CN110075069A - 包含活性剂-磷酸钙颗粒复合物的皮肤递送组合物及其应用 - Google Patents

包含活性剂-磷酸钙颗粒复合物的皮肤递送组合物及其应用 Download PDF

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CN110075069A
CN110075069A CN201910174558.4A CN201910174558A CN110075069A CN 110075069 A CN110075069 A CN 110075069A CN 201910174558 A CN201910174558 A CN 201910174558A CN 110075069 A CN110075069 A CN 110075069A
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calcium phosphate
activating agent
particle
acid
agent
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扎赫拉·曼苏里
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Laboratory Skin Protection Ltd Co
Laboratory Skin Care Inc
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Laboratory Skin Protection Ltd Co
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Abstract

本发明提供皮肤递送组合物。皮肤递送组合物的方面包括存在活性剂‑磷酸钙颗粒复合物，其中这些复合物包括与一种或多种活性剂结合的均匀刚性球形纳米多孔磷酸钙颗粒。本发明还提供在活性剂递送应用中使用所述组合物的方法。

Description

包含活性剂-磷酸钙颗粒复合物的皮肤递送组合物及其应用
本申请是于2010年5月6日向中华人民共和国国家知识产权局提交的申请号为201080030456.2、发明名称为“包含活性剂-磷酸钙颗粒复合物的皮肤递送组合物及其使用方法”的中国发明专利申请(PCT申请号PCT/US2010/033942，申请日2010年5月6日)的分案申请。
相关申请的交叉引用
根据35 U.S.C.§119(e)，本申请要求2009年5月6日提交的序列号为61/176,057的美国临时专利申请提交日的优先权；该申请的内容以引用的方式并入本文。
背景技术
已经并且还在持继地开发多种不同的活性剂以用于治疗多种不同的症状，包括疾病及非疾病症状。对于这种应用来说，必须将有效量的活性剂递送给有需要的受试者。已开发了多种不同的递送制剂及递送途径，其中这种途径可根据活性剂的性质而有所变化。通常情况下，微创递送途径得到更好的认可，因此是更理想的。
受到极大关注的一类递送途径是皮肤递送，因为其具有最小的创伤性。在皮肤递送中，将活性剂组合物被施用于皮肤部位，从而将活性剂递送给受试者。目前应用的或处于评估阶段的许多皮肤递送技术并不完全令人满意。例如，某些皮肤递送技术会破坏角质层(Sc)的完整性和/或依赖于渗透促进剂的存在，而渗透促进剂会造成不期望的损伤和/或刺激。此外，某些皮肤递送技术可能是基于聚合物和/或脂质体的技术，这两种技术都没有真正地经由Sc递送。此外，这些技术不能应用于大分子量生物活性物质等。
就此而言，仍然需要开发新的皮肤递送技术以克服目前皮肤递送方法所具有的一种或多种缺点。
发明内容
提供皮肤递送组合物。所述皮肤递送组合物的方面包括存在活性剂-磷酸钙颗粒复合物，其中这些复合物包括与一种或多种活性剂结合的均匀刚性球形纳米多孔磷酸钙颗粒。还提供在活性剂递送应用中使用所述组合物的方法。
附图说明
图1A至2B提供可应用于本发明递送组合物中的均匀刚性球形纳米多孔磷酸钙颗粒的扫描电子显微镜图像。
图3提供可应用于本发明递送组合物中的均匀刚性球形纳米多孔磷酸钙颗粒的粒径分布的图示。
图4显示附着于磷酸钙颗粒的活性剂的视觉图像。
图5A和5B显示对前臂施用10％磷酸钙颗粒浆料后的胶带剥离图像。图5A显示磷酸钙颗粒渗透到角质层的第一层。图5B显示磷酸钙颗粒渗透到角质层的第三层。
图6是施用磷酸钙颗粒之前的小鼠皮肤图像。上角质层中没有明显的Ca++。
图7A显示上角质层中的钙颗粒以及下角质层中的较小颗粒。图7B显示球形钙颗粒的完整性损失。
图8是显示局部施用后在整个角质层当中CTC荧光物质的渗透的照片。
图9显示进行和不进行磷酸钙颗粒胶带剥离时的STAY-C50的结果。
图10的表格显示通过胶带剥离测定的带有和不带有磷酸钙颗粒的溶菌酶的数量和百分比。
图11显示带有和不带有磷酸钙颗粒的单磷酸核黄素活性剂的Franz cell透皮递送。
具体实施方式
本发明提供皮肤递送组合物。所述皮肤递送组合物的方面包括存在活性剂-磷酸钙颗粒复合物，其中这些复合物包括与一种或多种活性剂结合的均匀刚性球形纳米多孔磷酸钙颗粒。还提供在活性剂递送应用中使用所述组合物的方法。
在进一步描述本发明之前要理解的是，本发明并不局限于所述的具体实施方案，因为这种具体实施方案是可以变化的。还要理解的是，本文中所使用的术语的目的仅是为了描述具体的实施方案，而非旨在具有限制的意义，因为本发明的范围仅由所附权利要求书来限定。
当提供数值范围时，要理解的是，介于该范围的上、下限之间的各中间值(除上下文另有明确的规定外，计算到下限单位的十分之一)以及在该所述范围内的任何其它提及的值或中间值均包括在本发明之内。这些较小范围的上、下限可独立地包括在该较小范围内，并且也包括在本发明之内，不算所述范围当中任何明确排除的限值。当所述范围包括一个或两个限值时，排除这些所包括的限值中的任一者或两者的范围也包括在本发明中。
本文中给出的某些范围在数值前面带有术语“约”。术语“约”在本文中用于对其后的确切数字以及对接近或近似于该术语后面的数字的数字提供文字支持。在确定一数字是否接近或近似于具体列举的数字时，接近或近似的未列举数字在其出现的上下文中可以是基本上等同于所具体列举数字的数字。
可以按所列举事件的任何逻辑上可行的顺序以及所列举的事件顺序实施本文中所列举的方法。
除另有定义外，本文中所使用的所有科技术语均具有与本发明所属领域的普通技术人员的通常理解相同的含义。虽然在本发明的实施或测试中也可以使用与本文中所述类似或等同的任何方法及物质，但现在要描述优选的方法及物质。
本文中提到的所有出版物均以引用的方式并入本文，以公开和描述与引用的出版物有关的方法和/或物质。提供本文中所讨论的出版物仅是针对本申请的提交日之前的公开内容。本文中的任何上述内容均不应被解释为由于在先发明的原因而承认本发明没有理由早于此类出版物。此外，所提供的出版日期可能不同于实际出版日期，而实际出版日期可能需要独立地进行确认。
必须注意的是，除上下文另有明确规定外，用在本文及所附权利要求书中的单数形式“一”、“一个”及“所述”包括复数的指代物。进一步指出的是，权利要求可撰写成不包括任何可选的要素。就此而论，这种陈述旨在用作就权利要求要素的陈述使用诸如“仅”、“只”等排他性用语或采用“负面”限制的先行基础。
在进一步描述本发明的各方面中，更详细地描述了根据某些实施方案的活性剂-磷酸钙颗粒，然后描述了包括所述活性剂-磷酸钙颗粒的递送组合物的实施方案，以及制备和使用所述复合物和包括所述复合物的递送组合物的方法。
递送组合物
如上文所概述，提供了活性剂递送组合物。本发明的活性剂递送组合物包括存在于递送载体中的活性剂-磷酸钙颗粒复合物。现在更详细地独立论述递送组合物的活性剂-磷酸钙颗粒复合物递送载体组分。
活性剂-磷酸钙颗粒复合物
存在于本发明的递送组合物中的活性剂-磷酸钙颗粒复合物包括与一种或多种活性剂结合的均匀刚性球形纳米多孔磷酸钙颗粒。当颗粒与一种或多种活性剂结合时，一种或多种活性剂以某种方式结合于所述颗粒。活性剂可经由许多不同的结合形式结合于所述颗粒，这些形式包括但不限于：离子键合、共价键合、范德华相互作用、氢键相互作用、正相及逆相分配相互作用等。就此而言，可以将所述颗粒描述成负载有一定量的一种或多种活性剂。“负载”是指颗粒包括一定量的一种或多种活性剂(换言之，一定量的单一活性剂或者两种或更多种不同的活性剂)，所述活性剂结合于所述颗粒。由于活性剂结合于所述颗粒，所以当所述颗粒存在于递送组合物当中时，活性剂不会以任何显著的量从颗粒中解离。因为基本上没有活性剂从颗粒中解离出来，所以按活性剂的初始结合量的重量计，任何确实解离的量为30％或更少，如20％或更少，例如为10％或更少，包括5％或更少。结合于颗粒的活性剂组分(由一种或多种不同的活性剂组成)的量可有所不同，这取决于组成活性剂结合颗粒的具体活性剂情况，在某些实施方案中该量为0.01mg/g至1000mg/g，如0.1mg/g至750mg/g，包括1mg/g至300mg/g活性剂/克颗粒。
活性剂与磷酸钙颗粒可逆地结合。“可逆地结合”是指在递送给受试者之后，例如，对皮肤位置施用包括所述复合物的递送组合物之后，活性剂被从磷酸钙颗粒中释放出来。如下文更详细的论述，复合物的磷酸钙颗粒在酸性条件下，例如在pH值为5或更小，例如pH值为4.9或更小、pH值为4.7或更小、pH值为4.5或更小、pH值为4.3或更小的条件下降解。当颗粒降解时，它们释放出其活性剂“有效载荷(payload)”。角质层(SC)是皮肤的最外层，由大约20层细胞组成，厚度大约10μm。SC的pH值视其深度而有所不同。其最外层的pH值从4.3到7.0不等，这取决于取样的位置或个体的性别。此pH值在粒层(SG)附近提高到7.0左右。如下所示，这一提高在贴近SG的SC的最后几层中最为显著。就此而言，随着本发明的复合物渗入SC，它们会降解并同时释放与其结合的任何活性剂。
释放出的活性剂尽管曾经与复合物中的磷酸钙颗粒结合，但还保持了其所需的活性。因此，活性剂同磷酸钙颗粒的结合及释放对活性剂产生的破坏基本上很小(如果有的话)。就此而言，活性剂的活性没有减小到不利地影响其效用的程度，其中例如按活性测定方法进行测定(例如在下文的实验部分中所述)，由给定的活性剂可能发生的同磷酸钙颗粒的结合所引起的任何活性减小为10％或更小，如5％或更小，包括1％或更小。
在一些实施方案中，复合物中活性剂与磷酸钙颗粒的结合保留了活性剂的一种或多种有利的特征，如稳定性。换言之，与没有磷酸钙颗粒的对照相比，复合物使活性剂稳定化。
均匀刚性球形纳米多孔磷酸钙颗粒
活性剂-磷酸钙颗粒复合物的磷酸钙颗粒为均匀刚性球形纳米多孔磷酸钙颗粒。“均匀”是指颗粒的形状基本上不变，从而颗粒具有基本上相同的球形形状。“刚性”是指颗粒很硬，从而它们不易弯曲。术语“球形”在常规意义上用来表示圆体，其表面的所有点基本上与中心等距。所关注的磷酸钙颗粒的中值粒径为20μm或更小，如10μm或更小，包括5μm或更小，其中在一些情况下，中值粒径为4μm或更小，如3μm或更小，包括2μm或更小。在给定的磷酸钙颗粒组合物中可存在粒径分布，其中在一些情况下，大多数(如60％或更多、75％或更多、90％或更多、95％或更多)的颗粒的直径范围在0.01μm至20μm，如0.1μm至10μm，包括0.1μm至2μm。在一些情况下，平均粒径为2μm或更小的颗粒的比例按数目计为50％或更多，如70％或更多，包括90％或更多。
所述颗粒是纳米多孔的。“纳米多孔”是指颗粒的孔隙率为30％或更大，如40％或更大，包括50％或更大，其中按ASTM D 4284-88“Standard Test Method for DeterminingPore Volume Distribution of Catalysts by Mercury Intrusion Porosimetry”中所述，采用压汞仪(mercury intrusion porosimeter)孔隙率测定方案进行测量，孔隙率的范围可以是30％至85％，如40％至70％，包括45％至55％。还通过“孔容(ml/g)”来描述孔隙率，在这种情况下许多为0.1ml/g至2.0ml/g。在一些情况下，颗粒具有这样的孔隙度，使得采用按ASTM D3663-03催化剂及催化剂载体表面积标准测试法中所述的BET气体吸附表面积测定方案进行测量时，其内表面积范围是10m2/g至150m2/g，如20m2/g至100m2/g，包括30m2/g至80m2/g。孔径可有所不同，在某些情况下其范围在2nm至100nm，如5nm至80nm，包括10nm至60nm。此外，颗粒的振实密度范围可以是0.2g/cm3至0.5g/cm3，如0.25g/cm3至0.45g/cm3，包括0.3g/cm3至0.4g/cm3。振实密度的测量可采用标准ASTM WK13023-通过恒定体积测量方法测定金属粉末的振实密度的新方法。
在一些情况下，颗粒是化学纯的。化学纯是指颗粒由基本上一种类型的磷酸钙矿物组成。在一些情况下，磷酸钙颗粒由分子式Ca10(PO4)6(OH)2描述。
在一些情况下，颗粒为陶瓷颗粒。陶瓷是指采用包括使颗粒经受高温条件的步骤的方法生产的，其中这种条件如下所示。高温的范围可以是200℃至1000℃，如300℃至900℃，包括300℃至800℃。在一些实施方案中，颗粒的压缩破裂强度范围在20MPa至200MPa，如50MPa至150MPa，包括75MPa至90MPa，这是采用岛津MCT-W500微压缩测试机颗粒强度测量方案测定的，颗粒经400℃至900℃温度下的烧结，如欧洲专利EP1840661中所述。
在一些实施方案中，所述颗粒是可生物降解的，这是指颗粒在生理条件下随着时间的推移而以某种方式(例如，溶解)降解。由于这些实施方案的颗粒在生理条件下可生物降解，因此它们在pH值为5或更低，如4.5或更低，包括4.3或更低的条件下至少以可检测的速率开始溶解。就此而言，颗粒在pH值为5或更低的酸性环境下，例如施用于皮肤时，显示出溶解性。
磷酸钙颗粒是无毒的(例如，经US-FDA 21CFR Part 58确定)、非致突变的(例如，经致突变性埃姆斯测试确定)和非刺激性的(例如，经皮肤敏感性RIPT(人类)确定)。
虽然递送组合物的均匀刚性球形纳米多孔磷酸钙颗粒的各种不同参数(包括如上所述在内)可以变化，但在一些实施方案中，递送组合物中所使用的颗粒是具有2μm平均直径的化学纯颗粒。
可以采用任何适宜的方案来制备本发明递送组合物的均匀刚性球形纳米多孔磷酸钙颗粒。所关注的制造方案的例子包括但不限于美国专利4,781,904、5,039,408、5,082,566和5,158,756中所描述的那些，上述内容以引用的方式并入本文。在所关注的一个方案中，所述颗粒的制造方式是，喷雾干燥包括纳米磷酸钙(例如，羟磷灰石)晶体(所述晶体可在2nm至100nm的范围)的浆料以产生均匀球形的纳米多孔磷酸钙颗粒。然后将所得到的颗粒烧结一段时间，所述时间足以得到机械及化学稳定的刚性球。在此步骤中，烧结温度可以是200℃至1000℃，如300℃至900℃，包括300℃至800℃，烧结时间为1小时至10小时，如2小时至8小时，包括3小时至6小时。序列号为61/108,805的美国临时申请中提供了有关均匀刚性球形纳米多孔磷酸钙颗粒的制造方法的更多细节，该申请的内容以引用的方式并入本文。
活性剂
如上文概述，本发明的复合物包括结合于均匀刚性球形纳米多孔磷酸钙颗粒的活性剂组分(由单一类型的活性剂或者两种或更多种不同类型的活性剂制成)。术语“活性剂”是指在与活生物体，例如哺乳动物，如人接触时产生生理效果，例如有益或有用效果的化合物或化合物的混合物。活性剂可区别于递送组合物的其它组分，如载体、稀释剂、润滑剂、粘结剂、着色剂等。活性剂可以是能够调节活受试者中的生物学过程的任何分子以及其结合部分或片断。在某些实施方案中，活性剂可以是用于诊断、治疗或预防疾病或作为药物、化妆品或药用化妆品的组分的物质。
活性剂是与活受试者中的标靶相互作用或者影响或以其它方式调整活受试者中的标靶的化合物。所述标靶可以为许多不同类型的天然结构，其中所关注的标靶包括细胞内标靶和细胞外标靶。活性剂可以包括一种或多种官能团，所述官能团提供与预定标靶的结构相互作用。所关注的官能团包括但不限于：参与氢键、疏水-疏水相互作用、静电相互作用的基团。所关注的具体基团包括但不限于胺、酰胺、巯基、羰基、羟基、羧基等。
所关注的活性剂可包括用一个或多个上述官能团取代的环碳或杂环结构和/或芳香或聚芳香结构。作为活性剂的部分还关注的有见于生物分子当中的结构，包括肽、糖类、脂肪酸、类固醇、嘌呤、嘧啶、它们的衍生物、结构类似物或组合。可以筛选这种化合物以识别所关注那些，其中各种不同的筛选方案是本领域中已知的。
活性剂可衍生自天然或合成的化合物，所述天然或合成化合物可得自广泛的来源，包括合成或天然化合物库。例如，许多方法可用于随机及定向合成广泛种类的有机化合物及生物分子，包括制备随机化寡核苷酸和寡肽。或者，细菌、真菌、植物及动物提取物形式的天然化合物库可供使用或易于产生。另外，天然或以合成方式产生的库及化合物易于通过常规的化学、物理及生物化学方法进行改性，并可用于产生组合库。可以对已知的药理试剂进行定向或随机的化学改性，如酰化、烷化、酯化、酰胺化等，以产生结构类似物。
就此而言，活性剂可得自天然或合成分子库，包括通过组合方法所产生的化合物库，即化合物多样性组合库。当得自这种库时，所使用的活性剂将会在适当的活性筛选分析中显示出一些理想的活性。组合库以及产生和筛选这种库的方法是本领域中已知的，并且在以下专利中有所描述：5,741,713、5,734,018、5,731,423、5,721,099、5,708,153、5,698,673、5,688,997、5,688,696、5,684,711、5,641,862、5,639,603、5,593,853、5,574,656、5,571,698、5,565,324、5,549,974、5,545,568、5,541,061、5,525,735、5,463,564、5,440,016、5,438,119、5,223,409，上述专利内容以引用的方式并入本文。
所关注的活性剂包括小、中等及大分子活性剂。小分子活性剂是分子量范围在18至2500道尔顿，如1000至1500道尔顿，包括250至1000道尔顿的活性剂。中等分子活性剂是分子量范围在2500至10,000道尔顿，如4,000至8,000道尔顿，包括5000至7000道尔顿的活性剂。大分子活性剂是分子量为10,000道尔顿或更大，如100,000道尔顿或更大的活性剂，其中在某些情况下这些大分子活性剂的范围在1百万至3千万道尔顿，如5百万至2千万道尔顿，包括1千万至1千5百万道尔顿。
在某些实施方案中，活性剂以其盐的形式存在，以使它们携带的电荷允许它们以所需的方式结合于递送组合物的均匀刚性球形纳米多孔磷酸钙颗粒。
所关注的活性剂包括但不限于序列号为61/176,057的美国申请的附录A中所列的活性剂；上述申请的内容以引用的方式并入本文。
所关注的广泛种类的活性剂包括但不限于：心血管药物；疼痛缓解剂，例如止痛剂、麻醉剂、抗炎药等；神经作用剂；化疗(例如抗肿瘤)剂；等等。所关注的活性剂包括但不限于：
抗生素，如：氨基糖苷类，例如丁胺卡那霉素(amikacin)、阿泊拉霉素(apramycin)、阿贝卡星(arbekacin)、班贝霉素(bambermycins)、丁苷菌素(butirosin)、地贝卡星(dibekacin)、双氢链霉素(dihydrostreptomycin)、福提霉素(fortimicin)、庆大霉素(gentamicin)、异帕米星(isepamicin)、卡那霉素(kaniamycin)、小诺霉素(micronomcin)、新霉素(neomycin)、奈替米星(netilmicin)、巴龙霉素(paromycin)、核糖霉素(ribostamycin)、西索米星(sisomicin)、大观霉素(spectinomycin)、链霉素(streptomycin)、妥布霉素(tobramycin)、丙大观霉素(trospectomycin)；酰胺醇类(amphenicols)，例如叠氮氯霉素(azidamfenicol)、氯霉素(chloramphenicol)、氟苯尼考(florfenicol)和塞马非尼可(theimaphenicol)；安沙霉素类(ansamycins)，例如利福酰胺(rifamide)、利福平(rifampin)、利福霉素(rifamycin)、利福喷汀(rifapentine)、利福昔明(rifaximin))；b-内酰胺类，例如碳头孢烯类(carbacephems)、碳青霉烯类(carbapenems)、头孢菌素类(cephalosporins)、头霉素类(cehpamycins)、单菌霉素类(monobactams)、氧头孢烯类(oxaphems)、青霉素类；林可酰胺类(lincosamides)，例如克林那霉素(clinamycin)、林可霉素(lincomycin)；大环内酯类，例如克拉霉素(clarithromycin)、第理霉素(dirthromycin)、红霉素(erythromycin)等；多肽类，例如双霉素(amphomycin)、杆菌肽素(bacitracin)、卷曲霉素(capreomycin)等；四环素类，例如阿哌环素(apicycline)、氯四环素(chlortetracycline)、氯莫环素(clomocycline)、米诺环素(minocycline)等；合成抗菌剂，如2,4-二氨基嘧啶类、硝基呋喃类、喹诺酮类及其类似物、磺酰胺类、砜类；
抗真菌剂，如：多烯类，例如两性霉素B、克念菌素(candicidin)、制皮菌素(dermostatin)、菲律宾菌素(filipin)、制霉色基素(fungichromin)、曲古霉素(hachimycin)、哈霉素(hamycin)、光明霉素(lucensomycin)、美帕曲星(mepartricin)、纳他霉素(natamycin)、制霉菌素(nystatin)、培西洛星(pecilocin)、表霉素(perimycin)；合成抗真菌药物，如烯丙胺类，例如布替萘芬(butenafine)、萘替芬(naftifine)、特比萘芬(terbinafine)；咪唑类，例如联苯苄唑(bifonazole)、布康唑(butoconazole)、氯登妥因(chlordantoin)、氯米达唑(chlormidazole)等；硫代氨基甲酸酯类，例如托昔拉酯(tolcilate)；三唑类，例如氟康唑(fluconazole)、伊曲康唑(itraconazole)、特康唑(terconazole))；
驱肠虫剂，如：槟榔碱(arecoline)、绵马素(aspidin)、绵马酚(aspidinol)、双氯酚(dichlorophen)、恩贝素(embelin)、苦辛(kosin)、萘、氯硝柳胺(niclosamide)、石榴碱(pelletierine)、奎纳克林(quinacrine)、木香内酯(alantolactone)、阿莫卡嗪(amocarzine)、硝硫氰胺(amoscanate)、驱蛔素(ascaridole)、苄酚宁(bephenium)、双硫氰苯(bitoscanate)、四氯化碳、香芹酚(carvacrol)、环苯达唑(cyclobendazole)、乙胺嗪(diethylcarbamazine)等；
抗疟药，如：醋氨苯砜(acedapsone)、氨酚喹(amodiaquin)、蒿乙醚(arteether)、蒿甲醚(artemether)、青蒿素(artemisinin)、青蒿琥酯(artesunate)、阿托伐醌(atovaquone)、比比林(bebeerine)、小檗碱(berberine)、獐芽菜(chirata)、氯胍、氯喹、氯丙胍(chlorproguanil)、金鸡纳皮(cinchona)、金鸡纳啶(cinchonidine)、金鸡纳宁(cinchonine)、环氯胍(cycloguanil)、龙胆苦甙(gentiopicrin)、卤泛曲林(halofantrine)、羟基氯喹、盐酸甲氟喹(mefloquine hydrochloride)、3-甲基醋氨苯胂(3-methylarsacetin)、帕马喹(pamaquine)、甲氧胺喹(plasmocid)、首喹(primaquine)、乙胺嘧啶(pyrimethamine)、奎纳克林(quinacrine)、奎尼啶(quinidine)、奎宁、喹西特(quinocide)、喹啉、砷酸氢二钠；
抗原生动物剂，如：安可拉尼(acranil)、替硝唑(tinidazole)、异丙硝唑(ipronidazole)、乙睇胺(ethylstibamine)、戊烷脒(pentamidine)、乙酰胂胺(acetarsone)、醋胺硝唑(aminitrozole)、大茴香霉素(anisomycin)、硝呋太尔(nifuratel)、替硝唑(tinidazole)、苯立达唑(benzidazole)、苏拉明(suramin)；
心脏保护剂，例如佐生(Zinecard)(右丙亚胺(dexrazoxane))；血液改良剂，包括抗凝血剂(例如，香豆定(Coumadin)(华法林钠(warfarin sodium)、法安明(fragmin)(达肝素钠)、肝素、印诺希(innohep)(亭扎肝素钠(tinzaparin sodium))、罗文诺司(lovenox)(依诺肝素钠(enoxaparin sodium))、欧干仁(orgaran)(达那肝素钠(danaparoid钠)))；抗血小板剂(例如，亚瓜司达(aggrasta)(盐酸替罗非班(tirofiban hydrochloride)、亚仁诺司(aggrenox)(阿斯匹林/延释双嘧达莫(dipyridamole))、亚桂林(agrylin)(盐酸阿那格雷(anagrelide hydrochloride))、艾克群(ecotrin)(乙酰基水杨酸)、福兰(folan)(依前列醇钠(epoprostenol sodium))、亥夫平(halfprin)(肠溶阿司匹林)、印特贵林(integrlilin)(依替巴肽(eptifibatide))、潘生丁(persantine)(双嘧达莫(dipyridamole USP))、帕拉唯司(plavix)(硫酸氢氯吡格雷(clopidogrel bisulfate))、帕雷它(pletal)(西洛他唑(cilostazol))、瑞欧破(reopro)(阿昔单抗(abciximab))、抵克立得(ticlid)(盐酸噻氯匹定(ticlopidine hydrochloride))、溶栓剂(爱克提畏斯(activase)(阿替普酶(alteplase))、瑞它飞(Retavase)(瑞替普酶(reteplase))、链激酶(链球菌致活酶(streptokinase))；肾上腺素能阻断剂，如可多华(cardura)(甲磺酸多沙唑嗪(doxazosin mesylate)、台苯齐林(dibenzyline)(盐酸苯氧苯扎明(phenoxybenzaminehydrochloride))、高特灵(hytrin)(盐酸特拉唑嗪(terazosin hydrochloride)、脉宁平(minipress)(盐酸哌唑嗪(prazosin hydrochloride))、米尼在(minizide)(哌唑嗪盐酸/泊利噻嗪((prazosin hydrochloride/polythiazide))；肾上腺素兴奋剂，如阿多克(aldoclor)(甲基多巴-氯噻嗪(methyldopa–chlorothiazide))、爱道美(aldomet)(甲基多巴(methyldopa)、盐酸甲基多巴乙酯(methyldopate HCl))、aldoril(甲基多巴-氢氯噻嗪(hydrochlorothiazide))、楷它波伊(catapres)(盐酸可乐定USP，可乐定(clonidine))、氯波伊(clorpres)(盐酸可乐定和氯噻酮)、孔必波伊(combipres)(盐酸可乐定/氯噻酮)、它尼司(tenex)(盐酸胍法辛(guanfacine hydrochloride))；α/β肾上腺素能阻断剂，如可瑞格(coreg)(卡维地洛(carvedilol))、诺莫代(normodyne)(盐酸拉贝洛尔(labetalolhydrochloride))；血管紧张素转化酶(ACE)抑制剂，如亚求普利(accupril)(盐酸奎那普利(quinapril hydrochloride))、亚司翁(aceon)(培哚普利特丁胺(perindoprilerbumine))、亚它司(altace)(雷米普利(ramipril))、卡托普利(captopril)、洛汀新(lotensin)(盐酸贝那普利(benazepril hydrochloride))、马畏(mavik)(群多普利(trandolapril))、单普利(monopril)(福辛普利钠片)、披瑞尼畏(prinivil)(赖诺普利(lisinopril))、优尼飞(univasc)(盐酸莫西普利(moexipril hydrochloride))、畏首克(vasotec)(依那普利拉(enalaprilat)、马来酸依那普利)、瑞司崔(zestril)(赖诺普利(lisinopril))；血管紧张素转化酶(ACE)抑制剂与钙通道阻断剂，如雷司索(lexxel)(马来酸依那普利-非洛地平ER)、罗崔(lotrel)(氨氯地平和盐酸贝那普利)、它卡(tarka)(群多普利(trandolapril)/盐酸维拉帕米ER)；血管紧张素转化酶(ACE)抑制剂与利尿剂，如亚求瑞替(accuretic)(盐酸喹那普利(quinapril HCl)/氢氯噻嗪)、洛汀新(lotensin)(盐酸贝那普利和氢氯噻嗪USP)、佐得普利(prinizide)(赖诺普利(lisinopril)-氢氯噻嗪)、优你瑞替(uniretic)(盐酸莫西普利(moexipril hydrochloride)/氢氯噻嗪)、畏色瑞替(vaseretic)(马来酸依那普利–-氢氯噻嗪)、捷赐托利(zestoretic)(赖诺普利(lisinopril)和氢氯噻嗪)；血管紧张素II受体拮抗剂，如阿他肯得(atacand)(坎地沙坦酯(candesartan cilexetil))、阿威普罗(avapro)(厄贝沙坦((irbesartan))、科素亚(cozaar)(氯沙坦钾(losartan potassium))、代文(diovan)(缬沙坦(valsartan))、美卡素(micardis)(替米沙坦(telmisartan))、太唯亭(teveten)(甲磺酸依普沙坦(eprosartanmesylate))；血管紧张素II受体拮抗剂与利尿剂，如avalide(厄贝沙坦-氢氯噻嗪)、代文(缬沙坦和氢氯噻嗪)、海捷亚(hyzaar)(氯沙坦钾-氢氯噻嗪)；抗心律不齐药，如第I组(例如，麦可息提(mexitil)(盐酸美西律，USP)、诺佩司(norpace)(磷酸丙吡胺(disopyramidephosphate))、坡坎必(procanbid)(盐酸普鲁卡因(procainamide hydrochloride))、奎那谷(quinaglute)(葡萄糖酸奎尼啶(quinidine gluconate))、奎尼得(quinidex)(硫酸奎尼啶(quinidine sulfate))、奎尼啶(葡萄糖酸奎尼啶注射剂，USP)、来特莫尔(rythmol)(盐酸普罗帕酮(propafenone hydrochloride))、淡波口(tambocor)(醋酸氟卡胺(flecainideacetate))、妥卡胺(tonocard)(盐酸妥卡尼(tocainide HCl)))、第II组(例如，贝他佩司(betapace)(盐酸索他洛尔(sotalol HCl))、背畏布落(brevibloc)(盐酸艾司洛尔(esmolol hydrochloride))、心得安(inderal)(盐酸普萘洛尔(propranololhydrochloride))、心施德(sectral)(盐酸醋丁洛尔(acebutolol hydrochloride)))、第III组(例如，贝他佩司(盐酸索他洛尔(sotalol HCl))、可达龙(cordarone)(盐酸胺碘酮(amiodarone hydrochloride))、口唯得(corvert)(富马酸伊布利特注射剂)、披色隆(pacerone)(盐酸胺碘酮(amiodarone)HCl)、提克塞(tikosyn)(多非利特(dofetilide)))、第IV组(例如，克拦(calan)(盐酸维拉帕米(verapamil hydrochloride)、合心爽(cardizem)(盐酸地尔硫卓(diltiazem HCl))以及亚登卡(adenocard)(腺苷)、雷诺司卡(lanoxicaps)(地高辛(digoxin))、拉诺辛(lanoxin)(地高辛))；降血脂酸类，包括胆汁酸螯合剂(例如，克雷司替(colestid)(微粉化盐酸考来替泊(colestipol hydrochloride))、唯口(welchol)(盐酸考来维仑(colesevelam hydrochloride)))、纤维酸衍生物(例如，阿托密(atromid)(安妥明(clofibrate))、吉非贝齐(lopid)(吉米吩扎(gemfibrozal)片，USP)、卓佳(tricor)(非诺贝特(fenofibrate)胶囊))、HMG-CoA还原酶抑制剂(例如，贝伊可(baycol)(西立伐他汀钠片)、来司可(lescol)(氟伐他汀钠)、立普妥(阿托伐他汀钙)、买唯可(mevacor)(洛伐他汀(lovastatin))、普拉固(pravachol)(普伐他汀钠)、柔可(zocor)(辛伐他汀(simvastatin)))、烟酸(例如，尼亚司本(Niaspan)(烟酸缓释片))；β肾上腺素能阻断剂，例如贝他佩司(betapace)(盐酸索他洛尔(sotalol HCl))、布罗卡春(blocadren)(马来酸噻吗洛尔(timolol maleate))、背畏布落(盐酸艾司洛尔)、卡挫(Cartrol)(盐酸卡替洛尔(carteolol hydrochloride))、心得安(盐酸普萘洛尔)、卡尔仑(kerlone)(盐酸倍他洛尔(betaxolol hydrochloride))、纳多洛尔(nadolol)、心施德(盐酸醋丁洛尔)、天诺敏(tenormin)(阿替洛尔(atenolol))、美多心安(toprol)(琥珀酸美托洛尔(metoprololsuccinate))、(zebeta)(富马酸比索洛尔(bisoprolol fumarate))；β肾上腺素能阻断剂与利尿剂，例如扣在(corzide)(纳多洛尔(nadolol)和苄氟噻嗪(bendroflumethiazide)片、印得艾(inderide)(盐酸普萘洛尔和氢氯噻嗪)、田诺瑞替(tenoretic)(阿替洛尔和氯噻酮)、提莫来(timolide)(马来酸噻吗洛尔-氢氯噻嗪)、才可(ziac)(富马酸比索洛尔和氢氯噻嗪)；钙通道阻断剂，例如拜新同(adalat)(硝苯地平)、克拦(盐酸维拉帕米)、卡地尼(cardene)(盐酸尼卡地平(nicardipine hydrochloride))、合心爽(盐酸地尔硫卓)、克维拉(covera)(盐酸维拉帕米)、异搏停(isoptin)(盐酸维拉帕米)、尼莫通(nimotop)(尼莫地平(nimodipine))、络活喜(norvace)(苯磺酸氨氯地平(amlodipine besylate))、波依定(plendil)(非洛地平(felodipine))、心痛定(procardia)(硝苯地平)、苏拉(sular)(尼索地平(nisoldipine))、替氮杂(tiazac)(盐酸地尔硫卓(diltiazem hydrochloride))、伐斯可(vascor)(盐酸苄普地尔(bepridil hydrochloride))、维尔宁(verelan)(盐酸维拉帕米(verapamil hydrochloride))；利尿剂，包括碳酸酐酶抑制剂(例如，氯苯磺胺(daranide)(双氯非那胺(dichlorphenamide)))、组合利尿剂(例如，(例如，阿打它在(aldactazide)(螺内酯(spironolactone)与氢氯噻嗪)、代在(dyazide)(氨苯蝶啶(triamterene)和氢氯噻嗪)、梅司在(maxzide)(氨苯喋啶和氢氯噻嗪)、武都力(moduretic)(盐酸阿米洛利(amiloride HCl)-氢氯噻嗪))、髓袢利尿剂(得马司(demadex)(托拉塞米torsemide))、利尿酸(edecrin)(依他尼酸(ethacrynic acid)、依他尼酸钠)、呋塞米(furosemide))、保钾利尿剂(阿德通(aldactone)(螺内酯(spironolactone))、代瑞宁(dyrenium)(氨苯蝶啶(triamterene))、米大摩(midamor)(盐酸阿米洛利(amiloride HCl))、噻嗪类(thiazides)及相关利尿剂(例如，丢卡定(diucardin)(氢氟甲噻(hydroflumethiazide))、代优你(diuril)(氯噻嗪(chlorothiazide)、氯噻嗪钠)、伊都隆(enduron)(甲氯噻嗪(methyclothiazide))、二氢氯噻氢氯噻嗪)、吲达帕胺(indapamide)、微在(microzide)(氢氯噻嗪)麦扣司(mykrox)(美托拉宗(metolazone)片)、任内西(renese)(泊利噻嗪(polythiazide))、泰利通(thalitone)(氯噻酮，USP)、乍落索林(zaroxolyn)(美托拉宗))；正性肌力药，例如地吉克(digitek)(地高辛)、多别克(dobutrex)(多巴酚丁胺(dobutamine))、雷诺司卡(lanoxicaps)(地高辛)、雷诺新(lanoxin)(地高辛)、披马扣(primacor)(乳酸米利酮(milrinone lactate))；活化酶(activase)(阿替普酶重组(alteplase recombinant))；肾上腺素氯化物(肾上腺素注射剂，USP)；丹舍(demser)(甲基酪胺酸(metyrosine))、美加明(inversine)(梅坎米胺盐酸盐(mecamylamine HCl))、瑞欧破(reopro)(阿昔单抗)、瑞它飞(瑞替普酶)、链激酶(链球菌致活酶)、替酶(tnkase)(替奈普酶(tenecteplase))；血管扩张剂，包括冠状动脉血管扩张剂(例如，依姆多(单硝酸异山梨醇酯)、益辛保(ismo)(单硝酸异山梨醇酯)、异帝(isordil)(二硝酸异山梨醇酯)、硝独(nitrodur)(硝化甘油)、永保心灵(nitrolingual)(硝化甘油舌喷剂)、硝司代(nitrostat)(硝化甘油片，USP)、消心痛(sorbitrate)(二硝酸异山梨醇酯))、末梢血管扩张剂及组合(例如，克罗半(corlopam)(甲磺酸非诺多巴(fenoldopam mesylate))、佛兰(fiolan)(依前列醇钠)、披马扣(乳酸米利酮))、血管升压药，例如阿拉明(aramine)(重酒石酸间羟胺)、艾匹本(epipen)(EpiPen 0.3毫克品牌肾上腺素自动注射器、EpiPen Jr.0.15毫克品牌肾上腺素自动注射器)、波阿马亭(proamatine)(盐酸米多君(midodrine hydrochloride))；等等。
精神药理制剂，如(1)中枢神经系统抑制剂，例如一般麻醉剂(巴比妥酸盐类、苯二氮卓类、类固醇类、环己酮衍生物及杂剂)、镇静催眠药(苯二氮卓类、巴比妥酸盐类、哌啶二酮类及三酮类、喹唑啉衍生物、氨基甲酸酯类、醛类及衍生物、酰胺类、无环酰脲类、苯并氮卓类及相关药物、吩噻嗪类等)、中央随意肌张力改良药(抗惊厥药，如乙内酰脲类(hydantoins)、巴比妥酸盐类、噁唑烷二酮类、琥珀酰亚胺类、酰基酰脲类(acylureides)、环戊酰亚胺类、苯二氮卓类、仲醇和叔醇、二苯并氮卓衍生物、丙戊酸及衍生物、GABA类似物等)、止痛剂(吗啡及衍生物、东罂粟碱衍生物、吗啡喃衍生物、苯基哌啶类、2,6-甲烷-3-苯唑卡因衍生物、二苯基丙胺类及同配体、水杨酸盐类、对氨基苯酚衍生物、5-吡唑啉酮衍生物、芳基乙酸衍生物、芬那酸盐类(fenamates)及同配体等)和止吐药(抗胆碱药、抗组胺药、抗多巴胺药等)，(2)中枢神经系统兴奋剂，例如兴奋剂(呼吸兴奋剂、惊厥兴奋剂、精神运动兴奋剂)、麻醉药品拮抗剂(吗啡衍生物、东罂粟碱衍生物、2,6甲烷-3-苯唑卡因衍生物、吗啡喃衍生物)、促智药，(3)精神药理剂，例如抗焦虑镇静剂(苯二氮卓类、丙二醇氨基甲酸酯类)抗精神病药(吩噻嗪衍生物、硫代黄嘌呤衍生物、其它三环化合物、苯丁酮衍生物及同配体、二苯基丁胺衍生物、取代的苯酰胺类、芳基哌嗪衍生物、吲哚衍生物等)、抗抑郁药(三环类化合物、MAO抑制剂等)，(4)呼吸道药物，例如中枢性镇咳药(鸦片生物碱类及其衍生物)；
药效剂，如(1)末梢神经系统药物，例如局部麻醉剂(酯衍生物、酰胺衍生物)，(2)作用于突触或神经效应器连接位置的药物，例如胆碱能剂、胆碱能阻断剂、神经肌肉阻断剂、肾上腺素能剂、抗肾上腺素能剂，(3)平滑肌活性药物，例如解挛药(抗胆碱能药、向肌肉性解挛药)、血管扩张剂、平滑肌兴奋剂，(4)组胺及抗组胺药，例如组胺及其衍生物(倍他唑(betazole))、抗组胺药(H1-拮抗剂、H2-拮抗剂)、组胺代谢药物，(5)心血管药物，例如强心剂(植物提取物、丁烯羟酸内酯类(butenolides)、戊二烯酸内酯类(pentadienolids)、来自格木属种的生物碱类、离子载体、-肾上腺素能受体兴奋剂等)、抗心律失常药、抗高血压药、抗血脂剂(降固醇酸(clofibric acid)衍生物、烟碱酸衍生物、激素及类似物、抗生素、水杨酸及衍生物)、抗静脉曲张药、止血药，(6)血液及造血系统药，例如抗贫血药、凝血药(止血药、抗凝血剂、抗血栓剂、溶栓剂、血蛋白及其部分)(7)胃肠道药物，例如消化剂(健胃药、利胆剂)、抗溃疡药、止泻剂，(8)局部作用药物；
化疗药物，如(1)抗感染剂，例如杀体外寄生虫药(氯化烃类、除虫菊酯类、硫化化合物)、驱肠虫剂、抗原虫剂、抗疟剂、抗阿米巴剂、抗利什曼虫药、抗滴虫剂、抗锥体虫剂(antitrypanosomal)、磺酰胺类、抗分支杆菌剂药、抗病毒化疗药物等，和(2)细胞抑制剂，即抗肿瘤剂或细胞毒素药物，如烷化剂，例如盐酸氮芥(Mechlorethamine hydrochloride)(氮芥、二氯甲二乙胺(Mustargen)、HN2)、环磷酰胺(Cytovan、Endoxana)、异环磷酰胺(ifosfamide)(IFEX)、苯丁酸氮芥(Chlorambucil)(瘤可宁(Leukeran))、美法仑(Melphalan)(苯丙氨酸芥末、L-沙可来新(sarcolysin)、马法兰(Alkeran)、L-PAM)、白消安(Busulfan)(马勒兰(Myleran))、塞替派(Thiotepa)(三伸乙基塞替派(Triethylenethiophosphoramide))、卡莫司汀(Carmustine)((BiCNU、BCNU)、洛莫司汀(Lomustine)(CeeNU、CCNU)、链佐星(Streptozocin)(链脲霉素(Zanosar))等；植物生物碱类，例如长春新碱(长春灭瘟碱(Oncovin))、长春碱(长春花碱(Velban)、硫酸长春碱(Velbe))、紫杉酚(Paclitaxel)(紫杉醇(Taxol))等；抗代谢药物，例如甲氨蝶呤(Methotrexate)(MTX)、巯嘌呤(嘌呤硫醇(Purinethol，6-MP)、硫鸟嘌呤(6-TG)、氟尿嘧啶(5-FU)、阿糖胞苷(Cytosar-U、Ara-C)、阿扎胞苷(Azacitidine)(Mylosar、5-AZA)等；抗生素，例如更生霉素(放线菌素D、Cosmegen)、阿霉素(Doxorubicin)(亚德里亚霉素(Adriamycin))、道诺霉素(Daunorubicin)(duanomycin，Cerubidine)、去甲氧正定霉素(Idarubicin)(去甲氧柔红霉素(Idamycin))、争光霉素(Bleomycin)(硫酸博来霉素(Blenoxane))、普卡霉素(Picamycin)(光神霉素(Mithramycin)、光辉霉素(Mithracin))、丝裂霉素(Mitomycin)(突变霉素(Mutamycin))等，及其它抗细胞增殖剂，例如羟基脲(羟脲(Hydrea))、甲基苄肼(Procarbazine)(Mutalane)、达卡巴嗪(Dacarbazine)(DTIC-Dome)、顺氯氨铂(Cisplatin)(顺铂(Platinol))卡铂(Carboplatin)(铂尔定(Paraplatin))、天冬酰胺酶(左旋天冬酰胺酶(Elspar))依托泊苷(VePesid,VP-16-213、安杀克宁(Amsarcrine)(AMSA，m-AMSA)、米托坦(Mitotane)(Lysodren)、米托蒽醌(Mitoxantrone)(Novatrone)等。
所关注的药物化合物还列于以下文献中：Goodman&Gilman's，ThePharmacological Basis of Therapeutics(第9版)(Goodman等人编辑)(McGraw-Hill)(1996)；和2001Physician’s Desk Reference。
活性剂的具体种类和例子包括但不限于：见于下表中的活性剂：
所关注的具体化合物还包括但不限于：
所关注的具体化合物还包括但不限于：
抗肿瘤药，如以下美国专利中所公开的：5880161、5877206、5786344、5760041、5753668、5698529、5684004、5665715、5654484、5624924、5618813、5610292、5597831、5530026、5525633、5525606、5512678、5508277、5463181、5409893、5358952、5318965、5223503、5214068、5196424、5109024、5106996、5101072、5077404、5071848、5066493、5019390、4996229、4996206、4970318、4968800、4962114、4927828、4892887、4889859、4886790、4882334、4882333、4871746、4863955、4849563、4845216、4833145、4824955、4785085、476925、4684747、4618685、4611066、4550187、4550186、4544501、4541956、4532327、4490540、4399283、4391982、4383994、4294763、4283394、4246411、4214089、4150231、4147798、4056673、4029661、4012448；
精神药理/精神科药物，如以下美国专利中所公开的：5192799、5036070、4778800、4753951、4590180、4690930、4645773、4427694、4424202、4440781、5686482、5478828、5461062、5387593、5387586、5256664、5192799、5120733、5036070、4977167、4904663、4788188、4778800、4753951、4690930、4645773、4631285、4617314、4613600、4590180、4560684、4548938、4529727、4459306、4443451、4440781、4427694、4424202、4397853、4358451、4324787、4314081、4313896、4294828、4277476、4267328、4264499、4231930、4194009、4188388、4148796、4128717、4062858、4031226、4020072、4018895、4018779、4013672、3994898、3968125、3939152、3928356、3880834、3668210；
心血管药物，如以下美国专利中所公开的：4966967、5661129、5552411、5332737、5389675、5198449、5079247、4966967、4874760、4954526、5051423、4888335、4853391、4906634、4775757、4727072、4542160、4522949、4524151、4525479、4474804、4520026、4520026、5869478、5859239、5837702、5807889、5731322、5726171、5723457、5705523、5696111、5691332、5679672、5661129、5654294、5646276、5637586、5631251、5612370、5612323、5574037、5563170、5552411、5552397、5547966、5482925、5457118、5414017、5414013、5401758、5393771、5362902、5332737、5310731、5260444、5223516、5217958、5208245、5202330、5198449、5189036、5185362、5140031、5128349、5116861、5079247、5070099、5061813、5055466、5051423、5036065、5026712、5011931、5006542、4981843、4977144、4971984、4966967、4959383、4954526、4952692、4939137、4906634、4889866、4888335、4883872、4883811、4847379、4835157、4824831、4780538、4775757、4774239、4771047、4769371、4767756、4762837、4753946、4752616、4749715、4738978、4735962、4734426、4734425、4734424、4730052、4727072、4721796、4707550、4704382、4703120、4681970、4681882、4670560、4670453、4668787、4663337、4663336、4661506、4656267、4656185、4654357、4654356、4654355、4654335、4652578、4652576、4650874、4650797、4649139、4647585、4647573、4647565、4647561、4645836、4639461、4638012、4638011、4632931、4631283、4628095、4626548、4614825、4611007、4611006、4611005、4609671、4608386、4607049、4607048、4595692、4593042、4593029、4591603、4588743、4588742、4588741、4582854、4575512、4568762、4560698、4556739、4556675、4555571、4555570、4555523、4550120、4542160、4542157、4542156、4542155、4542151、4537981、4537904、4536514、4536513、4533673、4526901、4526900、4525479、4524151、4522949、4521539、4520026、4517188、4482562、4474804、4474803、4472411、4466979、4463015、4456617、4456616、4456615、4418076、4416896、4252815、4220594、4190587、4177280、4164586、4151297、4145443、4143054、4123550、4083968、4076834、4064259、4064258、4064257、4058620、4001421、3993639、3991057、3982010、3980652、3968117、3959296、3951950、3933834、3925369、3923818、3898210、3897442、3897441、3886157、3883540、3873715、3867383、3873715、3867383、3691216、3624126；
抗微生物剂，如以下美国专利中所公开的：5902594、5874476、5874436、5859027、5856320、5854242、5811091、5786350、5783177、5773469、5762919、5753715、5741526、5709870、5707990、5696117、5684042、5683709、5656591、5643971、5643950、5610196、5608056、5604262、5595742、5576341、5554373、5541233、5534546、5534508、5514715、5508417、5464832、5428073、5428016、5424396、5399553、5391544、5385902、5359066、5356803、5354862、5346913、5302592、5288693、5266567、5254685、5252745、5209930、5196441、5190961、5175160、5157051、5096700、5093342、5089251、5073570、5061702、5037809、5036077、5010109、4970226、4916156、4888434、4870093、4855318、4784991、4746504、4686221、4599228、4552882、4492700、4489098、4489085、4487776、4479953、4477448、4474807、4470994、4370484、4337199、4311709、4308283、4304910、4260634、4233311、4215131、4166122、4141981、4130664、4089977、4089900、4069341、4055655、4049665、4044139、4002775、3991201、3966968、3954868、3936393、3917476、3915889、3867548、3865748、3867548、3865748、3783160、3764676、3764677；
抗炎药，如以下美国专利中所公开的：5872109、5837735、5827837、5821250、5814648、5780026、5776946、5760002、5750543、5741798、5739279、5733939、5723481、5716967、5688949、5686488、5686471、5686434、5684204、5684041、5684031、5684002、5677318、5674891、5672620 5665752、5656661、5635516、5631283、5622948、5618835、5607959、5593980、5593960、5580888、5552424、5552422 5516764、5510361、5508026、5500417、5498405、5494927、5476876、5472973、5470885、5470842、5464856、5464849、5462952、5459151、5451686、5444043、5436265、5432181、RE034918、5393756、5380738、5376670、5360811、5354768、5348957、5347029、5340815、5338753、5324648、5319099、5318971、5312821、5302597、5298633、5298522、5298498、5290800、5290788、5284949、5280045、5270319、5266562、5256680、5250700、5250552、5248682、5244917、5240929、5234939、5234937、5232939、5225571、5225418、5220025、5212189、5212172、5208250、5204365、5202350、5196431、5191084、5187175、5185326、5183906、5177079、5171864、5169963、5155122、5143929、5143928、5143927、5124455、5124347、5114958、5112846、5104656、5098613、5095037、5095019、5086064、5081261、5081147、5081126、5075330、5066668、5059602、5043457、5037835、5037811、5036088、5013850、5013751、5013736、500654、4992448、4992447、4988733、4988728、4981865、4962119、4959378、4954519、4945099、4942236、4931457、4927835、4912248、4910192、4904786、4904685、4904674、4904671、4897397、4895953、4891370、4870210、4859686、4857644、4853392、4851412、4847303、4847290、4845242、4835166、4826990、4803216、4801598、4791129、4788205、4778818、4775679、4772703、4767776、4764525、4760051、4748153、4725616、4721712、4713393、4708966、4695571、4686235、4686224、4680298、4678802、4652564、4644005、4632923、4629793、4614741、4599360、4596828、4595694、4595686、4594357、4585755、4579866、4578390、4569942、4567201、4563476、4559348、4558067、4556672、4556669、4539326、4537903、4536503、4518608、4514415、4512990、4501755、4495197、4493839、4465687、4440779、4440763、4435420、4412995、4400534、4355034、4335141、4322420、4275064、4244963、4235908、4234593、4226887、4201778、4181720、4173650、4173634、4145444、4128664、4125612、4124726、4124707、4117135、4027031、4024284、4021553、4021550、4018923、4012527、4011326、3998970、3998954、3993763、3991212、3984405、3978227、3978219、3978202、3975543、3968224、3959368、3949082、3949081、3947475、3936450、3934018、3930005、3857955、3856962、3821377、3821401、3789121、3789123、3726978、3694471、3691214、3678169、3624216；
免疫抑制剂，如以下美国专利中所公开的：4450159、4450159、5905085、5883119、5880280、5877184、5874594、5843452、5817672、5817661、5817660、5801193、5776974、5763478、5739169、5723466、5719176、5696156、5695753、5693648、5693645、5691346、5686469、5686424、5679705、5679640、5670504、5665774、5665772、5648376、5639455、5633277、5624930、5622970、5605903、5604229、5574041、5565560、5550233、5545734、5540931、5532248、5527820、5516797、5514688、5512687、5506233、5506228、5494895、5484788、5470857、5464615、5432183、5431896、5385918、5349061、5344925、5330993、5308837、5290783、5290772、5284877、5284840、5273979、5262533、5260300、5252732、5250678、5247076、5244896、5238689、5219884、5208241、5208228、5202332、5192773、5189042、5169851、5162334、5151413、5149701、5147877、5143918、5138051、5093338、5091389、5068323、5068247、5064835、5061728、5055290、4981792、4810692、4410696、4346096、4342769、4317825、4256766、4180588、4000275、3759921；
止痛剂，如以下美国专利中所公开的：5292736、5688825、5554789、5455230、5292736、5298522、5216165、5438064、5204365、5017578、4906655、4906655、4994450、4749792、4980365、4794110、4670541、4737493、4622326、4536512、4719231、4533671、4552866、4539312、4569942、4681879、4511724、4556672、4721712、4474806、4595686、4440779、4434175、4608374、4395402、4400534、4374139、4361583、4252816、4251530、5874459、5688825、5554789、5455230、5438064、5298522、5216165、5204365、5030639、5017578、5008264、4994450、4980365、4906655、4847290、4844907、4794110、4791129、4774256、4749792、4737493、4721712、4719231、4681879、4670541、4667039、4658037、4634708、4623648、4622326、4608374、4595686、4594188、4569942、4556672、4552866、4539312、4536512、4533671、4511724、4440779、4434175、4400534、4395402、4391827、4374139、4361583、4322420、4306097、4252816、4251530、4244955、4232018、4209520、4164514 4147872、4133819、4124713、4117012、4064272、4022836、3966944；
胆碱能剂，如以下美国专利中所公开的：5219872、5219873、5073560、5073560、5346911、5424301、5073560、5219872、4900748、4786648、4798841、4782071、4710508、5482938、5464842、5378723、5346911、5318978、5219873、5219872、5084281、5073560、5002955、4988710、4900748、4798841、4786648、4782071、4745123、4710508；
肾上腺素能剂，如以下美国专利中所公开的：5091528、5091528、4835157、5708015、5594027、5580892、5576332、5510376、5482961、5334601、5202347、5135926、5116867、5091528、5017618、4835157、4829086、4579867、4568679、4469690、4395559、4381309、4363808、4343800、4329289、4314943、4311708、4304721、4296117、4285873、4281189、4278608、4247710、4145550、4145425、4139535、4082843、4011321、4001421、3982010、3940407、3852468、3832470；
抗组胺剂，如以下美国专利中所公开的：5874479、5863938、5856364、5770612、5702688、5674912、5663208、5658957、5652274、5648380、5646190、5641814、5633285、5614561、5602183、4923892、4782058、4393210、4180583、3965257、3946022、3931197；
类固醇药，如以下美国专利中所公开的：5863538、5855907、5855866、5780592、5776427、5651987、5346887、5256408、5252319、5209926、4996335、4927807、4910192、4710495、4049805、4004005、3670079、3608076、5892028、5888995、5883087、5880115、5869475、5866558、5861390、5861388、5854235、5837698、5834452、5830886、5792758、5792757、5763361、5744462、5741787、5741786、5733899、5731345、5723638、5721226、5712264、5712263、5710144、5707984、5705494、5700793、5698720、5698545、5696106、5677293、5674861、5661141、5656621、5646136、5637691、5616574、5614514、5604215、5604213、5599807、5585482、5565588、5563259、5563131、5561124、5556845、5547949、5536714、5527806、5506354、5506221、5494907、5491136、5478956、5426179、5422262、5391776、5382661、5380841、5380840、5380839、5373095、5371078、5352809、5344827、5344826、5338837、5336686、5292906、5292878、5281587、5272140、5244886、5236912、5232915、5219879、5218109、5215972、5212166、5206415、5194602、5166201、5166055、5126488、5116829、5108996、5099037、5096892、5093502、5086047、5084450、5082835、5081114、5053404、5041433、5041432、5034548、5032586、5026882、4996335、4975537、4970205、4954446、4950428、4946834、4937237、4921846、4920099、4910226、4900725、4892867、4888336、4885280、4882322、4882319、4882315、4874855、4868167、4865767、4861875、4861765、4861763、4847014、4774236、4753932、4711856、4710495、4701450、4701449、4689410、4680290、4670551、4664850、4659516、4647410、4634695、4634693、4588530、4567000、4560557、4558041、4552871、4552868、4541956、4519946、4515787、4512986、4502989、4495102；上述的公开内容以引用的方式并入本文。
所关注的还有上述化合物的类似物。对于所有上述活性剂而言，活性剂可以以药学上可接受的盐类形式存在，如上所述。
递送载体组分
本发明的递送组合物是配制成用于将活性剂递送至局部位置的组合物，所述局部位置如哺乳动物受试者如人受试者的角质化皮肤表面或粘膜表面。角质化的皮肤表面是指受试者的皮肤位置，即动物身体的外部覆层或外皮的位置。粘膜表面是指受试者的包括粘膜的部位，如口腔内侧、鼻内侧等。
因为本发明的皮肤递送制剂是配制成用于递送至局部位置，所以将它们配制成与配制它们所针对的局部位置生理相容。因此，当与配制它们所针对的目标角质化皮肤表面或粘膜表面接触时，递送组合物基本上(如果有的话)不会引起使递送组合物不适用于局部施用的生理反应(如发炎或刺激)。
本发明的递送组合物包括一定量的活性剂-磷酸钙颗粒复合物，所述活性剂-磷酸钙颗粒复合物包括在递送载体组分中。递送载体组分是指递送组合物中不是活性剂-磷酸钙颗粒复合物组分的那部分。
本发明的递送组合物的递送载体组分可根据需要而改变，其中给定递送载体组分的具体成分至少部分地取决于具体组合物的性质。所关注的递送组合物包括：液体制剂，如洗剂(以悬浮液或乳液形式含有不溶物质的液体，拟用于外部施用，包括喷雾洗剂)和水溶液；半固体制剂，如凝胶(其中分散相已与分散介质合并而产生半固体物质如胶冻的胶体)、乳霜(软固体或稠液体)和软膏(软的、油膏制剂)；和固体制剂，如局部贴片。就此而言，所关注的递送载体组分包括但不限于：水包油(O/W)及油包水(W/O)型乳液、乳制剂、洗剂、乳霜、软膏、凝胶、浆液、粉末、面膜、敷料、喷雾剂、气雾剂或贴剂。
洗剂
洗剂是液体组合物，其中使用旋转粘度计测量时粘度为50,000cP或更小，如10,000cP或更小，所述旋转粘度计通过测量浸在样品中的圆筒形转子的运转扭矩来测量粘度，粘度测定方案在25℃的温度下实施，如JIS K 7117：Testing Methods For ViscosityWith A Rotational Viscometer Of Resins In The Liquid或ASTM D 2196-86：TestMethods for Rheological Properties on Non-Newtonian Materials by Rotational(Brookfield)Viscometer中所述。
所关注的洗剂递送载体组分可包括许多不同的成分，包括但不限于：水、软化剂、天然油类、硅油、增稠剂或粘度调节剂、合成或天然酯类、脂肪酸、醇类、保湿剂、乳化剂、防腐剂体系、着色剂、香料等。根据需要，这些物质的量可以为组合物重量的0.001％至99％，如0.1％至50％，包括1％至20％。
软化剂是替代皮肤中的脂质及天然油类或添加于皮肤中的脂质及天然油类的化合物。用在本文中的术语软化剂拟包括常规的脂质物质(例如，脂肪、蜡及其它水不溶性物质)、极性脂质(例如，已被改性而使其更具水溶性的脂质物质)、硅氧烷和烃。所关注的软化剂包括但不限于：己二酸二异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、棕榈酸乙基己酯、新戊酸异癸酯、苯甲酸C12-15醇酯、马来酸二乙基己酯、PPG-14丁基醚、PPG-2肉豆蔻基醚丙酸酯、蓖麻醇酸鲸蜡酯、胆固醇硬脂酸酯、胆固醇异硬脂酸酯、胆固醇乙酸酯、霍霍巴油、可可脂、牛油树籽油、羊毛脂及羊毛脂酯。
硅油可分为挥发性品种和非挥发性品种。用在本文中的术语“挥发性”是指在环境温度下具有可测量的蒸汽压的物质。所关注的挥发性硅油包括但不限于：含3至9个硅原子4至5个硅原子的环状或直链聚二甲基硅氧烷。直链挥发性硅氧烷物质在25℃下可具有5厘沲或更小的粘度，而环状物质可具有10厘沲或更小的粘度。所关注的非挥发性硅油包括但不限于：聚烷基硅氧烷、聚烷基芳基硅氧烷和聚醚硅氧烷共聚物。所关注的基本上非挥发性的聚烷基硅氧烷包括例如在25℃下粘度为5至100,000厘沲的聚二甲基硅氧烷。
合适的酯包括但不限于：具有10至20个碳原子的脂肪酸的烯基或烷基酯，如棕榈酸异丙酯、异硬脂酸异丙酯、异壬酸异壬酯、肉豆蔻酸油醇酯、硬脂酸油醇酯和油酸油酯；醚-酯类，如乙氧基化脂肪醇的脂肪酸酯；多元醇酯；乙二醇单脂肪酸酯及乙二醇二脂肪酸酯；二乙二醇单脂肪酸酯及二乙二醇二脂肪酸酯、聚乙二醇(200-6000)单脂肪酸酯及聚乙二醇(200-6000)二脂肪酸酯；丙二醇单脂肪酸酯及丙二醇二脂肪酸酯，如聚丙二醇2000单油酸酯、聚丙二醇2000单硬脂酸酯、乙氧基化丙二醇单硬脂酸酯；单脂肪酸甘油酯及二脂肪酸甘油酯；聚甘油聚脂肪酸酯，如乙氧基化单硬脂酸甘油酯、1,3-丁二醇单硬脂酸酯、1,3-丁二醇二硬脂酸酯；聚氧乙烯多元醇脂肪酸酯；山梨醇酐脂肪酸酯；和聚氧乙烯山梨醇酐脂肪酸酯，它们是令人满意的多元醇酯；蜡酯类，如蜂蜡、鲸蜡、肉豆蔻酸肉豆蔻酯、硬脂酸硬脂酯；固醇酯类，其例子有大豆固醇和胆固醇脂肪酸酯。可以使用这些化合物的植物及动物来源两者。这种油的例子包括但不限于：蓖麻油、羊毛脂油、C10-18三甘油酯、辛酸/癸酸三甘油酯、甜杏仁油、杏仁油、芝麻籽油、亚麻荠籽油、琼崖海棠(tamanu)籽油、玉米油、棉籽油、亚麻籽油、墨油、橄榄油、棕榈油、婆罗洲(illipe)脂、菜籽油、大豆油、葡萄籽油、葵花籽油、核桃油等。还合适的有合成或半合成的甘油酯，如脂肪酸单-、二-及三甘油酯，其为已被改性的天然脂肪或油类，例如多元醇(如甘油)的单-、二-或三酯。在一例子中，使脂肪(C12-22)羧酸与一个或多个重复的甘油基反应。硬脂酸甘油酯、二异硬脂酸二甘油酯、聚甘油基-3异硬脂酸酯、聚甘油基-4异硬脂酸酯、聚甘油基-6蓖麻醇酸酯、二油酸甘油酯、二异硬脂酸甘油酯、四异硬脂酸甘油酯、三辛酸甘油酯、二硬脂酸二甘油酯、亚麻油酸甘油酯、肉豆蔻酸甘油酯、异硬脂酸甘油酯、PEG蓖麻油、PEG油酸甘油酯、PEG硬脂酸甘油酯和PEG牛脂酸甘油酯。
所关注的脂肪酸包括但不限于：具有10至30个碳原子的脂肪酸，如壬酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、异硬脂酸、羟基硬脂酸、油酸、亚油酸、蓖麻油酸、花生酸、山嵛酸和芥酸。
多元醇类型的保湿剂也可应用于组合物中，其中多元醇的例子包括但不限于：丙三醇(也称为甘油)、聚烷二醇、烯二醇及其衍生物，包括丙二醇、二丙二醇、聚丙二醇、聚乙二醇及其衍生物、山梨醇、羟丙基山梨醇、己二醇、1,3-丁二醇、1,2,6-己三醇、乙氧基化甘油、丙氧基化甘油及其混合物。还关注的有糖类，例如，葡萄糖、果糖、蜂蜜、氢化蜂蜜、肌醇、麦芽糖、甘露醇、麦芽糖醇、山梨醇、蔗糖、木糖醇、木糖等。当存在保湿剂时，其量的范围按组合物的重量计可以是0.001％至25％，如约0.005％至20％，包括约0.1％至15％，其中在一些情况下，保湿剂量的范围是0.5％至30％，如介于1％与15％之间。
乳化剂也可存在于载体组合物中。当存在乳化剂时，按总的组合物重量计，其总浓度范围可以是0.01％至40％，如1％至20％，包括1％至5％。所关注的乳化剂包括但不限于：阴离子性、非离子性、阳离子性及两性活性物质。所关注的非离子性表面活性剂包括对每摩尔疏水物具有与约2至约100摩尔环氧乙烷或环氧丙烷缩合的C10-C20脂肪醇或酸疏水物的表面活性剂；与2至20摩尔环氧烷缩合的C2-C10烷基酚；乙二醇的单-及二-脂肪酸酯；脂肪酸单甘油酯；山梨醇酐、单-C8-C20脂肪酸和二-C8-C20脂肪酸；和聚氧乙烯山梨醇酐以及它们的组合。烷基多糖苷和糖脂肪酰胺(例如甲基葡糖酰胺)也是所关注的非离子性乳化剂。所关注的阴离子性乳化剂包括肥皂、烷基醚硫酸酯和磺酸酯、硫酸烷基酯及磺酸烷基酯、烷基苯磺酸酯、磺基琥珀酸烷基及二烷基酯、羟乙基磺酸C8-C20酰基酯、C8-C20烷基醚磷酸酯、烷基醚羧酸酯及其组合。
在需要时，组合物中可以包括防腐剂，例如以防止可能有害的微生物的生长。所关注的防腐剂包括对-羟基苯甲酸的烷基酯、乙内酰脲衍生物、丙酸盐和多种季铵化合物。所关注的具体防腐剂包括但不限于：氨基甲酸碘代丙炔基丁酯、苯氧基乙醇、对羟苯甲酸甲酯、对羟苯甲酸丙酯、咪唑烷基脲、脱氢乙酸钠、苯甲醇、苯甲基半缩甲醛、对羟苯甲酸苯甲酯、5-溴-5-硝基-1,3-二噁烷、2-溴-2-硝基丙烷-1,3-二醇、辛二醇、乙基己基甘油、苯氧基乙醇山梨酸、对羟苯甲酸甲酯、对羟苯甲酸丙酯、对羟苯甲酸乙酯、对羟苯甲酸丁酯、苯甲酸钠、山梨酸钾、乙二胺四乙酸的二钠盐、氯二甲苯酚、DMDM乙内酰脲、氨基甲酸3-碘-2-丙基丁酯、氯己定二葡萄糖酸盐、苯氧基乙醇、重氮烷基脲、双胍衍生物、苯甲酸钙、丙酸钙、辛二醇、双胍衍生物、卡普坦(captan)、氯己定二乙酸盐、氯己定二葡萄糖酸盐、氯己定二盐酸盐、氯乙酰胺、氯丁醇、对-氯-间-甲酚、苄氯酚(chlorophene)、氯瑞香草酚、氯二甲苯酚、间-甲酚、邻-甲酚、DEDM乙内酰脲、DEDM乙内酰脲二月桂酸盐、脱氢乙酸、重氮烷基脲，羟乙磺酸双溴丙脒(dibromopropamidine diisethionate)、DMDM乙内酰脲等。当存在防腐剂时，按组合物的重量计，其在组合物中的存在量范围可以是0.01％至约10％。
增稠剂或粘度调节剂可以包括在递送组合物中。所关注的增稠剂包括但不限于：多糖，如淀粉、天然/合成胶和纤维素。所关注的淀粉包括但不限于化学改性淀粉，如淀粉辛烯基琥珀酸铝。所关注的胶包括但不限于：黄原胶、菌核、果胶、梧桐胶、阿拉伯胶、琼脂、瓜尔胶、卡拉胶、海藻酸盐及其组合。合适的纤维素包括但不限于：羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素及羧甲基纤维素钠。合成的聚合物也是进一步有效类的增稠剂。这一类包括交联聚丙烯酸酯(如卡波姆(Carbomers))和聚丙烯酰胺(如305)。当存在增稠剂时，其量的范围可以是0.001至5重量％，如0.1至2重量％，包括0.2至0.5重量％。
在一些情况下，可以存在天然或合成有机蜡，例如一种或多种天然或合成蜡，如动物、植物或矿物蜡。在一些情况下，这种蜡的熔点范围在20至150℃，如30至100℃，包括35至75℃。这种蜡的例子包括诸如聚乙烯或合成蜡之类的蜡；或各种植物蜡，如蜡杨梅、蜡大戟、地蜡、刺槐、蜂蜡、纯白地蜡、鲸蜡酯、花蜡、柑桔蜡、棕榈蜡、霍霍巴蜡、日本蜡、聚乙烯、微晶、米糠、羊毛脂蜡、貂蜡、褐煤蜡、蜡杨梅、小冠椰(ouricury)、地蜡、棕榈仁蜡、石蜡、牛油果蜡、苹果蜡、虫胶蜡、鼠尾草蜡、废谷腊、葡萄蜡及其聚烷二醇衍生物，如PEG6-20蜂蜡或PEG-12棕榈蜡；或脂肪酸或脂肪醇，包括其酯，如羟基硬脂酸(例如12-羟基硬脂酸)、三硬脂精和三山嵛精。还受关注的有、格鲁椰子籽脂(Acrocomia Aculeata Seed Butter)、杏仁脂、芦荟脂、杏仁(Apricot Kernel)脂、摩洛哥坚果脂、美国油棕榈树(Attalea Maripa)籽脂、鳄梨脂、巴巴苏棕榈果脂、包可脂(Bacuri Butter)、Bagura软脂、猴面包树软脂、油拔树籽脂、阔叶拔树籽脂、黑加仑籽脂、巴西坚果脂、卡默利纳脂、山茶脂、蜡大戟脂、棕榈蜡脂、巴西大风子(Carpotroche Brasiliensis)籽脂、甘菊脂、可可脂、椰子脂、咖啡脂、棉花软脂、蔓越莓脂、古朴阿苏果脂、葡萄籽脂、榛坚果脂、麻籽脂、马尾脂、雾冰草脂、加蓬依苦木仁脂(Irvingia Gabonensis Kernel Butter)、霍霍巴脂、牛油果脂、烛果脂、卜魁脂(KukuiButter)、欧薄荷脂、柠檬脂、酸橙脂、澳洲坚果脂、芒果脂、马鲁拉脂、摩诺依脂、长叶雾冰藜脂、穆卡雅脂、星实榈脂、莱亚脂、橄榄脂、橙脂、棕榈油、百香果脂(Passion Butter)、Phulwara脂、开心果脂、石榴脂、南瓜脂、覆盆子脂、稻脂、萨尔脂、Sapucainha脂、芝麻脂、牛油树脂、大豆脂琼崖海棠脂、向日葵籽脂、甜杏仁脂、橘脂、Tucuma籽脂、黄蜡树脂和麦芽脂。
着色剂、香料及磨料也可包括在递送组合物中。这些物质每种的范围可以是0.05至5％重量，如0.1重量％和3重量％。所关注的着色剂包括二氧化钛(适当情况下经表面处理，参照CI 77,891下的颜色指数编码)、锰紫(CI 77,742)、群青(CI 77,007)、氧化铬(CI77,288)、水合氧化铬(CI 77,289)、铁蓝(CI 77,510)、氧化锌、二氧化锆。所关注的具体着色剂包括：D&C红色19号(CI 45,170)、D&C红色9号(CI 15,585)、D&C红色21号(CI 45,380)、D&C橙色4号(CI 15,510)、D&C橙色5号(CI 45,370)、D&C红色27号(CI 45,410)、D&C红色13号(CI 15,630)、D&C红色7号(CI 15,850:1)、D&C红色6号(CI 15,850:2)、D&C黄色5号(CI19,140)、D&C红色36号(CI 12,085)、D&C橙色10号(CI 45,425)、D&C黄色6号(CI 15,985)、D&C红色30号(CI 73,360)、D&C红色3号(CI 45,430)、炭黑(CI 77,266)、胭脂红(CI 75,470)、天然或合成黑色素和铝色淀。
所关注的香料包括：阿尔巴冷杉叶油、乙醛、乙酰替苯胺、乙酸、千叶蓍油、猕猴桃(奇异果)水果水、己二酸、琼脂、变性酒精、褐藻胶、芦荟叶、乙酸戊酯、苯甲酸戊酯、戊基肉桂醛、茴香脑、茴香醇、洋甘菊花水、苯甲醛、苯甲醇、白桦油、齿叶乳香树油、乙酸丁酯、乳酸丁酯、金盏菊花油、茶树叶水、樟脑、辣椒素、雪松醇、肉桂醛、柠檬醛、香茅醇、来檬(酸橙)油、甜橙(柑橘)油、柚(葡萄柚)油、红桔(柑橘)果皮油、香豆素、二丙酮醇、肉桂酸乙酯、乙醚、桉树石竹(丁香)花油、金合欢醇、栀子油、野生天竺葵油、己基肉桂醛、氢化松香、八角(茴香)油、乙酸异戊酯、墨西哥刺柏油、月桂树油、狭叶薰衣草(熏衣草)油、互叶白千层(茶树)叶油、蜜里萨香草叶油、洋薄荷(薄荷)油、薄荷醇、2-萘酚、马郁兰(Origanum majorana)叶油、人参根提取物、壬酸、天竺葵花油、欧洲赤松(Pinus Silvestris Cone)油、杏树(杏)仁油、狗蔷薇花油、迷迭香(迷迭香)叶油、檀香(檀香木)油、百里香(麝香草)油、香兰素、葡萄(葡萄)叶油、生姜(姜)根油。
半固体递送组合物
所关注的还有半固体递送组合物，如凝胶、乳霜及软膏。这种组合物可以是(除了活性剂-磷酸钙颗粒复合物之外还有)水、水溶性聚合物、防腐剂、醇、多价醇、乳化剂、保湿剂、蜡、溶剂、增稠剂、增塑剂、pH值调节剂、保水剂等的混合物。此外，这种组合物也可含有其它生理上可接受的赋形剂或其它次要的添加剂，如香料、染料、乳化剂、缓冲剂、抗生素、稳定剂等。这些化合物类型的例子在上文中给出。
局部贴片
所关注的还有固体制剂，如局部贴片制剂。局部贴片制剂可以有很大的不同。局部贴片制剂可以包括活性剂层、支撑物和离型衬垫。活性剂层可以在基质中包括一定量的活性剂-颗粒复合物，其中基质可以包括以下一种或多种：粘合剂，如压敏橡胶和丙烯酸；水凝胶；生理上可接受的赋形剂或其它次要的添加剂，如香料、染料、乳化剂、缓冲剂、抗生素、稳定剂等。支撑物可由柔性材料制成，所述柔性材料能够适应人体的运动，包括例如塑料膜、各种非织造织物、织造织物、氨纶等。可以使用各种惰性覆盖层，其包括下文所述可应用于石膏的各种物质。或者，可使用非织造或织造覆盖层，特别是允许热量及蒸汽传输的弹性体覆盖层。这些覆盖层可实现疼痛部位的冷却，这提供更好的舒适性，同时保护凝胶以免被机械移除。离型衬垫可由任何方便的材料制成，其中代表性的离型膜包括聚酯，如PET或PP等。
气雾剂组合物
所关注的还有经由吸入施用的气雾剂组合物制剂。可以将这些气雾剂制剂置于加压的可接受推进剂如二氯二氟甲烷、丙烷、氮等中。也可将它们配制成用于非加压制剂，如用于喷雾器或雾化器。在一些实施方案中，所述制剂为粉状气雾剂制剂，其包括悬浮或分散在推进剂或推进剂和溶剂中的活性剂结合颗粒。推进剂可以是液化氯氟烃(CFC)的混合物，选择液化氯氟烃以提供所需的蒸汽压及制剂稳定性。推进剂11、推进剂12和推进剂114是用于吸入施用的气雾剂制剂中最广泛使用的推进剂。其它常用的推进剂包括推进剂113、推进剂142b、推进剂152a、推进剂124和二甲醚。化合物1,1,1,2-四氟乙烷也是用于医药气雾剂制剂的常用推进剂。推进剂可以为总吸入组合物重量的40％至90％。
递送组合物的制备方法
本发明的方面进一步包括递送组合物的制备方法。虽然可采用任何适宜的制造方案，但在一些情况下，制造方案包括首先制备活性剂-颗粒复合物。制备活性剂-颗粒复合物之后，然后采用任何适宜的方案将所得到的复合物合并到递送组合物组分内。
可采用任何适宜的方案制备活性剂-颗粒复合物。所关注的一种方案包括首先制备活性剂的液体组合物，如活性剂的水性组合物，然后在足以产生所需活性剂-颗粒复合物的条件下将液体组合物与一定量的均匀刚性球形纳米多孔磷酸钙颗粒合并(根据需要进行搅拌)。就此而言，在某些实施方案中，将未结合颗粒的液体组合物例如合适的溶剂体系(如水或非水溶剂体系)中的未结合颗粒浆料与适量的活性剂合并。
颗粒预处理
根据需要，在与活性剂合并之前，可以按某种方式对未结合颗粒进行预处理。就此而言，活性剂结合颗粒的制备可包括预处理步骤，如初始pH值调节步骤。在这一步骤中，通过使未结合颗粒与一种或多种试剂如pH值调节剂接触而将其改性，以便提供结合于颗粒的所需活性剂。如采用pH值调节，则其具体性质依要结合于颗粒的活性剂的类型而变化。所关注的一类活性剂是这样的活性剂，其包括酸性和/或碱性带电部分，并且分子质量大于数千道耳顿，例如分子质量为3000道耳顿或更大，如5,000道耳顿或更大，例如10,000道耳顿或更大、25,000道耳顿或更大、50,000道耳顿或更大、75,000道耳顿或更大、100,000道耳顿或更大、250,000道耳顿或更大、500,000道耳顿或更大、750,000道耳顿或更大、1,000,000道耳顿或更大。这种活性剂的例子包括但不限于蛋白质、核酸和多糖。这种活性剂在广范的pH值条件下可与颗粒的钙和/或磷酸根位置发生强结合。因此，对于这些类型的活性剂来说，根据需要可以实施或可以不实施pH值调节。在需要pH值调节的情况下，可通过使用任何适宜的pH值调节剂例如酸或碱试剂来实施pH值调节。所关注的pH值调节剂包括但不限于：乳酸、乙醇酸、三乙醇胺和氢氧化钠。在一些情况下，选择不阻挡颗粒的钙和/或磷酸根结合位置的pH值调节剂。
所关注的另一类活性剂是这样的活性剂，其包括酸性和/或碱性带电部分，并且分子质量不超过数千道耳顿，例如分子质量为2500道耳顿或更小，如1500道耳顿或更小。这种活性剂的例子包括但不限于有机酸和胺化合物。这种活性剂在特定pH值下与颗粒结合。根据需要，可以采用通过优化pH值进行的颗粒预处理和/或向结合溶液(更详细描述于下文中)里添加特定的离子化合物。
所关注的又一类活性剂是具有非带电或弱带电部分的水溶性小分子。这种化合物的例子包括但不限于：糖、糖苷和氨基酸衍生物。关于此类活性剂，根据需要，可以使用水性和/或有机溶剂混合物，如乙醇/水或乙腈/水，用于预处理和活性剂结合。
所关注的再一类活性剂为具有疏水部分的水溶性小分子。对于这种活性剂，预处理可以包括使颗粒与表面改性剂例如包括一个或多个带电基团和一个或多个疏水尾部的试剂接触，所述试剂例如但不限于十二烷基硫酸钠、月桂基硫酸钠和月桂基磷酸钠等。
所关注的再一类活性剂为水不溶性分子。所关注的水不溶性分子的例子包括但不限于：氨基酸衍生物、多酚和类视色素。对于这种活性剂，根据需要，可以使用有机溶剂作为预处理剂，如使用乙醇和二甲基亚砜(DMSO)，和/或可以使用装载溶剂。
在一些情况下，用离子改性剂对颗粒进行预处理。离子改性剂包括但不限于：钙离子改性剂，如CaCl2；磷酸根离子改性剂，如磷酸钠，等等。
在任何颗粒预处理步骤之后，例如，如上所述，在一些实施方案中，使颗粒经受洗涤步骤。例如，在一些情况下，可取的是在活性剂结合之前通过洗涤、过滤或倾析颗粒来除去颗粒中多余的盐或离子。这一步可采用任何适宜的洗涤方案和流体。
复合物形成
在进行任何预处理和/或洗涤之后，比如如上所述(如有必要)，使未结合颗粒与活性剂合并以产生活性剂结合颗粒。根据需要，活性剂的形式可以是粉末或溶液。合并活性剂与颗粒可采用任何合适的方案，如在容器中进行简单的静态混合等。可选择结合期间组合物的pH值以提供最大的结合，例如通过使用pH值调节剂，如上所述。例如，在一些情况下，在碱性条件下使碱性活性剂与颗粒合并，在酸性条件下使酸性活性剂与颗粒合并。因此，在一些情况下复合物形成反应的pH值可以在5至14的范围。在某些情况下，pH值为10或更小，其中视复合物形成所用的时长，可以选择pH值以便基本上避免颗粒降解，例如可以选择为5.2或更大。
如上所示，对于制备活性剂-颗粒复合物可以使用任何适宜的溶剂体系。如上所示，使活性剂与颗粒结合以产生活性剂-颗粒复合物所用的溶剂体系可有所不同。可应用于制备活性剂-颗粒复合物的溶剂体系可由单一溶剂或两种或更多种不同的溶剂组成。存在于所关注的溶剂体系中的溶剂可以是极性的(即，它们具有15或更大的介电常数)或非极性的(即，它们具有小于15的介电常数)、质子性的(这样它们经由氢键而强烈地使阴离子(带负电的溶质)溶剂化)或非质子性的(即，它们具有足够大的偶极矩以经由它们的偶极将带正电的物质溶剂化)。
所关注的质子溶剂包括但不限于：醇，如甲醇、乙醇、丙醇、异丙醇、丁醇、戊醇、己醇、庚醇、辛醇、三氟乙醇、苯酚、苯甲醇、甘油、乙二醇、二乙二醇；羧酸/酰胺，如甲酸、乙酸、乳酸、丙酸、三氟乙酸、甲酰胺；胺，如氨、二乙胺、丁胺、丙胺；和水。所关注的非质子溶剂包括但不限于：烃，如戊烷、己烷、庚烷、环己烷、甲基环己烷、十氢萘；酮/醛，如丙酮、甲基乙基酮(MEK)、甲基异丁基酮、丁酮、戊酮、环己酮、苯甲醛；芳香族化合物，如苯、甲苯、三氟甲苯、二甲苯、苯甲醚、氯苯、苯胺、N,N-二甲基苯胺、苯甲腈；醚，如二甲氧基乙烷、二甲醚、二乙醚、二异丙醚、甲基叔丁基醚(MTBE)、四氢呋喃、二噁烷、甘醇二甲醚、二甘醇二甲醚、聚乙二醇(PEG)、PEG酯、PEG脱水山梨醇、PEG醚、PEG酯、聚丙二醇(PPG)、PPG酯、烷氧基化直链烷二醇、烷氧基化烷基葡萄糖醚、PPG烷基醚；酯/酰胺，如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸丁酯、乙酸戊酯、苯甲酸乙酯、苯甲酸苯甲酯、邻苯二甲酸二甲酯、邻苯二甲酸二丁酯、二甲基乙酰胺、二甲基甲酰胺(DMF)；腈，如乙腈；碳酸酯，如碳酸二甲酯、碳酸二乙酯、碳酸丙烯酯、碳酸乙烯酯；卤化化合物，如四氯化碳、氯仿、二氯甲烷、二氯乙烷、三氯乙烷、氟利昂11、BMIM-PF6离子液体；含硫/磷化合物，如二甲基亚砜(DMSO)、二硫化碳、环丁砜、六甲基磷酰胺(examethylphosphramide)；和胺，如吡啶、三乙胺、N-甲基吡咯烷酮(NMP)。
所关注的溶剂包括但不限于：乙醇、变性乙醇、苄二醇、月桂酸苯甲酯、月桂酸苯甲酯/肉豆蔻酸苯甲酯/棕榈酸苯甲酯、1,4-丁二醇、2,3-丁二醇、丁醇聚醚-3、丁氧基二甘醇、丁氧基乙醇、乙酸丁氧基乙酯、正丁醇、叔丁醇、肉豆蔻酸丁酯、丁二醇、丁二醇丙酸酯、乙基己酸丁基乙基丙二基酯、乳酸丁酯、丁基辛醇、苯甲酸丁基辛酯、水杨酸丁基辛酯、硬脂酸丁酯、丁基邻苯二甲酰亚胺、丁内酯、苯甲酸C12-15烷基酯、癸酸、辛醇、鲸蜡硬脂醇辛酸酯、十六烷基硬脂基辛酸酯、氯丁醇、C8-12酸三甘油酯、C12-18酸三甘油酯、C9-12烷、C10-13烷、C13-14烷、C13-15烷、C14-17烷、C14-19烷、C15-19烷、C15-23烷、C18-21烷、C8-9烷/环烷、C9-10烷/环烷、C9-11烷/环烷、C9-16烷/环烷、C10-12烷/环烷、C11-14烷/环烷、C11-15烷/环烷、C12-13烷/环烷、C8-10烷/环烷/芳香族烃、C12-15烷/环烷/芳香族烃、C9-10芳香族烃、C10-11芳香族烃、CD醇19、氯化石蜡、C7-8异链烷烃、C8-9异链烷烃、C9-11异链烷烃、C9-13异链烷烃、C9-14异链烷烃、C9-16异链烷烃、C10-11异链烷烃、C10-12异链烷烃、C10-13异链烷烃、C22-12异链烷烃、C11-13异链烷烃、C11-14异链烷烃、C12-14异链烷烃、C12-20异链烷烃、C13-14异链烷烃、C13-16异链烷烃、C20-40异链烷烃、薏苡(薏仁)种子水、C6-12全氟烷基乙醇、C10-18三甘油酯、环乙氧基聚甲基硅氧烷、环庚硅氧烷、环己烷二甲醇、环己硅氧烷、环聚甲基聚硅氧烷、环戊硅氧烷、环丁硅氧烷、环丙硅氧烷、癸烷、1,10-癸二醇、癸烯、癸醇、脱臭煤油、二醋精、二丙酮醇、己二酸二丁酯、苹果酸二丁基辛酯、癸二酸二丁基辛酯、草酸二丁酯、邻苯二甲酸二丁酯、癸二酸二丁酯、马来酸二-C12-15烷基酯、二乙氧基二甘醇、丁二酸二乙氧基乙酯、二乙二醇二苯甲酸酯、己二酸二乙基己酯马来酸二乙基己酯、2,6-萘二甲酸二乙基己酯、邻苯二甲酸二乙基己酯、癸二酸二乙基己酯、琥珀酸二乙基己酯、草酸二乙酯、邻苯二甲酸二乙酯、癸二酸二乙酯、琥珀酸二乙酯、己二酸二庚基、己二酸二庚基十一烷基酯、己二酸二己酯、癸二酸二己基癸酯、苹果酸二异戊酯、己二酸二异丁酯、草酸二异丁酯、己二酸二异辛酯、己二酸二异癸酯、己二酸二异壬酯、己二酸二异辛酯、己二酸二异丙酯、草酸二异丙酯、癸二酸二异丙酯、二甲氧基二甘醇、己二酸二甲酯、二甲基癸酰胺、戊二酸二甲酯、二甲基异山梨醇、马来酸二甲酯、草酸二甲酯、邻苯二甲酸二甲酯、琥珀酸二甲酯、二甲砜、己二酸二辛酯、琥珀酸二辛酯、癸二酸二辛基十二烷基酯、二氧戊环、二苯基甲烷、二-PPG-3肉豆蔻基醚己二酸酯、己二酸二丙酯、二丙二醇、二丙二醇二苯甲酸酯、二丙二醇二甲醚、草酸二丙酯、己二酸二(十三基)酯、十二烯、车前叶蓝蓟(Echium Plantagineum)籽油、二十烷、乙氧基二甘醇、乙氧基二甘醇乙酸酯、乙氧基乙醇、乙氧基乙醇乙酸酯、碳酸乙二酯、乙醚、乙基己二醇、苯甲酸乙基己基酯、乳酸乙酯、澳洲坚果油酸乙酯(ethyl macadamiate)、肉豆蔻酸乙酯、油酸乙酯、乙基全氟丁基醚、糠醛、甘油醚-7、苯甲酸酯、甘油醚-18苯甲酸酯、甘油醚-20苯甲酸酯、甘油醚-7二异壬酸酯、甘油醚-4,5-乳酸酯、甘油醚-5乳酸酯、甘油醚-7乳酸酯、甘油醚-7三乙酸酯、野生大豆(大豆)油、三缩四乙二醇(glycofurol)、二醇、十六碳稀、己二醇、1,2-己二醇、1,2,6-己三醇、己烯、己醇、苯甲酸己基癸酯、水杨酸己基十二酯、己二醇、氢化聚癸烯、氢化聚十二烯、羟甲基二氧戊环酮、乙酸异戊酯、异丁氧基丙醇、乙酸异丁酯、苯甲酸异丁酯、硬脂酸异丁酯、水杨酸异鲸蜡酯、苯甲酸异癸酯、异壬酸异癸酯、辛酸异癸酯、油酸异癸酯、异十二烷、异二十烷、异十六烷、异壬酸异壬酯、异辛烷、异戊烷、异戊二醇、乙酸异丙酯、柠檬酸异丙酯、月桂酸异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、异丙基邻苯二甲酰亚胺、乙醇酸异硬脂酯、异硬脂基硬脂酰基硬脂酸酯、laneth-5、羊毛脂油、月桂醇聚醚-2乙酸酯(laureth-2acetate)、苧烯、3-甲氧基丁醇、甲氧基二甘醇、甲氧基乙醇、甲氧基乙醇乙酸酯、甲氧基异丙醇、乙酸甲氧基异丙酯、甲氧基甲基丁醇、甲氧基PEG-7、甲氧基PEG-10、甲氧基PEG-16、甲氧基PEG-25、甲氧基PEG-40、甲氧基PEG-100、乙酸甲酯、二甲氧基甲烷(methylal)、苯甲酸甲酯、甲基丁烯、甲基葡糖醇聚醚-20苯甲酸酯(methyl gluceth-20benzoate)、甲基乙基醚、乳酸甲酯、甲基全氟丁基醚、甲基丙二醇、甲基吡咯啶酮、大豆油酸甲酯、葵花籽油甲酯、甲基三聚甲基聚硅氧烷、MIBK、矿物油、矿油精、混合萜烯、罗汉果果汁、吗啉、貂油酸/棕榈酸三甘油酯、新戊二醇、新戊二醇二辛酸酯、壬苯醇醚-9(nonocynol-9)、十八烷、十八烯、辛烷、辛烯、苯甲酸辛酯、乳酸辛基十二酯、辛基十二酸辛基十二酯、异壬酸辛酯、异硬脂酸辛酯、月桂酸辛酯、棕榈酸辛酯、硬脂酸辛酯、油醇、橄榄油PEG-6酯、花生油PEG-6酯、PBG-33蓖麻油、PEG-4、PEG-6、PEG-7、PEG-8、PEG-9、PEG-10、PEG-12、PEG-14、PEG-16、PEG-18、PEG-20、PEG-32、PEG-33、PEG-40、PEG-45、PEG-55、PEG-60、PEG-75、PEG-80、PEG-90、PEG-100、PEG-135、PEG-150、PEG-180、PEG-200、PEG-220、PEG-240、PEG-350、PEG-400、PEG-450、PEG-500、PEG-2苯甲醚、PEG-15丁二醇、PEG-3甲醚、PEG-4甲醚、PEG-6甲醚、PEG-7甲醚、PEG-50椰油酸甘油酯、PEG-20氢化蓖麻油、PEG/PPG-1/2共聚物、PEG/PPG-4/2共聚物、PEG/PPG-5/30共聚物、PEG/PPG-6/2共聚物、PEG/PPG-7/50共聚物、PEG/PPG-8/17共聚物、PEG/PPG-10/70共聚物、PEG/PPG-17/6共聚物、PEG/PPG-18/4共聚物、PEG/PPG-19/21共聚物、PEG/PPG-23/17共聚物、PEG/PPG-23/50共聚物、PEG/PPG-25/30共聚物、PEG/PPG-26/31共聚物、PEG/PPG-30/33共聚物、PEG/PPG-35/9共聚物、PEG/PPG-38/8共聚物、PEG/PPG-116/66共聚物、PEG/PPG-125/30共聚物、PEG/PPG-160/31共聚物、PEG/PPG-200/70共聚物、PEG/PPG-240/60共聚物、PEG-10丙二醇、1,5-戊二醇、季戊四醇四辛酸酯/四癸酸酯、戊二醇、全氟辛基溴、全氟十氢萘、全氟二甲基环己烷、全氟己烷、全氟甲基环戊烷、全氟全氢苯甲基四氢萘、全氟全氢菲、全氟四氢萘、石油馏分、苯氧基异丙醇、苯基丙醇、聚甘油基-3二异硬脂酸酯、聚甘油基-2二油酸酯、聚氧基乙二醇二苯甲酸酯、聚全氟乙氧基甲氧基二氟甲基醚、PPG-3、PPG-7、PPG-10丁二醇、PPG-2-丁醇聚醚-3(buteth-3)、PPG-3-丁醇聚醚-5、PPG-5-丁醇聚醚-7、PPG-7-丁醇聚醚-4、PPG-7-丁醇聚醚-10、PPG-12-丁醇聚醚-16、PPG-15-丁醇聚醚-20、PPG-20-丁醇聚醚-30、PPG-20羊毛脂醇醚、PPG-2肉豆蔻基醚丙酸酯、PPG-2丁基醚、PPG-3丁基醚、PPG-24-甘油醚-24、PPG-25-甘油醚-22、PPG-10甘油醚、PPG-55甘油醚、PPG-67甘油醚、PPG-70甘油醚、PPG-2甲醚、PPG-3甲醚、PPG-2甲醚乙酸酯、PPG-2丙醚、丙二醇、乙酸丙酯、碳酸丙二酯、丙二醇、丙二醇丁醚、丙二醇辛酸酯、丙二醇二苯甲酸酯、丙二醇甲醚、丙二醇肉豆蔻酸酯、丙二醇丙醚、蓖麻(蓖麻)籽油、SD醇1、SD醇3-A、SD醇3-B、SD醇3-C、SD醇23-A、SD醇23-F、SD醇23-H、SD醇27-B、SD醇30、SD醇31-A、SD醇36、SD醇37、SD醇38-B、SD醇38-C、SD醇38-D、SD醇38-F、SD醇39、SD醇39-A、SD醇39-B、SD醇39-C、SD醇39-D、SD醇40、SD醇40-A、SD醇40-B、SD醇40-C、SD醇46、海水、芝麻(芝麻)油、鲨鱼肝油、山梨醇聚醚-6(sorbeth-6)、山梨醇聚醚-20、山梨醇聚醚-30、山梨醇聚醚-40、山梨醇酐三油酸酯、苯甲酸硬脂酯、庚酸硬脂酯、十四烯、丙酸十四酯、四氢糠醇乙酸酯、四氢糠醇、四氢噻吩二醇、三醋精、柠檬酸三丁酯、三丁基甲酚丁烷、三氯乙烷、磷酸三乙酯、三甲基己醇、2,2,4-三甲基戊烷、三甲基戊醇羟乙基醚。
根据需要，可以用一种或多种改性剂对溶剂体系进行改性，如用缓冲剂、pH值调节剂(酸或碱)、亲水分子、疏水分子或兼有疏水基团和亲水基团的分子(例如，表面活性剂)进行改性。所关注的缓冲剂包括但不限于：HCl/柠檬酸钠、柠檬酸/柠檬酸钠、乙酸/乙酸钠、K2HPO4/KH2PO4、Na2HPO4/NaH2PO4、硼砂/氢氧化钠，以及生物缓冲剂，例如，TAPS(3{[三(羟甲基)甲基]氨基}丙磺酸)、N-二(羟乙基)甘胺酸(N,N-双(2-羟乙基)甘胺酸)、三羟甲基氨基甲烷(三(羟甲基)甲胺)、Tricine(N-三(羟甲基)甲基甘胺酸)、HEPES(4-2-羟乙基-1-哌嗪乙磺酸)、TES(2-[三(羟甲基)甲基]氨基)乙磺酸)、MOPS(3-(N-吗啉代)丙磺酸)、PIPES(哌嗪-N,N-双(2-乙磺酸)、二甲基砷酸盐(二甲基胂酸)、SSC(盐水柠檬酸钠)和MES(2-(N-吗啉代)乙磺酸)；等等。
可以根据要与颗粒复合的活性剂的一种或多种性质来选择具体溶剂体系的组分和性质，如pH值、组成、温度等，其中这种性质可以包括活性剂溶解性、结构、pKa、logP等。
制备活性剂-颗粒复合物之后，然后采用任何适宜的方案将所得到的复合物与递送组合物组分合并。所采用的具体方案可有所不同，这取决于递送组合物组分的性质，其中在某些情况下可以通过混合将递送组合物组分与负载活性剂的颗粒合并以产生所需的递送组合物。虽然在合并期间的温度可有所变化，但在一些情况下温度为80℃，如40℃或更低、如30℃或更低，例如室温或更冷。与递送载体合并的活性剂-颗粒复合物的量可以有所不同。在一些实施方案中，与递送载体合并的活性剂-颗粒复合物的量足以产生这样的最终递送组合物，在所述递送组合物中，对每克递送组合物组分来说，活性剂-颗粒复合物的量的范围是0.001mg/g至1000mg/g，例如0.1mg/g至200mg/g，包括1mg/g至50mg/g活性剂-颗粒复合物。在某些实施方案中，要避免螯合剂的存在。制剂的pH值为5.0或更大，如5.5或更大。
实用性
本发明的递送组合物可应用于对受试者的局部位置递送活性剂的方法，其中的局部位置可以为皮肤表面位置或粘膜位置。在对受试者的局部位置递送活性剂时，本发明的递送组合物可以将活性剂-颗粒复合物至少递送到受试者皮肤表面下方的表皮位置中。就此而言，本发明的实施方案包括将负载活性剂的颗粒递送到受试者角质层中的方法，其中该方法可导致将复合物递送到受试者的深部角质层和/或真皮中。“到角质层中”表示复合物被递送到皮肤表面以下的至少1个细胞层的区域。“深部角质层”是指皮肤表面以下的2个或更多个细胞层的区域，如皮肤表面以下的5个或更多个细胞层，包括皮肤表面以下的10个或更多个细胞层。在一些情况下，复合物被递送到皮肤表面以下2μm或更深的角质层区域，如5μm或更深，包括15μm或更深的角质层区域。
本发明的实施方案包括将负载活性剂的颗粒递送到受试者角质层中的方法，其中所述方法可以导致将复合物递送到受试者的真皮中。“到真皮中”是指复合物被递送到皮肤表面以下至少20个细胞层的区域。
当到达它们的目标皮肤位置时，在一些情况下，活性剂结合颗粒便开始释放其活性剂“有效载荷”。活性剂从颗粒中的释放可根据许多不同的机制发生。例如，皮肤的环境可以逆转试剂对颗粒的任何结合相互作用。除了这个机制之外或者作为代替的方案，皮肤的环境可以破坏磷酸钙颗粒(例如，通过由皮肤的pH值梯度引起的溶解)，使得均匀刚性球形纳米多孔颗粒在酸性条件下，例如在pH值为5或更低，如4.5或更低，包括4.3或更低的条件下，如在角质层的生理酸性条件下溶解。颗粒在角质层中溶解所需的时间可有所不同，在某些实施方案中在1分钟至72小时的范围，如10分钟至24小时，包括30分钟至12小时，经过这一时段，活性剂被从活性剂结合颗粒中释放出来。本发明的方面包括所有活性剂的释放。
本发明的方法因此导致将活性剂递送到至少受试者的角质层中。在一些实施方案中，活性剂保留在角质层中以发挥其所需的活性。还在其它实施方案中，活性剂可以在身体的一个或多个其它目标位置发挥其所需的活性。所关注的另外的目标位置包括另外的表皮区域，例如但不限于透明层、粒层、棘层(stratum spinusom)、基底层和真皮。在某些实施方案中，活性剂被递送到真皮区域。在某些实施方案中，活性剂被递送到真皮以下的区域，例如皮下组织中。
在一些情况下，可以将活性剂全身性地递送给受试者。当活性剂被全身性地递送给受试者时，达到了活性剂的治疗血浆水平。活性剂的治疗血浆水平可有所不同，这取决于具体的活性剂和要治疗的病症。在某些实施方案中，所达到的治疗活性水平在0.1pg至100μg的范围，如1pg至20μg、如1ng至1μg，包括10ng至100ng。
在实施本发明的方法时，将递送组合物施用于受试者的局部区域，并按足以如上所述导致所需对受试者递送活性剂的方式保持在该局部区域。在某些实施方案中，所述局部区域为角质化皮肤区域。角质化皮肤区域，包括毛囊、汗腺和皮脂腺，可存在于各种完好或受损的皮肤位置处，其中所关注的位置包括但不限于：四肢、臂、手、腿、脚；躯干，例如胸、背、腹部；头，例如颈部、面部；等等。在某些实施方案中，所述区域为头部区域，如面部区域，例如前额、枕骨区域、口部周围等。关于施用组合物的局部区域的面积可有所不同，在某些实施方案中为1mm2至300cm2或更大，如1cm2至50cm2，包括3cm2至10cm2。
在实施所述的方法时，可以在给定的时间段中对受试者施用单一剂量或两个或更多的剂量。例如，在给定的一个月治疗期，可以对受试者的局部位置施用1个或多个剂量，如2个或更多的剂量，3个或更多的剂量，4个或更多的剂量，5个或更多的剂量等，其中的剂量可以每周或每天施用，或者甚至可以每天施用多次。
与活性剂并非以与磷酸钙颗粒的复合物形式递送的对照组相比，根据本发明的活性剂复合物的递送可赋予一种或多种优点。例如，在一些情况下，活性剂在磷酸钙复合物中被稳定化，从而其活性被保持。在一些情况下，以根据本发明的实施方案的复合物的形式将活性剂与磷酸钙颗粒的复合可将活性剂递送到正常情况下递送不到的位置，例如递送到角质层中，而如果所述活性剂并非存在于磷酸钙颗粒复合物中，则递送将限于皮肤表面。在一些情况下，与适当的对照组相比，本发明的方法导致活性剂的渗透增强。适当的对照组可以为包括相同活性剂和递送载体组分的递送组合物，但没有均匀刚性球形纳米多孔磷酸钙颗粒。在一些情况下，与这种对照组相比，渗透的增强达2倍或更多，如5倍或更多，包括10倍或更多。还在其它实施方案中，复合物充当活性剂从角质层中的控释库，从而提供活性剂的所需缓释和递送曲线。
虽然在本文中已主要就皮肤递送应用的用途描述了活性剂-磷酸钙复合物，但在一些情况下它们被用于其它应用。例如，本发明的活性剂-磷酸钙复合物在一些情况下可应用于对受试者非皮肤递送活性剂。非皮肤递送制剂的例子包括但不限于：胶囊、片剂、丸剂、团剂、锭剂、粉剂、粒剂、糖浆、酏剂、溶液、悬浮液、乳液、栓剂或其缓释制剂，或任何适于对哺乳动物施用的其它形式。在一些情况下，按常规程序施用的药物组合物被配制为适合对人进行口服或静脉内施用的形式。合适的药用载体及其配制方法的例子描述在Remington的“The Science and Practice of Pharmacy,Alfonso R.Gennaro编,Mack PublishingCo.Easton,Pa.,第19版,1995”的第86、87、88、91和92章中，上述内容以引用的方式并入本文。
在某些实施方案中，提供将钙递送到至少角质层中的方法。在这些方法中，将本发明完整的磷酸钙颗粒递送到至少角质层的中，例如，如上所述。“完整”是指颗粒为充分完整未受损的颗粒。就此而言，它们将不同于已与螯合剂如EDTA接触的颗粒，在后者的情况下，螯合剂例如通过与钙离子的螯合作用破坏颗粒的结构。在这些实施方案中，磷酸钙颗粒可以不含任何结合的活性剂，例如它们是未与活性剂结合的磷酸钙颗粒。在这些实施方案中，递送载体组分可以不含任何螯合剂例如EDTA。这些方法可应用于为任何适宜的目的将钙递送到至少所述层中，并且可以对期望将钙递送到至少角质层中的受试者实施。可以使用任何上述的递送载体，其中所关注的是不含螯合剂的载体。
所述方法和组合物可用于各种不同种类的动物，其中所述动物通常是“哺乳动物”或“哺乳类动物”，其中这些术语广泛用于描述哺乳纲以内的生物体，包括食肉动物目(例如，狗和猫)、啮齿目(例如，小鼠、豚鼠和大鼠)、兔形目(例如，兔子)和灵长目(例如，人、黑猩猩和猴子)。在某些实施方案中，受试者或患者是人。
以下实施例是以说明而非限制的方式提供的。
实验
I.均匀刚性球形纳米多孔磷酸钙颗粒的制备和表征
A.制备
通过在温度、pH值、压力、气体、搅拌速度、试剂浓度、添加速度和老化时间的受控条件下将磷酸盐复合物水溶液滴加到钙复合物水溶液或悬浮液中来制备磷酸钙纳米-晶体浆料。通过使用具有气-液流体喷嘴的压力喷嘴型喷雾干燥器将浆料喷雾干燥以形成球形多孔粉末。在300℃至900℃范围的温度下用气体或电炉或窑将干燥粉末烧结1至24小时的一段时间。
B.表征
图1A和1B显示所得到的2微米均匀刚性球形纳米多孔磷酸钙颗粒(如上所述制备)的多孔结构，使用SEM(A)10,000X、(B)50,000X。图2A和2B显示2微米均匀刚性球形纳米多孔磷酸钙颗粒(如上所述制备)的外部和内部结构，使用SEM(A)和TEM(B)(15000X)。大的(25-50m2/g)内表面积和外表面积是相当大的，这提供与活性剂结合的高容量。图3显示颗粒的粒径分布，其通过Coulter Multi-sizer 3颗粒计数器测定，并经扫描电子显微镜确认。平均粒度为2μm。
C.磷酸钙颗粒的安全性
II.活性剂-磷酸钙颗粒复合物的制备
A.包括某些活性剂预处理在内的一般结合准则
磷酸钙颗粒结合广泛的生物分子，并且在一些情况下将它们稳定化。与磷酸钙颗粒的结合是基于离子相互作用。磷酸钙颗粒的官能团由带正电的钙离子(Ca++)和带负电的磷酸根离子(PO4-3)组成。这意味着生物材料的阴离子化羧基的量在酸性条件下将减少。因此生物分子的阴离子化羧基与磷酸钙颗粒的钙离子之间的结合将减弱。在碱性条件下对于生物分子的阳离子化氨基与磷酸钙颗粒的磷酸根官能团之间的相互作用来说，情况相反。
pH值和离子强度直接影响磷酸钙颗粒与生物材料之间的结合。磷酸钙颗粒能够结合广泛分子量(例如，200至10,000,000)和等电点(例如，2.0至12)的生物材料。
除了pH值和离子强度外，生物材料的分子量、形状和取向也影响对磷酸钙颗粒的结合。例如，具有相对较低分子量的BSA以90mg/g结合，具有相对较大分子量的DNA以1mg/g的比率与磷酸钙颗粒结合。大生物分子如DNA的结合能力由磷酸钙颗粒的外表面积决定。总而言之，影响磷酸钙颗粒与生物分子之间的结合的主要参数有pH值、离子强度、立体化学效应和分子量。
B.具体的活性剂-磷酸钙颗粒复合物
1.pH值对结合的影响
a.水杨酸
材料：
磷酸钙颗粒
水杨酸，Fisher Scientific公司，型号A277-500
方法：
i.将23.2mg水杨酸溶解在1ml乙醇中。
ii.将4g磷酸钙颗粒悬浮在39.8ml水中，用HCl将pH值调节到接近目标pH值。
iii.在磷酸钙颗粒的悬浮液中混合0.2ml水杨酸溶液(23.2mg/ml)。
iv.用HCl将pH值调节到各目标pH值(11.36、8.34、7.47、7.07、5.99)。
v.在各pH值下，从悬浮液中取4.8ml样品。所有样品单独以2000×g离心10分钟。
vi.通过UV分光光度计在297nm(水杨酸的检测波长)下测量上清液的吸光度。
vii.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
结果示于下表中，表明水杨酸以由水杨酸的pKa驱动的pH值依赖性方式与磷酸钙颗粒结合。
b.多酚复合物(PPC)对磷酸钙颗粒
材料：
磷酸钙颗粒
多酚复合物(PPC)
方法：
i.将33.98mg的PPC溶解在6.8ml水中。
ii.将2g磷酸钙颗粒悬浮在19.9ml水中，用HCl将pH值调节到9.62。
iii.在磷酸钙颗粒的悬浮液中混合0.1ml的PPC溶液(5mg/ml)；取2ml样品。
iv.用HCl将pH值调节到各目标pH值(8.58、8.07、7.49、7.21、6.75、6.08)。
v.在各pH值下，从悬浮液中取2ml样品。所有样品单独以2000×g离心10分钟。
vi.通过UV分光光度计在280nm(PPC的检测波长)下测量各上清液的吸光度。
vii.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
磷酸钙颗粒的结合能力汇总于下表。结果表明PPC结合可以在任何pH值下进行，因此与pH值无关。
pH 结合的PPC(μg/g)
9.62 242.5
8.58 242.5
8.07 235.0
7.49 215.0
7.21 220.0
6.75 212.5
6.08 197.5
2.具有不同分子量(MW)和等电点(pI)的蛋白质活性物质的结合实施例
a.牛血清白蛋白(BSA)(MW：66KD，pI：4.7)
材料：
磷酸钙颗粒
BSA，冻干粉末，Fisher Scientific公司，产品编号BP-671-10
方法：
i.将0.5g磷酸钙颗粒悬浮在1ml水中，用HCl将pH值调节到大致为7。将悬浮液混合10分钟。
ii.将BSA溶解在水中并轻轻地混合，以制备20mg/ml溶液。向各磷酸钙颗粒悬浮液中加入4ml的BSA溶液并混合30分钟。测定悬浮液的最终pH值。
iii.将悬浮液以2000×g离心5分钟。将上清液转移到新试管中，并以2000×g离心5分钟。
iv.开发尺寸排阻HPLC法对结合悬浮液的上清液中的BSA定量。使用Shimadzu10AS系统中的Phenomenex BioSepTM-SEC-S3000柱(7.8×300mm,5μm)进行分离。流动相为100％的50mM磷酸盐缓冲液(Na+，pH值6.8)，并以1.4毫升/分钟的速度洗脱。在280nm监测洗脱液。观察到BSA主峰，保留时间约6.8分钟。通过外部标准校正实现BSA的定量。
v.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
BSA以95.1mg/g与磷酸钙颗粒结合。
b.乳铁蛋白(MW:90KD，pI:8.5)
材料：
磷酸钙颗粒
来自于人乳的乳铁蛋白，Sigma Aldrich公司，产品编号0520-100MG
方法：
i.以4.98mg/ml在水中制备乳铁蛋白溶液。
ii.将0.3g磷酸钙颗粒悬浮在1.2ml水中并混合5分钟。
iii.加入1.8ml 4.98mg/ml的乳铁蛋白溶液以达到3.0mg/ml的最终浓度，且最终体积为3ml。
iv.将悬浮液混合30分钟，并在台式离心机中以5000×g离心10分钟。
v.通过UV分光光度计在280nm(乳铁蛋白的检测波长)下测量上清液的吸光度。
vi.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
vii.通过从结合悬浮液中的总初始量减去上清液中检测到的乳铁蛋白量来计算结合的乳铁蛋白。
结果：
经测定29.63mg/g乳铁蛋白与磷酸钙颗粒结合，结合浓度为2.99mg/ml。
c.溶菌酶(MW:14KD，pI:10.7)
材料：
磷酸钙颗粒
溶菌酶，MP biomedicals LLC.公司，产品编号ICN10083405
磷酸，Fisher Scientific公司，产品编号A260500
方法：
i.将364.7mg溶菌酶溶解在18.01水中(20.25mg/ml)。
ii.将0.8g磷酸钙颗粒与4ml水混合，用稀磷酸将悬浮液的pH值调节到中性。
iii.将4ml溶菌酶溶液(20.25mg/ml)加至磷酸钙颗粒的悬浮液中以达到10.124mg/ml的最终浓度，且最终体积为8ml。测量最终的pH值。
iv.将悬浮液混合30分钟，并在台式离心机中以2000×g离心10分钟。
v.通过UV分光光度计在280nm(溶菌酶的检测波长)下测量上清液的吸光度。
vi.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
经测定溶菌酶在pH值6.83下以6.8mg/g与磷酸钙颗粒结合。
3.溶剂对结合的影响
阿达帕林
材料：
磷酸钙颗粒
阿达帕林，Sekhsaria Chemicals Limited公司，印度
DMSO，Fisher Scientific公司，产品编号D159-4
乙醇，Fisher Scientific公司，产品编号AC61511-0010
方法：
i.将阿达帕林制成在乙醇和DMSO中的饱和溶液(在乙醇中0.087mg/ml，在DMSO中20.65mg/ml)
ii.将0.5g磷酸钙颗粒与5ml阿达帕林的乙醇或DMSO饱和溶液混合。
iii.将悬浮液混合30分钟，并在台式离心机中以2000×g离心10分钟。
iv.通过UV分光光度计在319nm(阿达帕林的检测波长)下测量上清液的吸光度。
v.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
阿达帕林在乙醇中与磷酸钙颗粒的结合能力为0.78mg/g。阿达帕林在DMSO中与磷酸钙颗粒的结合能力为12.55mg/g。
C.生物活性物质的预处理实施例
用月桂基硫酸钠预处理与磷酸钙颗粒结合的六胜肽(Argireline)
材料：
磷酸钙颗粒
六胜肽，(乙酰基六肽-8)，Lipotec S.A公司
月桂基硫酸钠(SLS)，Colonial Chemical,Inc.公司
方法：
i.将六胜肽溶解在水中成10mg/ml溶液。
ii.将磷酸钙颗粒与10ml的0.1％SLS混合5分钟。在台式离心机中以2000×g将悬浮液离心10分钟，去除上清液。将团块重新悬浮于20ml水中，以2000×g离心10分钟并弃掉洗涤的上清液。重复该洗涤步骤两次。测定团块中含有的水。将最终团块用于结合研究。
iii.将磷酸钙颗粒(经SLS处理或不经SLS处理的)与水混合。添加HCl(或NaOH)以将磷酸钙颗粒悬浮液的pH值调节到目标pH值，包括中性和pH值～10。
iv.向各结合悬浮液中加入10mg/ml的六胜肽储备液以到0.5mg/ml的最终浓度。将悬浮液混合30分钟后测定最终pH值。
v.将结合悬浮液在台式离心机中以2000×g离心10分钟。用连接至Shimadzu HPLC20A系统的折射率检测器分析上清液以对溶液中的游离六胜肽定量。开发尺寸排阻HPLC法以对结合混合物的上清液中的六胜肽定量。使用Shimadzu 20A系统中的PhenomenexBioSepTM-SEC-S3000柱(7.8×300mm，5μm)实现分离。流动相为100％水，并以1毫升/分钟的速度洗脱。在205nm下或通过折射率检测器(Shimadzu公司，型号RID-10A)监测洗脱液。色谱图中观察到六胜肽主峰，保留时间约14分钟。通过外部标准校正实现六胜肽的定量。
vi.然后通过从结合悬浮液中的总初始量减去上清液中检测到的六胜肽量来计算结合的六胜肽。
结果：
D.与磷酸钙颗粒结合的活性剂的可视化
将0.1g磷酸钙颗粒加到1ml的0.9％罗丹明B水溶液中，旋转所得到的悬浮液并去除上清液。将所得到的罗丹明B-磷酸钙颗粒在58℃下干燥24小时。将所得到的粉末重新悬浮于辛酸三甘油酯/癸酸三甘油酯中，并通过显微镜成像。所得到的图像示于图4A。图4B显示没有任何罗丹明B的磷酸钙颗粒。
E.另外的活性剂-磷酸钙复合物
采用如上所示的方案，按下表中的概述制备活性剂-磷酸钙复合物。在下表中，具体的溶剂体系是可以使用的溶剂体系的例子。
III.活性剂的释放
A.pH值依赖性释放
1.溶菌酶
在角质层中，pH值范围在4.3至5.0，且pH值随着角质层的深度而减小。为了研究磷酸钙颗粒在类似于皮肤的条件下释放活性剂，使两种溶菌酶磷酸钙复合物接触pH值4.8(0.5M乙酸钠)和pH值7.0(10mM Bis Tris)的缓冲液8小时。使缓冲液以1毫升/小时的速率流过样品，并且每小时进行收集，通过由UV光谱仪监测280nm峰来分析溶菌酶释放。将等质量的溶菌酶磷酸钙颗粒复合物在pH值4.8的缓冲液中涡旋以估计样品中的总可得溶菌酶。在pH值4.8下观察到溶菌酶从磷酸钙颗粒中快速释出，其中大部分溶菌酶在第一小时内释出。相比的下，在pH值7的情况下，经8小时没有观察到溶菌酶从磷酸钙颗粒中释出。
B.经由Hydroxysome降解释放
1.磷酸钙颗粒在pH值4.8下降解
在4.8(0.5mM乙酸钠)和7.1(0.1mM Bis Tris)两种pH值下以2mL培养50mg磷酸钙颗粒，在室温下将溶液在旋转装置上放置96小时。离心样品，干燥颗粒并称重。磷酸钙颗粒在pH值4.8和7.1下的失重百分比分别为12％和3％。此封闭系统的缓冲容量限制了磷酸钙颗粒的完全溶解。然后在流转系统中以相同的缓冲液研究溶解，其中使溶液缓慢地(5毫升/小时)流过样品(50mg)并轻轻地搅动样品，接着进行磷酸钙颗粒颗粒的收集和干燥。72小时之后，磷酸钙颗粒颗粒在pH值4.8和7.1下的失重百分比分别为31％和3％。这些结果表明磷酸钙颗粒在低pH值下溶解，并且这种溶解是溶液pH值和缓冲容量的函数。
C.活性剂与磷酸钙颗粒可逆地结合，且释放不改变活性剂的活性
1.BSA磷酸钙复合物
如上所述制备BSA-磷酸钙复合物。用水洗涤所得到的复合物，然后用0.2M磷酸钠进行处理以释放任何结合的BSA。
物质：
磷酸钙颗粒
BSA，冻干粉末，Fisher Scientific公司，产品编号BP-671-10
方法：
i.将0.1170g的BSA溶于11.7ml水中，成为10mg/ml的溶液。
ii.将0.5g磷酸钙颗粒与5ml的10mg/mlBSA溶液混合。将悬浮液混合30分钟，最终pH值测定为中性。
iii.将悬浮液以2000×g离心10分钟。将上清液转移到新试管中，并再次以2000g离心10分钟。
iv.用Shimadzu 10A HPLC系统分析最终上清液以定量BSA并计算结合。
v.将来自5ml结合悬浮液的颗粒与0.8ml水混合，并以2000×g离心10分钟。将漂洗的颗粒再次与0.8ml水混合，并以2000×g离心10分钟。
vi.将最终漂洗的颗粒与2ml的500mM磷酸钠缓冲液(PH值6.8)和2.235ml水混合，以在具有200mM磷酸钠的悬浮液中释放BSA。以2000×g离心释放悬浮液10分钟。用Shimadzu10A HPLC系统分析上清液以定量BSA。
v.使用Shimadzu 10AS系统中的Phenomenex BioSepTM-SEC-S3000柱(7.8×300mm，5μm)实现BSA定量。流动相为100％的50mM磷酸盐缓冲液(Na+，PH值6.8)，并以1.4毫升/分钟的速率洗脱。在280nm处监测洗脱液。观察到BSA主峰，保留时间约6.8分钟。通过外部标准校正实现BSA的定量。
vi.在没有磷酸钙颗粒的情况下按相同的程序进行对照组实验。
结果：
采用HPLC分析释放的BSA，并确定与未结合的对照组完全相同(保留时间6.85分钟)，表明同磷酸钙颗粒的结合及释放不影响BSA完整性。
2.生育酚磷酸酯钠磷酸钙复合物
材料：
磷酸钙颗粒
生育酚磷酸酯钠(TPNa)，Showa Denko KK公司
乙醇，Fisher Scientific公司，产品编号AC615090020
方法：
i.通过轻轻混合将20mg的TPNa溶解在40ml水中(0.5mg/ml)。
ii.将3g磷酸钙颗粒与30ml的0.5mg/ml TPNa溶液混合，混合30分钟。
iii.将结合悬浮液以2000×g离心10分钟。将上清液转移到新试管中，并再次以2000×g离心10分钟以澄清。用UV分光光度计在286nm下分析最终的上清液以定量游离的TPNa并计算结合。结合悬浮液中大约100％的TPNa附着于磷酸钙颗粒。
iv.将TPNa磷酸钙复合物团块重新悬浮于60％乙醇中以释放结合的TPNa。
v.将60％乙醇中的释放悬浮液以2000×g离心10分钟。用UV分光光度计在286nm下分析上清液以定量释放的游离TPNa。
结果：
用UV光谱法分析释放的TPNa，经测定与未结合的对照组相同，这表明同磷酸钙颗粒的结合及释放不影响TPNa完整性。
IV.制剂实施例
1.磷酸钙颗粒-单磷酸核黄素软膏制剂
步骤：
步骤1.在烧杯中添加蜂蜡和Protachem IPP。开始加热到70℃-75℃直到均匀。冷却到50℃。加入SonneNaturalTM和Capmul MCM。混合直到均匀。
步骤2.在单独的烧杯中加入1％水和单磷酸核黄素。在R.T下混合直到溶解。加入磷酸钙颗粒(用乳酸将pH值调节到7)。以500RPM旋转10分钟。
步骤3.在室温下将步骤1转移至步骤2。混合直到均匀。
B.活性剂在制剂中的稳定性
1.维生素C
a.方法：
将11.9mg抗坏血酸溶解在30ml水中。将2克2μm磷酸钙颗粒悬浮在19.5ml水中，并用HCl将pH值调节到7.14。将0.5ml抗坏血酸溶液(0.40mg/ml)混合在磷酸钙颗粒的悬浮液中，这将pH值降到7.05。将包含10μg/ml抗坏血酸的磷酸钙颗粒悬浮液(pH值7.05)在50℃下培养0.5至5小时。通过将悬浮液在冰浴中冷却15分钟来终止抗坏血酸的热变性。为了释放磷酸钙颗粒中结合的抗坏血酸以测量稳定化效果，用HCl将各悬浮液的pH值调节到5，并以3,000rpm离心10分钟。在265nm下测量得到的上清液。作为对照，在没有磷酸钙颗粒的情况下还按相同的程序培养10μg/ml的抗坏血酸溶液并进行测量。按下式计算抗坏血酸的活性：
抗坏血酸的活性(％)＝(培养后上清液的A265nm/培养前抗坏血酸的A265nm)×100
用10μm磷酸钙颗粒重复相同的程序。
b.结果
结果汇总于下表中。通过在50℃下培养0.5小时将抗坏血酸的活性减小到36％；当在相同期间使抗坏血酸附着于2μm磷酸钙颗粒时，这一活性增加到85％。在50℃下培养3小时之后，没有磷酸钙颗粒的抗坏血酸完全变性而没有活性。然而，在50℃下经相同的3小时期间，结合于2μm磷酸钙颗粒的抗坏血酸具有48％活性。
时间(小时) 对照(％) 2um(％)
0 100 100
0.5 36 85
2 18 59
3 0 48
5 0 35
C.为了获得活性物质在最终制剂中的磷酸钙复合物中的稳定性，可能有必要对溶剂体系添加另外的游离活性物质，这取决于所使用的溶剂体系的溶解度。
V.递送研究
1.递送到人体皮肤的角质层中
通过擦拭10秒将一定浓度的磷酸钙颗粒水悬浮液施用于活人的前臂(图5)。然后实施角质层的第一、第二及第三层的胶带剥离。磷酸钙颗粒渗入到角质层的第三层。
2.递送到小鼠皮肤的角质层的底层中
磷酸钙颗粒渗透角质层，并随着颗粒裂成较小的取代部分而进一步渗透到更低的层中。磷酸钙颗粒经7小时后不再完好，并且不再是球形，这表明颗粒完整性的丧失。
a.材料：
使用2μm磷酸钙颗粒。
b.制备：
将磷酸钙颗粒悬浮在70％乙二醇和30％乙醇中制成10％悬浮液。将所得到的悬浮液局部施用在无毛小鼠的皮肤表面上(1×1cm面积)。在施用期间麻醉小鼠。进行第一次施用(0.2ml)并将其保留，4小时后在相同部位以相同的量进行第二次施用。第一次施用七小时后移除皮肤并用Ca++处理。定位方法依照EM技术。
c.结果：
在用磷酸钙颗粒处理之前，检查表皮显示，在角质层中只有粒层区域中没有可检测到的Ca++(图6)。如上所述局部施用磷酸钙颗粒之后，在角质层中可以看到磷酸钙颗粒(图7A)，最小的颗粒移动到较深层中(图7B)。
3.角质层中活性剂的检测
a.研究目的
此项研究的目的是在局部施用附着于如以上实施例1中所述的2μm均匀刚性球形纳米多孔磷酸钙颗粒的活性剂(氯四环素，CTC)之后，检测角质层中的活性剂(CTC)。选择氯四环素(购自Sigma的CTC，产品号C-4881)是因为它允许通过荧光实现CTC的可视化，并因此可通过共聚焦显微镜在角质层内检测。
b.制备
通过在10ml水中溶解80mg的CTC制成CTC溶液。通过以3,000rpm离心10分钟来移除未溶解的CTC。将200mg颗粒与2ml的CTC溶液混合并涡旋1分钟。通过三轮水洗并接着以3,000rpm离心10分钟来移除游离的CTC。以1:10的稀释比例将所得到的CTC结合颗粒悬浮在水中。
c.局部施用
将在上述3.b中制备的悬浮液(大约0.2ml)局部施用在无毛小鼠的皮肤上(11cm面积)。施用期间麻醉小鼠。7小时后使用共聚焦显微镜(在380nm波长激发的510nm波长发射下)检查它们的皮肤。
d.结果
所得到的共聚焦显微镜图像示于图8(图8中放大率为300×)。图8中所示的代表性图像显示，CTC荧光(紫色)渗透皮肤，并且主要位于角质层中。
4.局部施用STAY-C50-磷酸钙和溶菌酶-磷酸钙复合物的胶带剥离分析表明递送到角质层中。
这项研究的目的是在局部施用活性物质-磷酸钙颗粒之后检测活性物质在角质层中的分布。
方法：通过对施用了STAY C50-磷酸钙颗粒制剂的皮肤进行系列胶带剥离来评价STAY C50在角质层中的分布。标记好受试人前臂上的施用位点，通过刮片涂敷200μl制剂。将所述位点干燥10分钟，然后接下来进行十个预称重胶带的剥离，使用施用于施用位点的条(3in2)。通过在水中对样品进行30分钟的声波处理从胶带条中提取STAY C50，并通过HPLC分析样品。胶带条显示将STAY-C50递送到角质层的第10(图9)。
方法：通过对施用了溶菌酶-磷酸钙颗粒制剂的皮肤进行系列胶带剥离来评价溶菌酶在角质层中的分布。标记人受试者前臂上的施用位点，通过刮片涂敷200μl制剂。将所述位点干燥10分钟，然后接下来进行十个预称重胶带的剥离，使用施用于施用位点的条(3in2)。通过在水中对样品进行30分钟的超声处理以从胶带条中提取溶菌酶，并通过HPLC分析样品。检测到溶菌酶达到6个胶带条的深度(图10)。
5.通过弗朗茨细胞进行活性剂的受控缓释
目的：这项研究的目的是检测附着于磷酸钙颗粒的核黄素中的核黄素。
方法：
从较大的腹部样本上切下6cm2圆片的全层猪皮。用剪刀移除真皮侧的脂肪，使用前将皮肤储存于-20℃下。将皮肤固定在玻璃扩散池(Laboratory Glass Apparatus公司，型号#LG-1084-LPCT)的两个室之间。这使皮肤在4.5ml接收器室体积之上的暴露面积为5cm2。将扩散池保持在37℃。
渗透条件
局部施用间隔为8小时和16小时。池体用石蜡膜覆盖，并以铝包装材料蔽光。以60rpm旋转接受器流体磷酸盐缓冲盐水(PBS)。
施用的制剂
制备单磷酸核黄素-磷酸钙颗粒以递送0.35-1.15mg核黄素(20％-38％悬浮液)。
按1.5mg/mL制备PBS中的单磷酸核黄素以递送0.3-0.45mg核黄素。
用移液管施用50-100μl体积的制剂。对施用的核黄素-磷酸钙复合物进行空气干燥，然后将等体积的0.5M乙酸钠缓冲液吸量到施用位点上。
对照组实验包括在没有磷酸钙颗粒等量地施用核黄素。
样品收集
皮肤表面仍保留在扩散室中的时候对其进行两次洗涤，每次用1mL PBS。从扩散池中取出皮肤并进行干燥和分析。
样品分析
洗涤及接受器流体：测定流体的近似体积。将样品以10,000rpm旋转30秒并将磷酸钙颗粒分离、干燥和称重。然后移除上清液并用UV谱仪分析。如果UV吸光度是饱和的(超过>2.0)，则用水稀释样品。记录370nm的UV吸光度值。
皮肤：将皮肤切碎并与5ml的10％三氯乙酸溶液混合。将样品在50℃下用超声装置进行1小时的超声处理。将样品以10,000rpm离心10分钟，移除上清液并用UV谱仪分析。如果UV吸光度是饱和的(超过>2.0)，则用水稀释样品。记录370nm的最大UV吸光度值。
结果
由于在8小时和16小时之后在接收器流体中检测到核黄素代谢物的存在，所以核黄素从水溶液以及从磷酸钙颗粒复合物都渗透过了皮肤。磷酸钙颗粒复合物导致较慢的活性物质释放。结果以图形方式示于图11。
虽然为了清楚理解的目的已借助于图示和实施例较详细地描述了前述发明，但本领域的普通技术人员根据本发明的教导内容可显而易见的是，在不偏离所附权利要求的实质及范围的情况下可以对其进行某些变动和修改。
因此，前文仅阐述了本发明的原则。应理解的是：本领域技术人员能够设计出各种方式，这些方式虽然未在本文中明确地描述或显示，但能体现本发明的原则，并且包括在本发明的实质和范围内。此外，本文中所列举的所有实施例及条件性表达方式主要是旨在帮助读者理解本发明的原则及发明人为丰富现有技术而提出的概念，并且应被解释为不限于这种具体列举的实施例及条件。此外，本文中所有列举本发明的原则、特点及实施方案的说明以及其具体的实施例均旨在包括其结构和功能上的等效物。另外，这种等效物旨在包括目前已知的等效物以及将来开发的等效物，即开发的实施相同功能的任何要素，无关乎其结构。因此，本发明的范围不旨在受限于本文中所示和描述的示例性实施方案。而是，本发明的实质和范围由所附权利要求来限定。

Claims (11)

1.一种包含均匀刚性球形纳米多孔磷酸钙磷酸钙颗粒的组合物，其中所述颗粒的60％或者更多具有范围在0.1微米到2微米的粒径并且与活性剂复合。
2.根据权利要求1所述的组合物，其中所述颗粒的孔隙量在30％至85％的范围。
3.根据权利要求2所述的组合物，其中所述颗粒的孔径在2nm至100nm的范围。
4.根据权利要求1所述的组合物，其中通过以下方式制得所述颗粒：
制备磷酸钙晶体的流体组合物；
按足以产生前体颗粒的方式干燥所述流体组合物；以及
按足以产生均匀刚性球形纳米多孔磷酸钙磷酸钙颗粒的方式使所述前体颗粒经受高温和高压。
5.根据权利要求4所述的组合物，其中所述干燥包括喷雾干燥。
6.根据权利要求1所述的组合物，其中所述组合物是局部制剂。
7.根据权利要求1所述的组合物，其中与所述颗粒复合的活性剂的量在每克颗粒0.01mg至300mg活性剂的范围。
8.一种组合物的应用，所述组合物包括：
均匀刚性球形纳米多孔磷酸钙磷酸钙颗粒，其中所述颗粒的60％或者更多具有范围在0.1微米到2微米的粒径并且与活性剂复合；
所述应用用于将活性剂递送到受试者的角质层。
9.根据权利要求8所述的应用，其中所述颗粒的孔隙量在30％至85％的范围。
10.根据权利要求9所述的应用，其中所述颗粒的孔径在2nm至100nm的范围。
11.根据权利要求8所述的应用，其中与所述颗粒复合的活性剂的量在每克颗粒0.01mg至300mg活性剂的范围。
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