CN105163720A - 远程装载略微水溶性药物至脂质体 - Google Patents
远程装载略微水溶性药物至脂质体 Download PDFInfo
- Publication number
- CN105163720A CN105163720A CN201480018947.3A CN201480018947A CN105163720A CN 105163720 A CN105163720 A CN 105163720A CN 201480018947 A CN201480018947 A CN 201480018947A CN 105163720 A CN105163720 A CN 105163720A
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- China
- Prior art keywords
- liposome
- reagent
- drug
- medicine
- lipid
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 280
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- 150000002632 lipids Chemical class 0.000 claims abstract description 114
- 238000000034 method Methods 0.000 claims abstract description 83
- 239000000203 mixture Substances 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000007900 aqueous suspension Substances 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 99
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 81
- -1 penicillin compound Chemical class 0.000 claims description 80
- 235000012000 cholesterol Nutrition 0.000 claims description 41
- BOFQWVMAQOTZIW-UHFFFAOYSA-N deferasirox Chemical compound C1=CC(C(=O)O)=CC=C1N1C(C=2C(=CC=CC=2)O)=NC(C=2C(=CC=CC=2)O)=N1 BOFQWVMAQOTZIW-UHFFFAOYSA-N 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 38
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- 239000000825 pharmaceutical preparation Substances 0.000 claims description 36
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- 238000005538 encapsulation Methods 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
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- 150000007942 carboxylates Chemical class 0.000 claims description 10
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 10
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 5
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Abstract
本发明提供了脂质体组合物,其包含用于治疗威胁生命的疾病的微溶性药物。将药物封装在脂质体内的优选的方法是通过远程或主动装载。通过共混合脂质体悬液与药物的溶液启动远程装载药物至包含跨膜电化学梯度的脂质体,由此中性形式的化合物自由进入脂质体并且成为带静电的,从而防止逆转移出脂质体。在脂质体内部持续积累化合物,直到电化学梯度消失或所有的药物封装在脂质体中。但是,如文献中描述的该方法限于在水溶液中自由可溶的或溶解为水溶性复合物的药物。本发明描述了用于远程装载具有低水溶解度(<2mg/mL)的药物的组合物和方法。在优选的实施方式中,增溶剂中的药物与水悬液中的脂质体混合,从而增溶剂的浓度下降至低于其完全溶解药物的能力。这使得药物沉淀但是保持了远程装载能力。该过程是可扩大规模的,并且在其中脂质组分和远程装载剂被优化的脂质体中,所得装载药物的脂质体特征在于当脂质体封装药物被施用至对象时高的药物与脂质比和延长的药物驻留。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求2013年2月1日提交的美国临时专利申请号61/759,914的优先权,为了所有的目的通过引用以其整体并入本文。
发明背景
本发明涉及药学组合物、制备它们的方法和所得组合物在药物治疗中的用途的领域。药学组合物包括封装在脂质体膜泡的水性内部内的活性治疗剂。
相关技术描述
制药工业,在其寻找改善的药物时,已经产生了许多有力的化合物,其略微可溶于使得可能有生命的无处不在的溶剂水中。这些新药物的低水溶解度已经使得其难以在包括人的动物中递送它们。这已经需要可溶解略微水溶性药物以确保能够在身体中递送它们的药物递送系统。
脂质体是膜泡结构,通常由捕获水性核心的双层膜的两性分子比如磷脂组成。各种类型的脂质体的直径和形态图解在图1中。药物封装在水性核心中或交错在双层膜中。当在身体中稀释时,膜中交错的药物转移离开脂质体。重要地,封装在水性核心或在水性核心中以复合物保持的药物明显比双层中的药物保持更长。充分阐释了药物封装在水性核心中的脂质体用于药物递送的应用(D.Drummond等,J.Pharm.Sci.,(2008)97(11):4696-4740,PMID10581328)。
可使用用于在脂质体中封装功能化合物,尤其药物的各种装载方法。例如,亲水化合物可通过水化功能化合物和形成膜泡的脂质的混合物封装在脂质体中。该技术称为被动装载。随着纳米颗粒形成,功能化合物封装在脂质体中。可用的脂质膜泡(脂质体)产生方法满足了封装水溶性药物的大部分应用(G.Gregoriadis,Ed.,LiposomeTechnology,(2006)LiposomePreparationandRelatedTechniques,3rdEd.)。但是,在脂质体的水性内部腔室中制造封装略微水溶性的药物(例如,水溶解度小于2mg/mL)的脂质膜泡非常困难(D.Zucker等JournalofControlledRelease(2009)139:73-80,PMID19508880)。
被动装载亲脂和在较小程度上两性分子功能化合物比亲水功能化合物些许更有效,因为它们在脂质双层和脂质体内(内部)水性介质中分开。但是,使用被动装载,最终功能化合物与脂质比例以及封装效率通常是低的。脂质体中药物的浓度等于周围流体的并且不捕获在内部水性介质的药物在封装之后被冲洗掉。而且装载至双层的药物当脂质体注入对象时,非常快速从脂质体释放。为了药物在患者中的持续释放,优选地药物被封装在脂质体的内部。
某些亲水或两性分子化合物可使用跨膜pH-或离子-梯度装载至实施的脂质体(D.Zucker等,JournalofControlledRelease(2009)139:73-80)。该技术称为主动或远程装载。容易主动装载的化合物应能够从可横跨脂质体膜扩散的不带电形式改变为不能这样的带电形式。典型地,通过将其添加至制备的脂质体悬液,以具有更低的内侧/更高的外侧pH-或离子-梯度,装载功能化合物。经主动装载,可实现高的功能化合物与脂质质量比和高的装载效率(多达100%)。例子是抗癌药物多柔比星、柔红霉素和长春新碱的主动装载(P.R.Cullis等,BiochimicaetBiophysicaActa,(1997)1331:187-211,和其中的参考文献)。
仅仅认为疏水药物能够通过膜插入经一些被动装载/装配机制装载至脂质体。Wasan等在使用胶束将微溶性试剂转移至脂质体双层的说明(US2009/0028931)中声称“具有疏水性质的试剂可插入脂质双层并且这可通过将试剂添加至实施的脂质体实现”。
在药物高于其溶解度界限并且为沉淀形式的条件下将微溶性药物远程装载至脂质体是出人意料的事件。D.Zucker等,JournalofControlledRelease(2009)139:73-80声称“疏水的分子可聚集,并且这些聚集横跨脂质体膜具有低的通透性。因此,当非极性/极性表面积比>2.31时(见Zucker等JournalofControlledRelease(2009)139:73-80的图4),药物必须具有合理的溶解度,>1.9mM,以便实现高装载,因为仅仅可溶性不带电的分子可进入脂质体。”(D.Zucker等,JournalofControlledRelease(2009)139:73-80)。
迄今为止,还未开发从沉淀用略微水溶性试剂主动装载脂质体的水性核心的方法。
附图说明
图1图解了各种类型的脂质体的直径和形态。
图2.由包含硫酸钠(浅阴影)或硫酸铵(深阴影)的HSPC/Chol/Peg-DSPE组成的脂质体制剂用卡非佐米以2的输入药物与脂质比使用下述条件温育。从未封装的药物纯化脂质体并且显示脂质体中封装的卡非佐米的量,表达为μg卡非佐米/μmol脂质。
图3是显示捕获试剂对卡非佐米的脂质体装载的作用的条形图。
图4是条形图,显示药物引入对卡非佐米的脂质体装载的作用的方法。
图5是线图,显示由在600nm下的光散射降低表明的卡非佐米从沉淀装载。
图6是卡非佐米的HPLC色谱图,为从沉淀装载至脂质体之前(上),以及装载至脂质体之后并且然后使用其中其在脂质体外溶液中逆向回到沉淀的反向硫酸铵梯度从脂质体释放(下)。
图7是显示作为[DMSO]函数的脂质体封装效率的线图。输入药物与脂质比例是200μg/μmol。
图8是显示卡非佐米溶液的光散射作为DMSO浓度的函数的线图。卡非佐米的浓度是0.2mg/mL。
图9是显示形成药物沉淀和沉淀的脂质体装载之间延迟时间作用的条形图。
图10是显示硫酸铵捕获试剂浓度对从沉淀装载的卡非佐米脂质体药物载荷的作用的线图。
图11是显示硫酸铵捕获试剂浓度对从沉淀的卡非佐米脂质体装载效率作用的线图。
图12是使用三乙基硫酸铵梯度将不溶解的卡非佐米沉淀装载至脂质体的线图。
图13是显示通过远程装载将不溶解的卡非佐米沉淀转移至脂质体的线图。
图14是显示当与作为SBCD复合物(Abilify)的脂质体混合或当从原料DMSO溶液直接稀释至脂质体产生药物悬液时比较阿立哌唑的脂质体装载的条形图。
图15是显示药物溶液(深色条)和脂质体药物混合物(灰色条)在600nm的吸光度(散射)的条形图。矩形指示其中当与脂质体温育时测量到散射明显下降的样品,指示药物装载。
图16是显示DFX在乙酸钙脂质体中装载效率的条形图。
图17是显示包含乙酸钙作为捕获试剂的脂质体中DFX装载容量的图。
图18是显示包含不同乙酸酯捕获试剂的脂质体中DFX装载容量的图。
发明内容
在使用脂质体用于递送功能化合物时,一般期望将脂质体装载至高浓度,产生高的功能化合物与脂质质量比,因为这减少每次治疗待施用的脂质体的量,以获得需要的疗效,所有的都因为脂质体中使用的数个脂质本身具有剂量限制性的毒性。装载百分数也对成本效率具有重要性,因为差的装载导致活性化合物的大量损失。
在示例性实施方式中,本发明提供了脂质体,其包含封装内部水性介质的脂质体脂质膜。内部水性介质包含捕获试剂和略微水溶性治疗剂之间的复合物的水溶液。
在进一步示例性实施方式中,本发明提供了药物制剂,其包含本发明的脂质体。制剂包括脂质体和药学上可接受的稀释剂或赋形剂。在各种实施方式中,药物制剂为单位剂量形式,提供单位剂量的封装在脂质体中的治疗剂。
在另一示例性实施方式中,本发明提供了制备本发明的脂质体的方法。在各种实施方式中,提供了用略微水溶性的试剂远程装载脂质体的方法。方法包括:a)温育水性混合物,其包含:(i)脂质体悬液,其具有横跨脂质体膜存在的质子和/或离子梯度;(ii)与微溶性药物的水悬液,(iii)其中通过将药物完全溶解在非质子溶剂或多元醇中并且将其稀释为超过形成沉淀的药物溶解度点的水溶液制备药物悬液,其中温育组合的脂质体药物沉淀混合物一段时间响应质子/离子梯度产生积聚在脂质体内部的药物。制备用于用试剂装载脂质体的混合物,以使横跨内部水性膜和外部水性介质之间的脂质体膜存在质子-和/或离子-梯度。温育可为任何有用的时间段,但是优选地为足以使至少部分不溶解的药物沉淀在质子和/或离子梯度的作用下积聚在内部水性介质中的时间段。
在下面详细说明中阐释了其他实施方式、目的和优势。
优选实施方式详述
介绍
在利用脂质体用于递送功能化合物时,一般期望将脂质体装载至高浓度,产生高的试剂-脂质质量比,因为这减少每次治疗待施用的脂质体的量,以获得需要的疗效,所有的都因为脂质体中使用的数个脂质本身具有剂量限制的毒性。装载百分数也对成本效率具有重要性,因为差的装载导致在将试剂装载至脂质体期间试剂的损失。
本发明提供了脂质体封装试剂,例如,略微水溶性的,制备这样的脂质体的方法,包含这样的脂质体的制剂和制备本发明的脂质体和制剂的方法。
在示例性实施方式中,本发明提供了具有封装水性腔室的膜的脂质体。制备脂质体使得横跨内部水性腔室和外部水性介质之间的脂质体膜存在质子-和/或离子-梯度。试剂以下述浓度溶解在非质子溶剂中,所述浓度是当稀释在脂质体悬液中形成远程装载混合物时其在悬液中的溶解度超出并且试剂形成沉淀。一部分试剂沉淀使用横跨内部水性腔室和外部水性介质之间脂质体膜的质子-和/或离子-梯度装载至脂质体水性腔室。
在一些实施方式中,远程装载混合物中基本上所有量的不溶解的试剂沉淀装载至脂质体的水性腔室。在示例性实施方式中,远程装载混合物中至少约95%,至少约90%,至少约85%,至少约80%或至少约70%的不溶解的药物沉淀装载至脂质体的水性腔室。
脂质体
本文根据其通常的含义使用术语脂质体,指由双层磷脂或任何类似的封装内部水性介质的两性脂质组成的显微脂质膜泡。本发明的脂质体可以是单层膜泡比如小单层膜泡(SUV)和大单层膜泡(LUV)和多层膜泡(MLV),尺寸通常从30nm至200nm改变。对本发明中的脂质体膜结构没有具体限制。术语脂质体膜指分离内部水性介质与外部水性介质的双层磷脂。
本发明使用的示例性脂质体膜可由各种形成膜泡的脂质形成,通常包括双脂族链脂质,比如磷脂、甘油二酯、双脂族糖脂,单个脂质比如鞘磷脂和鞘糖脂、胆固醇和其衍生物,和其组合。如本文定义,磷脂是两性分子试剂,具有长链烷基链形成的疏水基团,和包含磷酸盐部分的亲水基团。磷脂的基团包括磷脂酸、磷脂酰丙三醇、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸和其混合物。优选地,磷脂选自l,2-双棕榈酰-sn-甘油-3-磷酸胆碱(DPPC)、二肉豆蔻酰基-磷脂酰胆碱(DMPC)、氢化大豆卵磷脂(HSPC)、大豆磷脂酰胆碱(SPC)、二肉豆蔻酰基磷脂酰甘油(DMPG)、二硬脂酰磷脂酰甘油(DSPG)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二油酰-sn-甘油-3-磷酸胆碱(DOPC)二硬脂酰基磷脂酰胆碱(DSPC)、卵黄磷脂酰胆碱(EYPC)或氢化卵黄磷脂酰胆碱(HEPC)、固醇改性的脂质(SML)、阳离子脂质和反两性脂质。
根据本发明的脂质体膜可进一步包括离子载体,如尼日利亚菌素(nigericin)和A23187。
在根据本发明的方法中,示例性脂质体相变温度在-25℃和100℃之间,例如,在4℃和65℃之间。相变温度是诱导组成脂质体的脂质物理状态从有序的凝胶相变成无序的液晶相需要的温度,所述凝胶相中烃链充分延伸并且紧密堆积,所述液晶相中烃链是随机定向的和流动的。高于脂质体的相变温度,脂质体膜的通透性增加。选择其中脂质体总处在凝胶状态的高转变温度,可提供非渗漏脂质体组合物,即在暴露于环境期间,保持内部水性介质中略微水溶性试剂的浓度。可选地,转变温度在所暴露环境的开始和结束温度之间的脂质体提供当脂质体超过其转变温度时,释放略微水溶性试剂的方式。因此,主动装载技术的过程温度通常高于脂质体相变温度,以利于主动装载过程。如本领域通常已知的,脂质体的相变温度可受磷脂的选择和添加类固醇如胆固醇、羊毛固醇、胆甾烷醇、豆甾醇、麦角固醇等参数的影响。因此,在本发明的实施方式中,提供根据任何前述的方法,其中脂质体包含以数个摩尔比选自不同磷脂和胆固醇的一个或多个组分,以便改变转变、需要的过程温度和血浆中脂质体稳定性。混合物中较少的胆固醇导致血浆中较不稳定的脂质体。本发明中使用的示例性磷脂组合物包括约10和约50mol%之间的类固醇类,优选地胆固醇。
根据本发明,可通过现在已知的或随后为制备脂质体开发的任何技术制备脂质体。例如,脂质体可通过制备多层脂质膜泡(MLVs)的常规的技术形成,即,通过将一个或多个选择的脂质沉积在适当的容器的内侧壁上通过将脂质溶解在氯仿中并且然后蒸发氯仿,和然后通过添加待封装在容器中的水溶液,允许水溶液使脂质水合,和使所得脂质悬液漩涡或起涡流。该过程产生了包括期望脂质体的混合物。可选地,用于产生大单层脂质膜泡(LUV)的技术,比如反相蒸发、注入法和去污剂稀释,可用于产生脂质体。产生脂质膜泡的这些和其他方法的综述可见文本LiposomeTechnology,VolumeI,GregoryGregoriadisEd.,CRCPress,BocaRaton,Fla.,(1984),其通过引用并入本文。例如,包含脂质的颗粒可为下述形式:甾族脂质膜泡,稳定的多层脂质膜泡(SPLV)、单相膜泡(MPV)或脂质基质载体(LMC)。在MLV的情况下,如果期望,脂质体可进行多个(五个或更多个)冷冻-融化轮,以增强它们的捕获体积和捕获效率并且提供溶质更均匀层间分布。
脂质体制备之后,任选地调整脂质体的尺寸,以实现期望的尺寸范围和相对窄的脂质体尺寸的分布。约20-200纳米的尺寸范围使得脂质体悬液通过常规的过滤器,通常为0.22或0.4微米过滤器,过滤灭菌。如果脂质体的尺寸下降至约20-200纳米,可以高通量基础进行过滤器消毒方法。数个技术可用于调整脂质体的尺寸至期望的尺寸。通过浴或探针超声法超声脂质体悬液,产生连续尺寸下降至小单层膜泡,尺寸小于约50纳米。匀化是另一方法,其依赖于剪切能使大脂质体片段化成更小的脂质体。在典型的匀化方法中,通过标准乳液匀化器使多层膜泡再循环,直到观察到选择的脂质体尺寸,通常在约50和500纳米之间。在两种方法中,可通过常规的激光束颗粒尺寸测定,监测颗粒尺寸分布。通过小孔聚碳酸酯膜或不对称的陶瓷膜挤出脂质体也是使脂质体尺寸降低至相对良好限定尺寸分布的有效方法。典型地,悬液通过膜循环一次或多次,直到实现期望的脂质体尺寸分布。可通过连续更小的孔膜挤出脂质体,以实现逐渐减小的脂质体尺寸。可选地,可使用微流体技术制备控制尺寸的脂质体,其中有机溶剂中,比如乙醇或乙醇-非质子溶剂混合物中的脂质与水性介质快速混合,从而在尺寸小于300微米和优选宽度小于150微米和高度50微米的微通道中有机溶剂/水比例小于30%。然后从脂质体通过透析去除有机溶剂。其他可用的调整尺寸的方法比如超声法、溶剂蒸发或反相蒸发是本领域技术人员已知的。
用于本发明各种实施方式的示例性脂质体的尺寸为约30纳米至约40微米。
本文提及的内部水性介质,通常是其中制备脂质体并且当形成脂质体时初始封装的初始介质。根据本发明,新鲜制备的封装初始水性介质的脂质体可直接用于主动装载。但是,实施方式也设想其中脂质体制备之后脱水,例如用于储存。在这样的实施方式中,该方法可涉及直接添加脱水脂质体至用于产生跨膜梯度的外部水性介质。但是也可能首先在另一外部介质中使脂质体水合,如本领域技术人员理解的。任选地在减压下使用标准冷冻干燥装置或等同装置使脂质体脱水。在各种实施方式中,脂质体和它们的周围介质冷冻在液氮中,然后脱水并且放置在减压下。为了确保脂质体在脱水过程中幸存,而不损失大部分部分它们的内部包含物,通常采用一种或多种保护糖,以与脂质膜泡膜相互作用并且随着去除系统中的水,保持它们完整。可使用各种糖,包括这样的糖,如海藻糖、麦芽糖、蔗糖、葡萄糖、乳糖和葡聚糖。一般而言,已经发现二糖比单糖更好,二糖海藻糖和蔗糖是最有效的。也可使用其他更复杂的糖。例如,已经发现包括链霉素和双氢链霉素的氨基糖苷类在脱水期间保护脂质体。典型地,包括一种或多种糖作为脂质膜泡的内部或外部介质的一部分。最优选地,糖包括在内部和外部介质中,从而它们可与脂质体膜的内侧和外侧表面相互作用。通过在脂质体形成过程期间添加糖或糖至封装在脂质膜泡中的缓冲液实现包括在内部介质中。在这些实施方式中,在主动装载过程中使用的外部介质,也应优选地包括一种或多种保护糖。
如本领域技术人员一般理解,聚乙二醇(PEG)-脂质缀合物已经广泛用于改善脂质体-封装功能化合物的循环次数,以避免或减少功能化合物从脂质体组合物过早渗漏并且避免身体免疫系统的脂质体的探测。将PEG衍生的脂质附接至脂质体称为聚乙二醇化。因此,在本发明的示例性实施方式中,脂质体是聚乙二醇化的脂质体。可通过温育PEG的活性衍生物与靶脂质体实现聚乙二醇化。适当的根据本发明的PEG衍生的脂质,包括DSPE-PEG的缀合物,用下述之一官能化:羧酸、谷胱甘肽(GSH)、马来酰亚胺(MAL)、3-(2-吡啶基二硫)丙酸(PDP)、氟尿酸、叠氮化物、胺、生物素或叶酸,其中PEG的分子量在2000和5000g/mol之间。其他适当的PEG衍生的脂质是与神经酰胺缀合的mPEG,具有C8-或C16尾,其中mPEG的分子量在750和5000道尔顿之间。仍其他适当的配体是用甘油磷脂质缀合的mPEG或官能化的PEG,如l,2-二肉豆蔻酰基-sn-甘油-3-磷酸乙醇胺(DMPE)、1,2-双棕榈酰-sn-甘油-3-磷酸乙醇胺(DPPE)、l,2-二油酰-sn-甘油-3-磷酸乙醇胺(DOPE)和l,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺(DSPE)等。脂质体的聚乙二醇化是本领域技术人员通常已知的技术。
在各种实施方式中,用DSPE-PEG-GSH缀合物(至多5mol%)和/或DSPE-mPEG缀合物聚乙二醇化脂质体(其中PEG的分子量通常在750-5000道尔顿之间,例如2000道尔顿)。本发明示例性聚乙二醇化的脂质体的磷脂组合物可包括至多5-20mol%的PEG-脂质缀合物。
此外,在某些实施方式中,将脂质体特异性靶向具体细胞类型、组织等的一个或多个部分并入膜。先前已经描述了使用各种靶向部分(例如,配体,受体和单克隆抗体)的脂质体的靶向。这样部分的适当例子包括透明质酸,抗ErbB家族抗体和抗体片段、脂蛋白脂肪酶(LPL)、[α]2-巨球蛋白([α]2M)、受体相关的蛋白质(RAP)、乳铁蛋白、去氨普酶,组织和尿激酶型血纤维蛋白溶酶原活化剂(tPA/uPA)、血纤维蛋白溶酶原活化剂抑制剂(PAI-I)、tPA/uPA:PAI-l复合物、黑素转铁蛋白(或P97)、血小板反应蛋白1和2、肝脂肪酶、因子Vila/组织因子途径抑制剂(TFPI)、因子Villa、因子IXa、A[β]l-40、淀粉样蛋白-[β]前体蛋白质(APP)、CI抑制剂、补体C3、载脂蛋白E(apoE)、假单胞菌外毒素A、CRM66、HIV-ITat蛋白质、鼻病毒、基质金属蛋白酶9(MMP-9)、MMP-13(胶原酶-3)、鞘脂活化剂蛋白质(SAP)、妊娠带蛋白、抗凝血酶III、肝素辅因子II、[α]l-抗胰蛋白酶、热休克蛋白96(HSP-96)、血小板衍生生长因子(PDGF)、载脂蛋白J(apoJ,或成簇蛋白)、结合apoJ和apoE的A[β]、牛胰蛋白酶抑制剂、angiopep-2(TFFYGGSRGKRNNFKTEEY)、非常低密度脂蛋白(VLDL)、运铁蛋白、胰岛素、瘦蛋白、胰岛素样生长因子、表皮生长因子、凝集素、拟肽和/或人源化的单克隆抗体、对所述受体特异的单链链抗体或肽(例如,结合人运铁蛋白受体的序列HAIYPRH和THRPPMWSPVWP,或抗人运铁蛋白受体(TfR)单克隆抗体A24)、血红蛋白、白喉毒素多肽链的非毒性部分、所有或一部分白喉毒素B链、白喉毒素CRM197的所有或一部分无毒的突变体、载脂蛋白B、载脂蛋白E(例如,结合polysorb-80涂层之后)、维生素D-结合蛋白质、维生素A/视黄醇-结合蛋白质、维生素B12/钴胺素血浆载体蛋白、谷胱甘肽和钴胺传递蛋白-B12。
靶向机制一般要求靶向试剂位于脂质体的表面上,使得靶向部分可用于与靶,例如,细胞表面受体的相互作用。在示例性实施方式中,制备脂质体,以包括在形成膜时并入膜的连接体部分。示例性连接体部分具有亲脂部分,其牢固嵌入和锚定在膜中。示例性连接体部分也包括亲水部分,其在脂质体的水性表面上是化学可用的。选择亲水部分从而其化学上适于和稍后添加的靶向试剂形成稳定的化学键。用于将靶向部分并入脂质体膜的技术一般是本领域已知的。
在示例性实施方式中,脂质体包括HSPC、胆固醇、PEG-DSPE和其组合。在示例性实施方式中,脂质体包括约50mol至约70molHSPC,约30mol至约50mol胆固醇和约1mol至约10molPEG-DSPE。在一种实施方式中,脂质体包括约60molHSPC,约40mol胆固醇和约5molPEGDSPE。
略微水溶性试剂
如上面指示,本发明提供了封装略微水溶性试剂的脂质体。在本发明的背景下,术语‘略微水溶性’意思是在水中不溶解或具有非常有限的溶解度,更尤其具有的水性溶解度小于2mg/mL,例如,小于1.9mg/mL,例如,水性溶解度小于lmg/mL。如本文所使用,水溶解度指溶解度测量在环境温度下,其通常约20℃。在示例性实施方式中,在约pH=7下测量试剂的水溶解度。
根据本发明的示例性实施方式,略微水溶性试剂是选自下述的治疗剂:蒽环类化合物、喜树碱化合物、长春花生物碱、玫瑰树碱化合物、紫杉烷化合物、曼青霉素化合物、格尔德霉素化合物、吡唑并嘧啶化合物、基于肽的化合物比如卡非佐米、甾族化合物、任何前述的衍生物、任何前述的前药,和任何前述的类似物。
水溶解度小于约2mg/mL的示例性小分子化合物,包括但不限于卡非佐米、伏立康唑、胺碘酮、齐拉西酮、阿立哌唑、伊马替尼、拉帕替尼、环杷明、oprozomib、CUR-61414、PF-05212384、PF-4691502、toceranib、PF-477736、PF-337210、舒尼替尼、SU14813、阿西替尼、AG014699、维利帕尼、MK-4827、ABT-263、SU11274、PHA665752、克里唑蒂尼、XL880、PF-04217903、XR5000、AG14361、维利帕尼、bosutunib、PD-0332991、PF-01367338、AG14361、NVP-ADW742、NVP-AUY922、NVP-LAQ824、NVP-TAE684、NVP-LBH589、艾日布林、多柔比星、柔红霉素、丝裂霉素C、表柔比星、吡柔比星、红比霉素、癌霉素、N-乙酰基阿缀米辛、柔红霉素苯腙、5-酰亚胺道诺霉素、N-乙酰基道诺霉素、daunoryline、米托蒽醌、喜树碱、9-氨基喜树碱、7-乙基喜树碱、7-乙基-10-羟基-喜树碱、10-羟基喜树碱、9-硝基喜树碱、10,11-亚甲基二氧喜树碱、9-氨基-10,11-亚甲基二氧喜树碱、9-氯-10,11-亚甲基二氧喜树碱、伊立替康、勒托替康、silatecan、(7-(4-甲基哌嗪亚甲基)-10,11-亚乙基二氧-20(S)-喜树碱、7-(4-甲基哌嗪亚甲基)-10,11-亚甲二氧基-20(S)-喜树碱、7-(2-N-异丙基氨基)乙基)-(20S)-喜树碱、CKD-602、长春新碱、长春花碱、长春瑞宾、长春氟宁、长春西汀、长春地辛、玫瑰树碱、6-3-氨丙基-玫瑰树碱、2-二乙氨乙基-玫瑰树碱铵、达替铵、瑞替利汀、紫杉醇、多西他赛、双氯芬酸、丁哌卡因、17-二甲基氨基乙基氨基-17-脱甲氧格尔德霉素、西替利嗪、非索非那定、扑痫酮和其他儿茶酚胺、肾上腺素、(S)-2-(2,4-二羟苯基)-4,5-二氢-4-甲基-4-噻唑羧酸(deferitrin)、(S)-4,5-二氢-2-(3-羟基-2-吡啶基)-4-甲基-4-噻唑羧酸(desferrithiocin)、(S)-4,5-二氢-2-[2-羟基-4-(3,6,9,12-四氧三癸氧基)苯基]-4-甲基-4-噻唑羧酸、(S)-4,5-二氢-2-[2-羟基-4-(3,6-二氧庚氧基)苯基]-4-甲基-4-噻唑羧酸、乙基(S)-4,5-二氢-2-[2-羟基-4-(3,6-二氧庚氧基)苯基]-4-甲基-4-噻唑羧化物、(S)-4,5-二氢-2-[2-羟基-3-(3,6,9-三氧癸氧基)]-4-甲基-4-噻唑羧酸、desazadesferrithiocin、这些药学化合物的盐、前药和衍生物和其混合物。
示例性治疗剂选自:抗组胺乙二胺衍生物、溴苯那敏、苯海拉明、抗原生动物药物、喹诺酮、双碘喹啉、脒化合物、喷他脒、驱虫化合物、噻嘧啶、抗血吸虫药物、奥沙尼喹、抗真菌的三唑衍生物、氟康唑、伊曲康唑、酮康唑、咪康唑、抗菌头孢菌素、螯合剂、去铁胺、地拉罗司、去铁酮、FBS0701、头孢唑啉、头孢尼西、头孢噻肟、头孢他啶、头孢呋辛、抗菌剂β-内酰胺衍生物、氨曲南、头孢三唑、头孢西丁、红霉素族的抗菌剂、红霉素、阿奇霉素、克拉霉素、竹桃霉素、青霉素化合物、苄青霉素、苯氧基甲基青霉素、氯唑西林、二甲氧基苯青霉素、萘夫西林、苯唑西林、羧苄西林、四环素化合物、新生霉素、大观霉素、万古霉素;抗分歧杆菌药物、氨基水杨酸、卷曲霉素、乙胺丁醇、异烟肼、吡嗪酰胺、利福布汀、利福平、氯法齐明、抗病毒的金刚烷化合物、金刚烷胺、金刚乙胺、奎尼丁化合物、奎宁、奎纳克林、氯喹、羟化氯喹、伯氨喹啉、阿莫地喹、甲氟喹、抗菌剂、喹诺酮、环丙沙星、依诺沙星、洛美沙星、萘啶酸、诺氟沙星、氧氟沙星、磺酰胺;尿路抗菌剂、呋喃妥因、甲氧苄氨嘧啶;硝基咪唑类衍生物、甲硝唑、胆碱季胺化合物、ambethinium、新斯的明、毒扁豆碱、抗-阿尔茨海默病、他克林、抗帕金森药物、苯扎托品、比哌立登、普环啶、苯海索、抗蕈毒碱试剂、阿托品、莨菪碱、东莨菪碱、丙胺太林、肾上腺素能化合物、多巴胺、5-羟色胺、刺猬基因抑制剂、沙丁胺醇、多巴酚丁胺、麻黄碱、肾上腺素、去甲肾上腺素、异丙肾上腺素、间丙醇、沙美特罗、特布他林、5-羟色胺再摄入抑制剂、麦角胺衍生物、肌肉松弛剂、箭毒系列、中心作用肌肉松弛剂、巴氯芬、环苯扎林、丹曲林、尼古丁、尼古丁受体拮抗物、β-肾上腺素阻断剂、acebutil、胺碘酮、苯并二氮杂化合物、地尔硫草、抗心律失常药物、双异丙吡胺、encaidine、局部麻醉化合物、普鲁卡因、普鲁卡因胺、移多卡因、氟卡胺、奎尼丁、ACE抑制剂、卡托普利、依那普利、Hsp90抑制剂、福辛普利、喹那普利、雷米普利;阿片剂衍生物、可待因、哌替啶、美沙酮、吗啡、antilipidemic、氟伐他汀、吉非罗齐、HMG-coA抑制剂、普伐他汀、血压过低药物、可乐定、胍那苄、哌唑嗪、胍乙啶、granadril、肼苯哒嗪、非冠状血管舒张剂、双嘧达莫、乙酰胆碱酯酶抑制剂、匹罗卡品、生物碱、毒扁豆碱、新斯的明、任何前述的衍生物、任何前述的前药和任何前述的类似物。
但是,试剂的列举不旨在限制本发明的范围。事实上,封装在脂质体中的化合物可以是任何略微水溶性两性弱碱或两性弱酸。如上述,其中略微水溶性试剂的实施方式不是药学或医学试剂的实施方式也包括在本发明内。
典型地,在本发明的背景下,略微水溶性两性弱碱的辛醇-水分布系数(logD)在pH7下在-2.5和2之间和pKa<11,而略微水溶性两性弱酸的logD在pH7下在-2.5和2之间和pKa>3。
典型地,如前述中使用术语弱碱和弱酸分别指在水中仅仅部分质子化或去质子化的化合物。可质子化的试剂的例子包括具有氨基基团可在酸性介质中质子化的化合物,和在中性介质中是两性离子并且可也在酸性环境中质子化的的化合物。可去质子化的试剂的例子包括具有羧基的可在碱性介质中去质子化的化合物,和其在中性介质中是两性离子并且也可在碱性环境中去质子化的化合物。
术语两性离子指可同时在不同原子上携带正电荷和负电荷的化合物。如在前述中使用,术语两性的通常用于指具有亲脂和亲水部分的化合物。前述暗示化合物的水溶液是弱两性酸或碱,同时包括带电的和不带电形式的所述化合物。仅仅不带电形式可能够横跨脂质体膜。
当本发明使用的试剂包含相对碱性或酸性官能时,这样的化合物的盐包括在本发明的范围内。可通过使中性形式的这样的化合物接触足够量期望的纯净的或适当惰性溶剂中酸或碱获得盐。本发明相对酸性化合物的盐的例子包括钠、钾、钙、铵、有机氨基或镁盐,或类似的盐。当本发明的化合物包含相对碱性官能时,可通过使中性形式的这样化合物接触足够量的期望的纯净的或适当惰性溶剂中的酸获得酸性加成盐。酸加成盐的例子包括源自无机酸,如盐酸、氢溴酸、硝酸、碳酸、单氢碳酸、磷酸、单氢磷酸、二氢磷酸、硫酸、单氢硫酸、氢碘酸或亚磷酸等的那些,以及源自下述有机酸的盐,如:乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。也包括氨基酸的盐,比如精氨酸盐等,和有机酸的盐,如葡萄糖醛酸或半乳糖醛酸等(见,例如,Berge等,JournalofPharmaceuticalScience1977,66:1-19)。本发明的某些特定化合物包含允许化合物转化成碱或酸加成盐的碱性和酸性官能。
优选地通过使盐接触碱或酸并且通过常规方式分离亲本化合物再生中性形式的化合物。亲本形式的化合物与各种盐形式的某些物理特性不同,比如在极性溶剂中的溶解度,但是为了本发明的目的,盐以其他方式与化合物的亲本形式等同。
示例性试剂是分子量在约100Da和3000Da之间的小有机分子。
主动装载
主动装载的方法涉及使用跨膜势能。一般而言,本领域广泛描述了主动装载的原则。术语主动装载和远程-装载是同义的并且交替使用。
主动装载期间,略微水溶性试剂的沉淀通过跨膜质子-或离子-梯度从外部水性介质横跨脂质体膜转移至内部水性介质。术语具体化合物的梯度,如本文所使用指横跨脂质体膜从脂质体的外侧(外部水性介质)至内侧(内部水性介质)所述化合物浓度的不连续增加。
为了产生浓度梯度,脂质体通常在第一液体、通常水相中生成,随后替换或稀释所述第一液相。稀释或新的外部介质具有不同浓度带电的物质或完全不同带电的物质,从而产生离子-或质子-梯度。
可通过各种技术实现置换外部介质,比如,通过使制备的脂质膜泡穿过已经用新介质平衡的凝胶过滤柱,例如,Sephadex或琼脂糖柱,或通过离心、透析或相关的技术。
主动装载至脂质体的效率取决于待装载至复合物的化学特性和施加的梯度的类型和程度等。在本发明的实施方式中,提供了如任何前述限定的方法,其采用横跨脂质体膜的梯度,其中梯度选自pH-梯度、硫酸盐、磷酸盐、膦酸盐、柠檬酸盐或乙酸盐梯度、EDTA-离子梯度、铵盐梯度、烷基化的盐,例如甲基盐、乙基盐、丙基盐和戊基盐、铵盐梯度、Mn2+-、Cu2+-、Na+-、K+-梯度,使用或不使用离子载体,或其组合。现有技术已经广泛描述了这些装载技术。
优选地,预形成的内部水性介质,即,未装载的,脂质体包括所谓的主动装载缓冲液,其包含水,并且取决于主动装载期间采用的梯度的类型,可进一步包括硫酸盐、磷酸盐、膦酸盐盐、柠檬酸盐或乙酸盐、铵盐、烷基化的盐,例如,甲基盐、乙基盐、丙基盐和戊基盐、铵盐、Fe+2-、Mn2+-、Cu2+-、Na+和/或K+-盐、EDTA离子盐,和任选地pH-缓冲液,以维持pH梯度。盐可以是聚合的,比如葡聚糖硫酸盐,聚乙烯亚胺,聚酰胺树状聚合物、1.5羧酸末端形式的聚酰胺、多磷酸盐、低分子量肝素或透明质酸。在示例性实施方式中,未装载的脂质体的内部水性介质中盐的浓度在1和1000mM之间。
用于为主动装载产生跨膜梯度的外部水性介质包括水、待装载的略微水溶性试剂(一种或多种)的沉淀,和任选地蔗糖、调整渗透性的生理盐水或一些其他试剂和/或螯合剂,如EDTA以帮助离子载体活性,更优选地蔗糖和/或EDTA。
在示例性实施方式中,梯度选自下述的胺或金属盐:羧酸盐、硫酸盐、膦酸盐、磷酸盐或乙酸盐。如本领域技术人员一般已知的,跨膜pH梯度(较低的内侧pH,较高的外侧pH)或阳离子乙酸盐梯度可用于主动装载两性分子弱酸。两性弱碱可也使用硫酸铵或三乙胺硫酸或铵氯化物梯度主动装载至脂质体。
本发明中使用的羧化物包括但不限于羧酸盐、柠檬酸盐、二亚乙基三胺五乙酸盐、苯六酸乙酸盐、1,2,3,4-丁烷四羧化物、苯甲酸盐、异酞酸盐、邻苯二甲酸盐、3,4-双(羧甲基)环戊烷羧化物、羧酸代聚酰胺树状聚合物、苯三羧化物、苯四羧化物、抗坏血酸盐、葡糖醛酸盐和磺酸盐。
本发明中使用的硫酸盐包括但不限于硫酸盐、1,5-萘二磺酸盐、葡聚糖硫酸盐、磺酸丁基醚β环糊精、蔗糖八硫酸苯磺酸盐、聚(4-苯乙烯磺酸盐)顺白藜芦醇三硫酸盐。
本发明使用的磷酸盐和膦酸盐类包括但不限于磷酸盐、六偏磷酸盐、磷酸盐玻璃、多磷酸盐、三磷酸盐、三偏磷酸盐、双膦酸盐、乙烷羟基双膦酸盐、肌醇六磷酸盐。
本发明中使用的示例性盐包括羧酸盐、硫酸盐或磷酸盐的混合物,包括但不限于2-羧基苯磺酸盐、肌酸磷酸盐、磷酸胆碱、肉碱磷酸盐、羧基代聚酰胺。
本发明使用的胺包括但不限于一元胺、聚胺、三甲基铵、三乙基铵,三丁基铵、二乙基甲基铵、二异丙基乙基铵、三异丙基铵、N-甲基吗啉、N-乙基吗啉、N-羟基乙基哌啶、N-甲基吡咯烷、N,N-二甲基哌嗪、异丙基乙基铵、异丙基甲基铵、二异丙基铵、叔丁基乙基铵、二环已基铵、质子化形式的吗啉、吡啶、哌啶、吡咯烷、哌嗪、咪唑、叔丁基胺、2-氨基-2-甲基丙醇、2-氨基-2-甲基-丙二醇、三-(羟乙基)-氨基甲烷、二乙基-(2-羟乙基)胺,三-(羟甲基)-氨基甲烷四甲基铵盐、四乙基铵、N-甲基葡糖胺和四丁基铵、聚乙烯亚胺和聚酰胺树状聚合物。
取决于脂质膜泡膜的通透性,自发形成对应浓度梯度的完全跨膜潜能或通透性增强试剂,例如,质子离子载体可添加至介质。如果期望,可使用色谱或其他技术在完成装载复合物之后从脂质体制剂去除通透性增强试剂。
通常,主动装载期间介质的温度在约-25℃和约100℃之间,例如,约0℃和约70℃之间,例如,约4℃和65℃之间。
定义为内部水相中略微水溶性试剂的封装量除以外部水相中初始量乘以100%的封装或装载效率(例如,以试剂克数/磷脂摩尔数或药物g数/总脂质g数测量)是至少10%,优选地至少50%,至少90%。
在示例性实施方式中,本发明提供了将略微水溶性试剂装载至脂质体的方法。示例性方法包括,在适于在所述脂质体中封装略微水溶性试剂的条件下使所述脂质体的水悬液接触试剂的水悬液。脂质体具有脂质膜封装的内部水性环境。脂质体的水悬液包括横跨膜的选自下述的梯度:质子梯度、离子梯度和其组合。在适于略微水溶性试剂穿过膜并且在内部水性环境中浓缩的条件下温育略微水溶性试剂和脂质体悬液选择的时间段,从而形成所述药物制剂。
在各种实施方式中,上述反应混合物被温育选择的时间段并且在温育期间横跨脂质体膜存在pH梯度、硫酸盐梯度、磷酸盐梯度、膦酸盐梯度、羧酸盐梯度(柠檬酸盐梯度、乙酸盐梯度等)、EDTA离子梯度、铵盐梯度、烷基化的铵盐梯度、Mg+2、Mn+2、Cu+2、Na+、K+梯度或其组合。
在本发明的示例性实施方式中,略微水溶性治疗剂不共价连接至脂质体的组分,也不共价连接至用于形成本发明脂质体试剂制剂的pH或盐梯度的任何组分。
非质子溶剂
在示例性实施方式中,略微水溶性试剂完全溶解在与水混溶的非质子溶剂中。试剂溶液以大于药物试剂在脂质体悬浮或脂质体悬浮/非质子溶剂混合物中溶解度的浓度添加至水性脂质体悬液,因此形成沉淀。示例性非质子溶剂包括二甲亚砜、二噁烷、四氢呋喃、二甲基甲酰胺、乙腈、乙酰二甲胺、环丁砜、γ丁内酯、吡咯烷酮、l-甲基-2-吡咯烷酮、甲基吡咯啉、乙二醇一甲基醚、二甘醇一甲基醚、PEG400和聚乙二醇。
略微水溶性试剂沉淀
本发明提供了将不溶解的沉淀装载在脂质体的脂质膜内侧水性内部腔室的方法。示例性的沉淀的概念为悬液中试剂的一些不溶解的部分。不溶解的部分定义为不溶解的一部分试剂,如下述任何所指示:任何朦胧外观大于没有该试剂的脂质体悬液的外观,任何程度的增加在其中内容物不吸收光的波长下比如在600nm的光散射大于单独脂质体悬液、通过在小于12,000RPM离心15min可分离(小球化)的任何部分的药物,可通过0.2um过滤器过滤分离的任何部分的药物试剂。
示例性制剂
在示例性实施方式中,本发明提供了封装在脂质体的水性核心中的略微水溶性试剂的制剂,其包含胆固醇、PEG-DSPE和脂质组分,具有磷酸胆碱头基团和一个或两个脂肪酸残基。在各种实施方式中,脂质体包括HSPC、胆固醇和PEG-DSPE的组合。在示例性实施方式中,脂质体包括的组分的摩尔比为约50%摩尔至约70%摩尔HSPC,约25%摩尔至约50%摩尔胆固醇和约0%摩尔至约10%摩尔PEG-DSPE。在一种实施方式中,脂质体包括的组分的摩尔比为约60%摩尔HSPC,约40%摩尔胆固醇和约2.8%摩尔PEG-DSPE。在示例性实施方式中,试剂通过主动装载封装在脂质体中。
在进一步示例性实施方式中,本发明提供了封装在脂质体的水性核心中的略微水溶性试剂包括鞘磷脂(SM)、胆固醇和PEG-DSPE的组合。在示例性实施方式中,脂质体包括的组分的摩尔比为约45至约75SM,约25%摩尔至约50%摩尔胆固醇和约0%摩尔至约10%摩尔PEG-DSPE。在一种实施方式中,脂质体包括的组分的摩尔比为约55%摩尔SM、约45%摩尔胆固醇和约2.8%摩尔PEG-DSPE。
在示例性实施方式中,略微水溶性试剂(例如,卡非佐米)或其盐、类似物或衍生物:脂质比例是约30mg至约90mg的试剂与约90mg至约250mg的脂质。在示例性实施方式中,制剂试剂:脂质比例是约60mg试剂与约170mg脂质。
在各种实施方式中,试剂(μg):脂质(μmol)比例是约250与约450。在示例性实施方式中,该比例是约300至约400。
在示例性实施方式中,远程装载剂是碳水化合物硫酸盐的铵盐。在各种实施方式中,远程装载剂是三乙基葡聚糖硫酸铵盐。
在示例性实施方式中,本发明提供了药物制剂,其包含封装在质量是约90mg至约200mg的脂质体群的约60mg的试剂。脂质体包括限定内部水性腔室的脂质膜。试剂封装在由脂质膜限定的水性腔室中。脂质膜的组分的摩尔比是:(a)约55%摩尔鞘磷脂(SM);(b)约45%摩尔胆固醇;和(c)约2.8%摩尔PEG-(l,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺)(PEG-DSPE)。制剂选自冻干制剂和其中所述脂质体悬浮在药学上可接受的稀释剂中的制剂。
在示例性实施方式中,本发明提供了试剂的脂质体制剂,其中试剂在施用其的对象中的体内T1/2为约2小时至约12小时,例如,约3小时至约6小时。在示例性制剂中,试剂是游离的或封装形式。
本发明的示例性药物制剂包括进一步封装碳水化合物硫酸盐的脂质体。在示例性实施方式中,碳水化合物硫酸盐是葡聚糖硫酸盐。
在示例性实施方式中,通过包括下述的方法形成本发明的制剂:(a)在碳水化合物硫酸盐的铵盐水溶液中制备脂质体的悬液,形成封装在所述脂质体中的第一群体的所述铵盐和所述脂质体外部的第二群体的所述盐;(b)用水性缓冲液替换所述脂质体外部的盐,从而形成横跨所述脂质膜的所述碳水化合物硫酸盐的梯度;和(c)添加非质子溶剂中的试剂溶液至(b)中形成的悬液,形成允许试剂穿过脂质膜的试剂沉淀,在所述内部水性腔室中浓缩,从而封装试剂。
在示例性实施方式中,碳水化合物硫酸盐的铵盐是三乙基葡聚糖硫酸铵或葡聚糖硫酸铵。
在示例性实施方式中,装载试剂的脂质体的直径是约40nm至约150nm。
在各种实施方式中,封装试剂溶解在内部水性腔室中。在各种实施方式中,试剂为悬液的形式。在示例性实施方式中,试剂组分被部分溶解并且部分为悬液形式。
本领域技术人员认识到,以任何有用的形式自由组合上面阐释的单个参数。
试剂盒
在示例性实施方式中,本发明提供了试剂盒,其包含本发明的脂质体或制剂的一个或多个组分和如何组合和使用组分和从组合产生的制剂的说明书。在各种实施方式中,试剂盒包含在一个容器中的略微水溶性试剂和在另一容器中的脂质体制剂。示例性脂质体制剂包括脂质膜外侧和内侧的盐分布,以产生和/或维持离子梯度,比如本文所述的。也包括的是组合容器内容物的说明书,以产生本发明的脂质体或其制剂。在各种实施方式中,复合物和脂质体的量足够配制单位剂量形式的复合试剂。
在示例性实施方式中,一个容器包括脂质体或脂质体溶液,其用于将略微水溶性治疗剂制剂的容器的至少部分内容物(例如,批准的治疗剂)在施用至对象的护理点转化成封装治疗剂的脂质体。在示例性实施方式中,容器的内容物足够配制单位剂量形式的治疗剂。
在其中形成单位剂量形式的实施方式中,容器包括约1mg至约500mg的治疗剂,例如,约1mg至约200mg,例如,约5mg至约100mg,例如,约10mg至约60mg。
在示例性实施方式中,批准的治疗剂是卡非佐米并且其在容器中存在的量是约40mg至约80mg,例如,约50mg至约70mg。在示例性实施方式中,存在的卡非佐米是约60mg。
示例性制剂
在示例性实施方式中,本发明提供了封装在脂质体的水性核心中的略微水溶性试剂的制剂,其包含胆固醇、PEG-DSPE和脂质组分,具有磷酸胆碱头基和一个或两个脂肪酸残基。在各种实施方式中,脂质体包括HSPC、胆固醇和PEG-DSPE的组合。在示例性实施方式中,脂质体包括的组分的摩尔比为约50%摩尔至约70%摩尔HSPC,约25%摩尔至约50%摩尔胆固醇和约1%摩尔至约10%摩尔PEG-DSPE。在一种实施方式中,脂质体包括的组分的摩尔比为约60%摩尔HSPC,约40%摩尔胆固醇和约2.8%摩尔PEG-DSPE。在示例性实施方式中,试剂通过主动装载封装在脂质体中。
在进一步示例性实施方式中,本发明提供了封装在脂质体的水性核心中的略微水溶性试剂的制剂,其包含鞘磷脂(SM)、胆固醇和PEG-DSPE的组合。在示例性实施方式中,脂质体包括的组分的摩尔比为约45至约75SM,约25%摩尔至约50%摩尔胆固醇和约0%摩尔至约10%摩尔PEG-DSPE。在一种实施方式中,脂质体包括的组分的摩尔比为约55%摩尔SM,约45%摩尔胆固醇和约2.8%摩尔PEG-DSPE。
在示例性实施方式中,略微水溶性试剂(例如,卡非佐米)或其盐、类似物或衍生物:脂质比例是约30mg至约90mg的试剂与约90mg至约250mg的脂质。在示例性实施方式中,制剂试剂:脂质比例是约60mg试剂与约170mg脂质。
在各种实施方式中,试剂(μg):脂质(μmol)比例是约250至约450。在示例性实施方式中,该比例是约300至约400。
在示例性实施方式中,远程装载剂是碳水化合物硫酸盐的铵盐。在各种实施方式中,远程装载剂是三乙基葡聚糖硫酸铵。
在示例性实施方式中,本发明提供了药物制剂,其包括封装在质量是约90mg至约200mg的脂质体群体中的约60mg的试剂。脂质体包括限定内部水性腔室的脂质膜。试剂封装在由脂质膜限定的水性腔室中。脂质膜的组分的摩尔比为:(a)约55%摩尔鞘磷脂(SM);(b)约45%摩尔胆固醇;和(c)约2.8%摩尔PEG-(l,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺)(PEG-DSPE)。制剂选自冻干制剂和其中所述脂质体悬浮在药学上可接受的稀释剂中的制剂。
在示例性实施方式中,本发明提供了试剂的脂质体制剂,其中试剂在施用其的对象的体内T1/2为约2小时至约12小时,例如,约3小时至约6小时。在示例性制剂中,试剂为游离或封装的形式。
本发明的示例性药物制剂包括脂质体,其进一步封装碳水化合物硫酸盐。在示例性实施方式中,碳水化合物硫酸盐是葡聚糖硫酸盐。
在示例性实施方式中,通过包括下述的方法形成本发明的制剂:(a)在碳水化合物硫酸盐的铵盐水溶液中制备脂质体的悬液,形成封装在所述脂质体中的第一群体的所述铵盐和所述脂质体外部的第二群体的所述盐;(b)用水性缓冲液替换所述脂质体外部的盐,从而形成横跨所述脂质膜的所述碳水化合物硫酸盐的梯度;和(c)添加非质子溶剂中的试剂溶液至(b)中形成的悬液,形成允许试剂穿过脂质膜的试剂沉淀,在所述内部水性腔室中浓缩,从而封装试剂。
在示例性实施方式中,碳水化合物硫酸盐的铵盐是三乙基葡聚糖硫酸铵盐或葡聚糖硫酸铵。
在示例性实施方式中,装载试剂的脂质体的直径是约40nm至约150nm。
在各种实施方式中,封装试剂溶解在内部水性腔室中。在各种实施方式中,试剂为悬液的形式。在示例性实施方式中,部分溶解试剂组分并且部分为悬液的形式。
本领域技术人员认识到,以任何有用的形式自由组合上面阐释的单个参数。
治疗方法
在一个方面中,本发明提供了治疗对象,例如,人中增生性病症例如癌症的方法,所述方法包括以有效治疗病症的量向对象施用包括本发明的药物制剂的组合物,从而治疗增生性病症。
在一种实施方式中,与一个或多个另外抗癌剂,例如,化疗剂,例如,本文所述的化疗剂或化疗剂的组合,以及辐射,施用药物制剂。
在一种实施方式中,癌症是本文所述的癌症。例如,癌症可以是膀胱癌(包括加速的和转移膀胱癌)、乳腺癌(例如,雌激素受体阳性乳腺癌;雌激素受体阴性乳腺癌;HER-2阳性乳腺癌;HER-2阴性乳腺癌;孕酮受体阳性乳腺癌;孕酮受体阴性乳腺癌;雌激素受体阴性、HER-2阴性和孕酮受体阴性乳腺癌(即,三阴性乳腺癌);炎症乳腺癌),结肠癌(包括结肠直肠癌)、肾癌(例如,过渡性细胞癌)、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌、肺腺癌和鳞状的细胞癌症)、泌尿生殖道癌,例如,卵巢癌(包括输卵管癌和腹膜癌)、宫颈癌、前列腺癌、睾丸癌、肾癌和输尿管癌、淋巴腺系统癌、直肠癌、喉头癌、胰腺癌(包括外分泌胰腺癌)、食道癌、胃癌、胆囊癌、甲状腺癌、皮肤癌(包括鳞状细胞癌)、脑癌(包括多形性成胶质母细胞瘤)、头颈癌(例如,潜伏的原发性癌),和软组织癌(例如,卡波西氏肉瘤(例如,AIDS相关的卡波西氏肉瘤)、平滑肌肉瘤、血管肉瘤和组织细胞瘤)。
在示例性实施方式中,癌症是多发性骨髓瘤或实体瘤。在一种实施方式中,本发明的药物制剂包括作为略微水溶性治疗剂的卡非佐米。
在一个方面中,本公开描述了治疗对象例如人中与炎症相关的疾病或病症的方法,例如,过敏反应或自身免疫性疾病,所述方法包括:以有效治疗病症的量施用包含本发明药物制剂的组合物至对象,从而治与炎症相关的疗疾病或病症。
在一种实施方式中,与炎症相关的疾病或病症是本文所述的疾病或病症。例如,与炎症相关的疾病或病症可以是例如,多发性硬化、风湿性关节炎、银屑病关节炎、退行性关节疾病、spondouloarthropathies、痛风性关节炎、系统性红斑狼疮、幼年关节炎、风湿性关节炎、骨关节炎、骨质疏松症、糖尿病(例如,胰岛素依赖性糖尿病或幼年出现的糖尿病)、经期痉挛、囊性纤维化、炎性肠炎、过敏性肠综合症、克罗恩病、粘液性结肠炎、溃疡性结肠炎、胃炎、食管炎、胰腺炎、腹膜炎、阿尔茨海默氏疾病、休克、强直性脊柱炎、胃炎、结膜炎、胰腺炎(急性或慢性)、多器官损伤综合症(例如,败血症或创伤继发的)、心肌梗死、动脉粥样硬化、中风、再灌注损伤(例如,由于心肺转流术或肾透析)、急性肾小球性肾炎、血管炎、热损伤(即,晒伤)、坏死性小肠结肠炎、粒细胞输血相关的综合症、和/或斯耶格伦氏综合征。示例性皮肤炎症病况包括,例如,湿疹、遗传过敏性皮炎、接触性皮炎、荨麻疹、硬皮病、牛皮癣,和具有急性炎症组分的皮肤病。在一些实施方式中,自身免疫性疾病是器官-组织自身免疫性疾病(例如,Raynaud综合症)、硬皮病、重症肌无力、移植排斥、内毒素休克、脓毒、牛皮癣、湿疹、皮炎、多发性硬化、自身免疫甲状腺炎、葡萄膜炎、全身性红斑狼疮、阿狄森病、自身免疫性多腺疾病(也称为自身免疫多腺综合症),或Grave疾病。
在另一实施方式中,本发明的药物制剂或本文所述的方法可用于治疗或预防变态反应和呼吸病况,包括哮喘、支气管炎、肺的纤维化、过敏性鼻炎、氧毒性、气肿、慢性支气管炎、急性呼吸窘迫综合症,和任何慢性阻塞性肺部疾病(COPD)。本发明的药物制剂、颗粒或组合物可用于治疗慢性肝炎感染,包括乙型肝炎和丙型肝炎。
在一个方面中,本公开描绘了治疗对象例如人中心血管疾病例如心脏疾病的方法,所述方法包括以有效治疗病症的量施用本发明的药物制剂至对象,从而治疗心血管疾病。
在一种实施方式中,心血管疾病是本文所述的疾病或病症。例如,心血管疾病可以是心肌病或心肌炎;比如特发性心肌病,代谢心肌病,酒精性心肌病,药物诱导的心肌病,缺血性心肌病,和高血压心肌病。使用本发明的药物制剂,本文所述的颗粒、组合物和方法也可治疗或预防的是主要血管的动脉粥样硬化病症(大血管疾病)比如主动脉、冠状动脉、颈动脉、脑血管动脉、肾动脉、肠动脉、股动脉和腘动脉。可治疗或预防的其他血管疾病包括与下述相关的那些:血小板聚集、视网膜小动脉、小球小动脉、神经滋养血管、心脏小动脉和相关的眼睛的毛细管床、肾、心脏和中枢和周围神经系统。可用本发明的药物制剂治疗的仍其他病症包括再狭窄,例如,冠状动脉介入后,和与异常水平的高密度和低密度胆固醇相关病症。
在一种实施方式中,本发明的药物制剂可施用至正在经历或已经经历血管成形术的对象。在一种实施方式中,本发明的药物制剂、颗粒或组合物用施用至正在经历或已经经历具有支架植入的血管成形术的对象。在一些实施方式中,本发明的药物制剂、颗粒或组合物可用作支架的支柱或支架的涂层。
在一个方面中,本发明提供了治疗对象例如人中与肾相关的疾病或病症例如肾病症的方法,所述方法包括:以有效治疗病症的量施用本发明的药物制剂至对象,从而治疗与肾疾病相关的疾病或病症。
在一种实施方式中,与肾相关的疾病或病症是本文所述的疾病或病症。例如,与肾相关的疾病或病症可以是例如急性肾衰竭、急性肾综合症、镇痛药肾病、atheroembolic肾疾病、慢性肾衰竭、慢性肾炎、先天性肾病综合症、晚期肾疾病、肺出血肾炎综合征、间质性肾炎、肾损伤、肾感染、肾损伤、肾结石、狼疮肾炎、膜增生性GNI、膜增生性GNII、膜性肾病、微小病变、坏死性肾小球性肾炎、成肾细胞瘤、肾兮质沉着症、肾源性尿崩症、肾变性病(肾病综合症)、多囊性肾病,链球菌感染后肾小球肾炎、逆流肾病、肾动脉栓塞、肾动脉狭窄、肾乳头状坏死、I型肾管状酸中毒、II型肾管状酸中毒、肾灌注不足、肾静脉血栓形成。
在示例性实施方式中,本发明提供了治疗金属毒性或金属过载的方法。与金属相关的疾病或病症包括铁过载病症(例如,地中海贫血或镰刀细胞贫血)、铜过载病症(例如,Wilson疾病),和放射性同位素污染(例如,用钚、铀和其他放射性同位素污染之后发生的)。
“有效量”或“有效量的”指本发明的药物制剂当单个或多个剂量施用至对象时有效处理细胞或治愈、减轻、缓解或改善病症的症状的量。组合物的有效量可根据下述因素而改变:比如个体的疾病状态、年龄、性别和体重,和化合物在个体中引起期望应答的能力。有效量也是其中组合物的治疗有益的超过任何有毒或有害作用的量。
如本文所使用,术语“预防”或“预防的”,如在将试剂施用至对象的背景下使用,指使对象经历下述方案,例如,施用本发明的药物制剂使得相比在没有该方案的情况下,病症的至少一种症状的出现被延迟。
如本文所使用,术语“对象”旨在包括人和非人动物。示例性人对象包括具有病症,例如,本文所述病症的人患者,或正常对象。术语“非人动物”包括所有的脊椎动物,例如,非哺乳动物(比如鸡、两栖动物、爬行动物)和哺乳动物,比如非人灵长类、家养的和/或农业用途的动物,例如,绵羊、狗、猫、母牛、猪等。
如本文所使用,术语“治疗(treat)”或“治疗(treating)”具有病症的对象,指使对象进行方案,例如,施用本发明的药物制剂使得病症的至少一种症状被治愈、愈合、缓解、减缓、改变、补救、减轻或改善。治疗包括施用有效减轻、缓解、改变、补救、减轻、改善或影响病症或病症症状的量。治疗可抑制病症症状的劣化或恶化。
提供下述实施例,以阐释本发明的示例性实施方式并且不解释为限制本发明的范围。
实施例
实施例1
通过远程装载捕获的卡非佐米脂质体
材料和方法
通过将硫酸铵固体溶解至终浓度为250mM(500m当量的阴离子/L)制备硫酸铵溶液,不进行pH调节,以产生终pH为5.6。通过添加0.35g硫酸钠至10mL去离子水制备硫酸钠溶液(250mM)。
通过挤出形成脂质体。在65℃下脂质溶解在乙醇中,浓度为500mMHSPC(591mg/mL总脂质)并且加热至65℃的9体积的捕获试剂溶液添加至也在65℃的乙醇/脂质溶液。使混合物起漩涡并且转移至10mL恒温控制(65℃)Lipex挤出机。通过经具有0.1um孔的聚碳酸酯膜挤出10次形成脂质体。在挤出之后,脂质体在冰上冷却。通过在分子量截取为12,000-14,000的透析管道系统中透析纯化脂质体形成跨膜电化学梯度。用5mMHEPES,10%蔗糖pH6.5(在4℃下搅拌),以大于样品体积100倍体积透析样品。2h之后改变透析液,在每12h之后再4次。测量脂质体溶液的电导率并且不能与透析介质区分,~40μS/cm。
通过HPLC测量胆固醇而测量脂质浓度,使用Agilent1100HPLC用和AgilentZorbax5um,4.6x150mM,EclipseXDB-C8柱和流动相A=0.1%TFA,B=0.1%TFA/MeOH,无梯度洗脱为99%B。流速是1.0mL/min,柱温度是50℃,10μL注射和通过在205nm的吸光度检测。胆固醇的保留时间是4.5min。通过动态光散射测量脂质体尺寸。
卡非佐米(SelleckChemicals)溶解在DMSO中,浓度为10mg/mL。卡非佐米引入脂质体卡非佐米与HSPC比例为100g药物/molHSPC(药物与总脂质比例(wt/wt)为0.12)。用50mM柠檬酸盐、10%蔗糖pH4.0稀释脂质体,以增加体积至添加药物之后终DMSO浓度是2%的点。卡非佐米/DMSO添加至稀释的脂质体,其在室温下混合然后转移至65℃浴并且头3min每30s起漩涡并且然后在30min的总加热时间内每5min起漩涡。当添加药物时所有的样品非常浓,并且15min之后所有的都变透明(与没有药物添加的脂质体相同)。在加热30min之后,所有的样品放置在冰上15min。装载的脂质体起漩涡并且100μL的样品保持为“柱前”并且静置转移至微离心管并且在10,000RPM下旋转5min。在SephadexG25柱上纯化上清液,通过HPLC收集和分析。在如为分析胆固醇描述的相同的系统上进行卡非佐米的HPLC分析。流动相由A=0.1%TFA、B=0.1%TFA/MeOH组成,以50%B开始梯度洗脱并且在13min内增加至83%B,7min平衡回至50%B。流速是1.0mL/min,柱温度是30℃,10μl注射和通过在205nm的吸光度检测。卡非佐米的保留时间是12.2min。通过HPLC分析胆固醇测定脂质浓度。
结果
装载包含250mM硫酸铵的脂质体当以100g药物/mol的HSPC脂质添加药物(95.26±3.47%的效率)时,产生终药物与脂质比例为95.26±3.47g药物/mol的HSPC脂质体和当以200g药物/mol的HSPC脂质添加药物时(67.94±3.67%的效率)时,终药物与脂质比例为136.9±7.35g药物/mol的HSPC脂质体(图2)。这表明这些具体脂质体的装载容量在100和200g药物/mol磷脂之间。没有用于远程装载的电化学梯度的包含250mM硫酸钠的对照脂质体当以100和200g药物/mol的HSPC比例添加药物时分别产生的终药物装载为33.28±0.79和29.01±0.79g药物/mol的HSPC。这表明低于100g药物/mol的HSPC装载这些脂质体的容量是饱和的并且以该药物输入比例远程装载脂质体展示>3倍更高的装载容量。药物装载容量对于硫酸钠脂质体比硫酸铵脂质体的饱和至少3倍更低的比例,指示当远程装载没有电化学梯度时,药物分割进入脂质双层,但是不与内部捕获试剂形成盐。图5图解了在用硫酸钠脂质体的装载过程之后仍存在沉淀,但是用硫酸铵脂质体没有。
结论
具有相同脂质基质组成和尺寸,但是内部捕获的硫酸组成不同的脂质体盐的脂质体具有不同的装载卡非佐米容量。能够产生电化学梯度(硫酸铵)的脂质体在最佳条件下能够装载接近至100%的药物并且能够产生具有差装载效率的梯度,提示远程或主动装载是卡非佐米并入脂质体的主要机制。
实施例2
比较脂质体捕获试剂
介绍
在旨在作为盐复合装载药物的离子溶液中形成用于远程装载的脂质体。捕获试剂可与装载药物形成复合物并且该复合物的稳定性是指示脂质体药物装载能力、稳定性和药物释放速度的一个因素。通过评估卡非佐米装载的效率进行比较不同的脂质体捕获试剂。
方法
使用三个脂质体制剂,所有的摩尔比3HSPC/2Chol/0.15PEG-DSPE,每个具有不同的捕获试剂:1.苯六酸;2.硫酸铵;和3.萘二磺酸。
苯六酸(MA)溶解在水中并且用二乙胺滴定至终pH为5.5和浓度为83mM(500m当量的阴离子/L)。通过将硫酸铵固体溶解至终浓度为250mM(500m当量的阴离子/L)制备硫酸铵,不进行pH调节,以产生终pH为5.6。
萘二磺酸(NDS)溶解在水中并且用二乙胺滴定至终pH为8.0和浓度为250mM(500m当量的阴离子/L)。
如何制备、纯化和表征脂质体的细节见实施例1,通过远程装载捕获卡非佐米脂质体。
为了保完全去除与卡非佐米一起添加的DMSO,在分子量截取为12,000-14,000的透析管道系统中透析脂质体卡非佐米样品。用5mMHEPES,10%蔗糖pH6.5(在4℃下搅拌),以大于样品体积100倍体积透析样品。2h之后改变透析液,然后在12h之后每次另外2次。再次如上述分析药物和脂质浓度的卡非佐米脂质体。
结果
对于捕获试剂为苯六酸、硫酸铵和萘二磺酸的脂质体,卡非佐米以100g药物/mol的HSPC脂质远程装载至脂质体的效率分别为37.4%±2.01%、97.0%±2.38%和95.1%±1.76%(图3)。
结论
本文描述的发明确保可用包括苯六酸、硫酸铵和萘二磺酸的各种捕获试剂产生的各种使用电化学梯度实现来自不溶解沉淀的卡非佐米远程装载至脂质。
实施例3
比较引入药物的方法
方法
比较装载程序期间用于添加药物至脂质体的方法。装载程序如上面实施例1描述的相同,不同之处是药物作为固体粉末添加至脂质体装载溶液,作为10mg/mLDMSO溶液快速和作为10mg/mLDMSO溶液缓慢。
结果
对于作为固体粉末添加的药物,卡非佐米以100g药物/mol的HSPC脂质远程装载至脂质体的效率当加热至65℃30和120min时分别是3.88%±0.053%和3.47%±0.030%。当快速添加药物/DMSO时,作为10mg/mLDMSO溶液的装载药物的效率是97.0%±2.38%和当药物/DMSO在1min内以5个递增添加至脂质体溶液同时起涡流时是96.3%±1.09%。来自缓慢药物添加的药物/脂质体混合物比源自快速添加药物的药物/脂质体混合物更清澈。但是,在加热至65℃,30min之后,两个溶液都没有可见的沉淀(或以10,000rpm,5min的离心沉淀),其是由于所有的药物装载至脂质体,无论当添加药物时是否形成沉淀(图4)。
实施例4
在室温下卡非佐米装载至脂质体
介绍
在室温下将药物装载至脂质体的能力有利于降低热诱导的药物降解,简单地制造和允许床边脂质体装载。有效的运输横跨脂质体膜要求膜为流动相。这通过在装载过程期间将脂质体加热高于Tm,用具有高相变温度(Tm)的饱和的磷脂,比如HSPC(Tm=55℃)实现。加热的可选方式是使用在室温下为流动相的脂质。这些脂质的劣势是它们在循环中不稳定并且产生快速药物释放。固醇改性的脂质并入新的脂质构建,其中胆固醇(甾醇)共价连接至磷酸头基。已经证明了固醇改性的脂质使得甾醇在循环中与脂质双层不可交换的。固醇改性的脂质在室温下也是流动相,使得它们对于室温装载药物至待用于体内递送疗法的脂质体是理想的。
方法
通过使用两个脂质体制剂进行在室温下装载卡非佐米至脂质体,所述脂质体制剂由摩尔比95PChemsPC/5PEG-DSPE的和另一摩尔比3POPC/2Chol/0.15PEG-DSPE的组成,每个包含250mM硫酸铵作为捕获试剂。使用如实施例1中描述的程序、药物/脂质体比例、pH下的缓冲液制备脂质体。在室温下(20℃)搅拌脂质体并且卡非佐米作为10mg/mLDMSO溶液在1min内5个递增添加,以产生浑浊溶液。在室温下搅拌脂质体/药物混合物总共30min,以产生透明溶液,相同外观如添加药物之前的脂质体溶液。
结果
以100g药物/mol的PChemsPC,卡非佐米远程装载至脂质体的效率是95.5%±1.23%。以187g药物/mol的3POPC/2Chol/0.15PEG-DSPE,卡非佐米远程装载至脂质体的效率是100.52%±1.01%。
结论
本文描述的发明,不能通过直接将结晶形式的药物添加至装载溶液,将卡非佐米装载至脂质体。药物需要溶解在一些溶剂中,然后以高于药物溶解度的浓度添加至装载溶液。当将药物添加至装载溶液时形成的沉淀的脂质体装载效率不依赖于在该情况下使用卡非佐米的添加。
实施例5
药物沉淀装载至脂质体,如通过在600nm的光散射测定。
介绍
脂质体装载来自沉淀的药物至脂质体的证据是所得药物与脂质比例和随着药物沉淀转移至脂质体,溶液的清澈。为了获得从药物沉淀的定量测量脂质体装载,在装载过程期间,在600nm下测量光散射。
方法
脂质体包含250mM硫酸铵作为捕获试剂和250mM硫酸钠作为不远程装载药物的对照脂质体。制备脂质体不去使用实施例1中描述的程序装载,不同之处是一次性聚苯乙烯试管用作反应容器。用UV/vis分光光度计在装载过程期间测量在600nm处的光散射。
结果/结论
硫酸钠脂质体在装载程序期间不显示沉淀的任何澄清,指示药物不远程装载至脂质体。(见图5)。硫酸铵脂质体有效装载药物,在15min内使得溶液澄清。
实施例6
确认从远程装载脂质体的药物释放
介绍
反相梯度用于尝试从脂质体中释放活性药物。理论是如果药物可从脂质体内以反相梯度释放,体内发生药物释放的概率高。
方法
如在实施例1中描述描述用卡非佐米装载脂质体并且纯化至去离子水。样品分成两个等分试样。向第一等分试样,添加浓缩的HepespH7.4和NaCl,从而终浓度是5mMHepes、145mMNaCl(HBS)。向第二等分试样,添加浓缩的硫酸铵,从而终浓度是250mM。没有初始观察到明显的物理改变。然后在65℃下加热样品30min。将样品转移至清洁eppendorf管并且10,000rpm离心5min,其后分开上清液和沉淀并且通过HPLC试验测试卡非佐米含量。释放药物的沉淀,残留在上清液中封装药物的脂质体。如下计算释放的%卡非佐米:
结果
溶液组合物 | %释放的卡非佐米 |
Hepes缓冲生理盐水 | 10.6±0.28 |
硫酸铵 | 68.5±1.82 |
表2.从脂质体的反相梯度引导的药物释放
使用反相梯度的药物释放比从没有反相梯度对照的药物释放大6.5倍(表2)。释放药物的HPLC色谱图与开始材料相同,指示没有发生卡非佐米的降解(图7)。卡非佐米的原料液的HPLC保留时间是12.2min和从远程装载脂质体释放的卡非佐米的保留时间是12.3min,如图6中显示。这些两个分离时间在HPLC系统的变型内并且彼此不是统计上不同的。
结论
使用反相梯度从脂质体释放卡非佐米,以产生如HPLC分析指示的初始分子。
实施例7
作为DMSO含量的函数的卡非佐米装载
介绍
当添加至脂质体时,药物的物理形式对于装载效率是重要的,即,当作为干燥粉末添加时,几乎没有观察到装载,但是使用非质子溶剂中的预溶解的溶液添加可导致高的捕获效率。该研究研究非质子溶剂浓度对卡非佐米的药物装载效率的作用。
方法
包含硫酸铵的脂质体稀释在50mM柠檬酸蔗糖(10%wt/wt)缓冲液pH4.0至1mM磷脂。添加各种量的DMSO,从而当从10mg/mLDMSO的卡非佐米溶液添加200μg药物时,终DMSO浓度范围是1-10%v/v。
结果
DMSO对卡非佐米远程装载至脂质体的能力具有显著影响。当缺少时,实际上无装载。在浓度1%和之上,装载效率范围是74-94%,在更高的DMSO浓度下观察到更高的效率(图7)。应当注意,在所有样品中在开始装载之前观察到药物沉淀,提示本文使用的DMSO的浓度小于以使用的药物浓度(0.2mg/mL)有效溶解卡非佐米需要的最小浓度。
结论
引入预溶解的卡非佐米对于有效的远程装载是必要的。但是,高于1%DMSO,存在装载效率相对小的改变,多达10%。
实施例8
作为DMSO含量的函数的卡非佐米溶解度
介绍
在上述条件下,卡非佐米溶解在DMSO中,然后稀释在脂质体缓冲液溶液然后装载。其然后就在远程装载之前沉淀。该研究设计为在室温下和在脂质体装载至由高Tm脂质(65℃)组成的脂质体需要的温度下测定有效溶解卡非佐米的DMSO浓度。
方法
卡非佐米从DMSO中的原料10mg/mL溶液添加至1ml的柠檬酸/DMSO混合物,从而DMSO的组分是2%、25%、50%、75%和100%。终药物浓度是0.2mg/mL。制备溶液并且测量600nm处的光密度。600nm处的光密度是溶液中多少浑浊或多少散射材料(比如药物沉淀)的良好测量,一般而言,沉淀越多,吸光度越高。从图8,明显的是在小于50%vol/vol(25℃)和25%vol/vol(65℃)的DMSO浓度下,药物以沉淀形式残留。仅仅当DMSO的浓度增加时,其的确在0.2mg/mL的浓度下有效溶解。
为了测试25%DMSO中脂质体的完整性,我们尝试远程装载水溶性弱碱药物多柔比星和17-二甲基氨基乙基氨基-17-脱甲氧格尔德霉素(17-DMAG)并且比较没有DMSO的相同装载。我们发现不利影响装载效率(表3)。
结果
在0.2mg/mL卡非佐米下,药物沉淀和聚集足够大产生在600nm处的光散射信号。随着%DMSO增加,信号降低并且指示药物的溶解。我们观察到>25%vol/volDMSO对于以0.2mg/mL在65℃温度下完全溶解药物是必要的。
药物 | %DMSO | %与没有DMSO的对照相比的效率 |
阿霉素 | 25 | 92.7±0.43 |
17-DMAG | 25 | 73.1±1.4 |
表3.比较在存在和没有25%DMSO的情况下,远程装载阿霉素和17-DMAG至含硫酸铵的脂质体。
结论
使用10%v/v或更低的DMSO进行之前的研究装载卡非佐米,并且上面的光散射结果显示大部分药物在这些条件下是使用浓度的沉淀形式。添加足够非质子溶剂至完全溶解的药物(即大于25%DMSO,在65℃下)对于两性的弱碱药物的脂质体装载具有不利影响,指示由例如内容物渗漏或电化学梯度消失造成的脂质体不稳定。在维持好的脂质体稳定性的条件下,我们没有发现完全溶解卡非佐米的DMSO浓度或可选地我们没有发现药物完全溶解并且同时脂质体未不利不稳定的使用DMSO的条件。
实施例9
在形成药物沉淀之后,对卡非佐米的脂质体装载的延迟影响
介绍
该该申请中描述的发明允许不溶解的药物沉淀装载至脂质体。实施例9评估了药物沉淀的形成时间和起装载至脂质体时间的作用。
程序
由实施例1中描述的相同组合物和方法制备脂质体。
卡非佐米溶解在DMSO,浓度为10mg/mL并且我们添加至2%(v/v)的终浓度至50mM柠檬酸盐,10%蔗糖,pH3.5,不包含脂质体。当添加药物至柠檬酸盐缓冲液时,形成沉淀。在形成之后立即,1h延迟之后或12h延迟之后,将用于装载的脂质体添加至包含药物沉淀的溶液,并且然后将沉淀使用实施例1中描述的装载条件装载至脂质体。
结果/结论
形成药物沉淀的之间和装载沉淀的时间对卡非佐米的脂质体装载程序的效率没有明显影响,即使如果延迟时间多达12h。
实施例10
脂质体药物载荷对卡非佐米从沉淀装载的效率的影响
程序
由如比较捕获试剂中描述相同的组合物和方法制备脂质体,不同之处是捕获试剂内部硫酸铵的浓度是250mM或500mM。
卡非佐米溶解在DMSO中,浓度为10mg/mL。卡非佐米引入脂质体,对于250mM硫酸铵作为捕获试剂的脂质体,卡非佐米与HSPC比例为91.8、167、251、338和433g药物/molHSPC和对于500mM硫酸铵作为捕获试剂的脂质体,卡非佐米与HSPC比例未451、546、639和759g药物/molHSPC。用50mM柠檬酸盐、10%蔗糖pH4.0稀释脂质体以使体积增加至添加药物之后,终DMSO浓度是10%的点。卡非佐米/DMSO添加至稀释的脂质体,其在室温下混合,然后转移至65℃浴并且对于头3min每30s起漩涡,并且然后对于30min的总加热时间每5min起漩涡。当添加药物时,所有的样品非常浑浊并且在15min之后都变清澈(与没有添加药物的脂质体相同)。在加热30min之后,所有的样品放置在冰上15min。如实施例1中描述纯化和分析装载的脂质体。
结果/结论
随着装载溶液中药物与脂质体输入脂质比例增加,所得药物载荷增加。在用于每个不同浓度的硫酸铵捕获试剂的最低输入比例下,效率最大。使用该实施例中描述的条件,卡非佐米可从不溶解的沉淀装载至脂质体至终药物载荷为469±4.9g药物/molHSPC(药物/载体总脂质重量比为0.4),效率为61.7±1.2%。
实施例11
使用三乙基硫酸铵梯度,将不溶解的卡非佐米装载至脂质体
介绍
通常使用硫酸铵梯度实现远程装载药物至脂质体。包括使用本文的例子卡非佐米的一些药物分子具有环氧化物基团,其对于活性是必要的。这些药物的环氧化物潜在地经受从用于硫酸铵远程装载的任何残留氨氨解。在该实施例11中,硫酸铵用三乙基硫酸铵远程装载剂替换,以通过用非活性三乙胺置换来消除潜在的氨/环氧化物反应。
方法
通过使用如用远程装载卡非佐米脂质体捕获中描述的相同组合物和程序制备脂质体,不同之处是50mM三乙基硫酸铵用作捕获试剂。通过用三乙胺滴定1M硫酸至终pH为7.3和硫酸浓度为500mM制备三乙基硫酸铵。
卡非佐米溶解在DMSO中,浓度为10mg/mL。卡非佐米引入脂质体,卡非佐米与HSPC比例为650g药物/molHSPC。用50mM柠檬酸盐、10%蔗糖pH4.0稀释脂质体,以使体积增加至在添加药物之后终DMSO浓度是10%的点。卡非佐米/DMSO添加至稀释的脂质体,起在室温下混合,然后转移至65℃浴并且头3min每30s起漩涡并且然后每5min起漩涡。在装载程序期间10、20、30和40min去除装载混合物的样品并且放置在冰上15min。使装载脂质体起漩涡并且100μL的样品保持为“柱前”并且静置转移至微离心管并且在10,000RPM下旋转5min。在SephadexG25柱上纯化上清液,通过HPLC收集和分析。药物沉淀小球溶解在DMSO/MeOH(10:1)中并且通过HPLC分析。
结果/结论
使用三乙基硫酸铵梯度将不溶解的卡非佐米沉淀装载至脂质体,产生与使用硫酸铵梯度产生的那些类似的脂质体(实施例1)。图12图解了对于到10min快速开始的脂质体装载的时间依赖性。在30min实现了最大载荷是440±12.6g药物/molHSPC(效率为65.9±1.98%)。使用500mM三乙胺作为捕获试剂,药物与HSPC比例为650g药物/molHSPC的该结果与使用500mM硫酸铵作为捕获试剂的非常类似,药物与HSPC比例为639g药物/molHSPC,其产生的终药物与脂质比例为440±10.2g药物/molHSPC(效率为68.7±4.80%)。
脂质体外部上不溶解的药物沉淀转移(远程装载)至脂质体内部,如在装载过程期间混合物中的沉淀量降低所指示。图12显示脂质体外沉淀最大的减少发生在0-10min之间,其对应如图13中可见的将沉淀装载至脂质体。
实施例12
从沉淀装载另一微溶性药物
介绍
另一药物,阿立哌唑由磺丁基环糊精(SBCD)配制并且用于治疗双极性病症和精神分裂症(Abilify,Pfizer)。药物非常不溶于水并且当添加至脂质体悬液时,立即观察到精细沉淀。
测试阿立哌唑是否在上面为卡非佐米阐释的类似条件下远程装载。
方法
将包含250mM硫酸铵或250mM硫酸钠的脂质体(HSPC/Chol/PEG-DSPE3/2/0.15mol/mol/mol)稀释在1ml的50mM柠檬酸、10%(wt/wt)蔗糖,pH4.0至浓度为6mM磷脂。从DMSO中15mg/mL的原料液添加0.3mg的阿立哌唑,从而终DMSO浓度是2%(v/v)。在药物添加至两个脂质体样品之后,立即观察到精细沉淀。样品在65℃下加热30min,然后在冰上冷却。通过0.2um聚醚砜注射器过滤器过滤样品,以去除任何药物沉淀,随后在pH6.5的HBS平衡的SephadexG25柱上纯化至去除任何可溶性超脂质体药物。如上述收集和分析脂质和药物的浑浊部分。
结果
表5.将阿立哌唑装载至包含硫酸铵和硫酸钠的脂质体的结果。
发现包含硫酸铵的脂质体装载约85%的药物,而装载至硫酸钠脂质体小于2%,硫酸铵脂质体可获得的能力装载约50倍增加,以利于远程装载(表5)。
阿立哌唑,当以SBCD复合物(来自药学产品Abilify)形式引入脂质体溶液时,在相同浓度和装载条件下产生的装载效率为68%(图14)。
结论
这是可使用上述方法将差的可溶性药物远程装载至脂质体的另一实施例,并且比如果药物作为SBDC复合物引入,产生稍微更好的装载。
实施例13
通过将来自稀释各种药物溶剂溶液制备的沉淀的微溶性药物装载至脂质体溶液
该实施例描述了不良可溶性药物远程装载至脂质体的技术,其开始将药物溶解在起初当添加至脂质体的水溶液时形成药物沉淀的增溶剂。在一些温育时间响应电化学梯度药物进入脂质体积聚在脂质体核心中。可使用的溶剂包括但不限于二甲亚砜、二噁烷、四氢呋喃、二甲基甲酰胺、乙腈、乙酰二甲胺、环丁砜、γ丁内酯、吡咯烷酮、1-甲基-2-吡咯烷酮、甲基吡咯啉、乙二醇一甲基醚、二甘醇一甲基醚、聚乙二醇。
方法
阿立哌唑溶解在一系列溶剂中,指示低于4mg/mL。使用由在250mM硫酸铵中制备的HSPC/Chol/PEG-DSPE(3/2/0.15mol/mol/mol)组成的脂质体并且在Hepes缓冲的蔗糖10%(wt/wt)(HBSucpH6.5)中稀释至6mM。通过缓慢添加每种溶剂同时起涡流,引入0.3mg的药物。对于所有样品,终溶剂浓度是7.5%。作为对照,从每个溶剂将药物添加至相同体积的没有脂质体的pH6.5的HBSuc。样品在65℃下加热30min,然后在冰上冷却。在再次达到室温之后,测量样品在600nm处的吸光度(Cary100BioUV-Vis分光计)并且值显示在下方(图15)。
结果
所有没有脂质体的溶液变得非常浑浊或有粗糙的沉淀和沉降(尤其在甲醇和1-丁醇的情况下)。一些脂质体样品也非常浑浊,但是一些澄清药物沉淀与之前的结果一致,指示已经发生了药物沉淀的药物装载(即在药物初始溶解在DMSO、1-4-甲基吡咯烷酮、二亚乙基单乙醚或聚乙二醇(MW400)的情况,见图15。
实施例14
使用乙酸盐梯度将地拉罗司的不溶解沉淀远程装载至脂质体
将地拉罗司远程装载至包含乙酸钙的脂质体表明乙酸盐梯度对于装载铁螯合剂的用途。乙酸钙梯度远程装载与硫酸铵远程装载的不同在于装载的药物分子必须具有羧酸(或异羟肟酸)而不是胺。已知地拉罗司具有显著的肾毒性并且脂质体递送是用于减轻肾毒性的技术。
方法
以如Clerc和Barenholtz1995(PMID8541297)的乙酸盐装载可溶性羧基荧光素和萘啶酸的相同方式使用乙酸盐梯度进行远程装载地拉罗司不溶解的沉淀至脂质体。如实施例1中描述制备脂质体,但是在该情况下在pH8的120mM乙酸钙的溶液中挤出脂质体。通过外部介质替换为pH6.0的120mM硫酸钠形成乙酸盐梯度。地拉罗司溶解在DMSO中,浓度为10mg/ml并且添加至其形成沉淀的脂质体悬浮。通过加热至65℃,1h使装载至脂质体沉淀并且如实施例1中描述进行纯化和分析。
结果
当从10mg/mlDMSO原料液稀释至脂质体装载悬液中1mg/ml的浓度时,由于其差的水溶解度(~0.038mg/mL),地拉罗司形成沉淀。使用乙酸钙梯度,以大于其装载至包含硫酸钠和没有乙酸盐梯度的对照脂质体的至少5倍的效率将不溶解的地拉罗司沉淀装载至脂质体。
将不溶解的地拉罗司沉淀远程装载至脂质体提供了乙酸盐梯度从沉淀远程装载羧酸药物的用途的例子。在该例子中,装载的药物是螯合剂,尤其是铁螯合剂。相对对照脂质体,5倍更大装载至具有乙酸盐梯度的脂质体指示大部分地拉罗司被远程装载而不是插入脂质双层中。
实施例15
介绍
卡非佐米的脂质体递送的一个目标是避免药物降解和消除,其要求药物保留在脂质体中。评估药物在脂质体内驻留的一个技术,和因此从脂质体递送获得的好处是测量小鼠中药物的药物动力学。在脂质体中具有更大药物驻留的稳定制剂在小鼠血浆中相比较不稳定的制剂或未封装的药物,产生较高浓度的非代谢药物。
材料和方法
形成100nm由HSPC/胆固醇/PEG-DSPE(60/40/5mol/mol/mol)和鞘磷脂/胆固醇/PEG-DSPE(55/45/2.8,mol/mol/mol)组成的脂质体,使用实施例1中描述的方法纯化和药物装载卡非佐米。用于远程装载卡非佐米的捕获试剂是三乙基葡聚糖硫酸铵(1.0MSO4)或三乙基蔗糖八硫酸铵(1.0MSO4)。通过正切流过滤,用缓冲液替换成pH6.5的HBS,纯化药物装载脂质体。通过0.2um聚醚砜过滤器无菌过滤脂质体并且如实施例1中描述评估卡非佐米和脂质含量。计算药物与脂质比例、药物浓度和装载效率并且结果显示在表6中。
结果
表6.IV.施用脂质体制剂之后,小鼠血浆中的卡非佐米浓度。
制剂#3与#2相同,不同之处是储存在4℃下30天,然后PK分析
另外,我们检查了封装在脂质体制剂中的卡非佐米在雄性CD1小鼠中的药物动力学。经尾静脉以5mg/kg卡非佐米使用3小鼠/制剂,通过IV弹丸注射对小鼠给药。在4h,处死小鼠并且通过离心血液收获血浆。0.1ml的血浆混合0.2mL甲醇,充分混合并且通过HPLC如实施例1中描述测量卡非佐米浓度。装载效率、药物/脂质比例和尾静脉注射脂质体卡非佐米之后4小时之后血浆中残留的注射剂量的百分数(%ID4h)显示在表6中。尽管不尝试区分血浆中非脂质体捕获的和脂质体捕获的药物,如我们的分析测量总的药物含量,我们假设大部分测量的卡非佐米是脂质体捕获的,因为药物在血流中非常快速地消除(t1/2<20min)(Yang等2011,DrugMetabDispos.2011Oct;39(10):1873-82)。我们观察了100倍范围药物驻留从0.65%至66.3%ID,这取决于脂质体制剂组成。测试的最稳定的脂质体是基于鞘磷脂的并且包含内部葡聚糖硫酸铵溶液。上述脂质体使卡非佐米的血浆驻留在施用后4h增加46至4735倍大于SBCD制剂,或5至510倍大于公开的脂质体制剂。(Chu等2012AAPSMeeting,PosterT2082)。
实施例16
使用乙酸盐梯度远程装载不溶解的地拉罗司沉淀至脂质体
介绍
远程装载地拉罗司(DFX)至包含乙酸钙的脂质体表明乙酸盐梯度用于装载铁螯合剂的用途。乙酸钙梯度远程装载与硫酸铵远程装载的不同在于装载的药物分子必须具有羧酸(或异羟肟酸)而不是胺。已知地拉罗司具有明显的肾毒性并且脂质体递送是降低肾毒性的技术。
方法
使用实施例1中描述的挤出和纯化方法制备脂质体。脂质组分是HSPC/胆固醇(3/0.5,mol/mol)或POPC/胆固醇(3/0.5,mol/mol)。捕获试剂由每个浓度为120mM的乙酸钙或硫酸钠组成。DMSO中20mg/mL的DFX溶液在30秒内缓慢添加至脂质体溶液,同时起涡流,以在脂质体溶液中产生药物沉淀。靶药物与磷脂比例是100gDFX/mol磷脂。溶液加热30min(POPC脂质体在45℃下和HSPC脂质体在65℃下)并且然后在冰上冷却。去除样品,以测定输入药物与脂质比例和在离心机中以12,000RPM离心残留的溶液5分钟,使任何未装载的药物成为小球。使用SephadexG25尺寸排除柱,5mMHEPES,145mMNaCl,pH6.5洗脱进一步从未装载的药物纯化上清液。通过HPLC使用实施例1中描述的系统和下述程序分析纯化的脂质体的药物和脂质含量,所述程序由下述组成:6min中65%B至98%B的梯度洗脱,5min平衡回到65%B(A=0.1%TFA,B=0.1%TFA/MeOH,1.0mL/min),柱温度保持恒定在30℃,10ul注射,和通过在254nm处的吸光度检测。
结果
当将DMSO中的药物添加至包含乙酸钙作为捕获试剂的脂质体时,POPC脂质体的溶液较在装载之前都包含沉淀药物的HSPC脂质体的溶液不浑浊。加热之后,溶液澄清并且外观如没有药物沉淀的脂质体。包含硫酸钠作为对照捕获试剂的脂质体在加热期间从不澄清并且当离心时形成药物沉淀小球。装载由POPC和HSPC制备的包含乙酸钙的脂质体非常有效。包含捕获乙酸钙的脂质体产生>90%的装载效率。包含硫酸钠的脂质体产生3.3%的装载效率,其指示DFX装载至乙酸钙脂质体不是被动的而是可描述为远程装载。DFX装载结果显示在表7中(图16)。
表7.乙酸钙脂质体2中的DFX的装载效率
结论
远程装载地拉罗司的不溶解沉淀至脂质体提供了乙酸盐梯度从沉淀远程装载羧酸药物用途的例子。在该例子中,装载的药物是螯合剂,尤其是铁螯合剂。相比对照脂质体28倍更大的装载至具有乙酸盐梯度的脂质体,指示大部分地拉罗司被远程装载而不是插入脂质双层中。
实施例17
远程装载地拉罗司不溶解的沉淀至脂质体。评估药物与脂质比例和乙酸钙捕获试剂浓度。
介绍
通过使用脂质体内部上不同浓度的乙酸钙和不同DFX与脂质比例范围的装载,评估包含乙酸钙的脂质体中DFX远程装载容量。
方法
使用实施例1中描述的挤出和纯化方法制备脂质体。脂质组分是POPC/胆固醇(3/0.5,mol/mol)。捕获试剂由乙酸钙120mM、250mM或500mM组成。将DMSO中20mg/mL的DFX溶液在30秒内缓慢添加至脂质体溶液,同时起涡流,以在脂质体溶液中产生药物沉淀。靶药物与磷脂比例是100、200或300gDFX/mol磷脂。溶液在45℃下加热30min并且然后在冰上冷却。去除样品,以测定输入药物与脂质比例,以残留溶液在离心机中以12,000RPM离心5分钟,以使任何未装载的药物成小球。从未装载的药物使用SephadexG25尺寸排除柱,用5mMHEPES、145mMNaCl在pH6.5下洗脱进一步纯化上清液。通过HPLC如实施例16中描述分析纯化的脂质体的药物和脂质含量。
结果
当将DMSO中的药物添加至包含乙酸钙作为捕获试剂的脂质体时,DFX在装载之前形成沉淀。加热之后,溶液澄清并且看上去如没有药物沉淀的脂质体。最大药物装载相比120mM乙酸钙高于包含250和500mM乙酸钙的脂质体。以200gDFX/mol磷脂的输入,对于包含250mM乙酸钙或500mM乙酸钙的脂质体实现最大药物装载和效率。对于100gDFX/mol磷脂靶的装载效率范围对于所有三个浓度的内部乙酸钙是99.2至103%。当靶药物装载增加至200gDFX/mol磷脂时,具有250或500mM内部乙酸钙的脂质体的效率是至少两倍大于具有120mM内部乙酸钙浓度的脂质体。三个脂质体的容量在300gDFX/mol磷脂的输入时过度,产生<24%的效率。结果显示在图17中。
结论
当远程装载至脂质体时,通过增加脂质体内侧捕获试剂的浓度可大大增加DFX的药物载荷容量。该例子表明装载容量依赖于乙酸钙捕获试剂浓度。该例子也表明DFX脂质体装载可具有其中效率和药物装载都最大的最佳药物与脂质比例。实现的药物与脂质比例允许DFX使用耐受剂量的脂质施用至动物。
实施例18
远程装载地拉罗司不溶解的沉淀至脂质体。评估捕获试剂。
通过用在内部上不同的捕获试剂和一系列不同DFX与脂质比例的装载制备脂质体来评估DFX在包含乙酸钙、乙酸镁和乙酸锌的脂质体中的远程装载容量。
方法
使用实施例1中描述的挤出和纯化方法制备脂质体。脂质组分是POPC/胆固醇(3/0.5,mol/mol)。捕获试剂由120mM的乙酸钙、乙酸镁或乙酸锌组成。在30秒内缓慢将DMSO中20mg/mL的DFX溶液添加至脂质体溶液,同时起涡流,以在脂质体溶液中产生药物沉淀。靶药物与磷脂比例是100、150或200gDFX/mol磷脂。溶液在45℃下加热30min并且然后在冰上冷却。去除样品,以测定输入药物与脂质比例并且残留的溶液在离心机中以12,000RPM离心5分钟,以使任何未装载的药物成小球。使用SephadexG25尺寸排除柱,用5mMHEPES,145mMNaCl在pH6.5下洗脱,从未装载的药物进一步纯化上清液。通过HPLC如实施例16中描述分析纯化的脂质体的药物和脂质含量。
结果
当将DMSO中的药物添加至脂质体时,在装载之前DFX形成沉淀。加热之后,包含具有乙酸钙和乙酸镁的脂质体的溶液比包含乙酸锌作为捕获试剂的脂质体变得更不浑浊。对于包含镁的脂质体,最大药物装载最高,对于包含乙酸钙的脂质体第二高,和包含乙酸锌的脂质体产生最低的药物载荷。对于100gDFX/mol磷脂的靶使用乙酸锌的装载效率是5.3±0.07%,而使用乙酸钙和或乙酸镁的效率分别是97.6±0.41%和99.2±2.42%。结果显示在图18中。
结论
当远程装载至脂质体时,DFX的药物载荷容量可取决于用于远程装载的乙酸盐的具体金属盐。该例子表明了乙酸镁相比乙酸钙或乙酸锌是对于DFX更好的捕获试剂,并且二者都是比乙酸锌远远更优的捕获试剂。
实施例19
介绍
装载试剂和脂质体组合物影响可如何有效制备包含卡非佐米的脂质体制剂和脂质体的体内药物代谢动力学特性。
材料和方法
形成由HSPC/胆固醇/PEG-DSPE(60/40/5mol/mol/mol)和鞘磷脂/胆固醇/PEG-DSPE(55/45/2.8,mol/mol/mol)组成的100nm脂质体,纯化并且用卡非佐米使用实施例1中描述的方法药物装载。用于远程装载卡非佐米的捕获试剂是0.65M柠檬酸、0.65三乙基柠檬酸铵、0.33M三乙基苯六酸乙酸铵和三乙基萘硫酸氢铵(1.0MSO4)。通过用缓冲液替换成HBS,pH6.5透析纯化装载药物的脂质体。通过0.2um聚醚砜过滤器无菌过滤脂质体并且如实施例1中描述评估卡非佐米和脂质含量。计算药物与脂质比例、装载效率和尾注射至小鼠之后4h血浆中残留的注射剂量的百分数(%ID4h)并且结果显示在表8中。
结果
N.D.=因为样品聚集,未进行
表8.卡非佐米脂质体装载结果和IV施用脂质体制剂之后小鼠血浆中浓度。
当将DMSO中的药物添加至脂质体时,在装载之前卡非佐米形成沉淀。在加热之后,表8中的制剂1-3显示浑浊的增加,由于远程装载混合物中大的聚集,其不允许脂质体的纯化。表8的制剂4在加热之后变得较不浑浊并且产生的装载效率为85.7±4.67%。评估表8的制剂4在小鼠中IV注射之后在血浆中的药物驻留。注射后四小时,血浆中没有可检测的卡非佐米出现。这与表6中的结果相反,表6中所有四个制剂在注射后四小时在血浆中具有可测量的和大量的卡非佐米。
结论
从表6和8中的数据观察,清楚地脂质体制剂对于小鼠中静脉内注射之后卡非佐米在血浆中驻留的优化需要:精确控制脂质体组分和封装适当的远程装载剂。基于广泛使用的FDA批准的产品的制剂不如SM/Chol/PEG-DSPE(55/45/2.8)的最佳脂质组分。封装葡聚糖硫酸的胺盐。
为了阐释和描述的目的,已经呈现了本发明具体实施方式的前述说明。它们不旨在是穷举的或讲本发明限于公开的具体形式,并且显而易见,在上述教导下,许多修饰和变型是可能的。选择和描述实施方式,以便最佳阐释本发明的原理和其实际应用,从而使得本领域技术人员最佳使用本发明和具有各种修饰的各种实施方式适合考虑的具体用途。期望本发明的范围由所附的权利要求和它们的等同物限定。
为了所有的目的,本文引用的所有的公开、专利和专利申请通过引用以它们的整体并入。
Claims (17)
1.药物制剂,其包含封装在脂质体中的略微水溶性试剂,所述制剂通过包括下述的方法制造:
在适于将所述略微水溶性试剂封装在所述脂质体的条件下,使所述脂质体的水悬液接触所述试剂的所述水悬液,其中
所述脂质体具有脂质膜封装的内部水性环境并且所述脂质体的所述水悬液包括横跨所述膜的选自质子梯度、离子梯度和其组合的梯度,并且其中
所述条件适于所述略微水溶性试剂穿过所述膜并且在所述内部水性环境中浓缩,从而形成所述药物制剂。
2.根据权利要求1所述的药物制剂,其中所述略微水溶性试剂的所述水悬液通过包括下述的方法制备:
将所述试剂基本上完全溶解在非质子溶剂中,形成试剂溶液和随后使所述试剂溶液接触所述脂质体的所述水悬液,使得稀释所述非质子溶剂,降低所述试剂的溶解度,从而形成所述略微水溶性试剂的所述水悬液。
3.任一项前述权利要求所述的药物制剂,其中所述脂质体选自多层膜泡(MLV)、大单层膜泡(LUV)和小单层膜泡(SUV)、寡层状膜泡(OLV)、疏层膜泡(PLV)或反相蒸发膜泡(REV)。
4.任一项前述权利要求所述的药物制剂,其中所述试剂是低分子量治疗剂,其水溶解度小于或等于约2mg/mL。
5.前述权利要求任一项所述的药物制剂,其中,所述试剂选自蒽环类化合物、喜树碱化合物、长春花生物碱、玫瑰树碱化合物、紫杉烷化合物、曼青霉素化合物、格尔德霉素化合物、吡唑并嘧啶化合物、甾族化合物、基于肽的化合物、任何前述的衍生物、任何前述的前药,和任何前述的类似物。
6.根据任一项权利要求所述的药物制剂,其中所述试剂选自卡非佐米、伏立康唑、胺碘酮、齐拉西酮、阿立哌唑、伊马替尼、拉帕替尼、oprozomib、环杷明、CUR-61414、PF-05212384、PF-4691502、toceranib、PF-477736、PF-337210、舒尼替尼、SU14813、阿西替尼、AG014699、维利帕尼、MK-4827、ABT-263、SU11274、PHA665752、克里唑蒂尼、XL880、PF-04217903、XR5000、AG14361、维利帕尼、bosutunib、PD-0332991、PF-01367338、AG14361、NVP-ADW742、NVP-AUY922、NVP-LAQ824、NVP-TAE684、NVP-LBH589、艾日布林、多柔比星、柔红霉素、丝裂霉素C、表柔比星、吡柔比星、红比霉素、癌霉素、N-乙酰基阿缀米辛、柔红霉素苯腙、5-酰亚胺道诺霉素、N-乙酰基道诺霉素、daunoryline、米托蒽醌、喜树碱、9-氨基喜树碱、7-乙基喜树碱、7-乙基-10-羟基-喜树碱、10-羟基喜树碱、9-硝基喜树碱、10,11-亚甲基二氧喜树碱、9-氨基-10,11-亚甲基二氧喜树碱、9-氯-l0,11-亚甲基二氧喜树碱、伊立替康、勒托替康、silatecan、(7-(4-甲基哌嗪亚甲基)-10,11-亚乙基二氧-20(S)-喜树碱、7-(4-甲基哌嗪亚甲基)-10,11-亚甲二氧基-20(S)-喜树碱、7-(2-N-异丙基氨基)乙基)-(20S)-喜树碱、CKD-602、长春新碱、长春花碱、长春瑞宾、长春氟宁、长春西汀、长春地辛、玫瑰树碱、6-3-氨丙基-玫瑰树碱、2-二乙氨乙基-玫瑰树碱铵、达替铵、瑞替利汀、紫杉醇、多西他赛、双氯芬酸、丁哌卡因、17-烯丙氨基-格尔德霉素、17-二甲基氨基乙基氨基-17-脱甲氧格尔德霉素、西替利嗪、非索非那定、Onx0912、Onx0914、PD0332991、阿西替尼、乐伐替尼、PHA665752、SU11274、PF-02341066、foretinib、XL880、PX-478、GDC-0349、PD0332991、AZD4547、戈洛莫德、SCH900776、TG02、UNC0638、ARRY-520、盐酸依拉克达、golvatinib、MK-1775、PF-03758309、AT13387、BAY80-6946、可比西他、GDC-0068、INNO-206、MLN0905、瑞米司他、tariquidar、扑痫酮和其他儿茶酚胺、肾上腺素、这些药学化合物的盐、前药和衍生物和其混合物。
7.根据任一项权利要求所述的药物制剂,其中所述试剂选自抗组胺乙二胺衍生物、溴苯那敏、苯海拉明、抗原生动物药物、喹诺酮、双碘喹啉、脒化合物、喷他脒、驱虫化合物、噻嘧啶、抗血吸虫药物、奥沙尼喹、抗真菌的三唑衍生物、氟康唑、伊曲康唑、酮康唑、咪康唑、抗菌头孢菌素、螯合剂、去铁胺、地拉罗司、去铁酮、FBS0701、头孢唑啉、头孢尼西、头孢噻肟、头孢他啶、头孢呋辛、抗菌β-内酰胺衍生物、氨曲南、头孢三唑、头孢西丁、红霉素族的抗菌剂、红霉素、阿奇霉素、克拉霉素、竹桃霉素、青霉素化合物、苄青霉素、苯氧基甲基青霉素、氯唑西林、二甲氧基苯青霉素、萘夫西林、苯唑西林、羧苄西林、四环素化合物、新生霉素、大观霉素、万古霉素;抗分歧杆菌药物、氨基水杨酸、卷曲霉素、乙胺丁醇、异烟肼、吡嗪酰胺、利福布汀、利福平、氯法齐明、抗病毒的金刚烷化合物、金刚烷胺、金刚乙胺、奎尼丁化合物、奎宁、奎纳克林、氯喹、羟化氯喹、伯氨喹啉、阿莫地喹、甲氟喹、抗菌剂、喹诺酮、环丙沙星、依诺沙星、洛美沙星、萘啶酸、诺氟沙星、氧氟沙星、磺酰胺;尿路抗菌剂、呋喃妥因、甲氧苄氨嘧啶;硝基咪唑类衍生物、甲硝唑、胆碱季胺化合物、ambethinium、新斯的明、毒扁豆碱、抗-阿尔茨海默病、他克林、抗帕金森药物、苯扎托品、比哌立登、普环啶、苯海索、抗蕈毒碱试剂、阿托品、莨菪碱、东莨菪碱、丙胺太林、肾上腺素能化合物、多巴胺、5-羟色胺、刺猬基因抑制剂、沙丁胺醇、多巴酚丁胺、麻黄碱、肾上腺素、去甲肾上腺素、异丙肾上腺素、间丙醇、沙美特罗、特布他林、5-羟色胺再摄入抑制剂、麦角胺衍生物、肌肉松弛剂、箭毒系列、中心作用肌肉松弛剂、巴氯芬、环苯扎林、丹曲林、尼古丁、尼古丁受体拮抗物、β-肾上腺素阻断剂、acebutil、胺碘酮、苯并二氮杂化合物、地尔硫草、抗心律失常药物、双异丙吡胺、encaidine、局部麻醉化合物、普鲁卡因、普鲁卡因胺、移多卡因、氟卡胺、奎尼丁、ACE抑制剂、卡托普利、依那普利、Hsp90抑制剂、福辛普利、喹那普利、雷米普利;阿片剂衍生物、可待因、哌替啶、美沙酮、吗啡、抗血脂剂、氟伐他汀、吉非罗齐、HMG-coA抑制剂、普伐他汀、血压过低药物、可乐定、胍那苄、哌唑嗪、胍乙啶、granadril、肼苯哒嗪、非冠状血管舒张剂、双嘧达莫、乙酰胆碱酯酶抑制剂、匹罗卡品、生物碱、毒扁豆碱、新斯的明、任何前述的衍生物、任何前述的前药,和任何前述的类似物。
8.根据权利要求2-7任一项所述的药物制剂,其中所述非质子溶剂选自二甲亚砜、二噁烷、四氢呋喃、二甲基甲酰胺、乙腈、乙酰二甲胺、环丁砜、γ丁内酯、吡咯烷酮、l-甲基-2-吡咯烷酮、甲基吡咯啉、乙二醇一甲基醚、二甘醇一甲基醚、聚乙二醇。
9.任一项前述权利要求所述的药物制剂,其中所述脂质体由选自下述的一个或多个脂质制备:卵磷脂酰胆碱(EPC)、卵磷脂酰甘油(EPG)、二棕榈酰磷脂酰胆碱(DPPC)、鞘磷脂(SM)、胆固醇(Chol)、硫酸胆固醇和其盐(CS)、胆固醇半琥珀酸酯和其盐(Chems)、磷酸胆固醇和其盐(CP)、胆固醇邻苯二甲酸酯、胆固醇基磷酸胆碱、3,6,9-三氧辛-醇-胆甾醇基-3e-醇、二肉豆蔻酰基磷脂酰甘油(DMPG)、二肉豆蔻酰基磷脂酰甘油(DMPG)、二豆蔻酰磷脂酰胆碱(DMPC)、二硬脂酰磷脂酰胆碱(DSPC)、氢化大豆卵磷脂(HSPC)、二硬脂酰基磷脂酰甘油(DSPG)、固醇改性的脂质(SML)、反磷酸胆碱脂质、阳离子脂质和两性脂质。
10.任一项前述权利要求所述的药物制剂,其中来自封装在所述脂质体的所述内部水性介质中的所述试剂的所述水悬液的试剂的百分数范围是所述试剂的所述水悬液中总试剂的约10%至约100%。
11.任一项前述权利要求所述的药物制剂,其中所述离子梯度由横跨所述膜的下述成员的浓度差造成:胺盐和选自羧酸盐、硫酸盐、膦酸盐和磷酸盐的成员的金属盐。
12.根据权利要求11所述的药物制剂,其中所述羧酸盐是乙酸盐。
13.根据权利要求11所述的药物制剂,其中所述胺盐和所述金属盐选自下述盐:单价羧酸盐、多价羧酸盐、硫酸盐、膦酸盐和磷酸盐。
14.根据权利要求11所述的药物制剂,其中所述盐中的阳离子选自钠、钙、镁、锌、铜、钾、伯胺、仲胺、叔胺和季胺种类。
15.任一项前述权利要求所述的药物制剂,其中所述制剂是冻干的。
16.任一项前述权利要求所述的药物制剂,其中所述试剂作为单位剂量形式存在于所述内部水性介质中。
17.治疗对象中疾病状态的方法,所述对象需要所述治疗,所述方法包括向所述患者施用治疗有效量的任一项前述权利要求的所述制剂。
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