CN102802624A - 药物的纳米分散体以及它的制备方法 - Google Patents
药物的纳米分散体以及它的制备方法 Download PDFInfo
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- CN102802624A CN102802624A CN2010800270138A CN201080027013A CN102802624A CN 102802624 A CN102802624 A CN 102802624A CN 2010800270138 A CN2010800270138 A CN 2010800270138A CN 201080027013 A CN201080027013 A CN 201080027013A CN 102802624 A CN102802624 A CN 102802624A
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- nanodispersion
- acid
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- surfactant
- water
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
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- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
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- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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Abstract
本发明提供了一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于含有水溶性溶剂和水的载体中的纳米粒子,所述纳米粒子包括一种或多种药物,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
Description
技术领域
本发明涉及药物的‘纳米分散体’和它的制备方法。
背景技术
有许多药物在水溶液中难溶或不溶。这些药物面临的挑战是口服药物具有较差的生物利用度或只能将它们配制成通过静脉途径进行药物输送的形式。如果药物通过静脉给药,粒子必须足够小以安全地通过毛细血管而不会引起栓塞。为了进行静脉给药,以溶液,乳剂,脂质体,纳米分散体等形式进行给药被认为是安全的。另一个应该满足的要求是,当配制特别是疏水性药物的药物输送***时,配方应该是物理稳定的而且在室温储存需要的时间内基本没有药物的聚合或结晶或配方外观的变化。
一些药物在水和大多数药物可接受的溶剂中显示出非常差的溶解性,从而限制了它们对病人的给药。例如,市售产品注射剂包括西罗莫司脂化物和无水乙醇(39.5%w/v),dl-α-生育酚(0.075%w/v),丙二醇(50.3%w/v)和无水柠檬酸(0.0025%w/v),聚山梨醇酯80(40.0%w/v)。在Torisel(西罗莫司脂化物)注射剂小瓶已经用稀释液稀释后,溶液包括35.2%的乙醇。而另一种含有大量表面活性剂的市售的注射剂是用于I.V.给药的5mL无菌安瓿中的注射剂(环孢霉素注射剂,USP)。每mL含有:环孢霉素,USP50mg;EL(聚氧乙烯蓖麻油)650mg;乙醇,Ph.Helv32.9%(体积),其在使用前必须使用0.9%的氯化钠注射剂或5%的葡萄糖注射剂进一步稀释。使用Cremophor EL,聚氧乙烯蓖麻油载体和无水乙醇USP(1∶1,v/v)。虽然这些溶剂***是生物学上和药理学上可接受的,但已知它们具有包括急性过敏反应和外周神经病变的副作用。可能已经注意到了例如大量的CremophorTM EL的增溶剂的使用导致例如严重的或致命过敏和高血压反应,缓慢性心律失常,贫血,嗜中性白血球减少症和/或外周神经病变等各种不利影响。
WO2008127358A2(以下称为’358号专利)公开了一种用于水不溶性药物的水溶液,其使用了包含在脂质复合体中的磷脂。至少一种磷脂的比例占最终脂质复合体(例如,商业可用的形式)重量比的5%至98%。一般情况下,至少一种磷脂占最终脂质复合体重量的10%至90%。相反,本发明的组合物任选使用非常少量的磷脂。惊人地发现,包括水不溶性药物,例如多烯抗生素,他克莫司,西罗莫司的该组合物可以被有效地溶解而无需使用由’358号专利教导的大量的磷脂。
另一篇现有技术,即,PCT公开号第WO 2008144355A2公开了一种稳定的口服液体非诺贝特配方,其包括非诺贝特组分和药物可接受的液体载体,液体载体足量存在以使非诺贝特溶解,并且该配方包括亲脂性组分,表面活性剂组分,至少一种一元醇,以及任选在一些实施例中包括的水组分,其中该配方基本没有油相。同时包括的是稳定的液体非诺贝特配方,该配方包括预防或治疗有效量的非诺贝特和在室温下足以保持非诺贝特溶解的少于5ml的液体载体。非常重要的是注意到虽然在此公开的配方是没有油相的,但该出版物教导该配方含有亲脂性组分,该组分包括含有C至C10的一个或多个分馏植物油脂肪酸的至少一个甘油三酯;表面活性剂组分,其中该表面活性剂的含量高达30%至70%具有大于10的HLB,优选42.5%至65%和/或46%至57.5%。由于上面讨论的原因,不希望存在这些大量表面活性剂。
美国专利公开号第US20040005339(专利公开号第′339)要求保护一种具有改进的口服生物利用度的非诺贝特的药物配方,其包括选自非诺贝特,非诺贝特的衍生物或其混合物中的非诺贝特,其溶解于选自2-吡咯烷酮,乙二醇单醚,聚乙烯乙二醇,脂肪酸和其混合物的C8-12脂肪酸酯N-烷基衍生物的水溶性非诺贝特增溶剂中;其中非诺贝特与增溶剂的重量比是1∶1至1∶100。我们已经发现了用低于非诺贝特量的一定量的表面活性溶解非诺贝特的配方。
考虑到这些与市售的具有非常大量的表面活性剂或大量的磷脂的配方有关的问题,我们已经开发了使用非常,非常少量的表面活性剂的组合物。我们已经开发了一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于包括水溶性溶剂和水的载体中的纳米粒子,所述纳米粒子包括药物,聚合物和非常少量的表面活性剂并且还基本没有磷脂。此外,本发明人还发现当将非诺贝特类的药物与本发明的纳米分散体载体混合时可以讲具有很大溶解问题并因此具有不良的生物利用度的非诺贝特类的分子成功配制成所需要的溶液。这一结果是意想不到的,因为像非诺贝特类的药物的溶解特性完全是不可预知的。
发明目的
本发明的一个目的是提供一种在注射或口服给药之前和过程中所需要时间内可以稳定存在的药物的纳米分散体。
本发明的一个目的是提供一种在注射给药之前和过程中所需要时间内可以物理稳定的药物的纳米分散体。
本发明的另一个目的是提供一种在室温储存超过3小时没有药物的聚合或外观的变化的纳米分散体。
本发明的又一个目的是提供一种化学稳定的药物衍生物的预浓缩剂,并且该预浓缩剂在室温储存至少3个月没有药物的聚合或外观的变化并且一旦用水性液体载体稀释可获得稳定的纳米分散体。
发明内容
A.一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于载体中的纳米粒子,所述载体包括水溶性溶剂和水,所述纳米粒子含有一种或多种药物,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
B.根据上述A所述的纳米分散体,其中所述药物选自西罗莫司脂化物,他克莫司,西罗莫司,环孢霉素,非诺贝特,或其药物可接受的盐。
C.根据上述A所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶5至1∶10,并且其中所述纳米分散体至少稳定4小时。
D.根据上述A所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶5至1∶10,并且其中所述纳米分散体稳定24小时。
E.根据上述A所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶10,并且其中所述纳米分散体稳定8小时。
F.根据上述A所述的纳米分散体,其中所述纳米粒子的平均大小的范围在10nm至200nm之间。
G.根据上述A所述的纳米分散体,其中所述水溶性溶剂选自醇类,二醇类和其衍生物,聚亚烷基二醇类和其衍生物,丙三醇,四氢呋喃聚乙二醇醚和其混合物。
H.根据上述A所述的纳米分散体,其中所述的水溶性溶剂选自由乙醇和聚乙二醇(PEG)组成的组。
I.根据上述A所述的纳米分散体,其中所述聚合物是水溶性聚合物。
J.根据上述A所述的纳米分散体,其中所述水溶性聚合物选自由聚乙烯吡咯酮和聚乙二醇组成的组。
K.根据上述A所述的纳米分散体,其中使用的聚乙烯吡咯酮具有1000至50,000范围的分子量,并以0.001%w/v至10%w/v的用量范围使用。
L.根据上述A所述的纳米分散体,其中所述脂肪酸或它的盐选自由辛酸,油酸,硬脂酸和其混合物组成的组。
M.根据上述A所述的纳米分散体,其中所述固醇或它的衍生物或它的盐选自由胆固醇,极性酸胆固醇酯,植物固醇,胆汁酸和它们的衍生物,盐和它们的混合物组成的组。
N.根据上述A所述的纳米分散体,其中所述极性酸选自由琥珀酸,半琥珀酸,硫酸,磷酸,谷氨酸,天冬氨酸,硼酸组成的组。
0.根据上述A所述的纳米分散体,其中所述表面活性剂的用量范围在0.001%w/v至5.0%w/v之间。
P.包括一种或多种药物,聚合物和表面活性剂的溶液,所述表面活性剂包括水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,在用水性液体载体稀释所述溶液时获得纳米分散体。
Q.具有粒子平均大小小于300nm的纳米粒子,所述纳米粒子包括一种或多种药物,表面活性剂和聚合物,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
本发明提供了一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于载体中的纳米粒子,所述载体包括水溶性溶剂和水,所述纳米粒子含有一种或多种药物,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
本发明还提供了包括一种或多种药物,聚合物和表面活性剂的溶液,所述表面活性剂包括水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,在用水性液体载体稀释所述溶液时获得纳米分散体。
本发明还提供了粒子平均大小小于300nm的纳米粒子,所述纳米粒子包括一种或多种药物,表面活性剂和聚合物,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
具体实施方式
本发明提供了一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于水溶性载体中的纳米粒子,所述水溶性载体包括水溶性溶剂和水,所述纳米粒子含有药物,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
本发明还提供了包括药物,聚合物和表面活性剂的溶液,所述表面活性剂包括水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,在用水性液体载体稀释所述溶液时获得纳米分散体。
本发明还涉及粒子平均大小小于300nm的纳米粒子,所述纳米粒子包括药物,表面活性剂和聚合物,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。本发明的纳米分散体不含Cremophor类的毒性赋形剂并涉及需要用于配制稳定的药物的纳米分散体的添加剂的用量大大减少(如表面活性剂和磷脂),从而减少了有关的毒性反应。
在此使用的术语纳米粒子意思是具有受控大小的纳米级的粒子。本发明要求保护的纳米粒子可以是高分子纳米粒子(包埋药物的聚合物基体)和/或高分子纳米囊泡(封装药物的聚合物稳定的纳米大小的囊泡)和/或高分子纳米胶囊(包围药芯中药物的聚合物膜)和/或由表面活性剂稳定的药物的纳米大小的粒子,和具有平均大小小于300nm的类似物。确定纳米粒子的粒子大小使用传统的测量方法和如Malvern粒子大小分析,筛选,光散射光学显微镜,图像分析,沉降和现有技术中本领域技术人员已知的其它方法来表述粒子尺寸。粒子大小分布信息可以通过D10,D50和D90值获得,例如可以通过Malvern粒子大小测定产生而不希望受到任何理论的限制,本申请人认为通过包括具有平均大小小于300nm的纳米粒子的纳米分散体进行药物输送可以提高药物在靶向肿瘤组织和细胞中的内化和积聚。这一增加的内化水平为与癌症有关的肿瘤治疗提供了有效的治疗方案。
根据本发明的一个实施例,纳米粒子的粒子尺寸范围在10nm至275nm之间。在本发明的一个优选实施例中,粒子尺寸小于200nm。在本发明的最优选实施例中,粒子大小在10nm至200nm之间。
本发明提供了一种纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于包括水溶性溶剂和水的载体中的纳米粒子,所述纳米粒子包括一种或多种活性试剂,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
本发明还提供了包括一种或多种药物,聚合物和表面活性剂的溶液,所述表面活性剂包括水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,在用水性液体载体稀释所述溶液时获得纳米分散体。
本发明的纳米粒子具有小于300nm的平均大小,其中所述纳米粒子包括一种或多种药物,表面活性剂和聚合物,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
在本发明的实施例中提到的药物衍生物优选是例如西罗莫司,他克莫司,环孢霉素,非诺贝特类的极不溶于水的药物。优选地,这些药物是极不溶于水的并且由于结晶或聚集问题具有物理不稳定的问题,因此当口服或注射给药时导致生物利用度不高。
本发明的纳米粒子包括一种或多种聚合物。适用于本发明的纳米粒子的聚合物优选是水溶性的。聚乙烯吡咯烷酮是具有线性排列的1-乙烯基-2-吡咯烷酮的单体单元的三级酰胺聚合物,下面将其称为PVP,而且还称为聚维酮。它在商业上可获得具有平均分子量范围在10,000至700,000之间的一系列的产品。各种产品根据平均分子量指定的K-值进行销售;例如GAF公司提供具有下面K-值的PVP:
另一个供应商BASF提供了被称为科利当(Kollidon)的不同等级的水溶性聚乙烯吡咯烷酮,其具有例如分子量2000至3000(科利当12PF),7000-11,000(科利当17PF),28,000-34,000(科利当25),1,000,000-1,5000,000(科利当90F)的等级。在实施例中,聚乙烯吡咯烷酮作为水溶性聚合物。适用于本发明的聚乙烯吡咯烷酮的等级包括具有分子量范围在1,000至45,000,优选4,000至30,000的聚乙烯吡咯烷酮。根据本发明的一个实施例,用于纳米分散体中的聚合物的用量范围从0.001%v/v至20%v/v。优选聚合物的用量范围从0.01%v/v至5.0%v/v。最优选聚合物的用量范围从0.01%v/v至1.0%v/v。
本发明的纳米分散体包括一种或多种表面活性剂。术语表面活性剂是“表面活性试剂”的另一种名称。表面活性剂是包括水溶性(亲水)和脂溶性(亲脂)部分的分子。用于本发明的纳米分散体的表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
术语脂肪酸包括来自或以酯化形式含在动物或植物脂肪,油或蜡中的脂肪族(饱和或不饱和)一元羧酸。可以用于本发明的组合物中的脂肪酸或它的盐的例子包括但不限于具有“n”个碳原子的脂肪酸或它的盐,其中“n”的范围是从4至28。脂肪酸可以是饱和脂肪酸或不饱和脂肪酸,和它们的盐和它们的混合物。饱和脂肪酸和它的盐可以选自丁酸,己酸,辛酸,葵酸,月桂酸,肉豆蔻酸,棕榈酸,硬脂酸,花生酸,二十二酸,辛酸钠,月桂酸钠,肉豆蔻酸钠,棕榈酸酯钠等和/或它们的混合物。不饱和脂肪酸和它的盐可以选自肉豆蔻酸,棕榈油酸,油酸,亚油酸,α亚麻酸,花生四烯酸,二十碳五烯酸,芥酸,十二碳六烯酸,油酸钠,花生四烯酸钠等和/或它们的混合物。
可以用于本发明的纳米分散体或纳米粒子的固醇或它的衍生物或它的盐的例子可以是固醇的酸酯。可以适用于本发明的固醇包括但不限于胆固醇,植物固醇,麦角脂醇,胆汁酸盐和它们的混合物。可以使用的胆固醇的酸盐包括但不限于胆固醇硫酸盐,胆固醇乙酸盐,胆固醇氯乙酸盐,胆固醇苯甲酸盐,胆固醇肉豆蔻酸盐,胆固醇半瑚珀酸盐,胆固醇磷酸盐,磷酸盐,硼酸盐,硝酸盐,胆固醇桂皮酸盐,胆固醇crotanoate,胆固醇丁酸盐,胆固醇庚酸盐,胆固醇己酸盐,胆固醇辛酸盐,胆固醇壬酸盐,胆固醇癸酸盐,胆固醇油酸盐,胆固醇丙酸盐,胆固醇戊酸盐,双胆甾醇碳酸盐等和它们的混合物。可以用于本发明的组合物中的植物甾醇类包括谷甾醇,油菜甾醇,豆甾醇,菜籽甾醇和它的衍生物,盐和它们的混合物。例如,美国,Sigma公司销售的植物甾醇类*含有谷甾醇,油菜甾醇和二氢菜籽甾醇。胆汁酸包括胆酸,鹅去氧胆酸,脱氧胆酸,甘氨胆酸,牛磺胆酸,熊去氧胆酸和它的衍生物,盐和它们的混合物。固醇还可以是包括胆固醇半琥珀酸的胆固醇的酯,包括胆固醇氢硫酸和胆固醇硫酸的胆固醇的盐,麦角固醇,包括麦角固醇半琥珀酸的麦角固醇的酯,包括硫酸氢麦角固醇和麦角固醇硫酸的麦角固醇的盐,羊毛甾醇,包括羊毛甾醇半琥珀酸的羊毛甾醇的酯,包括硫酸氢羊毛甾醇和羊毛甾醇硫酸的羊毛甾醇的盐。
根据本发明的一个实施例,纳米粒子包括表面活性剂,其是固醇或它的衍生物或它的盐和脂肪酸和它的盐的混合物。在另一个优选实施例中,纳米粒子包括极性酸的胆固醇酯。在一个优选实施例中,用于纳米分散体中的表面活性剂是辛酸和胆固醇硫酸盐的混合物。辛酸(caprylic acid)同样称为辛酸(octanoic acid),可以0.001%w/v至5.0%w/v,优选0.01%w/v至1.0%w/v且最优选0.01%w/v至0.5%w/v的用量范围用于实施例中。用于本发明的实施例中的胆固醇硫酸盐用量范围是0.001%w/v至5.0%w/v,较优选是0.01%w/v至1.0%w/v且最优选是是0.01%w/v至0.5%w/v。
根据另一个优选实施例,使用的表面活性剂选自油酸和胆固醇硫酸和/或它们的混合物。
根据本发明的另一个实施例,使用的表面活性剂选自饱和脂肪酸和胆汁酸或胆盐和/或它们的混合物。根据优选实施例,使用的表面活性剂选自由辛酸和甘氨胆酸钠或熊去氧胆酸和/或它们的组合物组成的组。
使用的胆盐的用量范围是0.001%w/v至5.0%w/v,较优选的用量范围是0.01%w/v至1.0%w/v且最优选的用量范围是0.01%w/v至0.75%w/v。
本发明的组合物还可以包括低含量的卵磷脂/磷脂和/或它们的衍生物。在此使用的术语“低含量”意思是磷脂与药物的比例是1∶4至1∶10,即如果使用了磷脂,磷脂的用量很低,即与药物的用量相比,磷脂的用量非常低。通常,现有技术的组合物是脂质体,与药物的用量相比需要大量的磷脂。
在一些实施例中当使用少量磷脂时,这些磷脂的实例包括但不限于天然卵磷脂,部分氢化或氢化卵磷脂或鞘脂。天然卵磷脂是不同磷脂的混合物。用于本发明的组合物的磷脂选自磷脂酰胆碱,(二豆蔻酰磷脂酰胆碱,二棕榈酰磷脂酰胆碱(dipalmitotylphosphatidyl),二硬脂酰磷脂酰胆碱(distearyloylphosphatidyl),二油酰磷脂酰胆碱,二月桂酰磷脂酰胆碱,1-棕榈酰磷脂酰胆碱,1-豆蔻-2-棕榈酰磷脂胆碱,1-棕榈酰-2-豆蔻酰磷脂酰胆碱,1-硬脂酰-2-棕榈酰磷脂酰胆碱);磷脂酰乙醇胺(二肉豆蔻酰磷脂酰乙醇胺,二棕榈酰磷脂酰乙醇胺,二硬脂酰磷脂酰乙醇胺,溶血磷脂酰乙醇胺);鞘磷脂(脑磷脂,二棕榈酰神经鞘磷脂),溶血卵磷脂,脑苷脂等和它们的混合物。此外,例如聚乙二醇-二硬脂酰磷脂酰乙醇胺(PEG-DSPE),甲氧基聚乙二醇-二硬脂酰磷脂酰胆碱m-PEG-DSPC等和它们的混合物的脂质的聚乙二醇衍生物还可以用于本发明的组合物中。优选的,可以用于本发明的组合物的butylenesids是m-PEG-DSPE(甲氧基聚乙二醇-二硬脂酰磷脂酰乙醇胺)。
在本发明的一个实施例中,使用的磷脂是m-PEG-DSPE。它的用量范围是0.001%w/v至10.0%w/v,较优选0.01%w/v至5.0%w/v且最优选0.03%w/v至0.5%w/v。
用于本发明的组合物中的非水溶剂是药物相对可溶的溶剂。该非水溶剂是与水或水溶剂易混合的。用于本发明的这类水溶性溶剂的粒子包括但不限于例如乙醇,n-丙醇,异丙醇的醇类;例如乙二醇,丙二醇,丁二醇和它的衍生物的二醇类;像PEG400或PEG3350的聚乙二醇类;例如PPG-10丁二醇,PPG-10甲基葡萄糖醚,PPG-20甲基葡萄糖醚,PPG-15硬脂醚的聚丙二醇和它的衍生物;丙三醇;四氢呋喃聚乙二醇醚(glycofurol)等和它们的混合物。
在本发明的一个实施例中,非水溶剂可以选自由醇类,聚乙二醇类和/或它们的混合物组成的组中。在本发明的优选实施例中,乙醇和PEG(聚乙二醇)的混合物作为水溶性溶剂使用。用于本发明的纳米分散体组合物中的乙醇用量范围是0.001%w/v至5%w/v,较优选是0.05%w/v至0.5%w/v且最优选是0.1%w/v至0.25%w/v。优选使用的聚乙二醇包括PEG-400和PEG-3350。用于本发明的实施例的PEG-400的用量范围是0.01%w/v至20.0%w/v,较优选是0.05%w/v至5.0%w/v且最优选是1.0%w/v至2.5%w/v。用于本发明的实施例的PEG-3350的用量范围是是0.001%w/v至10.0%w/v,较优选是0.05%w/v至5.0%w/v且最优选是0.1%w/v至3%w/v。
通常,希望药物的预浓缩剂,即用水溶液载体稀释的溶液可以提供保持至少4小时稳定的纳米分散体。这一时间是将纳米分散体以注射形式给药至病人的时间。因此,一直希望本发明的纳米分散体能够获得至少4小时的稳定性。载体还可以在注射用水中包括5%至10.0%w/v葡萄糖溶液或任何其它的药物可接受的静脉水液体载体和它的混合物。本发明的一个实施例,其中药物是例如西罗莫司脂化物,西罗莫司的疏水药物,水性液体载体还包括5%的葡萄糖溶液以提高稳定性但其它的稳定剂也可以存在于所述水相中。这些稳定剂的例子是羟乙基淀粉,葡聚糖,透明质酸钠,谷胱甘肽,鸟氨酸-L-天冬氨酸盐等和它们的混合物。
在一个实施例中,当要求保护本发明的溶液时,它可以被设计用于口服给药。也被称为预浓缩剂的该溶液可以被填充至硬质或软质凝胶胶囊中。随着口服给药,该溶液分散在水性介质中并且因此像非诺贝特的药物以纳米范围的粒子大小的纳米粒子的形式分散,足以提供足量的溶解。纳米分散体载体允许药物粒子保持在分散体中,当该纳米分散体口服给药时,它物理稳定足以使药物被人体吸收所需要的时间,例如1小时至3小时。
在另一个实施例中,该溶液可以被干燥以形成纳米粒子。该纳米粒子可以与药物可接受的赋形剂一起配制以形成像片剂,粒子,药丸的固体剂型。
本发明的药物的纳米分散体通常可以通过下面列出的任何一种方法进行制备:
1)治疗活性组分(和/或其它试剂),聚合物和选自脂肪酸或它的盐,固醇或它的衍生物或它的盐和它们的混合物的表面活性剂被溶解于例如乙醇和/或PEG的水溶性溶剂中,同时伴随搅拌和加热以获得药物的浓缩溶液。这样获得的所述溶液通过薄膜过滤器进行过滤。在这一溶液中缓慢地添加水溶液液体载体(5%的葡萄糖溶液)并将混合物振荡/搅拌,从而形成本发明的纳米分散体。这样形成的纳米分散体可选地进行均质和/或超声,过滤或冻干。在给药给病人之前,所述药剂的冻干粉末可以用水性液体介质重新溶解配制再次形成本发明的纳米分散体。
2)药物,聚合物和选自脂肪酸或它的盐,固醇或它的衍生物或它的盐和它们的混合物的表面活性剂被溶解于例如乙醇和/或PEG的水溶性溶剂中,同时伴随搅拌和加热以获得药物的浓缩溶液。这样获得的所述溶液通过薄膜过滤器进行过滤,并被添加至水性介质中(5%的葡萄糖溶液)并将混合物振荡/搅拌,从而形成本发明的纳米分散体。这样形成的纳米分散体可选地进行均质和/或超声,过滤或冻干。在给药给病人之前,所述药剂的冻干粉末可以用水性液体介质重新溶解配制再次形成本发明的纳米分散体。
3)药物和包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物的表面活性剂通过在圆底烧饼中40℃的轻度加热被溶解于例如乙醇和/或PEG的水溶性溶剂中,并且将溶剂蒸发以形成药物的薄膜。聚合物被溶解于需要数量的水性液体介质中并且伴随适度搅拌将溶液添加至所述薄膜中并振荡3-4小时,从而形成本发明的纳米分散体。这样形成的纳米分散体可选地进行均质和/或超声,过滤或冻干。在给药给病人之前,所述药剂的冻干粉末可以用水性液体介质重新溶解配制再次形成本发明的纳米分散体。
由于本发明的纳米分散体是包括具有平均大小小于300nm的纳米粒子的药物的胶体纳米分散体,分析它们是物理和化学稳定的。观察到在室温8小时至24小时储存后粒子没有发生聚集,并且纳米分散体的外观没有显示变化,从而推断在给药之前和给药过程中纳米分散体在所需要的时间内是稳定的。
此外,当对水溶性溶剂中的药物和/或其它试剂的溶液进行试验时,观察到所述溶液在通过口服或注射组合物给药的至少需要的时间内保持物理和化学稳定,在药物试验中没有明显的变化且在配方的外观上基本没有聚集或变化。观察结果将在下面的例子中显示。
本发明的纳米分散体可以作为具有两个或多个容器的试剂盒提供,例如两个容器,其中第一容器包括药物溶液,聚合物和表面活性剂,其中所述表面活性剂包括在水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,且第二容器包括水性液体载体,使得第二容器的内含物一旦添加至第一个容器的内含物中时,或与之相反,随着适度搅拌或振荡,形成了本发明的纳米分散体并且它是适合于进行静脉给药。其它的容器可以包括在形成药物分散体之前或在药物的纳米分散体形成之后用于混合的第三组分。
本发明还提供了具有两个容器的试剂盒,第一容器包括冻干形式的纳米分散体且第二容器包括水溶液液体载体,使得在给药给病人之前,随着适度搅拌或振荡,第二容器的内含物添加至第一容器的内含物中时,或与之相反,形成了本发明的纳米分散体。
将本发明的纳米分散体对需要的病人进行给药可为现有技术中已知的各种类型的癌症的治疗提供有效的方法。
虽然上面总体公开了本发明,但其它的内容根据下面的例子进一步讨论和说明。然而,所公开的实施例仅仅是为了说明本发明而不能认为限制本发明。
例1
药物,胆固醇硫酸酯,辛酸和PVP K-12在玻璃瓶中被精确称重。内含物被溶解于需要数量的无水乙醇和PEG-400中并伴随搅拌以获得浓缩的药物溶液。溶液通过0.2μPVDF的薄膜过滤器进行过滤。需要数量的预浓缩剂被分散于葡萄糖溶液(5%w/v)(50ml)中并伴随缓慢振荡以获得具有0.1mg/ml稀释度的透明至半透明的纳米分散体。纳米分散体用于以下试验进行分析:外观,pH值(Mettler Toledo-seven easy,pH值计)和粒子大小(Nano-ZS,Malvern粒子大小分析器)。发现这样制备的预浓缩剂是无色透明并且是稍微有些粘性的溶液。它与例如葡萄糖溶液的水相进行混合以获得纳米分散体。纳米分散体的稳定性在最初以及储存几个小时后确定被分散粒子的粒子大小。
例2
药物,胆固醇硫酸酯,辛酸和PVP K-17在玻璃瓶中被精确称重。内含物被溶解于需要数量的无水乙醇和PEG-400中并伴随搅拌以获得浓缩的药物溶液。溶液通过0.2μPVDF的薄膜过滤器进行过滤。需要数量的预浓缩剂被分散于葡萄糖溶液(5%w/v)(50ml)中并伴随缓慢振荡以获得具有0.5mg/ml稀释度的透明至半透明的纳米分散体。纳米分散体用于以下试验进行分析:外观,pH值(Mettler Toledo-seven easy,pH值计)和粒子大小(Nano-ZS,Malvern粒子大小分析器)。
发现这样制备的预浓缩剂是无色透明并且是稍微有些粘性的溶液。它与例如葡萄糖溶液的水相进行混合以获得纳米分散体。纳米分散体的稳定性由最初以及储存几个小时后被分散粒子的粒子大小确定。
例3
组分 | 重量/重量% |
非诺贝特 | 17.5 |
羟丙基甲基纤维素(NE层) | 8.75 |
聚维酮K17 | 10.675 |
胆固醇硫酸酯钠盐 | 2.6875 |
辛酸 | 2.325 |
聚乙二醇3350适量 | 100 |
乙醇适量 | 适量 |
如果需要,全部组分随着加热在乙醇中被溶解。将乙醇蒸发。然后干燥混合物熔化并在silverson均质器中添加60℃的水。形成的纳米分散体具有小于1000nm(~300至1000nm)的平均粒子大小。该纳米分散体被喷雾干燥。喷雾干燥的粉末在水中溶解以获得平均粒子大小900nm至1700nm的纳米分散体。50mg的非诺贝特等价物的喷雾干燥的粉末的溶解度在15分钟内大于80%且在30分钟内大约90%。
例4
组成部分 | 含量(重量/重量%) | 含量(mg/g) |
非诺贝特 | 14.5 | 145 |
辛酸 | 12.0 | 120 |
胆固醇硫酸钠 | 1.0 | 10 |
聚维酮(K-12) | 1.2 | 12 |
无水乙醇 | 14.5 | 145 |
聚乙二醇400 | 适量至100 | 适量至100 |
药物,胆固醇硫酸酯,辛酸和聚维酮(K-12)在玻璃瓶中被精确称重。内含物被溶解于需要数量的无水乙醇和PEG-400中并伴随搅拌以获得澄清的浓缩药物溶液。溶液通过0.2μPVDF的薄膜过滤器进行过滤。发现这样制备的预浓缩剂是无色透明并且是稍微有些粘性的溶液。需要数量的预浓缩剂被分散于葡萄糖溶液(5%w/v)中并伴随缓慢振荡以获得具有5.0mg/ml稀释度的透明至半透明的纳米分散体。纳米分散体用于以下试验进行分析:外观,pH值(Mettler Toledo-seven easy,pH值计)和粒子大小(Nano-ZS,Malvern粒子大小分析器)。纳米分散体的稳定性由在最初以及例如在储存1小时后被分散粒子的粒子大小确定。
例5
组分 | 含量(重量/重量%) | 含量(mg/g) |
他克莫司 | 6 | 60 |
辛酸 | 0.5 | 5.0 |
胆固醇硫酸钠 | 0.40 | 4.0 |
聚维酮(K-17) | 5.0 | 50 |
无水乙醇 | 6 | 60 |
聚乙二醇400 | 适量至100 | 适量至1000 |
药物,胆固醇硫酸酯,辛酸和聚维酮(K-17)在玻璃瓶中被精确称重。内含物被溶解于需要数量的无水乙醇和PEG-400中并伴随搅拌以获得澄清的浓缩药物溶液。溶液通过0.2μPVDF的薄膜过滤器进行过滤。发现这样制备的预浓缩剂是无色透明并且是稍微有些粘性的溶液。需要数量的预浓缩剂被分散于葡萄糖溶液(5%w/v)中并伴随缓慢振荡以获得具有0.1mg/ml稀释度的透明至半透明的纳米分散体。纳米分散体用于以下试验进行分析:外观,pH值(Mettler Toledo-seven easy,pH值计)和粒子大小(Nano-ZS,Malvern粒子大小分析器)。
纳米分散体的稳定性由在最初以及例如在储存24小时后的被分散粒子的粒子大小确定。
例6
组分 | 数量(重量/重量%) | 数量(mg/g) |
布林佐胺 | 3 | 30 |
辛酸 | 0.67 | 6.7 |
胆固醇硫酸钠 | 0.67 | 6.7 |
聚维酮(K-17) | 7.5 | 75 |
无水乙醇 | 9 | 90 |
聚乙二醇400 | 适量至100 | 适量至1000 |
药物,胆固醇硫酸酯,辛酸和聚维酮(K-17)在玻璃瓶中被精确称重。内含物被溶解于需要数量的无水乙醇和PEG-400中并伴随搅拌并在60℃加热以获得透明的浓缩的药物溶液。溶液通过0.2μPVDF的薄膜过滤器进行过滤。发现这样制备的预浓缩剂是无色透明的至淡黄色的并且是稍微有些粘性的溶液。需要数量的预浓缩剂被分散于0.25%的羟丙基甲基纤维素(HPMC)溶液中并伴随缓慢振荡以获得具有0.1mg/ml稀释度的药物的纳米分散体。纳米分散体用于以下试验进行分析:外观,pH值(Mettler Toledo-seveneasy,pH值计)和粒子大小(Nano-ZS,Malvern粒子大小分析器)。纳米分散体的粒子大小在最初以及储存了2小时被确定。
Claims (17)
1.一种稳定的纳米分散体,所述纳米分散体包括具有平均大小小于300nm的分散于载体中的纳米粒子,所述载体包括水溶性溶剂和水,所述纳米粒子含有一种或多种药物,聚合物和表面活性剂,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
2.根据权利要求1所述的纳米分散体,其中所述药物选自由西罗莫司脂化物,他克莫司,西罗莫司,非诺贝特,环孢霉素,布林佐胺或其药物可接受的盐组成的组。
3.根据权利要求2所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶5至1∶10,并且其中所述纳米分散体至少稳定4小时。
4.根据权利要求3所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶5至1∶10,并且其中所述纳米分散体稳定24小时。
5.根据权利要求4所述的纳米分散体,其中所述表面活性剂与所述药物的比例是1∶10,并且其中所述纳米分散体稳定8小时。
6.根据权利要求5所述的纳米分散体,其中所述纳米粒子的平均大小的范围在10nm至200nm之间。
7.根据权利要求6所述的纳米分散体,其中所述水溶性溶剂选自醇类,二醇类和其衍生物,聚亚烷基二醇类和其衍生物,丙三醇,四氢呋喃聚乙二醇醚和其混合物。
8.根据权利要求7所述的纳米分散体,其中所述水溶性溶剂选自由乙醇和聚乙二醇组成的组。
9.根据权利要求8所述的纳米分散体,其中所述聚合物是水溶性聚合物。
10.根据权利要求9所述的纳米分散体,其中所述水溶性聚合物选自由聚乙烯吡咯酮和聚乙二醇组成的组。
11.根据权利要求9所述的纳米分散体,其中使用的聚乙烯吡咯酮的分子量的范围是1000至50,000,并以0.001%w/v至10%w/v的用量范围使用。
12.根据权利要求11所述的纳米分散体,其中所述脂肪酸或它的盐选自由辛酸,油酸,硬脂酸和其混合物组成的组。
13.根据权利要求12所述的纳米分散体,其中所述固醇或它的衍生物或它的盐选自由胆固醇,极性酸胆固醇酯,植物固醇,胆汁酸和它们的衍生物,盐和它们的混合物组成的组。
14.根据权利要求13所述的纳米分散体,其中所述极性酸选自由琥珀酸,半琥珀酸,硫酸,磷酸,谷氨酸,天冬氨酸,硼酸组成的组。
15.根据权利要求14所述的纳米分散体,其中所述表面活性剂的用量范围在0.001%w/v至5.0%w/v之间。
16.包括一种或多种药物,聚合物和表面活性剂的溶液,所述表面活性剂包括水溶性溶剂中的脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物,在用水性液体载体稀释所述溶液时获得纳米分散体。
17.粒子平均大小小于300nm的纳米粒子,所述纳米粒子包括一种或多种药物,表面活性剂和聚合物,所述表面活性剂包括脂肪酸或它的盐和固醇或它的衍生物或它的盐的混合物。
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