CN1870987A - 制备紫杉醇亚微米颗粒的方法 - Google Patents
制备紫杉醇亚微米颗粒的方法 Download PDFInfo
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- CN1870987A CN1870987A CNA2004800312690A CN200480031269A CN1870987A CN 1870987 A CN1870987 A CN 1870987A CN A2004800312690 A CNA2004800312690 A CN A2004800312690A CN 200480031269 A CN200480031269 A CN 200480031269A CN 1870987 A CN1870987 A CN 1870987A
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Abstract
本发明涉及形成抗肿瘤剂亚微米颗粒,所述抗肿瘤剂特别是紫杉醇或其衍生化合物,方法是在水性介质中沉淀抗肿瘤剂以形成前悬液,然后进行均化。含有结合到水溶性或亲水性聚合物例如PEG的磷脂的表面活性剂被用作该颗粒包衣。产生的颗粒通常平均粒径小于约1000nm并且不快速溶解。
Description
相关申请的交叉引用
本申请是2003年3月17日提交的美国专利申请No.10/390,333的部分继续申请,后者是2002年9月17日提交的No.10/246,802的部分继续申请,后者是2001年10月19日提交的No.10/035,821的部分继续申请,后者是2001年9月17日提交的No.09/953,979的部分继续申请,后者是2001年6月5日提交的No.09/874,637的继续申请,后者要求了2000年12月22日提交的临时申请No.60/258,160的优先权。此处将上述各申请引入作为参考并作为本申请的一部分。联邦资助的研究或开发
不适用
发明背景
技术领域
本发明涉及形成抗肿瘤剂亚微米颗粒,所述抗肿瘤剂特别是紫杉醇或其衍生化合物,方法是在水性介质中沉淀抗肿瘤剂以形成前悬液,然后进行均化。含有与水溶性或亲水性聚合物例如聚乙二醇(PEG)结合的磷脂的表面活性剂被用于包被该颗粒。产生的颗粒通常平均粒径小于约1000nm并且不快速溶解。
背景技术
有数量日益增加的在水溶液中难溶或不溶的有机化合物被配制用于治疗或诊断作用。这些药物给通过上述给药途径传递提供了挑战。水中不溶的化合物当配制成亚微米颗粒的稳定悬浮液时具有显著效果。准确控制粒径对安全和有效使用这些制剂是关键的。为了安全通过毛细管而不引起栓塞,颗粒的直径必须小于7μm(Allen等,1987;Davis和Taube,1978;Schroeder等,1978;Yokel等,1981)。解决此问题的一个方案是生产小颗粒的不溶性药物候选物,并生成微米微粒或纳米微粒悬浮液。以此途径,先前不能在水基系统中配制的药物可制成适于静脉内给药。静脉内给药的合适性包括小粒径(<7μm),低毒性(如来自毒性配方组分或残留溶剂),和药物颗粒施用后的生物利用度。
小颗粒水不溶性药物的制备也可适用于口服,肺,局部,眼,鼻,含服,直肠,阴道,经皮给药或其他给药途径。尺寸小的颗粒改进了药物的溶出率,从而提高了其生物利用度和潜在地改进了其毒性谱。当通过这些途径给药时,合需的是,粒径的范围在5-100μm,这取决于药物的给药途径、剂型、溶解性和生物利用度。例如,对于口服而言,理想的是,粒径小于约7μm。对于肺给药而言,粒径优选小于约10μm。
发明概述
本发明提供亚微米颗粒抗肿瘤剂的组合物以及制备亚微米颗粒抗肿瘤剂的方法,所述抗肿瘤剂尤其是紫杉醇(paclitaxel)或其衍生化合物。抗肿瘤剂在水可混第一溶剂中的溶解性大于在含水第二溶剂中的溶解性。所述方法包括下列步骤:(i)向水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中混入含有结合了水溶性或亲水性聚合物的磷脂的第一表面改性剂;(ii)将抗肿瘤剂溶解在水可混第一溶剂以形成溶液,(iii)将该溶液与第二溶剂混合以定义颗粒的前悬液;以及(iv)均化前悬液以形成平均有效粒径小于约1μm的颗粒的悬液。优选地,颗粒的平均有效粒径小于约400nm,更优选小于200nm,最优选小于约150nm。
在优选的实施方案中,连接到磷脂的水溶性或亲水性聚合物是聚乙二醇(PEG)。任选第二表面改性剂可以混入水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中。优选的第二表面改性剂是poloxamer。
在实施方案中,均化在大约30℃或更高的温度下进行。
所述方法还可以进一步包括从悬液中除去水可混第一溶剂或整个液相。在优选的实施方案中,水可混第一溶剂在均化同时除去。
所述方法还可以包括对组合物灭菌。
在优选的实施方案中,颗粒是不溶的。
在另外优选的实施方案中,颗粒在受力条件下或储存中不聚集。
本发明的这些和其他方面及特征将参照附图和说明书讨论。
附图简述
图1为本发明一个方法的图示;
图2为本发明另一方法的图示;
图3显示均化前的无定形颗粒;
图4显示通过均化退火后的颗粒;
图5为均化前后以聚乙二醇-660 12-羟基硬脂酸酯微沉淀伊曲康唑的X-射线衍射图;
图6显示均化前的卡巴咪嗪晶体;
图7显示均化(Avestin C-50)后的卡巴咪嗪微粒;
图8显示脱氢皮质醇(prednisolone)的微沉淀方法;
图9为均化前脱氢皮质醇悬浮液的显微照片;
图10为均化后脱氢皮质醇悬浮液的显微照片;
图11比较纳米悬浮液(本发明)和商购脂肪乳液的大小分布;
图12显示原料伊曲康唑(上图)和SMP-2-PRE(下图)的X-射线粉末衍射图。为清楚起见,原料图已向上位移;
图13a示出原料伊曲康唑的DSC迹线;
图13b示出SMP-2-PRE的DSC迹线;
图14举例说明SMP-2-PRE的DSC迹线,示出加热至160℃时较不稳定的多晶形的融化,冷却时的重结晶事件,以及在重加热至180℃时随后融化更稳定的多晶形;
图15举例说明SMP-2-PRE样品均化后的比较。实线=用原料伊曲康唑加晶种的样品。虚线=未加晶种的样品。为清楚起见,实线已位移1W/g;
图16举例说明在沉淀过程中加晶种的效果。虚线=未加晶种的样品,实线=用原料伊曲康唑加晶种的样品。为清楚起见,未加晶种的迹线(虚线)已向上位移1.5W/g;
图17举例说明加入晶种药物浓缩物随老化的效果。上部X-射线衍射图为制备自新鲜药物浓缩物的晶体,并且与稳定的多晶形一致(参见图12,上图)。下图为制备自老化(加晶种)的药物浓缩物的晶体,并且与亚稳的多晶形一致(参见图12,下图)。为清楚起见,上图已向上位移;
图18显示亚微米紫杉醇颗粒的两种制剂的溶解;
图19显示不同的受压条件对紫杉醇亚微米颗粒的粒径的影响;及
图20显示储存对于紫杉醇亚微米颗粒的粒径的影响。
发明详述
本发明容许以不同形式的实施方案。本发明优选的实施方案的公开应理解为,这些公开内容视为本发明原理的例证,并非旨在将本发明的广泛方面限制到所述的实施方案。
本发明提供小颗粒有机化合物的组合物和形成小颗粒有机化合物的方法。用于本发明方法的有机化合物为任何有机化合物实体,其溶解性从一个溶剂到另一溶剂降低。该有机化合物可以为药物活性化合物,选自治疗剂,诊断剂,美容品,营养补剂以及杀虫剂。
治疗剂可选自各种不同的已知药物,诸如,但不限于:止痛剂,麻醉剂,兴奋剂,肾上腺素剂,肾上腺素阻断剂,抑肾上腺素剂,肾上腺类皮质激素,肾上腺模拟物(adrenomimetics),抗胆碱能剂,抗胆碱酯酶,抗惊厥药物,烷化剂,生物碱,变构抑制剂,合成代谢类固醇,anorexiants,抗酸剂,抗腹泻剂,解毒剂,antifolics,退热剂,治疗风湿药剂,精神治疗剂,神经阻断剂,抗炎剂,antihelmintics,抗心律失常剂,抗生素,抗凝血剂,抗抑郁剂,抗糖尿病剂,抗癫痫剂,杀真菌剂,抗组胺药,抗高血压剂,抗蕈毒碱剂,杀分支杆菌剂,抗疟药,防腐剂,抗肿瘤剂,杀原生动物剂,免疫抑制剂,免疫刺激剂,抗甲状腺剂,抗病毒剂,抗焦虑药镇静剂,收敛剂,β-肾上腺受体阻断剂,造影剂,皮质类固醇,咳嗽抑制剂,诊断剂,诊断成像剂,利尿剂,多巴胺能剂,止血剂,血液剂,血红蛋白改性剂,激素,催眠药,免疫剂,抗高脂剂和其他脂类调节剂,蕈毒碱,肌肉松弛剂,拟副交感神经剂,甲状旁腺降钙素,前列腺素,放射性药物,镇静剂,性激素,抗变应性剂,刺激物,拟交感神经药,甲状腺剂,血管舒张剂,疫苗,维生素,以及黄嘌呤。抗肿瘤剂或抗癌剂,包括但不限于紫杉醇和衍生化合物,以及其他选自生物碱,抗代谢物,酶抑制剂,烷化剂和抗生素的抗肿瘤剂。治疗剂也可为生物制剂,包括但不限于蛋白,多肽,碳水化合物,多核苷酸和核酸。蛋白可为抗体,所述抗体为单克隆抗体或多克隆抗体。
诊断剂包括X-射线成像剂和造影剂。X-射线成像剂的例子包括WIN-8883(乙基3,5-二乙酰氨基-2,4,6-三碘代苯甲酸酯),也称为diatrazoic acid的乙基酯(EEDA),WIN 67722,即,(6-乙氧基-6-氧代己基-3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酸酯);乙基-2(3,5-双(乙酰氨基)-2,4,6-三碘代-苯甲酰氧基)丁酸酯(WIN 16318);乙基diatrizoxyacetate(WIN 12901);乙基2-(3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酰氧基)丙酸酯(WIN 16923);N-乙基2-(3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酰氧基乙酰胺(WIN 65312);异丙基2-(3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酰氧基)乙酰胺(WIN 12855);二乙基2-(3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酰氧基)丙二酸酯(WIN 67721);乙基2-(3,5-双(乙酰氨基)-2,4,6-三碘代苯甲酰氧基)苯基乙酸酯(WIN 67585);丙二酸,[[3,5-双(乙酰氨基)-2,4,5-三碘代苯甲酰]氧基]双(1-甲基)酯(WIN68165);以及苯甲酸,3,5-双(乙酰氨基)-2,4,6-三碘代-4-(乙基-3-乙氧基-2-丁烯酸)酯(WIN 68209)。优选的造影剂包括那些预计在生理条件下相对快速崩解,从而使任何与颗粒相关的炎性反应最小化的造影剂。崩解可来自酶水解,生理pH条件下羧酸的溶解,或其他机制。因此,溶解性差的碘化羧酸,诸如iodipamide,diatrizoic acid,和metrizoic acid,连同易水解的碘化物质,诸如WIN 67721,WIN 12901,WIN 68165,和WIN 68209或其他是优选的。
其他造影剂包括但不限于磁共振成像助剂,诸如钆螯合物或其他顺磁性造影剂的微粒制剂。这类化合物的例子为gadopentetatedimeglumine(Magnevist)和gadoteridol(Prohance)。
这些类型的治疗剂和诊断剂以及各类型中化合物名单的描述参见Martindale,The Extra Pharmacopoeia,第29版,The PharmaceuticalPress,London,1989,在此引作参考并成为本发明的一部分。治疗剂和诊断剂可商购,和/或通过本领域公知技术制备。
美容剂是能够具有美容活性的任何活性成分。这些活性成分的例子有润肤剂,保湿剂,自由基抑制剂,抗炎剂,维生素,褪色剂,抗粉刺剂,antiseborrhoeics,角质层分离剂,减肥剂,皮肤着色剂和防晒剂等,尤其有亚油酸,视黄醇,视黄酸,抗坏血酸烷基酯,聚不饱和脂肪酸,烟酸酯,生育酚烟酸酯,米、大豆或牛油的未皂化物,神经酰胺,羟基酸诸如乙醇酸,硒衍生物,抗氧化剂,β-胡罗卜素,γ-orizanol和硬脂酰甘油酸酯等。美容品可商购,和/或通过本领域公知技术制备。
预计用于本发明实施中的营养补剂的例子包括但不限于蛋白,碳水化合物,水溶性维生素(例如,维生素C,B-复合维生素等),脂溶性维生素(例如,维生素A,D,E,K等),以及草药抽提物。营养补剂可商购,和/或通过本领域公知技术制备。
术语杀虫剂的理解包括除草剂,杀虫剂,杀螨剂,杀线虫剂,外驱虫剂和杀真菌剂。属于本发明杀虫剂类的化合物的例子包括尿素,三嗪,三唑,氨基甲酸酯,磷酸酯,二硝基苯胺,吗啉,酰基丙氨酸,拟除虫菊酯,二苯乙醇酸酯,二苯基醚以及多环卤化烃。这些类别杀虫剂的具体例子分别列在杀虫剂手册(Pesticide Mannual),第9版,British Crop Protection Council。杀虫剂可商购,和/或通过本领域公知技术制备。
优选地,有机化合物或药物活性化合物的水溶性差。“水溶性差”表示化合物在水中的溶解度小于约10mg/ml,优选小于1mg/ml。这些水溶性差的试剂最适用于水悬液制剂,这些因为在含水介质中配制这些试剂的替代有限。
通过在固相载体基质(例如,聚乳酸-聚乙醇酸共聚物,白蛋白,淀粉)中截留这些化合物,或通过在对药物化合物不可通透的包围囊中包裹这些化合物,本发明也可以水溶性药物活性化合物实施。该包裹囊可以是聚合物包衣,诸如聚丙烯酸酯。进一步,制备自这些水溶性药剂的小颗粒可被改性以提高化学稳定性和通过控制药剂从颗粒中的释放来控制药剂的药代动力学属性。水溶性药剂的例子包括但不限于简单的有机化合物,蛋白,肽,核苷酸,寡核苷酸,以及碳水化合物。
通过动态光散射方法,例如,光校正光谱,激光衍射,低角度激光光散射(LALLS),中角度激光光散射(MALLS),消光法(例如,Coulter方法),流变学,或显微镜法(光学或电子),本发明颗粒测量后的平均有效粒径一般小于约100μm。然而,颗粒可以制备成广泛的大小范围,诸如约20μm至约10nm,约10μm至约10nm,约2μm至约10nm,约1μm至约10nm,约400nm至约50nm,约200nm至约50nm,或其中的任何范围,或上述范围的组合。优选的平均有效粒径取决于诸如下列因素:化合物想要的给药途径,剂型,溶解度,毒性和生物利用度。
为了适于肠胃外给药,颗粒的平均有效粒径优选小于约7μm,以及更优选小于约2μm,或其中的任何范围或上述范围的组合。肠胃外给药包括静脉内,动脉内,鞘内,腹膜内,眼内,关节内,硬脑膜内,心室内,心包内,肌内,皮内或皮下注射。
口服剂型的粒径可超过2μm。颗粒的大小范围高达约100μm,条件是颗粒具有足够的生物利用度以及口服剂型的其他特征。口服剂型包括片剂,胶囊,囊片,软胶和硬胶胶囊,或其他通过口服用于传递药物的传递媒介物。
本发明进一步提供适于肺部给药形式的有机化合物颗粒。肺部剂型的粒径可超过500nm,并一般小于约10μm。悬浮液中的颗粒可被气溶胶化,并通过喷雾器用于肺部给药。此外,在从悬浮液中去除液相之后,颗粒以干粉形式通过干粉吸入器给药,或干粉重悬浮在非水性推进剂通过计量吸入器给药。合适的推进剂的例子为氢氟碳(HFC),诸如HFC-134a(1,1,1,2-四氟乙烷)和HFC-227ea(1,1,1,2,3,3,3-七氟丙烷)。与氯氟碳(CFC)不同,HFC显示小的或没有的损耗臭氧的潜力。
对其他传递途径,诸如鼻,局部,眼,鼻,含服,直肠,阴道,经皮等的剂型也可从本发明制备的颗粒中配制。
制备颗粒的工艺可分成四种通用类别。各个类别工艺共有下列步骤:(1)溶解有机化合物于水可混第一溶剂中生成第一溶液,(2)将该第一溶液与第二溶剂水混合以沉淀有机化合物生成前悬浮液,以及(3)以高剪切混合或加热或两者组合的形式,加入能量至前悬浮液中,从而提供稳定形式的具有上述所需尺寸范围的有机化合物。混合步骤和加入能量步骤可以连续步骤或同时进行。
工艺类别的区分是基于有机化合物的物理属性,如在能量加入步骤之前和能量加入步骤之后,通过X-射线衍射研究,差示扫描量热法(DSC)研究或其他合适的研究来确定。在第一工艺类别中,能量加入步骤之前,前悬浮液中的有机化合物采取无定形形式,半晶体形式或超冷却液体形式,并且具有平均有效粒径。在能量加入步骤之后,有机化合物的晶体形式具有的平均有效粒径基本上相同或小于前悬浮液。
在第二工艺类别中,在能量加入步骤之前,有机化合物为晶体形式并具有平均有效粒径。在能量加入步骤之后,有机化合物的晶体形式与能量加入步骤之前具有基本相同的平均有效粒径,但是能量加入步骤后,晶体聚集的可能性较小。
有机化合物聚集的倾向性较低通过激光动态光散射和光学显微镜观察。
在第三工艺类别中,在能量加入步骤之前,有机化合物为晶体形式,该形式易碎且具有平均有效粒径。术语“易碎”的含义在于,颗粒易碎且更容易分解成较小颗粒。在能量加入步骤之后,有机化合物的晶体形式具有的平均有效粒径小于前悬浮液中的晶体。通过采取必要步骤将有机化合物置于易碎的晶体形式,当与晶体形态不易碎的有机化合物相比时,随后的能量加入步骤可更快和更有效地实施。
在第四类工艺类别中,第一溶液和第二溶剂同时进行能量加入步骤。因此,有机化合物的物理属性在能量加入步骤之前和之后未被测量。
能量加入步骤可以任何方式实施,其中前悬浮液,或第一溶液和第二溶剂暴露于空化作用,剪切或冲击力。在本发明一个优选形式中,能量加入步骤为退火步骤。退火在本发明中定义为通过单次或反复施加能量(直接加热或机械应力),接着热张弛,将热动力不稳定的物质转化成更稳定的形式的过程。这种能量的降低通过将固体形式从较少有序转化为更有序的晶格结构而实现。此外,通过表面活性分子在固-液界面上的重排可出现这种稳定化作用。
这四种工艺类别分别讨论如下。然而,应理解的是,对诸如表面活性剂,或表面活性剂的组合,所用表面活性剂的量,反应温度,溶液混合速率,沉淀速率等处理条件进行选择使所有药物在任一种如下所讨论的类别下加工。
第一工艺类别,以及第二,第三和第四工艺类别,可进一步划分成两个子类,方法A和B,如图1和2所示。
本发明的第一溶剂为目的有机化合物相对溶解其中并与第二溶剂可混的溶剂或溶剂的混合物。这样的溶剂包括但不限于水可混质子化合物,其中分子中的氢原子结合于负电原子,诸如氧,氮或其他元素周期表中的第VA,VIA和VII A族原子。这种溶剂的例子包括但不限于醇,胺(伯胺或仲胺),肟,异羟肟酸,羧酸,磺酸,膦酸,磷酸,酰胺和脲。
第一溶剂的其他例子包括非质子有机溶剂。其中一些非质子溶剂可与水形成氢键,但只充当质子受体,因为它们缺乏有效的质子供给基团。一类非质子溶剂为双极性非质子溶剂,如the International Unionof Pure and Applied Chemistry(IUPAC Compendium of ChemicalTerminology,第2版,1997)所定义:
介电常数相对高,大于约15和永久性偶极矩相当大的溶剂,不可供给合适易变的氢原子以形成强氢键,例如二甲基亚砜。
偶极非质子溶剂可选自:酰胺(完全取代的,氮缺乏连接的氢原子),脲(完全取代的,没有氢原子连接于氮),醚,环醚,腈,酮,砜,亚砜,完全取代的磷酸酯,膦酸酯,磷酰胺,硝基化合物等。二甲基亚砜(DMSO),N-甲基-2-吡咯啉酮(NMP),2-吡咯啉酮,1,3-二甲基咪唑啉酮(DMI),二甲基乙酰胺(DMA),二甲基甲酰胺(DMF),二烷,丙酮,四氢呋喃(THF),四亚甲基砜(sulfolane),乙腈,和六甲基磷酰胺(HMPA),硝基甲烷等是该类成员。
可选择的溶剂一般是水不混溶的,但在低体积(小于10%)时具有足够的水溶解度,从而以这些减少的体积担当水可混第一溶剂。例子包括芳烃,烯烃,烷烃,以及卤化芳族化合物,卤化烯烃,和卤化烷烃。芳族化合物包括但不限于苯(取代或未取代的),单环或多环芳烃。取代苯的例子包括但不限于二甲苯(邻,间或对),和甲苯。烷烃的例子包括但不限于己烷,新戊烷,庚烷,异辛烷,和环己烷。卤化芳族化合物的例子包括但不限于氯苯,溴苯,和氯甲苯。卤化烷烃和烯烃的例子包括但不限于三氯乙烷,二氯甲烷,二氯乙烯(EDC),等。
所有上述溶剂类别的例子包括但不限于:N-甲基-2-吡咯啉酮(也称为N-甲基-2-吡咯烷酮),2-吡咯啉酮(也称为2-吡咯烷酮),1,3-二甲基-2-咪唑啉酮(DMI),二甲基亚砜,二甲基乙酰胺,乙酸,乳酸,甲醇,乙醇,异丙醇,3-戊醇,正-丙醇,苄基醇,甘油,丁二醇,乙二醇,丙二醇,单-和二乙酰化的单甘油酯(诸如甘油基辛酸酯),二甲基异山梨酯,丙酮,二甲基砜,二甲基甲酰胺,1,4-二烷,四亚甲基砜(sulfolane),乙腈,硝基甲烷,四甲基脲,六甲基磷酰胺(HMPA),四氢呋喃(THF),二烷,二乙基醚,叔丁基甲基醚(TBME),芳烃,烯烃,烷烃,卤化的芳族化合物,卤化烯烃,卤化烷烃,二甲苯,甲苯,苯,取代苯,乙酸乙酯,乙酸甲酯,乙酸丁酯,氯苯,溴苯,氯甲苯,三氯乙烷,二氯甲烷,二氯乙烯(EDC),己烷,新戊烷,庚烷,异辛烷,环己烷,聚乙二醇(PEG,例如PEG-4,PEG-8,PEG-9,PEG-12,PEG-14,PEG-16,PEG-120,PEG-75,PEG-150),聚乙二醇酯(例子,如PEG-4二月桂酸酯,PEG-20二月桂酸酯,PEG-6异硬脂酸酯,PEG-8棕榈酰硬脂酸酯,PEG-150棕榈酰硬脂酸酯),聚乙二醇山梨聚糖(诸如,PEG-20山梨聚糖异硬脂酸酯),聚乙二醇单烷基醚(例子,如PEG-3二甲基醚,PEG-4二甲基醚),聚丙二醇(PPG),聚丙烯藻酸酯,PPG-10丁二醇,PPG-10甲基葡萄糖醚,PPG-20甲基葡萄糖醚,PPG-15硬脂酰醚,丙二醇二辛酸酯/二葵酸酯,丙二醇月桂酸酯,以及糖糠醛(glycofurol)(四氢糠基醇聚乙二醇醚)。优选的第一溶剂为N-甲基-2-吡咯啉酮。另一优选的第一溶剂为乳酸。
第二溶剂为含水溶剂。该含水溶剂可以为水本身。该溶剂也可含有缓冲液,盐,表面活性剂,水溶性聚合物,以及这些赋形剂的组合。方法A
在方法A(参见图1)中,有机化合物(“药物”)首先溶解在第一溶剂中生成第一溶液。以约0.1%(w/v)至约50%(w/v)加入有机化合物,这取决于有机化合物在第一溶剂中的溶解度。浓缩物从约30℃加热至约100℃对确保化合物在第一溶剂中的全部溶出是必需的。
第二含水溶剂提供有一种或多种任选的表面改性剂,诸如向其中加入的阴离子表面活性剂,阳离子表面活性剂,非离子表面活性剂,或生物表面活性分子。合适的阴离子表面活性剂包括但不限于烷基磺酸酯,烷基磷酸酯,烷基膦酸酯,月桂酸钾,三乙醇胺硬脂酸酯,月桂基硫酸钠,十二烷基硫酸钠,烷基聚氧乙烯硫酸酯,藻酸钠,二辛基硫代琥珀酸钠,磷脂酰胆碱,磷脂酰甘油,磷脂酰肌苷,磷脂酰丝氨酸,磷脂酸及其盐,甘油酯,羧甲基纤维素钠,胆酸及其他胆汁酸(例如,胆酸,脱氧胆酸,甘胆酸,牛黄胆酸,甘脱氧胆酸)和及盐(例如,脱氧胆酸钠等)。合适的阳离子表面活性剂包括但不限于季铵化合物,诸如苄烷铵氯化物,鲸蜡基三甲基铵溴化物,壳聚糖,月桂基二甲基苄基铵氯化物,酰基肉碱氢氯化物,或烷基吡啶卤化物。作为阴离子表面活性剂,可使用磷脂。合适的磷脂包括,例如,磷脂酰胆碱,磷脂酰乙醇胺,二酰基-甘油-磷酸乙醇胺(诸如二肉豆蔻酰-甘油-磷酸乙醇胺(DMPE),二棕榈酰-甘油-磷酸乙醇胺(DPPE),二硬脂酰-甘油-磷酸乙醇胺(DSPE),以及二油酰-甘油-磷酸乙醇胺(DOPE)),磷脂酰丝氨酸,磷脂酰肌醇,磷脂酰甘油,磷脂酸,溶血磷脂,卵磷脂或大豆磷脂,或其组合。磷脂可为成盐或脱盐,氢化或部分氢化或天然半合成的或合成的。磷脂也可与水溶性聚合物或亲水聚合物结合。优选的聚合物为聚乙二醇(PEG),其也称为单甲氧基聚乙二醇(mPEG)。PEG的分子量可变化,例如从200至50,000。一些常用的PEG可商购,包括PEG 350,PEG 550,PEG 750,PEG 1000,PEG 2000,PEG 3000,以及PEG 5000。磷脂或PEG磷脂结合物也可掺入官能团,该官能团可共价结合于配体,所述配体包括但不限于蛋白,肽,碳水化合物,糖蛋白,抗体,或药物活性剂。这些官能团,例如通过酰胺键形成,二硫化物或硫醚形成,或生物素/链亲和素结合,与配体结合。结合配体的官能团的例子包括但不限于己酰胺,十二烷酰胺,1,12-十二烷二羧酸酯,硫代乙醇,4-(p-马来酰亚胺基苯基)丁酰胺(MPB),4-(p-马来酰亚胺基甲基)环己烷-甲酰胺(MCC),3-(2-吡啶基二硫代)丙酸酯(PDP),琥珀酸酯,戊二酸酯,十二烷酸酯,以及生物素。
合适的非离子表面活性剂包括:聚氧乙烯脂肪醇醚(Macrogol和Brij),聚氧乙烯山梨聚糖脂肪酸酯(聚山梨醇酯),聚氧乙烯脂肪酸酯(Myrj),山梨聚糖酯(Span),甘油单硬脂酸酯,聚乙二醇,聚丙二醇,鲸蜡醇,十六醇十八醇混合物,硬脂醇,芳基烷基聚醚醇,聚氧乙烯-聚氧丙烯共聚物(poloxamers),保丽视明(poloxamines),甲基纤维素,羟甲基纤维素,羟丙基纤维素,羟丙基甲基纤维素,非晶体纤维素,多糖,包括淀粉和淀粉衍生物,诸如羟乙基淀粉(HES),聚乙烯醇,和聚乙烯吡咯烷酮。在本发明的优选形式中,非离子表面活性剂为聚氧乙烯和聚氧丙烯共聚物,以及优选的是丙二醇和乙二醇的嵌段共聚物。这样的聚合物以商标名POLOXAMER,有时也称为PLURONIC销售,并由若干供应商包括Spectrum Chemical和Ruger销售。在聚氧乙烯脂肪酸酯中包括那些具有短链烷基的化合物。这样的表面活性剂的一个例子为SOLUTOLHS 15,聚乙烯-660-羟基硬脂酸酯,由BASF Aktiengesellschaft制造。
表面活性生物分子包括诸如白蛋白,酪蛋白,水蛭素或其他合适蛋白的分子。多糖生物制剂也可包括,并且其组成为但不限于淀粉,肝素和壳聚糖。
理想的还可加入pH调节剂至第二溶剂,诸如氢氧化钠,盐酸,tris缓冲液,或柠檬酸,乙酸,乳酸,甲葡胺等。第二溶剂的pH应在约3至约11的范围内。
对口服剂型而言,可使用一种或多种下列赋形剂:明胶,酪蛋白,卵磷脂(磷脂),阿拉伯树胶,胆固醇,黄芪胶,硬脂酸,苄烷铵氯化物,硬脂酸钙,甘油基单硬脂酸酯,十六醇十八醇混合物,cetomacrogol乳化蜡,山梨聚糖酯,聚氧乙烯烷基醚,例如,macrogol醚,诸如cetomacrogol 1000,聚氧乙烯蓖麻油衍生物,聚氧乙烯山梨聚糖脂肪酸酯,例如可商购的TweensTM,聚乙二醇,聚氧乙烯硬脂酸酯,胶体二氧化硅,磷酸酯,十二烷基硫酸钠,羧甲基纤维素钙,羧甲基纤维素钠,甲基纤维素,羟乙基纤维素,羟丙基纤维素,羟丙基甲基纤维素邻苯二甲酸酯,非晶体纤维素,硅酸镁铝,三乙醇胺,聚乙烯醇(PVA),以及聚乙烯吡咯烷酮(PVP)。大多数这些赋形剂详细描述在药物赋形剂手册(Handbook of Pharmaceutical Excipients),共同由The American Pharmaceutical Association和The PharmaceuticalSociety of Great Britain出版,the Pharmaceutical Press,1986。表面改性剂可商购,和/或通过本领域公知技术制备。两种或多种表面改性剂可组合使用。
在本发明的优选形式中,小颗粒有机化合物的制备方法包括加入第一溶液至第二溶剂的步骤。加入速率取决于批次大小,和有机化合物的沉淀动力学。一般而言,对小规模实验室工艺(制备1升)而言,加入速率为约0.05cc/min至约10cc/min。加入过程中,溶液应处于恒定搅拌之下。利用光学显微镜已观察到,无定形颗粒,半晶体固体,或超冷却的液体形成前悬浮液。所述方法进一步包括下列步骤:将前悬浮液进行能量加入步骤,从而将无定形颗粒,超冷却的液体或半结晶固体转化成更稳定的晶体固态。所得颗粒的平均有效粒径在上述范围内,如通过动态光散射方法(例如,光校正光谱学,激光衍射,低角度激光光散射(LALLS),中角度激光光散射(MALLS),消光法(Coulter法,例如),流变学,或显微镜(光学或电子))测量。在第四类工艺类别中,第一溶液和第二溶剂组合的同时进行能量加入步骤。
能量加入步骤包括通过超声,均化,逆流流动均化,微流化,或其他体提供冲击力、剪切力或空化力的方法加入能量。在此阶段,样品可被冷却或加热。在本发明一个优选形式中,能量加入步骤通过诸如由Avestin Inc.以产品名称EmulsiFlex-C160销售的活塞隙均质机而实现。在本发明另一优选的形式中,能量加入步骤利用超声处理器,诸如由Sonics and Materials,Inc.制造的the Viabra-Cell UltrasonicProcessor(600W),通过超声而实现。在本发明另一优选的形式中,能量加入步骤通过使用如U.S.专利No.5,720,551中所述的乳化装置而实现,所述专利在此引作参考并成为本发明的一部分。
取决于能量加入速率,理想的是调节已加工的样品温度至大约-30℃至30℃的范围内。此外,为了在已加工固体中实现所需的相变,也有必要在能量加入步骤过程中加热前悬浮液至从约30℃至约100℃的范围内。
方法B
方法B与方法A的区别在如下方面。第一个区别为表面活性剂或表面活性剂的组合加至第一溶液。表面活性剂可选自如上所述的阴离子,非离子,阳离子表面活性剂,以及表面活性生物改性剂。
方法A和方法B以及USPN 5,780,062的比较实施例
美国专利No.5,780,062公开了通过首先在合适的水可混第一溶剂中溶解有机化合物而制备小颗粒有机化合物的方法。第二溶液的制备方法是在含水溶剂中溶解聚合物和两性分子。然后第一溶液被加入到第二溶液形成由有机化合物和聚合物-两性分子复合物组成的沉淀物。’062专利未公开利用方法A和B中本发明的能量加入步骤。缺乏稳定性通常表现为快速的聚集和颗粒生长。在有些情形下,无定形颗粒重结晶成大晶体。以上述公开的方式加入能量至前悬浮液一般使得颗粒显示出颗粒聚集和生长速率降低,以及在产品储存时没有重结晶。
方法A和B进一步区别于’062专利的方法在于,在沉淀前没有形成聚合物-两性分子复合物的步骤。在方法A中,这样的复合物不可形成,因为没有聚合物加入稀释(水)相中。在方法B中,也可充当两性分子的表面活性剂,或者聚合物,与有机化合物一起溶解于第一溶剂中。这排除了在沉淀前形成两性分子-聚合物复合物。在’062专利中,成功沉淀小颗粒依赖于在沉淀前形成两性分子-聚合物复合物。’062专利公开两性分子-聚合物复合物在含水第二溶液中形成聚集体。’062专利解释了疏水有机化合物与两性分子-聚合物复合物相互作用,由此降低这些聚集体的溶解性,并导致沉淀。在本发明中,已证明在第一溶剂中包括表面活性剂或聚合物(方法B),在随后加至第二溶剂中时,导致形成的微粒比由’062专利所述方法提供的更均一更细小。
为此目的,制备和分析两种制剂。各种制剂具有两种溶液,浓缩液和水性稀释液,其混合在一起后再进行超声。各个制剂中的浓缩物具有有机化合物(伊曲康唑),水可混溶剂(N-甲基-2-吡咯啉酮或NMP)和可能的聚合物(poloxamer 188)。含水稀释液具有水,tris缓冲液和可能的聚合物(poloxamer 188)和/或表面活性剂(脱氧胆酸钠)。有机颗粒的平均粒径在超声前后进行测量。
第一制剂A具有浓缩的伊曲康唑和NMP。含水稀释液包括水,poloxamer 188,tris缓冲液和脱氧胆酸钠。因此,含水稀释液包括聚合物(poloxamer 188)以及两性分子(脱氧胆酸钠),这可形成聚合物/两性分子复合物,所以与’062专利的公开内容一致。(然而,再次,’062专利未公开能量加入步骤。)
第二制剂B具有浓缩的伊曲康唑,NMP和poloxamer 188。含水稀释液包括水,tris缓冲液,和脱氧胆酸钠。根据本发明制备该制剂。由于含水稀释液不含有聚合物(poloxamer)和两性分子(脱氧胆酸钠)的组合,聚合物/两性分子复合物在混合步骤前不能形成。
表1显示通过激光衍射对三次重复悬浮液制剂进行测量的平均粒径。对起始大小进行确定,其后对样品超声1分钟。然后,重复确定尺寸。方法A的超声后大尺寸减少是颗粒聚集的指示。
表1:
方法 | 浓缩液 | 含水稀释液 | 平均粒径(μm) | 超声后(1分钟) |
A | 伊曲康唑(18%),N-甲基-2-吡咯啉酮(6ml) | Poloxamer 188(2.3%),脱氧胆酸钠(0.3%),tris缓冲液(5mM,pH 8),水(量补至94ml) | 18.710.712.1 | 2.362.461.93 |
B | 伊曲康唑(18%),poloxamer 188(37%),N-甲基-2-吡咯啉酮(6ml) | 脱氧胆酸钠(0.3%),tris缓冲液(5mM,pH 8)水(量补至94ml) | 0.1940.1780.181 | 0.1980.1790.177 |
由应用本发明所述方法产生的药物悬浮液可以直接作为可注射溶液给药,条件是制剂中使用注射用水,并应用适合溶液灭菌的方式。灭菌采用本领域众所周知的方法,诸如蒸汽或热灭菌,γ辐射等。其他灭菌方法,尤其对大于99%的颗粒小于200nm而言,还将包括首先通过3.0μm过滤器前过滤,接着通过0.45μm颗粒过滤器过滤,再通过两个多余的0.2μm膜过滤器进行蒸汽或热消毒或无菌过滤。另一灭菌方式为无菌过滤制备自第一溶剂的浓缩液和无菌过滤含水稀释液,所述第一溶剂含有药物和任选的一种或多种表面活性剂。接着在无菌混合容器,优选在分离的无菌环境中组合。在无菌条件下,对悬浮液进行混合,均化和进一步处理。
另一灭菌工艺为在均化步骤前,中或后在均质机内热消毒或高压灭菌。热处理后的加工在无菌条件下进行。
任选的,无溶剂悬浮液可在沉淀后通过去除溶剂产生。实现此的方法有离心,透析,透滤,力场级分,高压过滤,反渗透,或其他本领域众所周知的分离技术。完全移出N-甲基-2-吡咯啉酮一般通过1-3个连续离心轮次进行;每次离心(18,000rpm 30分钟)后,倾倒并丢弃上清液。没有有机溶剂的新鲜体积的悬浮液媒介物加至剩余固体中,并通过均化分散混合物。本领域技术人员会意识到,其他高剪切混合技术也可应用于此再生步骤中。或者,无溶剂颗粒视需要可被配制成各种不同的剂型,用于多种给药途径,诸如口服,肺部,鼻,局部,肌内等。
此外,任何不期望的赋形剂诸如表面活性剂,通过使用上段中所述的分离方法,可被更理想的赋形剂替换。离心或过滤后,溶剂和第一赋形剂与上清液一起被丢弃。然后,加入没有溶剂和第一赋形剂的新鲜体积的悬浮液媒介物。或者,加入新表面活性剂。例如,由药物,N-甲基-2-吡咯啉酮(溶剂),poloxamer 188(第一赋形剂),脱氧胆酸钠,甘油和水组成的悬浮液,在离心和去除上清液后可被磷脂(新表面活性剂),甘油和水替换。
I.第一工艺类别
第一工艺类别的方法一般包括溶解有机化合物于水可混第一溶剂的步骤,接着混合该溶液与含水溶剂形成前悬浮液的步骤,其中有机化合物通过X-射线衍射研究,DSC,光学显微镜或其他分析技术确定为无定形,半晶体形式或超冷却液体形式,并具有平均有效粒径在上述一种有效粒径范围之内。混合步骤之后为能量加入步骤。
II.第二工艺类别
第二工艺类别的方法包括与第一工艺类别基本相同的步骤,但在下列方面不同。X-射线衍射,DSC或其他合适的分析技术对前悬浮液分析显示,有机化合物为晶体形式,并具有平均有效粒径。能量加入步骤之后的有机化合物与能量加入步骤之前具有基本相同的平均有效粒径,但是与前悬浮液的颗粒相比,聚集成较大颗粒的倾向较少。无需受理论的束缚,据认为颗粒稳定性的差异可能归因于固-液界面处表面活性剂分子的重排。
III.第三工艺类别
第三类别的方法修改了第一和第二工艺类别方法中的前两步,以确保有机化合物的前悬浮液为易碎的形式,具有平均有效粒径(例如,细长针和薄板)。易碎颗粒的形成方法是选择合适的溶剂,表面活性剂或表面活性剂的组合,单个溶液的温度,混合速率和沉淀速率等。通过在混合第一溶液与含水溶剂的步骤过程中导入晶格缺陷(例如,晶体的裂开面)也可提高易碎性。这将起因于诸如沉淀步骤中所提供的快速结晶。在能量加入步骤中,这些易碎晶体被转化成动力学上稳定、且其平均有效粒径小于前悬浮液的晶体。动力学稳定的平均颗粒在与动力学不稳定的颗粒比较时聚集的倾向减少。在这种情形下,能量加入步骤导致易碎颗粒的破裂。通过确保前悬浮液的颗粒处于易碎状态,当与未采取步骤赋予有机化合物以易碎形式而处理有机化合物比较时,易碎形式的有机化合物可被更容易更快速地制备成所需尺寸范围之内的颗粒。
IV.第四工艺类别
第四工艺类别的方法包括第一工艺类别的步骤,除了混合步骤与能量加入步骤同时进行以外。
多晶形控制
本发明进一步提供额外步骤用于控制有机化合物的晶体结构从而最终生产出具有所需尺寸范围和所需晶体结构的化合物的悬浮液。术语“晶体结构”表示原子在晶体单位晶格内的排列。可被结晶成不同晶体结构的化合物据说是多晶形的。多晶形鉴定在药物配制中是重要步骤,这是因为相同药物的不同多晶形在溶解性,治疗活性,生物利用度和悬浮液稳定性方面存在差异。因此,重要的是控制化合物的多晶形形式,以确保产物纯度和批间再现性。
控制化合物的多晶形形式的步骤包括加晶种于第一溶液,第二溶剂或前悬浮液以确保形成所需的多晶形。加晶种包括利用晶种化合物或加入能量。在本发明优选的形式中,晶种化合物为药物活性化合物的所需多晶形形式。此外,晶种化合物还可为惰性杂质、在结构上与所需多晶形不相关但具有晶核模板特征的化合物,或者结构与所需多晶形相似的有机化合物。
晶种化合物可从第一溶液中沉淀。该方法包括以足量加入有机化合物,超过该有机化合物在第一溶剂中的溶解度而生成超饱和溶液的步骤。处理超饱和溶液以所需多晶形形式沉淀出有机化合物。处理超饱和溶液包括老化溶液一时间段直至观察到晶体形成以产生晶种混合物。还有可能向超饱和溶液中加入能量以使有机化合物从溶液中以所需多晶形沉淀出来。能量加入方式多种多样,包括上述的能量加入步骤。通过加热,或使前悬浮液暴露于电磁能,粒子束或电子束源,可加入更多能量。电磁能包括光能(紫外,可见或红外光)或诸如由激光器提供的相干辐射,由微波激射器(通过辐射的受激发射的微波放大)提供的微波能,动态电磁能,或其他辐射源。进一步可以预计,利用超声,静态电场或静态磁场,或其组合作为能量加入源。
在本发明优选的形式中,从老化超饱和溶液中生产晶种晶体的方法包括下列步骤:(i)加入一些有机化合物至第一有机溶剂生成超饱和溶液,(ii)使超饱和溶液老化形成可检测的晶体以产生晶种混合物,以及(iii)混合晶种混合物与第二溶剂而沉淀有机化合物以产生前悬浮液。然后,前悬浮液如上所述可被进一步处理,从而以所需多晶形和所需尺寸范围提供有机化合物的水悬液。
加晶种也可通过加入能量至第一溶液,第二溶剂或前悬浮液而完成,条件是被暴露的一种或多种液体含有有机化合物或晶种物质。能量也可以上述对超饱和溶液的同样方式加入。
因此,本发明提供具有所需多晶形形式、基本上不含一种或多种非指定多晶形的有机化合物物质的组合物。在本发明优选的形式中,有机化合物是药物活性物质。一种这样的例子阐述在下文实施例16,其中在微沉淀过程中加入晶种提供了基本上不含原材料的多晶形的伊曲康唑的多晶形。本发明的方法预计可用于为众多药物活性化合物选择性生产所需多晶形。
抗肿瘤剂的亚微米悬液
本申请前面描述的方法可用于制备含水不溶性抗肿瘤剂亚微米颗粒的悬液的制剂,所述抗肿瘤剂特别为紫杉醇或其衍生化合物,包括但不限于紫杉萜和其他紫杉醇类似物。这些制剂通常允许含有1-20%w/v药物的高药物载荷。高于20%w/v的药物载荷也可以用这些制剂完成。相同制剂可以通过不同途径给药,例如,口服,肠胃外和肺。
抗肿瘤剂的颗粒可以被配制以除去作为赋形剂的聚氧乙烯醚氢化蓖麻油(cremophor)以及获得具有长循环时间特性的剂型。用具有聚乙二醇(PEG)官能团的表面改性剂配制的颗粒可以用于避免颗粒调理作用和随后内质网系统(RES)的吸收。此外,粒径小于200nm,特别是小于150nm的颗粒可以用于帮助延长循环时间以及通过有孔的肿瘤血管渗透而靶向肿瘤。
制备这些抗肿瘤剂亚微米颗粒的优选方法由如下步骤组成:(i)向水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中混入含有结合了水溶性或亲水性聚合物的磷脂的第一表面改性剂;(ii)将抗肿瘤剂溶解在水可混第一溶剂以形成溶液,(iii)将该溶液与第二溶剂混合以定义颗粒的前悬液;以及(iv)均化前悬液以形成平均有效粒径小于约1μm的颗粒的悬液。优选的水可混第一溶剂是N-甲基-2-吡咯啉酮。优选地,颗粒的平均有效粒径小于约400nm,更优选小于200nm,最优选小于约150nm。
使用的磷脂可以是天然的或合成的。合适的磷脂的例子包括但不限于:磷脂酰胆碱,磷脂酰乙醇胺,二酰基甘油磷酸乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇,磷脂酰甘油,磷脂酸,溶血磷脂,卵磷脂或大豆磷脂或其组合。二酰基甘油磷酸乙醇胺可以选自:二肉豆蔻酰甘油磷酸乙醇胺(DMPE),二棕榈酰甘油磷酸乙醇胺(DPPE),二硬脂酰甘油磷酸乙醇胺(DSPE),二油酰甘油磷酸乙醇胺(DOPE)等。
在优选的实施方案中,连接到磷脂的水溶性或亲水性聚合物是聚乙二醇(PEG),例如但不限于PEG350,PEG550,PEG750,PEG1000,PEG2000,PEG3000,和PEG5000。其他亲水性聚合物连接物也可以使用,例如葡聚糖,羟丙基甲基丙烯酸酯(HPMA),聚谷氨酸酯等。
任选地,第二表面改性剂可以被混合到水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中。第二表面改性剂可以是进一步稳定颗粒所需要的。第二表面改性剂可选自本申请已经详细描述的阴离子表面活性剂,阳离子表面活性剂,非离子表面活性剂和表面活性生物改性剂。优选的第二表面改性剂是poloxamer,例如poloxamer188。
可以通过均化时的温度而控制如实施例19的例子中所述的粒径。在实施方案中,均化在约30℃或更高温度下进行,例如约40℃或约70℃。
该方法还可以进一步包括从悬液中除去水可混第一溶剂以形成基本无溶剂的颗粒的水悬液。在优选的实施方案中,如共同未决和共同转让的US专利申请律师卷号113957-375中详细描述的与均化同时除去水可混第一溶剂。
该方法还可以进一步包括除去悬液中的全部液相以形成颗粒的干粉。干粉可用于通过肺途径给药,或者干粉可以重悬于合适的稀释剂,例如适合用于肠胃外或口服给药的稀释剂。颗粒还可制成口服制剂。用于肠胃外和口服给药的制剂对于本领域技术人员是公知的。同样的制剂可以用于通过以下各种途径给药到对象,例如但不限于肠胃外,口服,肺,局部,眼,鼻,含服,直肠,阴道,经皮等。
所述方法还可以进一步包括如本申请前面的描述对组合物进行灭菌。对药物组合物灭菌的方法包括但不限于过滤、加热灭菌和γ辐射。可以在均质机内部进行加热灭菌,其中均质机作为灭菌的加热和受压源。
在优选的实施方案中,颗粒是不溶性的。通过溶解动力学使用400nm处的透射%作为溶解度的量度而检测颗粒的溶解度。如果透射%不返回到初始值的95%或更大,则该颗粒是不溶性的。
在另外的优选实施方案中,颗粒在受压条件或储存后不聚集。受压条件的例子包括但不限于,热循环,重复冻融循环,搅拌和离心。颗粒的应力(stress)检测方法是本领域公知的。典型的应力检测方法描述于Novel Injectable Formulations of Insoluble Drugs,Pace等,PharmTech,1999年3月,第116-134页。可以通过测量超声前后1分钟的粒径并通过下列等式比较差异而估计聚集:
聚集%=(P99-P99S)/P99S×100
其中P99代表超声前颗粒的百分位数99的粒径分布而P99S代表超声后颗粒的百分位数99的粒径分布。
实施例
A.工艺类别1的实施例
实施例1:使用工艺类别1,方法A通过均化制备伊曲康唑悬浮液
向3L烧瓶中加入1680ml的注射用水。加热液体至60-65℃,然后缓慢加入44g的Pluronic F-68(poloxamer 188),以及12g的脱氧胆酸钠,每次加入后搅拌以使固体溶解。固体加入完成后,在60-65℃另搅拌15分钟以确保完全溶解。将6.06g tris溶解在800ml的注射用水中制备50mM tris(tromethamine)缓冲液。以0.1M盐酸滴定该溶液至pH 8.0。用额外注射用水稀释所得溶液至1升。加入200ml的tris缓冲液至poloxamer/脱氧胆酸盐溶液。充分搅拌以混合溶液。
在150ml烧杯中加入20g的伊曲康唑和120ml的N-甲基-2-吡咯啉酮。加热混合物至50-60℃,并搅拌使固体溶解。目测全部溶解后,继续搅拌15分钟以确保完全溶解。冷却伊曲康唑-NMP溶液至室温。
以120ml事先制备的伊曲康唑溶液装填注射泵(两支60ml玻璃注射器)。同时将所有表面活性剂溶液倾倒至已冷却至0-5℃的均质机漏斗(这可通过利用冷却剂从中循环的夹套漏斗或通过用冰环绕漏斗而实现)。使机械搅拌器置于表面活性剂溶液中,以致完全浸没刀片。使用注射泵,缓慢(1-3ml/分钟)加入所有的伊曲康唑溶液至搅拌冷却的表面活性剂溶液。搅拌速率推荐至少700rpm。采用光学显微镜(Hoffman Modulation Contrast)和激光衍射(Horiba)分析所得悬浮液(悬浮液A)的等份试样。通过光学显微镜观察悬浮液A,发现其组成为大致球形的无定形颗粒(1μm以下),以聚集体彼此结合,或通过布朗运动自由移动。参见图3,动态光散射测量通常提供双峰式分布模式,表示存在聚集体(10-100μm大小)和存在中值粒径为200-700nm的单个无定形颗粒。
悬浮液立即均化(10,000-30,000psi)10-30分钟。均化结束时,悬浮液在漏斗中的温度不超过75℃。均化的悬浮液收集在500ml瓶中,立即在冰箱(2-8℃)中冷却。通过光学显微镜分析该悬浮液(悬浮液B),发现其由长0.5-2μm、宽0.2-1μm的小长片组成。参见图4。动态光散射测量一般显示中值直径为200-700nm。
悬浮液A的稳定性(“前悬浮液”)(实施例1)
在显微检查悬浮液A的等份试样过程中,直接观察到结晶的无定形固体。悬浮液A在2-8℃存储12小时,并通过光学显微镜检查。对样品粗目测发现有严重的絮凝,有些内容物沉降至容器的底部。显微镜检查显示存在长度10μm以上、大的细长片样晶体。
悬浮液B的稳定性
与悬浮液A的不稳定性相反,悬浮液B在2-8℃和稳定性预研究的持续时间(1个月)是稳定的。对老化样品的显微镜检查清晰地表明,颗粒的形态或尺寸没有发生显著的变化。通过光散射测量也证实如此。
实施例2:利用工艺类别1,方法A通过超声制备伊曲康唑悬浮液
向500ml不锈钢容器加入252ml的注射用水。加热液体至60-65℃,然后缓慢加入6.6g的Pluronic F-68(poloxamer 188),以及0.9g的脱氧胆酸钠,每次加入后搅拌以使固体溶解。固体加入完成后,在60-65℃另搅拌15分钟以确保完全溶解。将6.06g tris溶解在800ml的注射用水中制备50mM tris(tromethamine)缓冲液。以0.1M盐酸滴定该溶液至pH 8.0。用额外注射用水稀释所得溶液至1升。加入30ml的tris缓冲液至poloxamer/脱氧胆酸盐溶液。充分搅拌以混合溶液。
在30ml容器中加入3g的伊曲康唑和18ml的N-甲基-2-吡咯啉酮。加热混合物至50-60℃,并搅拌使固体溶解。目测全部溶解后,继续搅拌15分钟以确保完全溶解。冷却伊曲康唑-NMP溶液至室温。
以18ml上述步骤制备的伊曲康唑溶液装填注射泵。将机械搅拌器置于表面活性剂溶液中,以致完全浸没刀片。在冰浴中浸没以使容器冷却至0-5℃。使用注射泵,缓慢(1-3ml/分钟)加入所有的伊曲康唑溶液至搅拌冷却的表面活性剂溶液。搅拌速率推荐至少700rpm。浸没超声仪角状物(horn)在所得悬浮液0中,以使探头高于不锈钢容器底部近1cm。超声(10,000-25,000Hz,至少400W)15-20分钟,间隔时间为5分钟。在第一个5分钟超声之后,移去冰浴,进一步超声。超声结束时,悬浮液在容器中的温度不超过75℃。
悬浮液收集在500ml I型玻璃瓶中,立即在冰箱(2-8℃)中冷却。该悬浮液的颗粒形态特征在超声前后与均化前后方法A中见到的非常相似(参见实施例1)。
实施例3:利用工艺类别1,方法B通过均化制备伊曲康唑悬浮液
将6.06g tris溶解在800ml的注射用水中制备50mM tris(tromethamine)缓冲液。以0.1M盐酸滴定该溶液至pH 8.0。用额外注射用水稀释所得溶液至1升。向3L烧瓶中加入1680ml的注射用水。加入200ml的tris缓冲液至1680ml的水中。充分搅拌以混合溶液。
在150ml烧杯中加入44g的Pluronic F-68(poloxamer 188)和12g的脱氧胆酸钠至120ml的N-甲基-2-吡咯啉酮。加热混合物至50-60℃,并搅拌使固体溶解。目测全部溶解后,继续搅拌15分钟以确保完全溶解。向该溶液中加入20g的伊曲康唑,搅拌直至完全溶解。冷却伊曲康唑-表面活性剂-NMP溶液至室温。
以120ml事先制备的浓伊曲康唑溶液装填注射泵(两支60ml玻璃注射器)。同时将稀释的上述制备的tris缓冲溶液倾倒至已冷却至0-5℃的均质机漏斗(这可通过利用冷却剂从中循环的夹套漏斗或通过用冰环绕漏斗而实现)。将机械搅拌器置于缓冲溶液中,以致完全浸没刀片。使用注射泵,缓慢(1-3ml/分钟)加入所有的伊曲康唑-表面活性剂浓缩液至搅拌冷却的缓冲溶液。搅拌速率推荐至少700rpm。所得冷却的悬浮液立即均化(10,000-30,000psi)10-30分钟。均化结束时,悬浮液在漏斗中的温度不超过75℃。
均化的悬浮液收集在500ml瓶中,立即在冰箱(2-8℃)中冷却。悬浮液的颗粒形态特征在均化前后非常相似于实施例1中所见的,除了在工艺类别1B中,预先均化的材料倾向于形成更少和更小的聚集体,导致小得多的总粒径,如激光衍射所测量。均化后,动态光散射结果通常与实施例1中所示的相同。
实施例4:利用工艺类别1,方法B通过超声制备伊曲康唑悬浮液
向500ml烧瓶加入252ml的注射用水。将6.06g tris溶解在800ml的注射用水中制备50mM tris(tromethamine)缓冲液。以0.1M盐酸滴定该溶液至pH 8.0。用额外注射用水稀释所得溶液至1升。加入30ml的tris缓冲液至水。充分搅拌以混合溶液。
在30ml烧杯中加入6.6g的Pluronic F-68(poloxamer 188)和0.9g的脱氧胆酸钠至18ml的N-甲基-2-吡咯啉酮。加热混合物至50-60℃,并搅拌使固体溶解。目测全部溶解后,继续搅拌15分钟以确保完全溶解。向该溶液中,加入3.0g的伊曲康唑,并搅拌直至完全溶解。冷却伊曲康唑-表面活性剂-NMP溶液至室温。
以18ml上述步骤制备的浓伊曲康唑溶液装填注射泵(一支30ml玻璃注射器)。将机械搅拌器置于缓冲溶液中,以致完全浸没刀片。在冰浴中浸没以使容器冷却至0-5℃。使用注射泵,缓慢(1-3ml/分钟)加入所有的伊曲康唑-表面活性剂浓缩液至搅拌冷却的缓冲溶液。搅拌速率推荐至少700rpm。所得冷却的悬浮液立即超声(10,000-25,000Hz,至少400W)15-20分钟,间隔时间为5分钟。在第一个5分钟超声之后,移去冰浴,进一步超声。超声结束时,悬浮液在漏料中的温度不超过75℃。
所得悬浮液收集在500ml瓶中,立即在冰箱(2-8℃)中冷却。该悬浮液的颗粒形态特征在超声前后与实施例1中所见的非常相似,除了在工艺类别1,方法B中,预先超声的材料倾向于形成更少和更小的聚集体,导致小得多的总粒径,如激光衍射测量。超声后,动态光散射结果一般与实施例1中所示的相同。
B.工艺类别2的实施例
实施例5:利用0.75%SolutolHR(PEG-66012-羟基硬脂酶酯)工艺类别2,方法B制备伊曲康唑悬浮液(1%)
称重Solutol(2.25g)和伊曲康唑(3.0g)至烧杯中,加入36ml过滤的N-甲基-2-吡咯啉酮(NMP)。该混合物在低加热(最高达40℃)下搅拌约15分钟直至溶液成分溶解。溶液冷却至室温,并在真空下通过0.2μm的过滤器过滤。两支60ml注射器装填过滤的药物浓缩液,置于注射泵中。该泵设定使近1ml/min的浓缩液传递至快速搅拌(400rpm)的水性缓冲溶液。缓冲溶液由22g/L甘油的5mM tris缓冲液组成。在整个浓缩液加入过程中,缓冲溶液保持在2-3℃的冰浴中。沉淀结束时,浓缩液全部加至缓冲溶液后,约100ml的悬浮液离心1小时,丢弃上清液。将沉淀物重悬浮于20%NMP溶液的水中,再次离心1小时。所得材料在真空箱中25℃下干燥过夜。干燥材料转移至小瓶中,然后利用铬辐射通过X-射线衍射进行分析(参见图5)。
另100ml等份试样的微沉淀悬浮液在20,000Hz下以80%满振幅(满振幅=600W)超声30分钟。超声样品在3个相等等份试样中均化,各45分钟(Avestin C5,2-5℃,15,000-20,000psi)。组合级分离心约3小时,移出上清液,并将沉淀物重悬浮于20%NMP中。重悬浮的混合物再次离心(15,000rpm,5℃)。倾倒上清液,沉淀物在25℃真空干燥过夜。沉淀物提交X-射线衍射分析(参见图5)。如图5所示,处理样品的X-射线衍射模式在均化前后基本上是相同的,然而与起始原料的模式比较仍显示显著的差异。未均化的悬浮液是不稳定的,室温下储存时聚集。作为均化的结果,稳定性据信起源于表面活性剂在颗粒表面上的重排。该重排导致颗粒聚集的倾向降低。
C.工艺类别的实施例
实施例6:利用工艺类别3,方法A通过均化制备卡巴咪嗪悬浮液
2.08g的卡巴咪嗪溶解于10ml的NMP。1.0ml的该浓缩液随后以0.1ml/min滴加至20ml1.2%卵磷脂和2.25%甘油的搅拌溶液。卵磷脂系统的温度在整个加入过程中维持在2-5℃。接着,前分散体以15,000psi冷(5-15℃)均化35分钟。压力升高至23,000pis,并继续均化20分钟。由此工艺产生的颗粒的平均直径为0.881μm,其中99%的颗粒小于2.44μm。
实施例7:利用工艺类别3,方法B通过均化制备含有0.125%Solutol的1%卡巴咪嗪悬浮液
制备20%卡巴咪嗪和5%甘脱氧胆酸(Sigma Chemical Co.)的N-甲基-2-吡咯啉酮的药物浓缩液。微沉淀步骤包括向接受液(蒸馏水)中以0.1ml/min的速率加入药物浓缩液。搅拌接受液,并在沉淀过程中维持在近5℃。沉淀后,成分最终浓度为1%卡巴咪嗪和0.125%Solutol。在光学显微镜下利用正相差(400×)检查药物晶体。颗粒组成为直径近2μm和长度50-150μm的细针。
在近20,000psi均化(Avestin C-50活塞隙均质机)约15分钟导致小的颗粒,尺寸小于1μm,而且大部分未聚集。均化材料的激光衍射分析(Horiba)显示,颗粒的平均尺寸为0.4μm,其中99%的颗粒小于0.8μm。低能量超声适于打破聚集的颗粒,但其能量不足以引起在Horiba分析前样品的单个颗粒的粉碎,低能量超声对结果没有影响(有超声和没有超声数目一样)。该结果与没有颗粒聚集是一致的。
由上述工艺制备的样品离心,上清液用由0.125%Solutol组成的替换液替换。离心和上清液替换后,悬浮液成分浓度为1%卡巴咪嗪和0.125%Solutol。样品经活塞隙均质机重新均化,并储存在5℃。存储4周后,悬浮液的平均粒径为0.751,其中有99%小于1.729。报告的数目来自Horiba对未超声样品的分析。
实施例8:利用工艺类别3,方法B通过均化制备含有0.06%甘脱氧胆酸钠和0.06%poloxamer 188的1%卡巴咪嗪悬浮液
制备含有20%卡巴咪嗪和5%甘脱氧胆酸的N-甲基-2-吡咯啉酮的药物浓缩液。微沉淀步骤包括向接受液(蒸馏水)中以0.1ml/min的速率加入药物浓缩液。因此,下列实施例证明,在上述方法A和B中向含水沉淀溶液中加入表面活性剂或其他赋形剂是任选的。接受液被搅拌,并在沉淀过程中维持在近5℃。沉淀后,成分最终浓度为1%卡巴咪嗪和0.125%Solutol。在光学显微镜下利用正相差(400×)检查药物晶体。测定物组成为直径近2μm和长度50-150μm的细针。沉淀物与沉淀前原料的比较表明,在表面改性剂(甘脱氧胆酸)存在下的沉淀步骤导致非常细小的晶体,比起始原料要细得多(参见图6)。
在近20,000psi均化(Avestin C-50活塞隙均质机)约15分钟产生小的颗粒,尺寸小于1μm,而且大部分未聚集。参见图7。均化材料的激光衍射分析(Horiba)显示,颗粒的平均尺寸为0.4μm,其中99%的颗粒小于0.8μm。Horiba分析前,样品的超声对结果没有影响(有超声和没有超声数目一样)。该结果与没有颗粒聚集是一致的。
由上述工艺制备的样品离心,上清液用组成为0.06%甘脱氧胆酸(Sigma Chemical Co.)和0.06%Poloxamer 188的替换液替换。样品经活塞隙均质机重新均化,并储存在5℃。存储2周后,悬浮液的平均粒径为0.531μm,其中有99%小于1.14μm。报告的数目来自Horiba对未超声样品的分析。
数学分析(实施例8)与破坏起始原料(卡巴咪嗪)的颗粒所需的力相比破坏沉淀颗粒所需的力:
卡巴咪嗪原料中可见的最大晶体的宽度(图6,左幅图)大致比微沉淀材料(图6,右幅图)中晶体的宽度大10倍。假设晶体厚度之比(1∶10)与晶体宽度(1∶10)之比成比例,裂开原料中较大晶体所需的力矩应大致是破坏微沉淀材料所需力的1000倍,这是因为:
eL=6PL/(Ewx2) 方程式1
其中,
eL=破坏晶体所需的纵向应变(“屈服值”)
P=梁上负荷
L=从负荷到支点的距离
E=弹性模数
w=晶体宽度
x=晶体厚度
假设原料和沉淀材料的L和E相同。另外,假设w/w0=x/x0=10。则,
(eL)0=6P0L(Ew0x0 2),其中‘0’下标指原料
eL=6PL(Ewx2),对于微沉淀而言
使(eL)0=eL,
6PL(Ewx2)=6P0L(Ew0x0 2)
简化后,
P=P0(w/w0)(x/x0)2=P0(0.1)(0.1)2=0.001P0
由此,破坏微沉淀固体所需的屈服力P为破坏出发结晶固体所需力的千分之一。如果因为快速沉淀,引入晶格缺陷或无定形属性,则模数(E)应降低,使得微沉淀甚至更易切开。
实施例9:利用工艺类别3,方法B制备含有0.05%脱氧胆酸钠和3%N-甲基-2-吡咯啉酮的1.6%(w/v)脱氢皮质醇悬浮液
总的制备过程示意图如图8所示。制备脱氢皮质醇和脱氧胆酸钠的浓缩液。将脱氢皮质醇(32g)和脱氧胆酸钠(1g)加至足够体积的1-甲基2-吡咯啉酮(NMP)生成终体积60ml。所得脱氢皮质醇浓度为近533.3mg/ml,以及脱氧胆酸钠浓度约16.67mg/ml。60ml的NMP浓缩液以2.5ml/min的加入速率加到2L冷却至5℃的水中,同时以约400rpm搅拌。所得悬浮液含有细针型晶体,宽度小于2μm(图9)。沉淀悬浮液中所含浓度为1.6%(w/v)脱氢皮质醇,0.05%脱氧胆酸钠,和3%NMP。
沉淀悬浮液的pH利用氢氧化钠和盐酸调节至7.5-8.5,然后在10,000psi下均化(Avestin C-50活塞隙均质机)10次。通过连续两次离心步骤移出NMP,每次用新鲜表面活性剂溶液替换上清液,所述新鲜表面活性剂溶液含有稳定悬浮液所需浓度的表面活性剂(参见表2)。悬浮液在10,000psi下另均化10次。最终悬浮液含有的颗粒平均粒径小于1μm,其中99%的颗粒小于2μm。图10为均化后最终脱氢皮质醇悬浮液的显微照片。
不同浓度的各种表面活性剂用于离心/表面活性剂替换步骤(参见表2)。表2列出了对粒径(平均<1μm,99%<2μm)pH(6-8),药物浓度(损失小于2%)和可重悬浮性(在60秒或更短时间内重悬浮)稳定的表面活性剂的组合。
显然,该工艺允许在没有表面活性剂或其他添加剂存在下向含水稀释液加入活性化合物。这是对图2中工艺方法B的修改。
表2:通过图8的微沉淀工艺制备的稳定脱氢皮质醇悬浮液列表
(实施例9)
2周 | 2月 | ||||||||||
初始 | 40℃ | 5℃ | 25℃ | 40℃ | |||||||
配方 | 平均 | >99% | 平均 | >99% | 平均 | >99% | 平均 | >99% | 平均 | >99% | %损失* |
1.6%脱氢皮质醇,0.6%磷脂,0.5%脱氧胆酸钠,5mMTRIS,2.2%甘油** | 0.79 | 1.65 | 0.84 | 1.79 | 0.83 | 1.86 | 0.82 | 1.78 | 0.82 | 1.93 | <2% |
1.6%脱氢皮质醇,0.6%Solutol,0.5%脱氧胆酸钠,2.2%甘油 | 0.77 | 1.52 | 0.79 | 1.67 | 0.805 | 1.763 | 0.796 | 1.693 | 0.81 | 1.633 | <2% |
1.6%脱氢皮质醇,0.1%poloxamer188,0.5%脱氧胆酸钠,2.2%甘油 | 0.64 | 1.16 | 0.82 | 1.78 | 0.696 | 1.385 | 0.758 | 1.698 | 0.719 | 1.473 | <2% |
1.6%脱氢皮质醇,5%磷脂,5mMTRIS,2.2%甘油 | 0.824 | 1.77 | 0.87 | 1.93 | 0.88 | 1.95 | 0.869 | 1.778 | 0.909 | 1.993 | <2% |
*伊曲康唑浓度在样品于5和25℃下存储2个月之间的差异。
**至少6个月的稳定。
粒径(通过激光散射测定),μm:
5℃:0.80(平均),1.7(99%)
25℃:0.90(平均),2.51(99%)
40℃:0.99(平均),2.03(99%)
伊曲康唑浓度在样品于5和25℃下存储之间的差异:<2%
实施例10:利用工艺类别3,方法A通过均化制备脱氢皮质醇悬浮液
32g的脱氢皮质醇溶解于40ml的NMP。为实现溶解需在40-50℃下温和加热。随后以2.5ml/min将药物NMP浓缩液滴加至2L的搅拌溶液,搅拌溶液的组成为0.1.2%卵磷脂和2.2%甘油。不添加其他表面改性剂。表面活性剂系统用5mM tris缓冲液在pH=8.0缓冲,并在整个沉淀工艺中温度维持在0-5℃。接着沉淀后的分散体在10,000psi下冷(5-15℃)均化20次。均化后,悬浮液离心去除NMP,移出上清液,并用新鲜表面活性剂溶液替换上清液。该离心后的悬浮液在10,000psi下冷(5-15℃)重均化另外20次。由此工艺生产的颗粒的平均直径为0.927μm,其中99%的颗粒小于2.36μm。
实施例11:利用工艺类别3,方法B通过均化制备萘丁美酮悬浮液
将表面活性剂(2.2g的poloxamer 188)溶解于6ml的N-甲基-2-吡咯啉酮。该溶液在45℃下搅拌15分钟,其后加入1.0g的萘丁美酮。药物快速溶解。制备的稀释液组成为5mM tris缓冲液和2.2%甘油,调节至pH 8。100ml份的稀释液冷却在冰浴中。剧烈搅拌下向稀释液缓慢加入(近0.8ml/min)药物浓缩液。该粗悬浮液在15,000psi下均化30分钟,然后在20,000pis下均化30分钟(温度=5℃)。最终纳米悬浮液的有效平均直径为930nm(通过激光衍射分析)。99%的颗粒小于近2.6μm。
实施例12:利用工艺类别3,方法B通过均化以及利用SolutolHS 15作为表面活性剂制备萘丁美酮悬浮液
以磷脂介质替换上清液
将萘丁美酮(0.987g)溶解于8ml的N-甲基-2-吡咯啉酮。向该溶液中加入2.2g的SolutolHS 15。搅拌该混合物直至表面活性剂完全溶解在药物浓缩液中。制备的稀释液组成为5mM tris缓冲液和2.2%甘油,调节至pH 8。稀释液在冰浴中冷却,剧烈搅拌下向稀释液缓慢加入(近0.5ml/min)药物浓缩液。该粗悬浮液在15,000psi下均化20分钟,以及在20,000pis下均化30分钟。
悬浮液以15,000rpm离心15分钟,并移出和丢弃上清液。将剩余固体球粒重悬于组成为1.2%磷脂的稀释液。该介质的体积与前步移出的上清液的量相等。然后,所得悬浮液以近21,000psi均化30分钟。最终悬浮液由激光衍射分析,发现含有的颗粒平均直径为542nm和99%累积的颗粒分布尺寸小于1μm。
实施例13:制备颗粒平均直径约220nm、含有poloxamer的1%伊曲康唑悬浮液
通过溶解10.02g的伊曲康唑于60ml的N-甲基-2-吡咯啉酮制备伊曲康唑浓缩液。为溶解药物需加热至70℃。然后溶液冷却至室温。制备50mM三(羟甲基)氨基甲烷缓冲液(tris缓冲液)的部分,pH以5M盐酸调节至8.0。含水表面活性剂溶液的制备方法是组合22g/Lpoloxamer 407,3.0g/L卵磷脂,22g/L甘油以及3.0g/L胆酸钠二水合物。900ml的表面活性剂溶液与100ml的tris缓冲液混合提供1000ml的含水稀释液。
含水稀释液加至均质机(APV Gaulin Model 15MR-8TA)的漏斗,该漏斗利用冰夹套冷却。溶液快速搅拌(4700rpm)和监控温度。利用注射泵,以约2ml/min的速率缓慢加入伊曲康唑浓缩液。约30分钟后加入完成。所得悬浮液另搅拌30分钟,同时漏斗仍冷却在冰夹套中,移出等份试样用于光学显微镜和动态光散射分析。随后剩余悬浮液以10,000psi均化15分钟。至均化结束时,温度已升至74℃。均化悬浮液收集在1L I型玻璃瓶中,并用橡胶封闭物密封。含有悬浮液的瓶子存储在5℃冰箱中。
均化前的悬浮液样品显示样品由游离颗粒,颗粒块和多层脂质体(lipid body)组成。由于布朗运动,游离颗粒不能被清楚地看见;然而,许多聚集体似乎由无定形,非晶体材料组成。
均化样品含有尺寸均一性优异、没有可见脂类囊泡的游离亚微米颗粒。动态光散射显示单分散对数尺寸分布,中值直径约220nm。99%以上的累积尺寸截留约500nm。图11显示制备的纳米颗粒的尺寸分布与典型肠胃外脂肪乳液产品(10%Intralipid,Pharmacia)的比较。
实施例14:制备含有羟乙基淀粉的1%伊曲康唑纳米悬浮液
溶液A的制备:羟乙基淀粉(1g,Ajinomoto)溶解于3ml的N-甲基-2-吡咯啉酮(NMP)。该溶液在水浴中加热至70-80℃,历时1小时。在另一容器中,加入1g的伊曲康唑(Wyckoff)。加入3ml的NMP,该混合物加热至70-80℃以实现溶解(近30分钟)。向该热溶液中加入磷脂(Lipoid S-100)。在70-90℃下继续加热30分钟,直至所有磷脂溶解。羟乙基淀粉溶液与伊曲康唑/磷脂溶液组合。该混合物在80-95℃下另加热30分钟以溶解混合物。
溶液A加至Tris缓冲液:94ml的50mM三(羟甲基)氨基甲烷缓冲液冷却在冰浴中。随着tris溶液快速搅拌,热溶液A(如上所述)缓慢滴加(小于2cc/min)。
加入完成后,所得悬浮液超声(Cole-Parmer超声处理器-20,000Hz,80%振幅设定),同时仍冷却在冰浴中。利用1英寸固体探头。超声持续5分钟。去除冰浴,移出探头,重新调整后再次浸没在悬浮液中。悬浮液在没有冰浴时另超声5分钟。超声探头再次移出和重新调整,并在浸没探头后使样品超声另5分钟。此时,悬浮液的温度已升至82℃。悬浮液再次快速冷却在冰浴中,并在低于室温时倾入I型玻璃瓶中和密封。显微镜下可见颗粒的单个粒径在1μm或更少的量级。
室温下存储1年后,重新评价悬浮液的粒径,发现平均直径约300nm。
实施例15.利用HES方法A的预示实施例
本发明预计在实施例14的步骤之后,利用方法A制备含有羟乙基淀粉的1%伊曲康唑纳米悬浮液,例外之处在于HES加至tris缓冲液而非加至NMP溶液。水溶液有可能必须被加热以溶解HES。
实施例16:在均化过程中加入晶种使多晶形的混合物转化成更稳定的多晶形
样品制备。采用微沉淀均化方法如下制备伊曲康唑纳米悬浮液。伊曲康唑(3g)和Solutol HR(2.25g)在低热和搅拌下溶解于36ml的N-甲基-2-吡咯啉酮(NMP),形成药物浓缩液。该溶液冷却至室温,并在真空下通过0.2μm尼龙过滤器过滤,以去除未溶解的药物或微粒物质。在偏振光下观察该溶液以确保过滤后没有晶体材料存在。然后,药物浓缩液以1.0ml/min的速率加至约264ml的含水缓冲液(22g/L甘油的5mM tris缓冲液)。水溶液保持在2-3℃,并在加入药物浓缩液过程中以近400rpm持续搅拌。约100ml的所得悬浮液离心,并将固体重悬浮于20%NMP的水的预过滤溶液中。该悬浮液重离心,固体转移至真空箱,25℃下过夜干燥。所得固体样品标记SMP 2PRE。
样品表征。利用粉末X-射线衍射分析SMP 2PRE样品和原料伊曲康唑。测量采用配有铜辐射的Rigaku MiniFlex+仪,步长为0.02°22和扫描速度为0.25°22/min。所得粉末衍射图示于图12中。衍射图显示SMP-2-PRE显著区别于原料,提示存在不同的多晶形或假多晶形。
样品的差示扫描量热法(DSC)迹线示于图13a和b。两样品皆在密封铝盘以2°/min加热至180℃。
原料伊曲康唑的迹线(图13a)显示吸热峰在约165℃。
SMP 2 PRE的迹线(图13b)显示在约159℃和153℃处有两个吸热峰。该结果与粉末X-射线衍射图组合,提示SMP 2 PRE由多晶形的混合物组成,并且主要形式为多晶形,比原料中存在的多晶形更不稳定。
该结论的进一步证据由图14中的DSC迹线提供,其显示通过第一转变加热SMP 2 PRE,接着冷却和重加热,较不稳定的多晶形熔化,并重结晶形成更稳定的多晶形。
加入晶种。通过组合0.2g的固体SMP 2 PRE和0.2g的原料伊曲康唑与蒸馏水至终体积20ml制备悬浮液(晶种样品)。搅拌悬浮液,直至所有固体湿润。以同样方式制备第二悬浮液,但是未加入原料伊曲康唑(未加晶种样品)。两悬浮液在约18,000psi下均化30分钟。均化后悬浮液的终了温度为约30℃。然后,离心悬浮液,并在30℃下干燥固体约16小时。
图15显示加入晶种和未加晶种的样品的DSC迹线。在密封铝盘中,两样品的加热速率为2°/min直至180℃。未加晶种的样品的迹线显示两个吸热峰,表明多晶形的混合物均化后仍存在。加入晶种的样品的迹线显示,加入晶种和均化导致固体转化成稳定的多晶形。所以,加入晶种似乎影响从较不稳定向较稳定多晶形转变的动力学。
实施例17:在沉淀过程中加入晶种优先形成稳定的多晶形
样品制备。在搅拌和温和加热下溶解1.67g的伊曲康唑于10ml的NMP,制备伊曲康唑-NMP药物浓缩液。利用0.2μm注射过滤器过滤溶液两次。然后,在约3℃下加入1.2ml的药物浓缩液至20ml的水性接受液,并在约500rpm下搅拌,制备伊曲康唑纳米悬浮液。采用约0.02g的原料伊曲康唑的蒸馏水的混合物作为接受液而制备加入晶种的纳米悬浮液。仅用蒸馏水作为接受液来制备未加晶种的纳米悬浮液。将悬浮液离心,倾倒上清液,并在真空箱中30℃下干燥固体约16小时。
样品表征。图16显示加入晶种和未加晶种悬浮液的固体DSC迹线的比较。样品在密封铝盘中以2°/min加热至180℃。虚线代表未加晶种的样品,其显示两个吸热峰,表明存在多晶形混合物。
实线代表加入晶种的样品,其仅显示一个吸热峰,靠近原料的预计熔化温度,表明晶种材料诱导只形成更稳定的多晶形。
实施例18:通过加入晶种药物浓缩液控制多晶形
样品制备。室温(约22℃)下伊曲康唑在NMP中的溶解度通过试验确定为0.16g/ml。加热和搅拌下,使2.0g的伊曲康唑和0.2gPoloxamer 188溶解于10ml NMP中,制备0.20g/ml药物浓缩液。然后让该溶液冷却至室温生成超饱和溶液。立即进行微沉淀实验,其中1.5ml药物浓缩液加至30ml含有0.1%脱氧胆酸盐,2.2%甘油的水溶液。在加入步骤过程中,水溶液维持在约2℃,搅拌速率为350rpm。所得前悬浮液以约13,000psi在50℃下均化近10分钟。然后离心悬浮液,倾倒上清液,固体晶体在真空箱中30℃下干燥135小时。
随后,超饱和药物浓缩液在室温下保存老化以诱导结晶。12天后,药物浓缩液变浊,显示已发生晶体形成。以与第一次实验相同的方式,通过加入1.5-30ml含有0.1%脱氧胆酸盐,2.2%甘油的水溶液,从药物浓缩液中制备伊曲康唑悬浮液。在加入步骤过程中,水溶液维持在约5℃,而搅拌速率为350rpm。所得前悬浮液以约13,000psi在50℃均化近10分钟。然后,离心悬浮液,倾倒上清液,固体晶体在真空箱中30℃下干燥135小时。
样品表征。X-射线粉末衍射分析用于确定干燥晶体的形态学。所得衍射图示于图17。第一次实验的晶体(利用新鲜药物浓缩液)经确定组成为更稳定的多晶形。与之相反,第二次实验的晶体(老化的药物浓缩液)主要组成为较不稳定的多晶形,也有少量的更稳定的多晶形存在。因此,据认为老化诱导较不稳定的多晶形晶体在药物浓缩液中的形成,然后在微沉淀和均化步骤过程中担当晶种材料,从而较不稳定的多晶形优先形成。
实施例19:制备紫杉醇颗粒的微沉淀和均化方法
实施例A:
在含有0.5%poloxamer 188和0.05%mPEG-DSPE(含2%甘油作为张力剂)的表面活性剂溶液中,低温(<10℃)沉淀紫杉醇的NMP溶液。总悬液体积为10mL,药物浓度为1%(w/v)。沉淀后立即进行高压均化,条件为温度40℃和压力25,000psi。在均化后(20分钟),使用光散射检查悬液的粒径。平均粒径为186nm。
实施例B:
在含有0.5%poloxamer 188和0.05%mPEG-DSPE(含2%甘油作为张力剂)的表面活性剂溶液中,低温(<10℃)沉淀紫杉醇的NMP溶液。总悬液体积为20mL,药物浓度为1%(w/v)。沉淀后立即进行高压均化,条件为温度40℃和压力25,000psi。在均化30分钟后,使用光散射检查悬液的粒径。平均粒径为204nm。
实施例C:
在含有0.5%poloxamer 188和0.05% mPEG-DSPE(含2%甘油作为张力剂)的表面活性剂溶液中,低温(<10℃)沉淀紫杉醇的NMP溶液。总悬液体积为10mL,药物浓度为1%(w/v)。沉淀后立即进行高压均化,条件为温度70℃和压力25,000psi。均化后,使用光散射检查悬液的粒径。平均粒径为158nm。大约45%的颗粒小于150nm。
实施例D:
在含有0.05%mPEG-DSPE(含2%甘油作为张力剂)的表面活性剂溶液中,低温(<10℃)沉淀紫杉醇的NMP溶液。总悬液体积为10mL,药物浓度为1%(w/v)。沉淀后立即进行高压均化,条件为温度40℃和压力25,000psi。均化后,使用光散射检查悬液的粒径。平均粒径为244nm。
实施例20:紫杉醇亚微米颗粒的溶解特性
抗肿瘤药物亚微米制剂合需的性质之一是它们不溶解以利于在给药到对象后的长时间循环。通过实施例19描述的方法制备的两种紫杉醇颗粒的制剂,通过溶解动力学,利用400nm的透射率%作为溶解量度来检测其溶解性。如果透射率%没有返回到添加悬液后的100%则该颗粒是不溶性的。一种制剂含有表面改性剂poloxamer 188(P188)和mPEG-DSPE。另一种制剂只含有表面改性剂mPEG-DSPE。结果示于图18中。在两种情形下,透射率%在初始下降至约60%后不上升,表明颗粒不会溶解。
实施例21:受压条件下和储存后紫杉醇亚微米颗粒的稳定性
使用加速应力检测以及在5℃下储存一个月对按照实施例19中的实施例A制备的亚微米紫杉醇颗粒的稳定性进行检测。如图19和20所示,平均粒径和99百分位数都保持实质上未改变。即使在所有的压力测试后也没有观察到制剂的聚集。通过测量超声前后1分钟的粒径并通过下列方程式比较差异而估计聚集:
聚集%=(P99-P99S)/P99S×100
其中P99代表超声前百分位数99的粒径分布而P99S代表超声后百分位数99的粒径分布。
尽管已阐述和说明了具体实施方案,但在不背离本发明实质的情形下可有多种修改,本发明的范围仅受随附权利要求书的范围的限制。
Claims (34)
1.紫杉醇或其衍生化合物亚微米颗粒的药物组合物的制备方法,其中紫杉醇或其衍生化合物在水可混第一溶剂中的溶解性大于含水第二溶剂中的溶解性,所述方法包括下列步骤:
(i)向水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中混入含有结合了水溶性或亲水性聚合物的磷脂的第一表面改性剂;
(ii)将紫杉醇或其衍生化合物溶解在水可混第一溶剂以形成溶液,
(iii)将该溶液与第二溶剂混合以定义颗粒的前悬液;以及
(iv)均化前悬液以形成平均有效粒径小于约1000nm的小颗粒的悬液。
2.权利要求1的方法,其中磷脂是天然的或合成的。
3.权利要求1的方法,其中磷脂是磷脂酰胆碱,磷脂酰乙醇胺,二酰基-甘油-磷酸乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇,磷脂酰甘油,磷脂酸,溶血磷脂,卵磷脂或大豆磷脂,或其组合。
4.权利要求3的方法,其中二酰基-甘油-磷酸乙醇胺选自:二肉豆蔻酰-甘油-磷酸乙醇胺(DMPE),二棕榈酰-甘油-磷酸乙醇胺(DPPE),二硬脂酰-甘油-磷酸乙醇胺(DSPE),以及二油酰-甘油-磷酸乙醇胺(DOPE)。
5.权利要求1的方法,其中结合到磷脂的水溶性或亲水性聚合物是聚乙二醇(PEG)。
6.权利要求5的方法,其中PEG选自PEG350,PEG550,PEG750,PEG1000,PEG2000,PEG3000,和PEG5000。
7.权利要求1的方法,其中结合到磷脂的水溶性或亲水性聚合物选自:葡聚糖,羟丙基甲基丙烯酸酯(HPMA)和聚谷氨酸酯。
8.权利要求1的方法,进一步包括将第二表面改性剂混合到水可混第一溶剂或第二溶剂或水可混第一溶剂和第二溶剂两者中,所述第二表面改性剂选自:阴离子表面活性剂,阳离子表面活性剂,阴离子表面活性剂,阳离子表面活性剂,非离子表面活性剂和表面活性生物改性剂。
9.权利要求8的方法,其中第二表面改性剂是氧乙烯和氧丙烯的共聚物。
10.权利要求9的方法,其中氧乙烯和氧丙烯的共聚物是氧乙烯和氧丙烯的嵌段共聚物。
11.权利要求8的方法,其中第二表面改性剂是poloxamer。
12.权利要求1的方法,其中水可混第一溶剂是N-甲基-2-吡咯啉酮。
13.权利要求1的方法,其中均化在大约30℃或更高的温度进行。
14.权利要求1的方法,其中小颗粒平均有效粒径小于约400nm。
15.权利要求1的方法,其中小颗粒平均有效粒径小于约200nm。
16.权利要求1的方法,其中小颗粒平均有效粒径小于约150nm。
17.权利要求1的方法,进一步包括对组合物灭菌。
18.权利要求17的方法,其中组合物灭菌包括在混合前无菌过滤该溶液和第二溶剂以及在无菌条件下实施随后的步骤。
19.权利要求17的方法,其中组合物灭菌包括无菌过滤颗粒。
20.权利要求17的方法,其中灭菌包括热灭菌。
21.权利要求20的方法,其中热灭菌在均质机中实现,其中均质机用作灭菌的热源和受压源。
22.权利要求17的方法,其中灭菌包括γ辐射。
23.权利要求1的方法,还包括从悬液中除去水可混第一溶剂。
24.权利要求23的方法,其中除去水可混第一溶剂是通过过滤除去该第一溶剂。
25.权利要求24的方法,其中过滤是横流超滤。
26.权利要求23的方法,其中除去水可混第一溶剂与均化同时进行。
27.权利要求1的方法,还包括除去悬液中的液相从而形成颗粒的干粉。
28.权利要求27的方法,其中除去液相选自:蒸发,旋转蒸发,冻干,冷冻干燥,透滤,离心,力场级分,高压过滤,和反渗透。
29.权利要求27的方法,还包括向干粉中添加稀释剂。
30.权利要求29的方法,其中该稀释剂适于肠胃外给药颗粒。
31.权利要求1的方法,其中组合物被制成通过选自以下途径给药的制剂:肠胃外,口服,肺部,局部,眼,鼻,含服,直肠,阴道和经皮。
32.权利要求1的方法,其中该颗粒是不溶性的。
33.权利要求1的方法,其中该颗粒在受压条件和储存后不聚集。
34.权利要求1的方法制备的紫杉醇或其衍生化合物亚微米颗粒的药物组合物。
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CN108348468A (zh) * | 2015-08-11 | 2018-07-31 | Eyesiu医疗股份有限公司 | 具有生物活性亲脂性化合物的聚乙二醇化脂质纳米粒 |
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RU2402313C2 (ru) | 2010-10-27 |
BRPI0416239A (pt) | 2007-01-09 |
KR101152458B1 (ko) | 2012-06-01 |
AU2004289233A1 (en) | 2005-05-26 |
JP2007510657A (ja) | 2007-04-26 |
US20040245662A1 (en) | 2004-12-09 |
NZ546439A (en) | 2010-04-30 |
ES2388924T3 (es) | 2012-10-19 |
DK1682116T3 (da) | 2012-09-03 |
NO20062552L (no) | 2006-06-02 |
KR20060118455A (ko) | 2006-11-23 |
PL1682116T3 (pl) | 2012-10-31 |
US8067032B2 (en) | 2011-11-29 |
AU2004289233B2 (en) | 2010-10-21 |
ZA200603547B (en) | 2007-04-25 |
EP1682116A1 (en) | 2006-07-26 |
IL174031A (en) | 2012-04-30 |
RU2006119916A (ru) | 2007-12-20 |
US20120070498A1 (en) | 2012-03-22 |
WO2005046671A1 (en) | 2005-05-26 |
IL174031A0 (en) | 2006-08-01 |
CA2540383A1 (en) | 2005-05-26 |
EP1682116B1 (en) | 2012-05-30 |
CN100551365C (zh) | 2009-10-21 |
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