CN104324366B - 以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法 - Google Patents

以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法 Download PDF

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CN104324366B
CN104324366B CN201410508203.1A CN201410508203A CN104324366B CN 104324366 B CN104324366 B CN 104324366B CN 201410508203 A CN201410508203 A CN 201410508203A CN 104324366 B CN104324366 B CN 104324366B
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diketopiperazine
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马克·霍更森
凯斯·A·奥伯格
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Abstract

本申请涉及以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法，提供了通过修饰活性试剂的结构特征从而促进同微粒的有利缔合来促进微粒吸附活性试剂的方法。

Description

以提高活性试剂对结晶微粒表面的亲和力 为基础的药物配制方法
与相关申请的交叉引用
本申请是申请日为2006年9月14日、题目为“以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法”的第200680033768.2号中国发明专利申请的分案申请。
本申请基于35U.S.C.§119(e)要求于2005年9月14日提交的美国临时连续申请No.60/717,524和2006年4月14日提交的美国临时连续申请No.60/744,882的优先权，每份文献的整体内容都通过引用整体并入本文。
技术领域
本发明涉及药物配制，特别涉及方法。更特别地，公开了结晶微粒表面上活性试剂的结合或吸附。
背景技术
治疗剂的递送一直是主要的问题。口服施用由于易于施用、患者顺从和降低的成本而是最常见和优选的递送途径之一。然而，该途径的缺点包括治疗物的效能低或多变以及吸收无效。当待递送的化合物在胃肠道条件下不稳定时，这特别明显。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。。
已经开发了广泛的药物配制体系来解决最佳药物递送的问题，所述体系基于将药物掺入基质(其作为运载体作用)。药物配制中考虑到的因素包括以下需求：所述体系是无毒的并与待递送的药物是不反应的，制造成本低，由易于获得的成分形成，并与最终组合物和物理特性(包括稳定性和释放率)一致。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。
微粒技术中的进展已经促进了改良的药物配方的开发。然而，尽管有这些进步，但是本领域仍然需要稳定的药物配方，其具有长期有效性并在作为药物(特别是通过肺途径)施用时具有最优的吸附。解决该缺陷的一个途径是靶向所述活性试剂结构特性/特征，这可促进其对微粒表面的吸附并降低其存留在溶液中的倾向。
发明内容
提供了用于将活性试剂结合、包覆或吸附在结晶微粒表面的方法。通常如下用活性试剂包覆微粒：修饰包含微粒和溶解的活性试剂的体系，使得与残留在溶液中相比，所述活性试剂对所述微粒表面具有更大的亲和力。本发明特别地寻求通过修饰/利用活性试剂的特征进一步促进溶液中多种条件下活性试剂与微粒表面的吸附。
因此，在本发明中提供了用于促进活性试剂与悬浮液中预先形成的结晶微粒结合的方法，所述方法包括步骤：i)修饰所述活性试剂的化学势，其中所述修饰允许所述活性试剂和微粒之间在能量上有利的相互作用而不依赖于溶剂的去除；和ii)将所述活性试剂吸附在所述微粒的表面上。
在本发明特定的实施方案中，修饰化学势包括(独立或组合地)修饰活性试剂的结构、柔性、刚性、可溶性或稳定性。修饰活性试剂的化学势包括改变溶液条件。改变溶液条件包括向溶液中添加活性试剂改性剂。
在特定的实施方案中，活性试剂改性剂选自盐、表面活性剂、离子、渗透物(osmolyte)、醇、离液剂(chaotrope)、补偿溶质(kosmotrope)、酸、碱和有机溶剂。在一个实施方案中，盐为氯化钠。
还在本发明的另一实施方案中，该方法还包括将所述活性试剂溶解在微粒悬浮液的流动相中并改变所述流动相pH的步骤。一方面，将活性试剂溶解在流动相中的步骤是指固体的溶解。另一方面，溶解活性试剂的步骤是指添加活性试剂的浓缩溶液。
在本发明的另一实施方案中，活性试剂改性剂促进了活性试剂的结构稳定性。
还在本发明的另一实施方案中，活性试剂为蛋白质、肽、多肽、小分子或核酸分子。在本发明的另一实施方案中，活性试剂选自胰岛素、脑肠肽(ghrelin)、生长激素和甲状旁腺激素(PTH)。活性试剂可包含抗体或抗体片段。在本发明的多个方面，抗体可以识别疾病相关的抗原，包括但不限于肿瘤相关抗原或传染性病原体相关抗原。
还在本发明的另一实施方案中，小分子为可离子化的分子或疏水分子，例如但不限于环孢菌素A。
在本发明的另一实施方案中，修饰活性试剂的化学势包括调节活性试剂和微粒表面之间的一种或多种在能量上有利的相互作用，例如但不限于静电相互作用、疏水作用和/或氢键相互作用。在一个实施方案中，微粒包括二酮哌嗪，例如但不限于富马酰二酮哌嗪。
还在本发明的另一实施方案中，该方法还包括去除或交换溶剂的步骤。本文使用的“溶剂”是指活性试剂和微粒“沐浴”在其中的流体介质。其不应被解释为要求所有的成分为溶液。事实上在许多情况下，其可用于表示微粒被悬浮在其中的液体介质。
在本发明的另一实施方案中，提供了用于制备药物递送组合物的过程，所述组合物包含活性试剂和结晶微粒，所述过程包括步骤：提供包含活性试剂分子的活性试剂溶液；修饰所述活性试剂的化学势；提供微粒悬浮液或粉末；和将所述活性试剂溶液与所述微粒悬浮液或粉末组合。所述粉末可以例如被过滤，但不经干燥。
在本发明的另一实施方案中，修饰活性试剂化学势的过程允许活性试剂和微粒之间的相互作用。在一个实施方案中，修饰活性试剂的化学势包括向溶液中添加活性试剂改性剂。这类活性试剂改性剂可选自盐、表面活性剂、离子、渗透物、醇、离液剂、补偿溶质、酸、碱和有机溶剂。还在另一实施方案中，所述活性试剂改性剂降低所述活性试剂分子的溶解度，促进所述活性试剂和微粒(如二酮哌嗪颗粒)之间的缔合，和/或促进所述活性试剂分子的结构稳定性。
附图说明
以下的图表来自本说明书的部分并被包括以进一步阐述本文公开的实施例的某些方面。参考一个或多个这些图表，结合本文存在的具体实施方案的详细描述，本发明能够被更好地理解。
图1A-1C描述了根据本发明的教导离液剂和补偿溶质对富马酰二酮哌嗪(FDKP)微粒上活性试剂负载曲线的效应，该效应是pH和100mM离液剂/补偿溶质的函数。图1A描述了存在离液剂和补偿溶质时、pH 3.0-5.0下0.75mg/mL胰岛素在5mg/mL FDKP微粒上的负载。图1B描述了存在离液剂和补偿溶质时、pH 2.0-4.0下0.25mg/mL高血糖素样肽1(GLP-1)在5mg/mL FDKP微粒上的负载。图1C描述了存在强离液剂(NaSCN和NaClO4)时、pH 4.0-5.0下0.25mg/mL甲状旁腺激素(PTH)在5mg/mLFDKP微粒上的负载。
图2A-2C描述了根据本发明的教导描述了渗透物对FDKP微粒上活性试剂负载曲线的效应，该效应是pH和渗透物(100mM)的函数。图2A描述了pH 3.0-5.0下存在渗透物时，5mg/mL FDKP微粒上0.75mg/mL的胰岛素负载。图2B描述了pH 2.0-4.0之间存在渗透物时5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。图2C描述了pH 4.0-5.0下存在强渗透物时5mg/mL FDKP上0.10mg/mL脑肠肽肽的负载。
图3A-3D描述了根据本发明的教导醇对FDKP微粒上活性试剂负载曲线的效应，该效应是pH和醇的函数。图3A描述了pH 2.0-4.0之间存在5％、10％、15％和20％v/v的六氟异丙醇(HFIP)时5mg/mL FDKP微粒上0.10mg/mL脑肠肽的负载。图3B描述了pH 2.0-4.0之间存在5％、10％、15％和20％v/v的三氟乙醇(TFE)时5mg/mL FDKP微粒上0.10mg/mL脑肠肽的负载。图3C和3D描述了pH 2.0-5.0下分别存在HFIP和TFE时，5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。
图4A-4D描述了根据本发明的教导盐对FDKP微粒上活性试剂负载曲线的效应，该效应是pH和NaCl浓度的函数。图4A描述了pH 2.0-5.0下存在0-500mM NaCl时5mg/mL FDKP微粒上0.75mg/mL胰岛素的负载。图4B描述了pH 2.0-5.0下存在0-500mM NaCl时5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。图4C描述了pH 2.0-5.0下存在0-1000mMNaCl时5mg/mL FDKP微粒上0.25mg/mL PTH肽的负载。图4D描述了多种盐浓度(20℃)下PTH的二级结构分析。pH 5.8下4.3mg/mL PTH的远UV CD阐明了当NaCl浓度上升时，肽的二级结构采取了更加螺旋的构象。
图5A-5B描述了根据本发明的教导，微粒上疏水分子的吸附。图5A描述了有提高的抗溶剂(水)浓度(60％、80％和90％)时，环孢菌素A对FDKP微粒的结合。图5B描述了存在90％的抗溶剂时，在不同的环孢菌素A/FDKP微粒质量比下对环孢菌素A所达到的理论最大负载百分比。
图6描述了根据本发明的教导，在90％的抗溶剂下使用多种环孢菌素A/FDKP微粒质量比时，在大鼠中单一静脉注射(IV)和肺吹入(IS)的药物代谢动力学。
发明详述
本文描述了用于稳定与结晶微粒组合的药物活性试剂的方法。得到的组合物提供了包覆在结晶微粒表面上的稳定活性试剂。
要被包覆或吸附在结晶微粒上的物质在本文中是指活性试剂。活性试剂种类的例子包括具有治疗、预防和/或诊断用途的药物组合物、合成的化合物和有机大分子。
通常，大部分活性试剂可以被包覆或吸附在结晶微粒的表面，包括但不限于有机大分子、核酸、合成的有机化合物、多肽、肽、蛋白质、多糖和其他糖，和脂质。肽、蛋白质和多肽均为通过肽键连接的氨基酸链。肽通常被认为少于30个氨基酸残基，但是可以包含更多。蛋白质是能够含有多于30个氨基酸残基的多聚体。在本领域和本文使用术语“多肽”可以表示肽、蛋白质或任意长度的含有多个肽键的任何其他氨基酸链，尽管通常含有至少10个氨基酸。包覆配方中使用的活性试剂可以属于大量生物活性类别，例如血管活性物质、神经活性试剂、激素、抗凝血剂、免疫调节剂、细胞毒素剂、抗生素、抗病毒剂、抗原和抗体。
可用于本发明中的活性试剂的例子(以非限制的方式)包括：生长激素、抗体及其片段、炔、环孢菌素(例如环孢菌素A)、PPACK(D-苯丙氨酰基-L-脯氨酰-L-精氨酸氯甲基酮)、CMFDA(5-氯甲基荧光素二乙酸酯)、得克萨斯红(Texas Red)、clopiogrel、粒细胞巨噬细胞集落刺激因子(GM-CSF)、高血糖素样肽1(GLP-1)、脑肠肽、甲状旁腺素(PTH)、胰岛素和胰岛素类似物(例如速效胰岛素制剂(aspart insulin)和胰岛素)和抗体及其片段，包括但不限于：人源化的或嵌合的抗体；F(ab)，F(ab)2或单链抗体(单独的或与其他多肽融合)；针对癌症抗原的治疗或诊断的单克隆抗体、细胞因子、传染剂、炎症介体、激素和细胞表面抗原。针对肿瘤抗原的抗体的非限制性例子包括抗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(黑色素瘤优先表达的抗原)、抗PSMA(前列腺特异膜抗原)、抗-Melan-A(黑色素瘤肿瘤相关抗原)、抗酪氨酸酶(黑色素瘤相关抗原)和抗-MOPC-21(骨髓瘤浆细胞蛋白质)。
微粒
基本上，术语“微粒”是指具有约0.5-1000μm直径的颗粒，不考虑精确的外部或内部结构。在微粒的广泛范畴内，“微球”是指具有均匀球形性状的微粒。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。可离子化的晶体表面是指下述结晶微粒，其具有携带电荷的额外能力。在一些实施方案中，微粒可以是单个规则性状的晶体。在多种优选的实施方案中，微粒性状不规则、是多孔的、具有溶解的活性试剂可接近的内部表面，或包含有任意组合的多种晶体。这类特征会一般地增加表面区域，从而增加负载能力。这类特征也可有助于有利的气动力学(aerodynamic)特征，如果活性试剂要通过干粉(其包含微粒)吸入来递送的话，这是重要的。
优选地，组成结晶微粒的化学物质与要递送的活性试剂是可逆反应的、无毒的以及不被啮齿类和人代谢的。尽管有前述内容，但是一些水平的毒性是可以忍受的，取决于例如要被处理的病症的严重性或患者暴露于物质的量。类似地，不要求该物质是完全代谢惰性的。另外，在用活性试剂包覆或结合的过程中，优选的微粒的晶体结构不被显著破坏。结晶微粒的组成决定了何种类型的化学相互作用可以被操作，以驱动活性试剂到微粒表面的吸附。
大量物质可用于形成结晶微粒。这样的微粒具有表面，所述表面的性质能够如与本申请同日提交的未决的美国专利申请No._/_(代理人档案号No.51300-00025)和美国临时申请No.60/717,524(2005年9月14日)中所述在包覆过程中被操作，每个参考文件通过引用整体并入本文。可形成结晶微粒的代表性材料包括，但不限于：芳香族氨基酸或在给定pH范围中具有有限溶解度的化合物，例如二酮哌嗪和吗啉硫酸盐。
本发明中考虑的微粒的一个特别的例子为二酮哌嗪(DKP)微粒。如本文所讨论的，使用DKP微粒以便吸收活性试剂。美国专利No.5,352,461和5,503,852(每个参考文献通过引用整体并入本文)描述了一种药物递送体系，该体系基于由在低pH下稳定并在血或小肠的pH下溶解的二酮哌嗪衍生物形成二酮哌嗪(DKP)微粒为基础，所述衍生物例如3，6-二[N-富马酰-N-(正-丁基)氨基]-2，5-二酮哌嗪(也称作富马酰二酮哌嗪或FDKP；也称作(E)-3，6-二[4-(N-羧基-2-丙烯基)酰胺基丁基]-2，5-二酮哌嗪)。以二酮哌嗪结构元件或其取代衍生物之一为基础的体系(包括但不限于吗啉二酮和二氧六环二酮)形成具有预期的尺寸分布和pH范围以及良好的有效负载耐性(payload tolerance)的微粒。用取代基的适当操作能够产生大范围的稳定的、可再现的特性。这些专利公开了存在活性试剂时沉淀DKP以形成包含所述活性试剂的微粒。合成、制备和使用二酮哌嗪和二酮哌嗪微粒的其他细节公开于美国专利6,071,497；6,331,318；6,428,771和美国专利申请公开No.20060040953和No.20060041133中，每个参考文献通过引用整体并入本文。包含二酮哌嗪颗粒的组合物公开于美国专利No.6,991,779和美国专利申请公开No.20040038865；每个参考文献通过引用整体并入本文。
本发明关注的其他二酮哌嗪包括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(乙二酰-4-氨基丁基)-2，5-二酮哌嗪及来自它们的衍生物。二酮哌嗪盐也可用于本发明中并可包括例如可药用盐，如Na、K、Li、Mg、Ca、铵盐或单、双或三烷基铵盐(如衍生自三乙胺、氨基丁烷、二乙醇胺、三乙醇胺或吡啶等等)。所述盐可以是单、双或混合的盐。对二酮哌嗪而言也考虑更高级别的盐，其中R基团含有多于一个酸基团。在本发明的其他方面，试剂的碱性形式可以与二酮哌嗪混合以在药物和二酮哌嗪之间形成盐键，从而所述药物成为二酮哌嗪的反阳离子。用于药物递送的DKP盐在美国专利申请公开No.20060040953中更详细地公开，其通过引用整体并入本文。
美国专利No.6,444,226和No.6,652,885(每个参考文献通过引用整体并入本文)描述了在水性悬浮液(活性试剂溶液被加入所述悬浮液中)中制备并提供DKP微粒，然后是冻干悬浮液以得到具有活性试剂包衣的微粒的关键步骤。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。(还可参阅美国专利No.6,440,463，其通过引用整体并入本文)。与现有技术中的教导相反，本发明提供了去除溶剂前调节活性试剂与微粒结合的手段。因此，通过批量物理方法(例如过滤或沉降)或蒸发方法(例如冻干法或喷雾干燥)去除液体介质可得到相当的负载。
促进活性试剂的吸附
将活性试剂吸附在结晶微粒的表面可涉及在多种溶液条件下改变溶液或流体悬浮液中活性试剂的特征，从而促进到微粒表面的吸附并减少溶液中残余的活性试剂的量。可以使用改性剂对活性试剂进行改变或修饰，所述改性剂例如，但不限于离液剂和补偿溶质、盐、有机物(例如但不限于醇)、渗透物和表面活性剂。这些改性剂可以作用于活性试剂以改变其化学势，从而改变其结构、柔性、刚性或稳定性，而不在化学上改变试剂本身。术语“化学势”是普通技术人员所公知的。在本发明的实施方案中，“化学势”是指驱动化学反应(例如活性试剂和溶剂之间的相互作用，或活性试剂吸附在微粒上)必需的自由能。本文使用术语“在能量上有利的”是指活性试剂在微粒上的已吸附状态的自由能水平相对于未包覆的微粒或未结合的活性试剂和/或不溶形式(包括聚集或沉淀)的活性试剂的自由能水平较低。本文使用术语“结构”是指活性试剂分子的二级结构，并包括活性试剂分子(例如蛋白质)的α螺旋结构、β片层或随机螺旋(无序的)。另外，术语结构也可包括分子的三级或四级结构，但不仅限于此，并也可表示分子的自缔合、聚集、多聚化、二聚化等等。本文使用术语“稳定性”是指存在改性剂时活性试剂结构的稳定或去稳定。
另外，改变溶液或流体悬浮液中活性试剂的特征很可能影响由活性试剂和/或微粒的疏水特性、氢键特性和静电特性引起的相互作用。
疏水相互作用是水性溶液中非极性基团由于它们在水中的不溶性引起的彼此间的缔合。疏水相互作用可以影响大量分子过程，包括但不限于(单个分子、两个或三个分子的复合物，或更大的集合的)结构稳定和动力学，并对蛋白质-蛋白质和蛋白质-配体结合过程有重大贡献。这些相互作用也已知在蛋白质折叠的早期事件中起到重要作用，并涉及复合物装配和自我装配现象(例如膜的形成)。
氢键相互作用是分子之间特别强的偶极-偶极力；极性键(例如H-F、H-O或H-N)中的氢原子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)。氢键是造成水的独特特征的原因，并在生物分子的组构中非常重要，特别是在影响蛋白质和DNA的结构时非常重要。
静电相互作用是相反电荷之间的吸引或相同电荷之间的排斥，其随着电荷彼此更加接近而变得更强。静电相互作用构成了理解离子溶液中带电体之间相互作用的关键成分。例如，分散于溶剂中的胶粒的稳定性可以通过考虑排斥的静电相互作用和吸引的范德华相互作用之间的竞争来解释。当考虑颗粒之间的相互作用和粘附时，静电相互作用也是重要的。
盐
在本发明的一些实施方案中，使用盐(例如但不限于氯化钠)改变活性试剂的特征。活性试剂(例如PTH和GLP-1)在存在盐时发生显著的结构变化。如实施例5(图4D)所示，盐的存在通过促进肽构象的更加螺旋来提高PTH的二级结构。盐也被发现影响GLP-1的结构，如2006年4月14日提交并通过引用整体并入本文的美国临时专利申请No.60/744,882中所公开。另外，盐和其他离子化合物能够通过与带电残基特异结合来稳定或去稳定蛋白质和肽，特别是当溶液pH和蛋白质或肽的pI之间的差异变大时(Antosiewiez J，et al.，J.MoI.Biol.238：415-436，1994)。
离液剂
本领域公知，离液剂是与水显示弱相互作用并从而将分子(例如蛋白质或肽)去稳定的离子。这些化合物破坏水的氢键网络并降低其表面张力，从而促进蛋白质和肽更多的结构自由和变性。离液剂的例子包括，但不限于NaSCN、(CH3)3N-HCl、Na2NO3和NaClO4和氯化铯(CsCl)。
另一方面，补偿溶质(kosmotrope)或感胶离子(lyotrope)是与水显示强相互作用的离子，通常稳定大分子如蛋白质和肽。该稳定效应通过提高水分子的有序和提高其表面张力引起。补偿溶质的例子包括，但不限于柠檬酸钠(Na Citrate)和硫酸钠(Na2SO4)。
醇
本发明中使用的另一类活性试剂改性剂为醇。醇能够破坏蛋白质和肽的天然结构，也能够在大分子中稳定和诱导α-螺旋构象，最值得注意的是在未结构化的蛋白质和多肽中。这类醇可包括，但不限于甲醇(MeOH)、乙醇(EtOH)、三氟乙醇(TFE)和六氟异丙醇(HFIP)。其中，TFE和HFIP分别是用于在肽和蛋白质中诱导螺旋转换的最有效的醇之一(Hirota et al.，Protein Sci.，6：416-421；1997，通过引用将其涉及肽和蛋白质中螺旋转换的所有内容并入本文)。这些醇可以通过它们破坏溶剂氢键特征的能力影响蛋白质和肽的结构(参阅Eggers and Valentine，Protein Sci.，10：250-261；2001，通过引用将其含有的涉及醇对蛋白质结构效应的所有内容并入本文)。
渗透物
影响活性试剂对微粒亲和力的另一类改性剂为渗透物。本领域技术人员公知，渗透物是由大部分生物细胞在高胁迫处境(例如极端温度波动、高盐环境等)中产生以稳定其大分子的小化合物。它们不直接与大分子反应，而是通过改变细胞环境中溶剂的特征来起作用，从而它们的存在间接地影响蛋白质的稳定性。这些化合物包括多种多元醇、糖、多糖、有机溶剂和多种氨基酸及其衍生物。尽管渗透物的机制尚未阐明，但是据推测，这些化合物很可能通过提高变性状态相对于天然状态的化学势，从而提高天然的和变性的总体之间(正的)吉布斯能差异(ΔG)来起作用(Arakawaand Timasheff，Biochemistry 29：1914-1923；1990)。
本发明所关注的渗透物以非限制性的方式包括己烯二醇(Hex-Gly)、海藻糖、甘氨酸、聚乙二醇(PEG)、三甲胺N-氧化物(TMAO)、甘露醇和脯氨酸。
方法概述
在本发明的方法中，至少三种成分在液体介质中组合：至少一种活性试剂、(预先形成的)微粒，和至少一种如上所述的活性试剂改性剂。该体系的成分可以以任何顺序组合。在一些实施方案中，改性剂和活性试剂在混合物与微粒悬浮液组合之前彼此组合。在其他实施方案中，试剂和微粒首先组合，然后添加改性剂。在一些实施方案中，提供活性试剂或改性剂并与其他成分组合为溶液。在其他实施方案中，任何成分可以以固体形式提供或溶解于(或在微粒的情况下悬浮于)含另一成分的液体介质中。其他的变化会是本领域技术人员显而易见的。
微粒在与体系的其他成分组合之前形成，其本身作为悬浮液存在。但是微粒悬浮在其中的液体介质有时在本文中被称作溶剂。本方法中使用的液体介质通常是水性的。然而在一些情况下，液体介质可以包含多于一种有机化合物，例如将醇而不是水用作改性剂。
将所有成分聚集在体系中后，活性试剂将吸附在微粒表面上。在本发明递进优选的实施方案中，体系中至少50％、60％、70％、80％、90％、95％或几乎所有的活性试剂被吸附至微粒上，至多100％。在本发明的一些实施方案中，微粒上可接近的表面区域应足够使得所有被吸附的活性试剂与微粒表面直接接触，即所述包覆是单层的。然而，应当理解可存在额外的相互作用。在一些情况下，例如活性试剂的自缔合也可以是在能量上有利的，从而多层活性试剂包覆所述颗粒。不要求这些层中任一是完整的或包覆的厚度是均一的。两种形式的自缔合可以被识别：多聚化和聚集。多聚化由特异的分子间相互作用和固定的化学计量表征。聚集通过非特异的分子间相互作用和不确定的化学计量表征。应当理解多聚的活性试剂可以在多聚状态下被吸附，或解聚为单体或较低等级的多聚体并在该状态下被吸附至表面。在任一情况下，聚集可调节活性试剂在微粒上成层。
经负载的微粒组成了药物递送组合物，其可以以多种形式使用。颗粒可以用作粉末，固体剂型如片剂或含在胶囊中，或悬浮于液体载剂中。通常这会需要交换和/或去除其中发生负载的液体介质。这可通过多种手段之任一完成，包括物理方法(例如但不限于沉降或过滤)和蒸发方法(例如但不限于冻干或喷雾干燥)。这些技术为本领域技术人员已知。在本发明的一个实施方案中，通过喷雾干燥去除溶剂。喷雾干燥二酮哌嗪微粒的方法公开于例如2006年2月22日提交的美国临时专利申请号No.60/776,605中，其通过引用将涉及喷雾干燥二酮哌嗪微粒的所有内容并入本文。
如果负载不是基本完全的，则使用物理溶剂去除法的本发明实施方案会典型地丢失未吸附的活性试剂，但是例如可以用于确保包覆不会发展到单层之外。相反，使用蒸发干燥用于溶剂去除的实施方案在一些情况下能够将额外的活性试剂沉积在颗粒上从而避免其丢失，但是所涉及的吸附相互作用与在该方法较早步骤中结合的分子所建立的可能有所差异。在其他实施方案中，通过蒸发进行的溶剂去除不导致显著的活性试剂进一步沉积，包括几乎所有活性试剂已被吸附在颗粒上的情况。
实施例
包括以下的实施例以阐述本发明优选的实施方案。本领域技术人员应当明白，下文实施例中公开的技术代表了本发明人发现在本发明的实践中作用良好的技术，因此可以被认为构成了用于其实践的优选模型。尽管讨论可集中在特定的机制上，但是应当理解一些改性剂可对所述试剂具有多重效应，或事实上对所述颗粒表面也有多重作用，每种作用可有助于促进颗粒对试剂的吸附。然而，在本公开的启发下，本领域技术人员应当理解可以在公开的具体实施方案中进行许多修改并仍然获得相似或类似的结果，而不偏离本发明的精神和范围。
实施例1
实验操作：活性试剂/FDKP微粒吸附研究
活性试剂胰岛素、PTH、脑肠肽和GLP-1购自American Peptide(Sunnyvale，CA)或AnaSpec(San Jose，CA)或内部制作(MannKindCorporation，Valencia，CA)。分析处于多种pH下和20℃下(除非另有说明)的水性样品。样品通常为新鲜制备的，并在添加FDKP微粒之前与特定添加剂(例如盐、pH缓冲液等，如果有的话)混合。
活性试剂与悬浮液中二酮哌嗪(DKP)颗粒的缔合通过进行吸附研究来评估。吸附研究中研究的参数探测了静电相互作用、氢键、水结构、蛋白质柔性和特异的盐配对相互作用对活性试剂/富马酰二酮哌嗪(FDKP)微粒相互作用的影响。另外，测试了若干常见的蛋白质稳定剂对活性试剂与FDKP微粒表面吸附的干扰。
研究了促进活性试剂在预先形成的FDKP颗粒表面上吸附的多种条件。将15mg/mL FDKP微粒悬浮液与3X pH缓冲液和3X的添加剂或赋形剂溶液组合。最终的溶液含有5mg/mL的FDKP微粒浓度和0.25mg/mL(5％w/w)的GLP-1浓度，或0.25mg/mL(5％w/w)的PTH浓度，或0.75mg/mL(15％w/w)的胰岛素浓度或0.10mg/mL(2％w/w)的脑肠肽浓度。从悬浮液中滤除上清液中未缔合的活性试剂。带有已缔合的活性试剂的FDKP颗粒溶解(重溶)于100mM碳酸氢铵中并过滤以分离出任何聚集的活性试剂分子。通过HPLC定量上清液和重溶的级分中的活性试剂量。进行一组实验，其中使用的条件包括添加剂(如盐、渗透物、离液剂和补偿溶质和醇)的使用。这些研究的结果描述于下文。
实施例2
离液剂和补偿溶质对FDKP颗粒上活性试剂吸附的效应
研究影响水和蛋白质结构的离子种类(离液剂和补偿溶质)以调查活性试剂通过疏水机制(低pH下)在FDKP微粒表面上的吸附。在5mg/mL微粒和0.25mg/mL(5％w/w)的GLP-1浓度，或0.25mg/mL(5％w/w)的PTH浓度，或0.75mg/mL(15％w/w)的胰岛素浓度下进行活性试剂在FDKP颗粒上的负载。样品中离液剂或补偿溶质的浓度被保持恒定在100mM，pH从2.0到5.0变化。离液剂或补偿溶质选自以下：NaSCN、CsCl、Na2SO4、(CH3)3N-HCl、Na2NO3、柠檬酸钠、和NaClO4。对照实验没有添加离液剂或补偿溶质。
图1A-1C描述了存在多种离液剂或补偿溶质时，胰岛素、GLP-1和PTH分别在FDKP微粒表面上的负载曲线，所述负载曲线是pH的函数。在低pH(3.0)下与对照相比，所有被分析的离液剂和补偿溶质促进了胰岛素对微粒表面的亲和力并显示了显著的负载。在pH 4下，未观察到该效应(图1A)。在更高的pH(5.0)下，离液剂和补偿溶质通过沉淀胰岛素蛋白质干扰胰岛素对微粒表面的吸附(与对照相比)。因此，这些试剂在低pH下促进胰岛素对FDKP颗粒的结合，但是在更高的pH条件下很少具有效应或甚至具有有害效应。
存在离液剂和补偿溶质时，在pH2.0-4.0下GLP-1显示对FDKP微粒的提高的亲和力，pH更低时效应更大(图1B)。相似的观察结果公开于美国临时申请No.60/744,882中。其中注意到存在NaSCN、NaClO4、Na2SO4、NaNO3和柠檬酸钠时在重溶的不含微粒的对照样品中检测到约0.02-0.04mg/mL的GLP-1肽(其对应于0.004到0.008的质量比)，表明小部分的GLP-1沉淀，而不是吸附在颗粒上。
存在强离液剂NaSCN和NaClO4时，PTH对FDKP微粒表面的亲和力在pH 4.0到约4.5时(图1C)。
该数据支持离液剂和补偿溶质在促进活性试剂对FDKP微粒表面吸附中起重要作用，在低pH时最为显著。因为这些改性剂在低pH(此时微粒表面离子性较弱)具有更大的效应，所以很可能吸附由疏水机制引起。在更高pH观察到的吸附减少可由颗粒表面带更多电荷与离液剂和补偿溶质对提高活性试剂疏水性的效应相结合而引起。另外，由于离子种类的关系，这些改性剂可与活性试剂竞争结合微粒，或破坏活性试剂与微粒之间的静电相互作用。最后也注意到德拜(Debye)屏蔽可有助于降低对带更多电荷的表面的吸附。
实施例3
渗透物对活性试剂与FDKP颗粒的吸附的效应
为了评估活性试剂稳定性对吸附的重要性，通过HPLC分析检查渗透物对活性试剂与FDKP颗粒结合的效应。图2A-2C显示存在常见稳定剂(渗透物)时胰岛素(图2A)、GLP-1(图2B)和脑肠肽(图2C)在FDKP颗粒上的负载曲线，其为pH的函数。活性试剂在FDKP微粒上的负载在5mg/mL微粒和0.75mg/mL(15％w/w)胰岛素浓度，或0.25mg/mL(5％w/w)的GLP-1浓度或0.10mg/mL(2％w/w)的脑肠肽浓度下进行。样品中渗透物(稳定剂)的浓度保持恒定在100mM，pH从约2.0变化到约5.0。渗透物选自己烯二醇(Hex-Gly)、海藻糖、甘氨酸、PEG、TMAO、甘露醇和脯氨酸；对照实验没有渗透物。
在研究的活性试剂中，在存在渗透物(PEG、甘氨酸、海藻糖、甘露醇和Hex-Gly)时和在3.0到5.0的pH范围内胰岛素显示显著提高的对FDKP颗粒表面的亲和力(图2A)。在研究的渗透物中，PEG和脯氨酸在从2.0到4.0的pH范围内提高GLP-1在FDKP颗粒表面上的吸附亲和力。在低pH(2.0)下，渗透物TMAO在将GLP-1结合至FDKP微粒表面上较之PEG或脯氨酸更为有效，但是在pH 3.0及以上时轻度有害(图2B)。然而，在约4.0到5.0的pH范围内，存在100mM甘露醇、PEG、甘氨酸、Hex-Gly和海藻糖时，与对照相比脑肠肽显示了对微粒表面更大的亲和力(图2C)。
这些负载曲线提示了渗透物能够增强活性试剂对FDKP微粒表面的吸附。很可能该效应由改性剂稳定活性试剂的能力引起，所述能力使得吸附更加在能量上有利。
实施例4
醇对活性试剂对FDKP颗粒的亲和力的效应
在评估改性剂对活性试剂的效应(其允许通过疏水机制吸附至微粒表面)时，检测醇的效应。已知能通过提高氢键强度在未结构化的肽和蛋白质中诱导螺旋构象的醇被评价，以确定螺旋构象在活性试剂与FDKP颗粒表面吸附中所起的作用。分析了如GLP-1和脑肠肽的活性试剂。活性试剂在FDKP颗粒上的负载在5mg/mL的微粒和0.25mg/mL(5％w/w)的GLP-1浓度或0.10mg/mL(2％w/w)的脑肠肽浓度下进行。每种醇的效应在2.0到5.0的pH范围内观察。使用的醇为三氟乙醇(TFE)和六氟异丙醇(HFIP)。每种醇在多种浓度(其包括5％、10％、15％或20％v/v)下评价。
图3A-3D显示了对于每种醇和每种活性试剂而言活性试剂在FDKP微粒上的负载曲线，其为pH的函数。在pH 2.0-4.0下，存在所有测试浓度(5％、10％、15％和20％，通过脑肠肽对FDKP颗粒的质量比所确定)的HFIP和TFE时，脑肠肽显示大大提高的对微粒表面的亲和力(图3A-3B)。
在pH 2.0-5.0下，存在所示浓度(5％和10％)的HFIP和TFE时，GLP-1显示对微粒表面提高的亲和力(图3C-3D)。TFE的效应较不显著，并且在测试的较低pH下是有害的。注意到在pH 4.0下存在10％HFIP和TFE时，重溶的不含颗粒的对照样品中检测到了大量的GLP-1肽(0.13-0.19mg/mL，其对应于0.026到0.038的质量比)，表明一些GLP-1已经沉淀。然而，在较低的pH(2.0-3.0)下，存在10％HFIP或TFE时，重溶的不含微粒的对照中GLP-1肽的数量显著减少。在pH 3.0下，检测到0到0.02mg/mL(其对应于0到0.004的质量比)的GLP-1肽，而在pH2.0下的对照样品未检测到GLP-1。图3C-D中的质量比反映了吸附的和沉淀的活性试剂，尽管当pH朝3.0降低时沉淀是越来越次要的成分。
数据指出醇能够促进活性试剂在FDKP微粒表面上的吸附。吸附的该提高很可能是由存在醇时活性试剂和微粒表面增强的疏水相互作用引起的。
实施例5
盐对活性试剂与FDKP颗粒吸附的效应
为了进一步研究结合的疏水机制，通过HPLC分析观察盐对活性试剂与FDKP微粒吸附的效应。
在存在0、25、50、100、250和500mM NaCl时，在5mg/mL微粒和0.75mg/mL(15％w/w)的胰岛素浓度，或0.25mg/mL(5％w/w)的GLP-1浓度，或0.25mg/mL(5％w/w)的PTH浓度下进行活性试剂在FDKP颗粒上的负载(图4A-4C)。也在1000mM NaCl下评估PTH在FDKP上的负载。评估了重溶的不含微粒的对照样品中检测的活性试剂量，其为pH和NaCl浓度的函数。用20mM磷酸钾/20mM醋酸钾混合物控制pH。
如图4A中所观察到的，在从约2.5到约3.5的pH下，胰岛素在FDKP颗粒上提高的结合(吸附)在100-500mM的高盐浓度下是明显的。在从约4.0到约5.0的pH下，对于检测的所有盐浓度而言，观察到胰岛素对FDKP颗粒吸附的降低。
在从约2.0到约3.5的pH下，在检测的所有盐浓度下GLP-1对FDKP的增强的结合(吸附)都是明显的(图4B)。在pH 4.0及以上，也注意到了结合的降低。
使用PTH作为活性试剂的类似研究显示了在从约2.0到约3.5的pH下，在250到1000mM的高盐浓度下，PTH对FDKP颗粒的增强的结合(图4C)。在从约3.5到约5.0的pH下，存在盐时PTH对微粒的结合减少。
在低pH下(此时吸附不是有利的)，添加盐能够修饰活性试剂的化学势，从而提高其对微粒表面的亲和力。这类结合的增强很可能由疏水机制引起。另外，数据表明pH提高时，吸附随着盐浓度的提高而降低。当微粒表面随着提高的pH而带有更多电荷时，假设的疏水机制可以被预期在促进活性试剂吸附上不太有效。该减少也可以由盐竞争微粒表面上的结合位点而引起。注意到德拜屏蔽也有助于所观察到的减少的吸附。
数据还显示了盐能够改变活性试剂的结构。例如，PTH的圆二色性测量显示当盐浓度上升时，肽的二级结构采取了更为螺旋的构象(图4D)。这提示了PTH结构的改变可促进其在低pH下与微粒表面的结合。
在水性溶液中，盐的存在也显示将染料得克萨斯红分配在微粒的表面上。
实施例6
环孢菌素A对FDKP颗粒吸附的效应
使用环孢菌素A作为活性试剂，体外和体内研究了对小疏水分子在FDKP颗粒上吸附的效应。通过改变活性试剂的溶解度促进吸附。
研究了一种亲脂的环状多肽——环孢菌素A，以显示疏水分子如何被加工以吸附在微粒上。另外，环孢菌素A的尺寸(1202.61MW)被用于证明微粒对较小化合物的负载能力。
为了完成负载，使用溶剂/抗溶剂方法。该方法的基本原则在于将化合物溶解在溶剂(甲醇)中，然后使用抗溶剂(水)将化合物赶出溶剂并处在微粒的表面上。利用该溶剂/抗溶剂途径，将环孢菌素A成功地负载在了微粒的表面上。
在测定溶解度模式的预实验中，环孢菌素A在甲醇中溶解为10mg/mL，并通过HPLC分析具有多种浓度的抗溶剂(10-90％H2O，增量10％)时其在1mg/mL的溶解度。将环孢菌素A峰面积与只含有甲醇的样品比较，以确定沉淀的损失百分比。观察到在低于60％的H2O中溶解度被大量保持。在70％的H2O中，明显的大部分试剂不溶，在80-90％的H2O中，保持了少于5％的溶解度。
为了评估颗粒负载，将FDKP微粒悬浮于环孢菌素A的甲醇溶液中。然后以分步的方式添加水至60％、80％和90％的终浓度。沉淀一半样品，将另一半冻干。然后重溶每半份样品，使得最终百分比为20％FDKP微粒/环孢菌素A，20％的0.5M碳酸氢铵(AmBicarb)和60％的甲醇(溶解微粒和环孢菌素A二者所必需的浓度)。通过HPLC分析每份的环孢菌素A含量，并进行比较来确定已被颗粒吸附的比例。结果在图5A中显示。在60％H2O中，观察到约20％的环孢菌素A与颗粒结合。在80％和90％的H2O中，负载分别为约90％和95％，表明环孢菌素A与FDKP微粒的强结合。
在90％的抗溶剂水平下，通过改变环孢菌素A的输入(从而假设所有的环孢菌素被吸附时，回收的固体的最终含量将是从2％到20％)来分析微粒对环孢菌素A的负载能力。观察到当输入量沿着该范围提高时，与微粒结合的可获得的环孢菌素A的百分比从输入量的50％的提高到输入量的90％(图5B)。应当注意，考虑到在90％的H2O中环孢菌素A的溶解度为0.05mg/mL，这些结果表明实质上所有可溶的环孢菌素A都被吸附在颗粒上而不是沉淀出来。
实施例7
环孢菌素A/DKP颗粒的肺吹入
为了检查环孢菌素A/FDKP微粒的药物代谢动力学，在通过肺吹入或静脉注射被施用了多种环孢菌素A/FDKP微粒配方的雌性Sprague Dawley大鼠中评价环孢菌素A的血浆浓度。使用在90％抗溶剂中配制的环孢菌素A/FDKP微粒和如上文实施例中所述的0.05、0.10或0.20的理论最大质量比进行这些研究。它们被称作5％、10％和20％负载。
单剂2.5mg的环孢菌素A/FDKP微粒通过肺吸入或静脉注射被递送给八组大鼠。在每组给药的给药前(时间0)和给药后5、20、40、60、240、480分钟和24小时采取血样。在每个时间点，将来自侧尾静脉(lateral tail vein)的约100μL全血收集在冷冻管中，倒置并存于冰上。在4000rpm将血样离心，将约40μL血浆移液入96孔板中，将其储存在-80℃直到分析。
如图6所示，通过肺吸入施用2.5mg FDKP微粒/环孢菌素A在给药后24小时引起雌性Sprague Dawley大鼠中最大的血清环孢菌素水平。在该时间点，10％的负载达到了32.4ng/mL的Cmax。通过静脉注射施用了0.1mL的2.5mg of FDKP微粒/环孢菌素A的动物直到给药后24小时都显示最小水平的环孢菌素。观察到对静脉注射和肺吸入组而言，FDKP微粒水平均在给药后20分钟出现峰值并在4小时中回归基线水平。
总之，数据显示环孢菌素A/FDKP微粒的生物可利用度。应注意到240分钟处的单峰是异常的。对处理的所有动物而言，通过肉眼和显微镜观察确定的病理学均是正常的。
除非另有说明，用于说明书和权利要求书中的表达成分数量、如分子量的性质、反应条件的所有数字等应理解为在所有情况下由术语“约”修饰。因此，除非指出反例，以下说明书和附加的权利要求书中公开的数量参数是近似值，其可根据本发明想要获得的所需性质而变化。至少，并不企图限制将等同原则应用于权利要求书的范围，每个数量参数至少应按照经报导的有效数字的位数并通过应用常规约数技术解释。不反对公开本发明广大范围的数量范围和参数为约数，而特定实施例中公开的数量值则是尽可能精确地报导的。然而，任何数量值固有地包含误差，这是从它们各自检测测量中发现的标准差必然地产生的。
除非在本文另有说明或同上下文明显抵触，描述本发明的上下文中(特别是在所附的权利要求书上下文中)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″)和类似的指代被解释为包括单数和复数。对本文数值范围的叙述仅意图用作为引用落入该范围的每个单独的值的速记方法(shorthand method)。除非本文另有说明，每个单独的值都被并入说明书，就像其被单独地并入本文一样。除非在本文另有说明或与上下文明显抵触，本文所述的所有方法可以以任何合适的顺序进行。本文所提供的任何和所有实例或举例文字(例如“例如”)的使用仅意欲用来更好地阐述本发明，而非对本发明所要求保护的范围设定限制。说明书中没有提及的文字应被解释为指代实施本发明必需的任何不要求保护的元素。
权利要求书中术语“或”的使用用于表示“和/或”，除非明确地指出仅表示备选方案或备选方案是排他性唯一的，尽管本公开支持表示仅为备选和“和/或”的定义。
本文公开的备选元素或实施方案的分组不应解释为限制。各组成员可被单独提到或要求保护，或与本文发现的组的其它成员或其它元素任意组合。应当理解，由于便利和/或专利的原因，一组的一个或多个成员可以被包括进一组中或从该组删除。当任何这类包括或删除发生时，本申请文件被认为含有经改写的组，以满足对附加的权利要求书中所用的所有马库什组的书面描述。
本文描述了根据本发明的某些实施方案，包括本发明的发明人已知的实现本发明的最佳模式。当然，本领域常规技术人员阅读上述描述后会明白这些实施方案的变更。本发明人预期熟练的技术人员能适当地采用这类变更，且本发明者意欲使得本发明以与本文特定描述不同的方式应用。因此，至少可适用的法律允许，本发明包括附加的权利要求书中所述的主体内容的所有修饰和等价物。另外，除非本文另有说明或与上下文明显抵触，在其所有可能变化中，上述元件的任何组合由本发明所包括。
另外，在本申请文件中，引用了大量专利和印刷出版物作为参考文献。上述各参考文献和印刷出版物通过引用其整体并入本文。
另外，应理解本文公开的本发明的实施方案仅用于阐述本发明的原则。其它可使用的修饰也在本发明的范围内。因此，通过示例而非限制的方式，可根据本文的教导利用本发明的备选形式。因此，本发明并非被限制为如精确地所示和所述的。

Claims (16)

1.促进活性试剂与悬浮液中预先形成的结晶微粒结合的方法，所述活性试剂包括胰岛素，所述方法包括步骤：
i)获得包含二酮哌嗪的预先形成的微粒；
ii)修饰所述活性试剂的结构、柔性、刚性、可溶性或稳定性从而修饰所述活性试剂的化学势，其中所述修饰包括通过向溶液中添加活性试剂改性剂而改变溶液条件，并且允许所述活性试剂和微粒之间在能量上有利的相互作用而不依赖于溶剂的去除，其中所述活性试剂改性剂选自酸和碱；和
iii)允许所述活性试剂吸附在所述微粒的表面上；
其中所述修饰步骤促进了所述活性试剂到所述微粒的表面的吸附，从而在所述微粒上提供所述活性试剂的包覆层。
2.如权利要求1所述的方法，其还包括将所述活性试剂溶解在微粒悬浮液的流动相中并改变所述流动相pH的步骤。
3.如权利要求2所述的方法，其中在添加活性试剂之前改变所述pH。
4.如权利要求2所述的方法，其中在添加活性试剂之后改变所述pH。
5.如权利要求1所述的方法，其中所述活性试剂改性剂促进所述活性试剂的结构稳定性或药物效应动力学。
6.如权利要求1所述的方法，其中修饰所述活性试剂的化学势包括调节与所述微粒表面的一种或多种在能量上有利的相互作用。
7.如权利要求6所述的方法，其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括静电作用。
8.如权利要求6所述的方法，其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括疏水作用。
9.如权利要求6所述的方法，其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括氢键相互作用。
10.如权利要求1中所述的方法，其中所述二酮哌嗪为富马酰二酮哌嗪。
11.如权利要求1中所述的方法，其还包括去除所述溶剂的步骤。
12.用于制备药物递送组合物的方法，所述组合物包含活性试剂和结晶微粒，所述方法包括步骤：
提供包含活性试剂分子的活性试剂溶液，其中所述活性试剂分子包括胰岛素；
修饰所述活性试剂的结构、柔性、刚性、可溶性或稳定性从而修饰所述活性试剂的化学势，其中所述修饰包括通过向溶液中添加活性试剂改性剂而改变溶液条件，其中所述活性试剂改性剂选自酸和碱；
提供微粒悬浮液或粉末，其中所述微粒包含二酮哌嗪；和
将所述活性试剂溶液与所述微粒悬浮液或粉末组合，其中所述修饰步骤促进了所述活性试剂到所述微粒的表面的吸附。
13.如权利要求12所述的方法，其中所述活性试剂改性剂降低所述活性试剂分子的溶解度。
14.如权利要求12所述的方法，其中所述活性试剂改性剂促进所述活性试剂和微粒之间的缔合。
15.如权利要求12所述的方法，其中所述活性试剂改性剂促进所述活性试剂分子的结构稳定性。
16.如权利要求12所述的方法，其中所述二酮哌嗪为富马酰二酮哌嗪。
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