]二硅氧烷基]丙基]-;Dimethicodiethylbezalmalonate;苯磺酸,3-(2H-苯并三唑-2-基)-4-羟基-5-(1-甲基丙基)-,单钠盐;苯甲酸,2-[4-(二乙基氨基)-2-羟基苯甲酰基]-,己酯;1-十二烷基铵,N-[3-[[4-(二甲基氨基)苯甲酰基]氨基]丙基]N,N-二甲基-,与4-甲基苯磺酸的盐(1∶1);N,N,N-三甲基-3-[(1-氧代-3-苯基-2-丙烯基)氨基]-1-丙基氯化铵;1H-苯并咪唑-4,6-二磺酸,2,2′-(1,4-亚苯基)二-1,3,5-三嗪,2,4,6-三(4-甲氧基苯基)-;1,3,5-三嗪,2,4,6-三[4-[(2-乙基己基)氧基]苯基]-;1-丙基铵,3-[[3-[3-(2H-苯并三唑-2-基)-5-(1,1-二甲基乙基)-4-羟基苯基]-1-氧代丙基]氨基]-N,N-二乙基-N-甲基-,甲基硫酸(盐);2-丙烯酸,3-(1H-咪唑-4-基)-;苯甲酸,2-羟基-,[4-(1-甲基乙基)苯基]甲酯;1,2,3-丙三醇,1-(4-氨基苯甲酸酯);苯乙酸,3,4-二甲氧基-a-氧代-;2-丙烯酸,2-氰基-3,3-二苯基-,乙酯;邻氨基苯甲酸,对薄荷-3-基酯;2,2’-二(1,4-亚苯基)-1H-苯并咪唑-4,6-二磺酸单钠盐或苯基二苯并咪唑四磺酸二钠或Heliopan AP);
抗虫活性成分(驱虫剂(repellent);例如二乙基甲苯酰胺(DEET);或可在“Pflegekosmetik”(W.Raab和U.Kindl,Gustav-Fischer-VerlagStuttgart/New York,1991),第161页中发现的其它常见驱虫剂);
具有角质促成作用(keratoplastic effect)的活性成分(例如过氧苯甲酰、视黄酸、胶态硫和间苯二酚);
抗微生物剂(例如三氯生(triclosan)或季铵化合物);
抗氧化剂;
有机色素类例如酞菁类、偶氮类等;
有机染料例如溶剂染料,直接染料等。
本发明并不限于上列有机物质。
下述测试方法和实施例仅用于举例说明的目的,不应解释为以任何方式限制本发明。室温(r.t.或RT)描述了20-25℃的温度;过夜表示12-16小时。除非另有说明,百分比是按重量计的,温度是按摄氏度(摄氏温度)计。
在实施例或别处使用的缩写:
ACN 乙腈
API 活性药用成分
BSA 牛血清白蛋白(Fluka)
IPA 异丙醇
PO 来自糙皮侧耳的I类疏水蛋白
PP 聚丙烯
RT 室温
SC 来自裂褶菌的I类疏水蛋白
TR 来自里氏木霉的II类疏水蛋白
TT 来自嗜热篮状菌的I类疏水蛋白
WCA PP片上的水接触角(静止座滴法)
w/w 按重量计相对于总重的份数或百分比
疏水蛋白的制备
疏水蛋白溶液:使用含有10mg蛋白质/ml溶液的水溶液。
在大肠杆菌中重组地制备疏水蛋白;这些疏水蛋白是:
I类疏水蛋白:
来自糙皮侧耳的PO、
来自嗜热篮状菌的TT、
来自裂褶菌的SC;
和II类疏水蛋白:
来自里氏木霉的TR。来自里氏木霉的疏水蛋白也可通过野生型的深层发酵和后处理而得。
应用实施例
实施例1:对乙酰氨基酚在疏水蛋白的存在下的结晶
疏水蛋白溶液通过将10mg冻干粉末(蛋白质含量为至少60-80%)溶解于1mL纯水中而制得。不溶性残渣通过离心除去。
将15g API(对乙酰氨基酚,Sigma)溶解于150mL纯水中。将所得溶液的10mL等份试样转移到15mL可密封聚丙烯管中,该聚丙烯管已预热至95℃以防结晶起始。为确保均一温度,将各管在热混合器(EppendorfThermomixer Comfort)上在95℃和750rpm下振摇15-30分钟,然后于95℃在持续的混合下加入100μL疏水蛋白溶液;样品中的最终蛋白质浓度为100ppm。在1-2min后,将各管撤出热混合器以允许在RT和无振摇下冷却。以相同方法处理对照样品,除了加入100μL纯水而不是疏水蛋白溶液,或不存在API。目测评价结晶行为;结果汇总于下表中。
表1
“条痕(Streak)”表示观察到初始浓缩物痕纹(initial concentrationstreaks)而无混浊。
混浊(clouding)由小的对乙酰氨基酚晶体的形成而产生。缺少API的对照显示没有蛋白质变性发生(无混浊)。
形成的所有晶体均是可分散的。
注射后几分钟(<5min),将5mL上述的母液倒入盘中以便允许通过蒸发进行结晶。目测检查在约20小时后所得的经干燥的晶体;对于所有I类疏水蛋白,获得类似的晶形和晶体大小,而在存在TR时的结晶导致大的树枝状样晶体(图1)。
实施例2:苯甲酰胺在存在SC、PO、TT或TR下的结晶
将15g苯甲酰胺(Fluka)溶解于150mL纯水中。将所得溶液的10mL等分试样转移到15mL可密封聚丙烯管中,该聚丙烯管已预热至95℃以防结晶发生。为确保均一温度,将各管在热混合器(EppendorfThermomixerComfort)上在95℃和750rpm下振摇15-30分钟,然后加入100μL疏水蛋白溶液(根据实施例1所给出的方法而制得)(仍振摇各管以允许均匀混合和调和(tempering))。在1-2min后,将各管撤出热混合器以允许在RT和不振摇下冷却。以相同方法处理对照样品,除了加入100μL纯水而不是疏水蛋白溶液,或不存在API。
疏水蛋白注射后(样品中的终浓度为100ppm),视觉评价的结果汇于下表中。
表2
“条痕”表示观察到初始浓缩物痕纹而无混浊。
混浊是由于小的对乙酰氨基酚晶体的形成、而不是所加入蛋白质的变性而引起的。*所有晶体是可分散的。
注射后几分钟(<5min),将5mL母液倒入盘中以便允许通过蒸发进行结晶。目测检查在约20小时后所得的经干燥的晶体;对于所有I类疏水蛋白,获得类似的晶形和晶体大小,而在存在TR时的结晶导致成束的伸长的晶体(图2)。
实施例3:文法拉辛的结晶和再分散
将15g文法拉辛(Ciba)溶解于150mL IPA中。将所得溶液的10mL等分试样转移到已预热至95℃的15mL可密封聚丙烯管中。为确保均一温度,将各管在热混合器(Eppendorf Thermomixer Comfort)上在80℃和750rpm下振摇15-30分钟,然后加入100μL蛋白质溶液(根据实施例1所给出的方法而制得)。以相同方法处理对照样品,除了加入100μL纯水而不是疏水蛋白溶液,或不存在API。
疏水蛋白注射后(样品中的终浓度为100ppm),视觉评价的结果汇于下表中。
表3:视觉评价晶体的结晶和可分散性(RT)
混浊解释为形成小API晶体。
在室温,结晶被远远地提前,管中充满大块晶体聚集体,其不允许确定晶体大小。
母液过夜完全结晶,其中粘在一起的晶体被溶剂所覆盖。剧烈振摇(Vortex)10-15秒伴有不同程度的再悬浮:对于含有SC和TR的样品,将悬浮液倒入盘中,导致管的完全排空;而对于含有PO、TT的样品和对照样品,主要倒出剩余的母液。
在SC或TR的存在下获得最佳可分散性。
对于文法拉辛,所得晶体的结晶温度和可分散性受到所述蛋白质的影响。
实施例4:阿托伐他汀的结晶
a)通过加热至50℃并搅拌2小时,将15g阿托伐他汀(Ciba)溶解于75mL纯水和75mL乙腈中。过滤所得溶液(0.45μm)。将10mL等份试样转移到15mL可密封聚丙烯管中,该聚丙烯管已预热至95℃以防结晶发生。为确保均一温度,将各管在热混合器(Eppendorf Thermomixer Comfort)上在50℃和750rpm下振摇15-30分钟,然后加入100μL蛋白质溶液(根据实施例1所给出的方法而制得)(终浓度为100ppm)。以相同方法处理对照样品,除了加入100μL纯水而不是疏水蛋白溶液,或不存在API。
b)在另外一组试验中,通过在如根据实施例1所给出的方法制得的溶液(100μg蛋白质/mL)中温育过夜,使载玻片包被上蛋白质。然后洗涤载玻片,空气干燥,之后将50μL如上所述的阿托伐他汀溶液覆盖在载玻片上。如图4中显示,通过在疏水蛋白包被的玻璃表面上蒸发进行的结晶,伴有更规则的晶体生长,尤其是在用PO或SC包被之后。
实施例5:不同蛋白质浓度下对乙酰氨基酚或苯甲酰胺的结晶
所有溶液和等份试样如实施例1和2中所述进行制备,除了加入500μL具有不同量TR的溶液(以调节100/250/500/750/1000ppm的终浓度)。TR储备液通过将30mg冻干TR溶解于1.5mL纯水中而制得。注射TR溶液未伴有浊度,但是对于高于250ppm的浓度,在<5min后液体开始变得轻微混浊。在那时,将5mL各自样品倒入盘中以允许通过蒸发进行结晶。
对于对乙酰氨基酚和苯甲酰胺两者(图5+6),更高的TR浓度清楚地表现出如下特征:晶体大小下降以及晶体在母液中更稳定的分散。
对于对乙酰氨基酚样品,通过单粒子光学传感(SPOS)方法(AccuSizer780/A,Particle Sizing Systems)测定晶体粒度级分(size fractions)(重量/颗粒表面积)。在没有疏水蛋白的情况下,晶体粒度主要在0.1-2mm范围;加入TR形成一类粒度范围在5-50μm的较小颗粒。此外,TR的存在明显降低“大”级分中富度最大颗粒的大小(参见图7)。疏水蛋白诱导的在这两种主要粒度级分之间的迁移汇于表5中。
表5:对乙酰氨基酚晶体粒度级分的百分比(w/w)
TR浓度 | 级分1(5-50μm) | 级分2(0.1-2mm) |
0ppm | 1.2% | 98.8% |
500ppm | 34.8% | 65.2% |
1000ppm | 57.1% | 42.9% |
附图简述
图1:与不含疏水蛋白的对照相比,在存在TR下进行结晶后的对乙酰氨基酚(放大50倍)揭示了对晶体习性的明显改变。
图2:与不含疏水蛋白的对照相比,在存在TR下进行结晶后的苯甲酰胺(放大50倍)揭示了对晶体习性的明显改变。
图3:通过蒸发进行结晶后的阿托伐他汀溶质(放大倍数:50倍):与不含疏水蛋白的对照相比,存在100ppm疏水蛋白(SC、PO、TT、TR)导致更均匀的晶体生长。
图4:通过在载玻片上蒸发进行结晶后的阿托伐他汀溶质(放大50倍):与未包被的对照相比,用PO或SC包被导致更均匀的晶体生长。
图5(放大倍数:50x):对乙酰氨基酚在存在渐增的TR浓度(100-1000ppm)下结晶后,导致平均晶体大小的降低。
图6(放大倍数:50x):苯甲酰胺在存在渐增的TR浓度(100-1000ppm)下结晶后,导致平均晶体大小的降低。
图7:对乙酰氨基酚晶体在缺少或存在TR下的表面重量粒度分布;蛋白质加入影响粒度分布并产生更小的颗粒。
图8:与纯水相比,1%b.w.蛋白质溶液在聚丙烯板(Borealis HC115MO)上的水接触角的相对变化,表明疏水蛋白的高度两亲性。
图9:典型结晶过程的图解步骤。
Claims (15)
1.用于改变有机物质的形态学和/或多晶型的方法,所述方法包括用一种或多种两亲性蛋白质处理固体物质或其溶液或分散体,所述两亲性蛋白质的特征在于,其1%b.w.水溶液或分散体显示在聚丙烯表面上的接触角比就纯水能观察到的接触角低20度或更多。
2.权利要求1的方法,其包括所述有机物质的沉淀、结晶或固-固相转变;尤其是用于降低微晶大小,增加无定形部分,改变晶体习性和/或改变晶体的多晶型;优选其中所述有机物质的沉淀或结晶通过将其溶液或分散体与两亲性蛋白质的溶液或分散体组合而诱导。
3.根据任何前述权利要求的方法,其包括:
i)将所述蛋白质在极性溶剂中的溶液或分散体与所述有机物质在可与所述蛋白质的溶剂混溶的极性溶剂中的溶液或分散体混合,或
ii)将所述有机物质在极性溶剂中的溶液或分散体与用所述蛋白质浸渍的表面接触。
4.根据任何前述权利要求的方法,其包括在所述两亲性蛋白质的存在下对所述有机物质进行湿磨。
5.根据任何前述权利要求的方法,其包括在添加所述两亲性蛋白质之前或之后将所述有机物质的晶种加到有机物质的溶液中。
6.根据任何前述权利要求的方法,其中溶液含有另外的添加剂,例如盐和/或聚合物。
7.根据任何前述权利要求的方法,其中所述有机物质是有机化合物,在0℃为固体,并且可溶、部分可溶或可分散于极性溶剂中,例如以胶体的形式。
8.根据任何前述权利要求的方法,其中所述有机物质是分子量80-1000g/mol、尤其为100-500g/mol的有机化合物,其优选选自生物活性化合物,例如药物、药用和化妆品用成分、农药和杀真菌剂。
9.根据任何前述权利要求的方法,其用于降低微晶大小,增加无定形部分,改变晶体习性和/或改变晶体的多晶型。
10.根据任何前述权利要求的方法,其中所述蛋白质为疏水蛋白,例如II类疏水蛋白或尤其是I类疏水蛋白。
11.根据任何前述权利要求的方法,其中所述有机物质的沉淀或结晶通过将其溶液或分散体与两亲性蛋白质的溶液或分散体组合而诱导。
12.如权利要求1或10中所表征的两亲性蛋白质用于改变有机物质的形态学和/或多晶型的用途。
13.根据权利要求12的用途,其用于改变如权利要求5和/或6中所表征的有机物质的形态学和/或多晶型。
14.组合物,其包括固体有机物质,尤其如权利要求5或6中所定义的有机物质、和如权利要求1、或尤其是权利要求7中所表征的两亲性蛋白质,其中所述固体有机物质是细颗粒形式的有机生物活性物质,平均粒度,取决于所需的最终用途,为例如0.1-1000微米,或在其它情况下可通过动态光散射检测,为例如5-5000nm,尤其是20-2000nm。
15.权利要求14的组合物,其中所述颗粒是自由流动的,分散在液体中的,或尤其是聚集的或压紧的。
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