CN102614131A - 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 - Google Patents

以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 Download PDF

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CN102614131A
CN102614131A CN2012100686356A CN201210068635A CN102614131A CN 102614131 A CN102614131 A CN 102614131A CN 2012100686356 A CN2012100686356 A CN 2012100686356A CN 201210068635 A CN201210068635 A CN 201210068635A CN 102614131 A CN102614131 A CN 102614131A
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diketopiperazine
microgranule
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amino butyl
insulin
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凯斯·A·奥伯格
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Mannkind Corp
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Abstract

本发明涉及以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法。提供结晶微粒表面对活性试剂的亲和力是通过改变微粒的表面性质以促进活性试剂缔合在微粒上来实现的。该方法所改变的表面性质包括静电性质、疏水性质和氢键合性质。

Description

以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法
本申请是申请日为2006年9月14日，申请号为200680033816.8，发明名称为“以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法”的发明专利申请的分案申请。
相关申请
本申请根据35U.S.C.§119(e)要求2005年9月14日递交的美国临时专利申请No.60/717524和2006年4月14日递交的美国临时专利申请No.60/744882的优先权，通过引用将上述文献全文结合在本文中。
技术领域
本发明一般性地涉及药物制剂领域，具体涉及在结晶微粒表面上包覆活性试剂的方法。
背景技术
治疗剂的输送已经成为一个主要问题。口腔给药因其简便性、患者依从性以及低成本而成为一种最常见的优选输送途经。然而，这种途经的缺点包括药效低或不稳定以及治疗剂吸附效率低。当待输送化合物在肠胃道条件下不稳定时尤为如此。本领域已开发了大量包覆和封装方法，但很少能够有效地解决上述问题。而且，有些治疗化合物在肠胃道条件下容易损失活性，因此为了以有效量吸收到血管中，必须以更大的剂量给药。
已经开发出大量药物配制体系来解决最佳药物输送的问题，这些方法是基于将药物结合到作为载体的基体中。药物配制需要考虑的因素包括体系应当对于待输送药物不具有毒性和反应性、制造成本低、所需组分易于获得并且与最终的组合物相容，还应当考虑物理特性，包括稳定性的释放速率。而且优选地，药物输送体系由容易通过常规生理过程从人体中移除的材料制成。
微粒药物制剂可用于各种给药途经，特别适用于肺部输送。通过肺部来输送具有全身效果的药剂的优点包括表面积大并且易于被粘膜表面吸收。美国专利No.6071497描述了一种基于形成二酮哌嗪微粒以及聚合物基微粒的肺部药物输送体系，通过引用将其结合于此。
发明内容
本发明提供了在结晶微粒上形成活性试剂包覆层的方法。一般地，将微粒的表面性质改性，以使活性试剂对微粒表面的亲合性高于对溶液中其它物质的亲合性，由此微粒被活性试剂包覆。
本发明提供了通过静电、疏水或氢键引起的缔合作用来用活性试剂(例如蛋自质)包覆结晶颗粒(例如富马酰基二酮哌嗪(FDKP)微粒)的改进方法。在本发明中，可选地，可通过过滤或干燥去除液体(用于回收经活性试剂包覆的微粒)，或通过交换一种不同的溶液介质来置换液体。在各种情况下，液体介质的去除都不是形成活性试剂-微粒复合体的必须步骤。本发明公开了一种包覆微粒的方法，该方法以改变结晶微粒的表面性质为基础，以使活性试剂吸附到微粒上。
在本发明的具体实施方式中，提供了一种在悬浮液中用活性试剂来包覆预先形成的结晶微粒的方法，包括：i)不依赖于是否去除溶剂，调节活性试剂与结晶微粒之间的能量相互作用；以及ii)容许活性试剂有时间吸附在微粒表面上。在某些实施方式中，所述在悬浮液中用活性试剂来包覆预先形成的结晶微粒的方法还可以包括如下步骤：在对活性试剂与微粒之间的相互作用不产生实质影响的条件下，去除或更换溶剂。
在本发明的其它具体实施方式中，用活性试剂包覆微粒的方法是通过改性微粒表面性质来实现的。微粒表面性质的改性通过改变溶液条件实现。这些条件包括但不限于改变pH。在本发明的其它实施方式中，通过以下方式来改性微粒表面性质：1)改变溶液的极性；2)添加单价或多价离子；以及3)微粒的化学衍生。
在另一种实施方式中，本发明还包括将活性试剂溶解在微粒悬浮液的液相中然后改变pH的步骤。这种将活性试剂溶解在液相中的步骤是指固体的溶解。此外，溶解活性试剂的步骤是指除了添加固体之外还添加一种更加浓缩的活性试剂溶液。
在另一种实施方式中，在添加活性试剂之前或之后，改变微粒悬浮液的pH条件以促进活性试剂与微粒之间的相互作用。
在其它实施方式中，活性试剂与微粒表面之间存在至少一种类型的能量方面有利的相互作用。
在本发明的另一种具体实施方式中，活性试剂为胰岛素或其类似物。
在本发明的其它具体实施方式中，在活性试剂与微粒之间形成有利的相互作用的表面性质选自静电性质、疏水性质和氢键合性质。
在本发明的另一种实施方式中，微粒是多孔的，并具有与溶液主体连通的内表面。在一种实施方式中，微粒包含二酮哌嗪，例如富马酰基二酮哌嗪，但不限于此。
在本发明的实施方式中，该包覆方法在微粒表面上形成单层。在本发明的其它实施方式中，所述单层是连续的。在本发明的其它实施方式中，单层中的活性试剂可以具有优选的取向。
在另一种实施方式中，提供了一种在悬浮液中用胰岛素包覆预先形成的结晶微粒的方法，包括：不依赖于是否去除溶剂，调节活性试剂与结晶微粒之间的能量相互作用；以及将胰岛素吸附在微粒表面上。
本文所用术语“溶剂”是指活性试剂和微粒浸在其中的流体介质。不应当认为，所有组分均为溶液形式。实际上，在许多情况下，“溶剂”是指微粒悬浮于其中的液体介质。
附图说明
以下附图构成本说明书的一部分，用于进一步说明本实施例的特定方面。通过以下附图，并结合具体实施方式的详细描述，可以更好地理解本发明。
图1示出了富马酰基二酮哌嗪(FDKP)悬浮液、FDKP颗粒和缓冲液组分的超声HCl滴定曲线。滴定曲线的超声速度变化的大小(图1，A区)反映出样品组分的可离子化羧基由于质子化所引起的水合作用变化。过量的超声衰减峰(图1，B区)是饱和点处质子交换反应中的快速松弛所造成的。频率(F)为15MHz，温度为25℃。
图2示出了FDKP颗粒+胰岛素和单独FDKP颗粒的超声冰醋酸滴定曲线。通过减去胰岛素的作用来计算超声速度，频率为8MHz，温度为25℃。图中还示出了作为所添加的冰醋酸的浓度的过量超声衰减。冰醋酸导致酸化的两个阶段与HCl滴定所观测到的类似。左侧插入图(A区)示出了pH大于约2.9时的活性试剂与FDKP微粒的缔合。右侧插入图(B区)示出了pH低于约2.9时活性试剂与微粒之间减弱的相互作用。
图3示出了根据本发明的可离子化的微粒上的蛋白质吸附。在pH调节之后将蛋白质加入微粒悬浮液，过滤掉未结合的蛋白质，并将微粒溶解以释放结合的蛋白质。
图4示出了pH对活性试剂到FDKP微粒的吸附的影响。图4A示出了胰岛素的吸附，图4B示出了抗-SSX-241-49单克隆抗体的吸附，图4C示出了甲状旁腺激素(PTH)的吸附，图4D示出了脑肠肽的吸附。
图5示出了pH对限制浓度的胰岛素到FDKP微粒的吸附的影响。
图6示出了用蛋白质(10mg/mL)逐步滴定FDKP微粒时的FDKP微粒悬浮液(11mg/mL)中的超声速度变化。游离蛋白质的作用以及FDKP微粒稀释液的影响已被扣除。温度为25℃。
图7示出了根据本发明活性试剂到FDKP微粒上的吸附饱和曲线。所示的活性试剂/FDKP微粒的加载曲线是pH为5.0时的活性试剂浓度的函数。图7A示出了胰高血糖素样肽-1(GLP-1)的吸附，图7B示出了PTH的吸附，图7C示出了抗-SSX-241-49单克隆抗体的吸附，图7D示出了抗-MOPC-21单克隆抗体的吸附。
图8示出了增大盐浓度对pH为5.0时的活性试剂到微粒的吸附的影响。在pH调节之后将活性试剂加入微粒悬浮液，过滤掉未结合的活性试剂，并将微粒溶解以释放结合的活性试剂。图8A示出了胰岛素的吸附，图8B示出了抗-SSX-241-49单克隆抗体的吸附，图8C示出了PTH的吸附，图8D示出了脑肠肽的吸附。
具体实施方式
待输送的试剂
包覆在结晶微粒上的物质在此被称为活性试剂。活性试剂的实例包括具有治疗、预防和/或诊断用途的药物组合物、合成化合物和有机大分子。
一般地，可以在结晶微粒表面上包覆任何形式的活性试剂。这些材料可以是有机大分子，包括核酸、合成有机化合物、多肽、肽、蛋白质、多糖和其它糖以及脂类。肽、蛋白质和多肽均为通过肽键连接的氨基酸链。肽一般被认为包含小于30个氨基酸残基，但也可以包含更多。蛋白质是可包含大于30个氨基酸残基的聚合物。如同本领域所知，术语“多肽”在本文中是指包含多个肽键的肽、蛋白质或任意长度的氨基酸链(通常包含至少10个氨基酸)。用于形成包覆层的活性试剂可以属于各种生物活性类别，例如血管活性试剂、神经活性试剂、激素、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、抗原和抗体。更具体地，活性试剂可以包括但不限于，胰岛素及其类似物、生长激素、甲状旁腺激素(PTH)、脑肠肽(ghrelin)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、胰高血糖素样肽-1(GLP-1)、Texas Red、炔、环胞霉素、clopiogrel和PPACK(D-苯丙氨酰基-L-脯氨酰基-L精氨酸氯甲基甲酮)、抗体及其片段，包括但不限于：人源化抗体或嵌合抗体；F(ab)、F(ab)2或单链抗体(单独的或结合到其它多肽上)；癌症抗原、细胞因子、传染性试剂、炎症介体、激素合细胞表面抗原的治疗性或诊断性单克隆抗体。肿瘤抗原的抗体的非限定性实例包括抗-SSX-241-49(滑膜肉瘤，X断裂点2)、抗-NY-ESO-1(食管肿瘤相关抗原)、抗-PRAME(黑色素瘤特异性抗原)、抗-PSMA(前列腺特异性膜抗原)、抗-Melan-A(黑色素瘤相关抗原)、抗-tyrosinase(黑色素瘤相关抗原)以及抗-MOPC-21(骨髓瘤血浆细胞蛋白)。
输送系统-结晶微粒
术语“微粒”基本上是指直径约为0.5-1000μm的颗粒，而与其确切的外部或内部结构无关。在广义上的微粒范围内，“微球”是指形状微均匀球形的微粒。本文使用结晶微粒是指下述微粒，所述微粒具有晶体的内部结构但不必须具有晶体的外部结构，并且在空间点阵中具有规则的原子排列。可离子化的结晶表面是指结晶微粒具有额外的能力来携带电荷。
优选地，构成结晶微粒的化学物质可与待输送活性试剂可逆地反应，并且至少对啮齿类动物和人类是无毒且不可代谢的。此外，优选的微粒的结晶结构在包覆活性试剂的过程中基本上不被破坏。结晶微粒的组成决定了可以例如何种类型的化学相互作用来促使活性试剂吸附在微粒表面上。
大量物质可被用于形成结晶微粒。微粒本身具有外表面，其性质可在包覆过程中被操控。可形成结晶微粒的代表性材料包括但不限于：芳族氨基酸，在规定的pH范围内具有有限的溶解度的盐，例如二酮哌嗪和吗啉硫酸盐。
美国专利No.5352461和5503852(通过引用将其整体结合于此)描述了一种药物输送系统，该系统基于由在低pH下稳定且在血液或小肠的pH下溶解的二酮哌嗪衍生物(例如3，6-二[N-富马酰-N-(正丁基)氨基]-2，5-二酮哌嗪，也称为富马酰二酮哌嗪或FDKP，即(E)-3，6-二[4-(N-羧基-2-丙烯基)酰胺丁基]-2，5-二酮哌嗪)来形成二酮哌嗪(DKP)微粒。如上述专利所公开，通过在药物(加载量)的存在下形成DKP微粒，使二酮哌嗪颗粒结合或负载待输送药物。基于二酮哌嗪结构元素或其一种取代衍生物(包括但不限于二酮吗啉和二酮二氧杂环己烷)的系统形成具有期望的尺寸分布和pH范围以及良好的加载容许量的微粒。通过对取代基进行适当的操控，可以得到大量稳定且可重复的特性。
可用于本发明的其它二酮哌嗪包括3，6-二(4-氨基丁基)-2，5-二酮哌嗪、3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪(琥珀酰二酮哌嗪或SDKP)、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪及其衍生物。二酮哌嗪盐也可用于本发明，所述二酮哌嗪盐例如可以包括药学上可接受的盐，例如Na、K、Li、Mg、Ca、铵或一、二或三烷基铵(源自三乙胺、丁基胺、二乙醇胺、三乙醇胺或吡啶等)盐。所述盐可以是单盐、二盐或混合盐。还可以考虑二酮哌嗪的更高级别盐，在二酮哌嗪中，R基团包含一个以上酸基团。在本发明的其它方面，碱性试剂可以与二酮哌嗪混合以形成二酮哌嗪的药物盐，结果该药物是二酮哌嗪的反阳离子。
美国专利No.6444226和6652885(通过引用将其整体结合于此)描述了在含水悬浮液(向其中添加活性试剂溶液)中制备和提供DKP微粒，然后冷冻干燥该悬浮液以得到具有活性试剂包覆层的微粒的关键步骤。这种配制方法是基于通过冷冻干燥来去除液体介质从而在微粒上包覆活性试剂(还可参见美国专利No.6440463，通过引用将其整体结合于此)。与现有技术的教导相反，本发明提供了在去除溶剂之前调节活性试剂与微粒之间的结合的方法。因此，通过大多数物理方法(例如过滤或沉降)或蒸发方法(例如冷冻干燥或喷雾干燥)来去除溶剂，可以得到相当的加载量。
结晶微粒的受控包覆
受控包覆是指将活性试剂吸附在结晶微粒表面上的可控工艺。包覆工艺包括改变悬浮液中的结晶微粒的表面性质，这可以通过改变溶液条件(例如pH、温度、极性、离子强度和助溶剂)、与单价或多价离子复合或通过化学衍生来实现。在添加活性试剂之前或之后改变微粒的表面性质，可以影响其与活性试剂的化学相互作用，从而使活性试剂吸附到结晶微粒上。微粒与活性试剂之间的化学相互作用促进吸附并导致在微粒表面上形成活性试剂单层。一旦活性试剂分子被吸附，则该部分微粒表面不再受到进一步的相互作用，并且在该特定的表面点处不再吸附其它活性试剂。得到的单层可以是连续的(在吸附表面上，被吸附的活性试剂分子之间无间隙)，或者是非连续的(被吸附的活性试剂分子之间存在间隙，暴露出微粒表面)。
活性试剂到微粒表面的吸附
如上所述，将活性试剂吸附在微粒表面上，使得微粒上形成活性试剂单层(包覆层)。然而，关于在结晶微粒上吸附活性试剂(例如胰岛素)，存在不止一种机理：
在微粒上包覆活性试剂(例如胰岛素)的单层仅为将胰岛素到微粒上的加载过程的一个阶段而不一定是加载过程的最终结果，因为根据系统的能量学，既可以形成单个层可以形成多个层。
在容许的溶解度条件下(例如胰岛素浓度较低和/或pH较低(基本上低于5.0))，胰岛素与FDKP颗粒表面之间的吸引力远大于胰岛素的自缔合力。因此，胰岛素到微粒的包覆以单层方式发生并达到饱和，而不在微粒表面上聚集或形成多层(见实施例6)。随着溶解度接近饱和，由于胰岛素浓度较高和/或pH接近5.0(野生型胰岛素的最小溶解度)，胰岛素的自缔合在能量上变得更加有利。因此，包覆可以越过单层饱和点，并可在颗粒上附加其它层。存在两种类型的自缔合：多聚化和聚集。多聚化的特征在于特定的分子间相互作用和固定的化学计量。聚集的特征在于不特定的分子间相互作用和不确定的化学计量。一般来说，多聚活性试剂可以以多聚状态被吸附，或分解成单体或较低级的多聚体，并以该状态吸附到表面上。在这两种情况下，聚集均可调节活性试剂在微粒上形成层。根据本发明人目前的理解，在本文实施例中所用的一般条件(例如胰岛素溶解在醋酸中)下，随着非六聚胰岛素的聚集，产生了额外的胰岛素层的沉积。
包覆微粒的方法
用活性试剂包覆结晶微粒(例如预先形成的结晶微粒)的方法一般性地描述如下：将通过沉淀或其它方法预先形成的结晶微粒悬浮在液体介质(例如水)中；在添加活性试剂之前或之后调节介质以使颗粒表面改性。这时，活性试剂将吸附到微粒表面上，在一段时间间隔后(例如，＜1、1、2、3、4、5、6、7、8、9或10分钟，优选从小于1到至少5分钟)，加载过程完成。可以通过包括过滤、离心、冷冻干燥或喷雾干燥的任何方法来去除液体介质，或者通过介质交换来置换液体介质。可以通过以下实验方法来验证吸附：1)证实在滤出液或上层清液中不存在显著量的活性试剂，和/或2)证实在固体相中存在活性试剂，同时表明活性试剂在经历不存在微粒的相同过程时不沉淀。
操控微粒表面性质
如本文其它部分所公开，微粒的表面性质可以通过各种方法来操控。可以操控的微粒表面性质包括但不限于，静电性质、疏水性质和氢键合性质。在各种实施方式中，这些操控在存在或不存在活性试剂、或者在微粒与活性试剂混合之前或之后进行。当操控在活性试剂的存在下进行时(例如，通过改变溶液条件)，同时可以调整活性试剂对表面的亲合性。因此，在本发明的某些实施方式中，微粒的包覆可以包括操控表面的性质和调整活性试剂的性质。调整活性试剂性质的方法公开在名称为“METHODOF DRUG FORMULATION BASED ON INCREASING THE AFFINITY OFACTIVE AGENTS FOR CRYSTALLINE MICROPARTICLE SURFACES”共同待审的美国专利申请No.__/_______(代理人档案号No.51300-00035)中，该申请与本申请同日递交，通过引用将其整体结合于此。
静电相互作用是异性电荷之间的吸引力或同性电荷之间的排斥力，该力随着电荷彼此接近而增强。静电相互作用是理解离子溶液中带电体之间相互作用的关键。例如，通过考虑到排斥性静电相互作用与吸引性范德华相互作用的竞争，可以解释分散在溶剂中的胶体颗粒的稳定性。而且，微粒表面的化学官能团(例如但不限于COOH、NH等)可用作离子活性试剂的反离子，以使活性试剂/颗粒复合物形成盐。当考虑颗粒之间的相互作用和粘附性时，静电相互作用也很重要。
改变周围溶液体系的pH，可以改变悬浮液中可离子化的结晶微粒的静电性质。如实施例3所表明，改变溶液的pH使微粒的离子化发生变化，从而将活性试剂吸附到微粒表面。特别地，实施例4表明，由FDKP(3，6-二[N-富马酰-N-(正丁基)氨基]-2，5-二酮哌嗪)组成的微粒是可离子化的。当pH小于3.5时，微粒不溶于水，但溶解度在pH为3.5-5.0时迅速增大，这可能是由于羧基的离子化。FDKP微粒在pH为5时部分地离子化，然后在更高的pH下完全溶解，这可以通过超声频谱间接观察到。实施例5说明了蛋白质到FDKP微粒表面上的受控包覆。在一种实施方式中，二酮哌嗪微粒悬浮在酸性溶液中，活性试剂加入该悬浮液，然后在活性试剂与微粒混合后升高溶液的pH。升高的pH改变了微粒的表面性质，以使活性试剂对微粒的亲合性高于对溶剂的亲合性。
或者，可在升高微粒悬浮液的pH之后立即将活性试剂加入溶液。通过pH的变化来改变微粒的表面电荷性质，以使活性试剂对微粒的亲合性高于对溶液中其它物质的亲合性。
实施例6和7说明了通过操控pH条件将胰岛素加载到FDKP颗粒上。最后，实施例6中描述了微粒吸附蛋白质达到饱和以及单层的形成。
操控微粒表面的其它方法
除静电性质以外，还可以利用微粒表面的其它性质来控制活性试剂的吸附。可以操控具有如下官能团的化合物的微粒来使表面性质改性：咪唑、吡啶、Schiff碱、酮、羧酸生物电子等排体、酰胺或其它可以多种结构存在的官能团。
疏水相互作用是指非极性基团由于不溶于水而在水溶液中彼此缔合。疏水相互作用可以影响一系列分子过程，包括但不限于，结构稳定化(单个分子、两个或三个分子复合、或更大的组装)和动力学，还对蛋白质-蛋白质和蛋白质-配体结合过程有重要作用。还已知这些相互作用对蛋白质折叠前期有作用，并且参与了复合组装和自组装现象(例如，形成膜)。
可以通过改变由组氨酸组成的结晶微粒的质子化来操控疏水相互作用。组氨酸的质子化会降低结晶微粒的亲核性并赋予正电荷。
氢键合相互作用是指分子间极强的偶极-偶极力，极性键中的氢原子(例如，H-F、H-O或H-N)可以受到附近电负性分子或离子的吸引力，所述电负性分子或离子具有未成对电子(通常是另一个分子上的F、O或N原子)。氢键赋予了水独特的性质，并且对于生物分子组织十分重要，尤其会影响蛋白质和DNA的结构。
在本发明中，可以通过化学衍生来控制微粒表面的氢键合性质。可以以化学方式增加氢键供体/受体来改变微粒表面。例如，N-H键中的氢可以与C＝O键中的氧发生氢键合。如果N-H被N-CH3取代，则此特殊的氢键合相互作用消失。类似地，用C＝C基团取代C＝O基团也会消除此特殊的键合相互作用。
当可离子化的芳基被离子化时，具有包含该芳基的表面的微粒是极性的，而当该芳基未被离子化时，微粒是疏水的。通过将表面质子化并操控溶液条件来减少颗粒表面的离子化，可使疏水性或芳族活性试剂包覆在微粒表面上。
可以通过改变溶液极性来操控具有酮表面基团的微粒。通过降低溶剂极性(向水溶液中添加低极性的有机溶剂)，在颗粒表面上形成烯醇形式的主要物质。此烯醇形式是氢键供体，而酮形式为氢键受体。以此方式来促进含氮药物吸附在微粒表面上。
通过操控溶液条件还可以导致具有表面基团(进行pH或温度诱导的异构化)的微粒吸附药物分子。对于这些表面，异构化会使线性的表面基团出现扭结，这增大了微粒表面上的基团的移动性(流动性)。这使得表面与活性试剂形成更多的接触(与有序的表面相比)。如果与活性试剂的其它相互作用都是有利的，则净相互作用能量也有利于将药物吸附到微粒表面上。
液体介质去除技术
通过包括但不限于沉降、过滤或干燥的方法，可以在用活性试剂受控包覆结晶表面后将溶剂去除。干燥技术包括但不限于冷冻干燥和喷雾干燥。这些技术对本领域技术人员是已知的。在本发明的一种实施方式中，通过喷雾干燥来去除溶剂。对二酮哌嗪微粒进行喷雾干燥的方法例如公开在2006年2月22日递交的美国临时专利申请No.60/776605中，通过引用将其中与喷雾干燥二酮哌嗪微粒相关的内容结合于此。
表面性质改性分析
本发明采用超声频谱技术来分析悬浮液中结晶微粒的表面性质变化，这些变化促进或增强了活性试剂到结晶微粒的吸附。如本文其它部分所述，这些变化包括改变溶液条件(例如pH、温度、极性、离子强度和助溶剂)，这是通过复合到单价或多价离子、或者在添加活性试剂之前或之后通过化学衍生改变微粒的表面性质来实现的。
超声频谱技术是一种本领域技术人员已知的分析工具。简言之，超声频谱技术利用声波。特别地，超声频谱技术使用能够探测样品/材料中的分子间力的高频声波。超声波的振荡压缩(和减压)导致样品中的分子排列振动，这反映为分子间的吸引或排斥。
超声波穿过样品而损失能量(振幅减小)并改变速度。分析振幅的下降和速度的变化来作为样品的特征。因此，超声波的传播由超声速度和衰减来确定。
超声速度由介质的弹性和密度决定。固体的分子间相互作用最强，液体和气体次之，因此固体比液体和气体更具刚性。超声衰减是超声波穿过样品时的能量损失的度量。它表征了样品的超声透明度，并且可以表现为波幅的减小。
通过多频测定均匀体系中的超声衰减，可以分析快速化学反应，例如但不限于质子交换、结构转化(例如异构化)、自缔合(例如二聚合)、聚集、配体与大分子的结合等。
实施例
以下实施例用于说明本发明的实施方式。本领域技术人员应当理解，实施例中与本发明人发现的代表性技术一起公开的技术可以有效地用于实施本发明，因此这些技术被认为构成了实施本发明的优选方式。然而，根据本说明书，本领域技术人员应当认识到，在不脱离本发明的精神和范围的前提下，还可以对具体实施方式进行许多改变，同时获得相同或类似的效果。
实施例1
用活性试剂包覆微粒的一般过程
下表1为通过静电来包覆可离子化的结晶微粒(FDKP微粒)的实施例，该实施例采用pH控制吸附。在这些实验中，制备pH为2.0和4.5的FDKP微粒悬浮液。然后在各种悬浮液中添加蛋白质(生长激素)，得到最终条件：5mg/mL的FDKP颗粒和200μg/mL的蛋白质。搅拌之后，通过过滤将大部分液体从悬浮液中去除。然后将过滤器上截留的材料溶解并收集。通过HPLC来定量分析所有部分中的蛋白质浓度。
在低pH(2.0)下，蛋白质并未吸附到颗粒上，所有蛋白质存在于第一滤出液中。通过将pH升至4.5，改变颗粒的表面性质，使其对蛋白质具有较高的亲合性。在这些条件下，蛋白质与微粒相结合，而且并未在滤出液中观测到。为了确定与微粒缔合的蛋白质的量，在微粒溶解后回收蛋白质。无颗粒的对照实验表明，在所用的条件下，蛋白质本身并没有滞留在过滤器上，即蛋白质并未自缔合或聚集成尺寸大于过滤器滤孔的颗粒。
表1.使用FDKP微粒的吸附实验中的蛋白质浓度
Figure BSA00000685350500131
所示值根据过滤后溶液的HPLC定量分析获得
实施例2
通过操控pH来控制FDKP微粒的离子化
FDKP是在每一端具有羧酸官能团的棒状分子，该分子在羧酸被质子化时基本不溶于pH低于3.5的水，并且不带电荷。随着羧基的离子化，FDKP的溶解度在pH大于3.5时迅速增大。FDKP晶体(形成具有两个较大平坦表面和较窄边缘的平板状)的模型表明，棒状FDKP分子垂直于平板边缘排列，使得分子的羧酸末端排列在平板的较大表面上。根据理论，FDKP晶体的表面应当在大约5.0的pH下部分地离子化，这时溶解度约为1mg/mL，该pH刚好低于可以溶解10mg/mL的微粒悬浮液的pH。
使用超声频谱可以间接地观测到FDKP晶体表面的离子化。在图1中，示出了FDKP微粒和缓冲液的超声滴定曲线。在此实验中，分小份将含有200mM HCl的溶液加入FDKP微粒在20mM醋酸铵缓冲液中的10mg/mL的搅拌悬浮液中。初始pH为4.8。在每次添加HCl之后，使体系平衡并收集超声数据。
通过升高酸浓度(降低pH)观测到的超声速度的下降反映了体系中羧酸基团的质子化。随着该基团被质子化并变得不带电，其周围的水结构变松弛并且超声波传输变慢(超声速度降低)。由于FDKP微粒的羧酸盐表面与醋酸盐缓冲液中的羧酸盐基团在化学上十分相似，因此得到的曲线也类似。然而，差异是FDKP微粒所致。首先，FDKP微粒的速度变化的程度较大。这种差异是FDKP微粒表面上的离子化羧酸盐基团的质子化的结果。衰减曲线的峰值在完全质子化时附近出现，对于FDKP悬浮液，该峰值向着较高的酸浓度稍微偏移。最后，当pH从3.5降至2.3时，两个FDKP参数继续改变。这些变化表明了颗粒表面性质的其它改变，包括表面羧基的有序化或其它微观结构改变。
实施例3
通过表面性质的pH操控将蛋白质加载到FDKP微粒上
以两种方式，可以实现通过pH操控将蛋白质吸附到可离子化的微粒表面上。可以添加蛋白质然后调节pH，以使表面离子化同时吸附蛋白质。该过程是可逆的。或者，可以调节颗粒悬浮液的pH，从而在添加蛋白质之前将表面离子化。
图2所示的超声滴定数据表明了：当pH大于约2.9时，蛋白质(胰岛素)与FDKP微粒缔合，当pH低于约2.9时，相互作用减弱。
在20mM的醋酸铵缓冲液(pH为4.8)中制备FDKP微粒的悬浮液，然后与胰岛素原液混合，得到800μL的悬浮液，在最终的悬浮液中，FDKP微粒的浓度为10mg/mL，胰岛素浓度为1mg/mL。将该悬浮液引入超声频谱仪。一边轻微搅拌，一边以5μL的小份逐渐添加冰醋酸，从而降低pH。在滴定的每个步骤中，收集超声数据。
超声速度的变化与样品中的颗粒和/或大分子的表面积(结合水)的大小相关(成正比)。图2表明，当pH大于约2.9时(添加了10％v/v的醋酸)，微粒(单独的FDKP颗粒)的速度曲线与具有胰岛素的微粒(FDKP颗粒+胰岛素)的速度曲线重合。这说明体系(FDKP颗粒+胰岛素)的表面积基本上等于单独FDKP微粒的表面积。与微粒相比，胰岛素极小，因此胰岛素对表面积的贡献可忽略。当pH低于2.9时，FDKP颗粒的曲线与FDKP颗粒+胰岛素的曲线分离。FDKP颗粒+胰岛素曲线的超声速度此时较高，表明相比于单独的FDKP颗粒样品，有更多的表面积暴露于水。这种额外的表面积源自悬浮液中的游离胰岛素。当pH从约2.7升至约2.9时，胰岛素吸附到FDKP微粒表面上，导致胰岛素表面积损失，并且由于系统中不再存在游离的胰岛素，FDKP微粒+胰岛素曲线的较高值消失。
如上所述，通过pH而在颗粒上包覆蛋白质的方法是将颗粒悬浮在液体介质中，然后调节溶液条件以使颗粒表面离子化。然后可将蛋白质加入悬浮液，蛋白质分子将立即被吸附。图3示出了加入经pH调节的FDKP微粒悬浮液之后被吸附的蛋白质(胰岛素)的量。
制备5mg/mL的FDKP微粒悬浮液并添加过量的蛋白质(2mg/mL)(这里的“过量的蛋白质”是指，其量超过在FDKP微粒的可接触表面上形成覆盖单层所必须的量)。培养之后，通过过滤去除未吸附的蛋白质。将滞留在过滤器的固体(滞留物)溶解，并通过HPLC定量分析滞留在过滤器上的FDKP微粒和蛋白质的量。根据定量结果确定蛋白质/颗粒质量比。基于已知的这些颗粒的表面积以及蛋白质的分子尺寸，估计当质量比约为0.07时形成被吸附蛋白质的连续单层。基于这个估计，从此实施例可以看出，当pH为5.0时形成连续单层，当pH为3.5-4.5时形成非连续单层。
此外，将不同批量的干燥的经活性试剂包覆的FDKP微粒悬浮在酸溶液(最终pH约为2.0)中或水(最终pH约为4.5)中。如表2所述，不同的活性试剂包括胰岛素、生长激素和胰岛素aspart(一种速效胰岛素)。过滤掉这些悬浮液的溶剂，然后溶解滞留的颗粒并收集。通过HPLC定量分析全部样品中的活性试剂的量。结果示于表2。
对于每个样品，活性试剂均在酸性溶液中从颗粒上释放。因此，通过将微晶体表面质子化，可使活性试剂从晶体表面上解吸。颗粒再次悬浮在水中并不改变颗粒表面的离子化状态，因此这时蛋白质保持被吸附。表2.包覆在FDKP微粒上的活性试剂
表中各值为HPLC定量分析的积分峰面积(mAU*sec，215nm)
实施例4
通过pH将胰岛素吸附到FDKP微粒的表征
在pH控制过程中，通过将FDKP微粒的悬浮液与胰岛素水溶液混合，将胰岛素吸附(加载)到FDKP微粒上。为了描述pH对胰岛素与FDKP微粒结合的影响，制备不同pH值的5mg/mL的FDKP颗粒悬浮液。然后添加过量的溶解胰岛素，吸附约5分钟，然后过滤去除未结合的胰岛素。从过滤器(滞留物)回收具有被吸附的胰岛素的固体颗粒，将其溶解并收集。通过HPLC定量分析胰岛素和溶解的FDKP微粒的量。基于滞留物总质量计算被吸附的胰岛素的量。PH与胰岛素吸附量的关系示于图4A，胰岛素吸附量作为pH的函数增加。如图4B、4C和4D分别所示，对于SSX-241-49单克隆抗体、PTH和脑肠肽，得到类似的结果。
此外，将FDKP颗粒悬浮在不同pH的胰岛素溶液(10mg/mL)中。FDKP颗粒与胰岛素的质量比为10∶1。通过离心将上层清液与颗粒分离，然后通过HPLC确定上层清液中的未结合胰岛素的浓度。根据与初始胰岛素浓度的差异来确定胰岛素的结合。图5所示的数据说明，升高pH使得溶液中的胰岛素减少，并且FDKP颗粒上的胰岛素含量增加。
因此，随着pH从约3.0升至约5，结合到FDKP颗粒上的胰岛素增加。优选地，在pH为3.6时添加胰岛素溶液，在这些条件下，约75％的胰岛素从溶液中被吸附到颗粒上。当pH升至≥4.0时，结合的胰岛素增至＞95％。当pH约≥4.2、优选≥4.4时，胰岛素基本上完全结合。在pH大于5.0时，FDKP微粒开始溶解，并且不再保持结晶微粒的结构。
实施例5
用胰岛素加载FDKP微粒的描述
在生产规模方式(2-5kg)中，通过用醋酸沉淀来形成FDKP微粒并洗涤。向FDKP颗粒悬浮液中添加pH为3.6的胰岛素溶液。胰岛素原液包含10wt％的胰岛素和2.5wt％的醋酸(pH约为3.6)。用氢氧化铵将混合物的pH调节至4.5。表3示出了每千克用于制备包含约11.4wt％胰岛素的颗粒的制剂中的各种组分的量。聚山梨醇酯80可在形成颗粒时加入，它可以改善最终颗粒的操纵特性。容许胰岛素有时间吸附到FDKP颗粒上，并确保充分混合。然后将混合物逐滴加入液氮，以使悬浮液迅速冻结。通过冷冻干燥去除液体介质，从而制造FDKP颗粒/胰岛素主要药物产品。或者将混合物喷雾干燥。表4示出了去除溶剂后的主要产品中的各种组分的量。
表3.FDKP颗粒/胰岛素配方组成
表4.FDKP颗粒/胰岛素组成
Figure BSA00000685350500181
在表3和表4中，NF表示美国国家处方集(National Formulary)
*聚山梨醇酯80含量由HPLC/MS分析估算
**FDKP/胰岛素制剂在冷冻干燥后包含约1.2％的残余水，也可存在痕量的醋酸和氢氧化铵。
实施例6
蛋白质在微粒表面饱和(形成连续的单层)
在微粒表面包覆单层应当是可饱和的过程。即，微粒的可接触表面积和活性试剂分子的直径决定了微粒表面的容量。图6示出了这种饱和情况。
制备FDKP微粒的悬浮液，并将pH调节至3.0-3.5，在此pH下表面部分地离子化。在此过程中，不能使用更高的pH，因为这会引起活性试剂(胰岛素)的自缔合。将小部分的浓缩胰岛素溶液添加至搅拌悬浮液。在每次添加之后，使样品稳定，并收集超声数据。
图6表明，随着蛋白质浓度增大，观测到超声速度降低。超声速度的这种变化对于水溶液中的配体结合是常见的，并且说明活性蛋白质吸附到FDKP微粒表面上。速度降低是结合水从FDKP微粒和蛋白质表面上释放的结果。当结合水由于活性试剂的吸附而被取代时，其结构变松弛，并且超声速度在穿过样品时产生净减小。当FDKP微粒表面上的所有结合位点都已饱和时(即形成蛋白质单层)，曲线变平。图7A-7D的数据示出了各种活性试剂(GLP-1[图7A]；PTH[图7B]；抗-SSX-241-49单克隆抗体[图7C]；抗-MOPC-21单克隆抗体[图7D])在微粒上的附吸达到了饱和，因为活性试剂的浓度在恒定的FDKP浓度(5mg/mL)下增大，这些数据也表明形成了单层。这些研究在pH为5.0下进行，在此pH下，活性试剂到微粒上的吸附达到最优化。GLP-1无法在所用的浓度下自缔合(如美国临时专利申请No.60/744882所公开)。
实施例7
静电相互作用机理的证据
静电相互作用机理的证据是通过减弱静电相互作用来阻碍吸附的能力。这通过在离子化的颗粒/活性试剂体系中添加盐来说明。图8A-8D说明，增大活性试剂-FDKP微粒体系中的离子强度减少了活性试剂到微粒上的吸附。
当pH为5.0是，活性试剂到FDKP微粒表面上的吸附较强，在此pH下制备一系列样品。各个样品包含不同量的盐(氯化钠)，如图8A-8D的横坐标(单位为mM)所示。将活性试剂混入悬浮液，得到最终浓度为5mg/mL的FDKP微粒和0.75mg/mL的胰岛素(过量，图8A)。在短暂培养之后，过滤去除未结合的活性试剂并重新溶解吸附有活性试剂的颗粒。通过HPLC定量分析回收的活性试剂和颗粒的量，以质量比(加载百分比)表示。图8A-8D表明，增大活性试剂-FDKP微粒体系的离子强度降低了活性试剂的吸附程度，其中活性试剂包括抗-SSX-241-49单克隆抗体(0.2mg/mL；图8B)、脑肠肽(0.1mg/mL；图8C)和PTH(0.25mg/mL，图8D)，FDKP微粒为5mg/mL。
图8示出了加载悬浮液中的所测量的吸附与盐浓度之间的负相关关系。这可以解释为，盐和活性试剂竞争与颗粒表面相互作用。随着盐浓度增大，盐对表面结合位点的竞争力更强且更有效，并且基本上取代了颗粒表面的活性试剂。也可以推测，可能是德拜屏蔽效应导致了活性试剂与微粒结合的减少。
除非另有指明，本说明书和权利要求书中使用的表示成分数量，以及分子量、反应条件等性质的所有数字都应当被理解为：在所有情况下，用术语“约”加以了修饰。因此，除非有相反含义的说明，本说明书和所附权利要求书中示出的数量参数都是约数，它们可以根据本发明想要获得的性质而变动。至少，并且并非对权利要求书范围等同原则的应用加以限制，每个数量参数至少应按照报道的有效数字的数，以及应用普通的凑整技术来解释。虽然示出本发明宽广范围的数字范围和参数是约数，但是特别实施例中所示的数值却被尽可能地精确报道。但是，任何数值，必然含有一定误差，这是它们各自的检验测量方法中发现的标准偏差必然导致的。
除非本文另有指明，或与上下文明显矛盾，描述本发明的上下文中未明确提及数量的名词(用″a″，″an″修饰的)和使用的术语“该”、“所述”(″the″)和类似提法应当被理解为既包括单数又包括复数。本文中数值范围的叙述仅仅用作该范围内每个单独的值的速记方法。除非本文另有指明，每个单独的值被包括进说明书，这与在本文个别叙述一样。本文所述的所有方法都可以以任何合适的顺序来进行，除非本文另有指明，或与上下文明显矛盾。除非另有指明，本文提供的任何及所有例子，或者示例性的语言(例如，“例如”)仅用来更好地阐述本发明，而非对发明范围加以限制。说明书中任何语句都不应被解释为：表示对本发明的实践来说必要的、不要求保护的要素。
除非明确指出某个可选方式或可选方式之间互相排斥，尽管说明书支持某个可选方式和“和/或”的表述，但是权利要求中所用术语“或”是指“和/或”。
本文公开的本发明的替换性要素或实施方式的分组不应被理解为限制。每个组成员可被个别提到和被个别要求保护，或以与该组其它成员或本文中找到的其它要素的任何组合被提到和要求保护。可以预见到，为了方便和/或可专利性的理由，组中的一个或多个成员可被包括进一组或从中删除。当任何此类包括或删除发生时，说明书在本文中被看作为含有经过改动的组，因此满足说明书对所附权利要求书中所用的马库什组的支持。
本文中描述了本发明的优选实施方式，其包括发明人已知用来开展本发明的最佳方式。当然，在阅读前述说明书的基础上，对这些优选实施方式中的改动对于本领域普通技术人员来说将是明显的。本发明的发明人期待本领域技术人员合适地采用此类改动，发明人希望本发明以除了本文特别描述的方式之外的方式被实现。因此，只要适用法律允许，本发明包括对所附权利要求中提到的主题进行的所有改动和等同物。此外，所有可能的变化中，上面提到的要素的任何组合都被包括进本发明，除非本文另有指明，或与上下文明显矛盾。
此外，本说明书中提到了大量参考文献，包括专利和印刷公开物。上述参考文献和印刷公开物中的每种在此都通过引用被个别地整体包括进本文。
最后，应当理解，本文公开的本发明实施方式是为了阐述本发明的原理。可以进行的其它改动也落在本发明的范围内。因此，举例而言，而非限制，可按照本文的教导来使用本发明的替代性构造。因此，本发明不被限制为严格拘泥于本文所述和所示出的。

Claims (15)

1.一种微粒，所述微粒包含二酮哌嗪和聚山梨醇酯80。
2.权利要求1的微粒，还包含活性试剂。
3.权利要求2的微粒，其中所述活性试剂吸附在所述二酮哌嗪的结晶表面上。
4.权利要求3的微粒，其中所述活性试剂在所述结晶表面上形成单层。
5.权利要求4的微粒，其中所述单层是连续的。
6.权利要求5的微粒，其中所述活性试剂的吸附通过静电、极性、离子、疏水、氢键合或范德华相互作用介导。
7.权利要求1的微粒，其中所述二酮哌嗪选自3，6-二(4-氨基丁基)-2，5-二酮哌嗪、3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪和3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪组成的组。
8.权利要求1的微粒，其包含约0.8％w/w的聚山梨醇酯80。
9.权利要求2或3的微粒，其中所述活性试剂选自由胰岛素或其类似物、生长激素、甲状旁腺激素(PTH)、脑肠肽、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、胰高血糖素样肽-1(GLP-1)、抗体及其片段和环孢霉素组成的组。
10.权利要求9的微粒，其中所述活性试剂包括胰岛素或其类似物。
11.一种制备二酮哌嗪粒子的方法，其包括：
通过向含有聚山梨醇酯80和二酮哌嗪的溶液中添加酸来沉淀含有聚山梨醇酯80的二酮哌嗪粒子，
其中所述二酮哌嗪在低pH下具有有限的溶解性。
12.权利要求11的方法，其中所述二酮哌嗪选自3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪和3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪组成的组。
13.权利要求12的方法，其中所述二酮哌嗪是3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪。
14.权利要求12的方法，其中所述酸是乙酸。
15.一种在包含预形成的结晶微粒、活性试剂和溶剂的悬浮液中涂布所述预形成的结晶微粒的方法，所述方法包括：
改变悬浮条件以调节所述活性试剂与所述预形成的结晶微粒之间的能量相互作用，其中所述改变悬浮条件是改变所述溶剂的pH、添加单价或多价离子、改变所述溶剂的极性、或添加氢键供体或受体；
其中所述改变悬浮条件并不包括从所述悬浮液中去除溶剂；并且
其中所述改变悬浮条件使得所述活性试剂吸附在所述预形成的结晶微粒的表面上，从而涂布所述预形成的结晶微粒。
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