CN108379230A - 一种胆汁酸修饰的口服颗粒 - Google Patents
一种胆汁酸修饰的口服颗粒 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,具体涉及一种用于口服的表面修饰胆汁酸颗粒,颗粒内包载治疗药物的组成及制备方法。首先制备包载治疗药物的带正电荷的复合物,然后再用带有负离子的胆汁酸聚合物来偶联形成颗粒。本发明包括带有胆汁酸‑磷脂复合物插入到包裹的颗粒表面,形成胆汁酸修饰的颗粒。药物包裹的颗粒可以是脂质体,胶束,乳剂,微球,纳米粒等。口服体内后,由于肠肝循环的作用下,在肠道内选择性的吸收颗粒入血,可提高口服药物的生物利用度。药物包括基因、蛋白质,多肽,抗体,核酸,病毒,小分子药物。
Description
技术领域
本发明属于生物医药技术领域,阐明了颗粒表面修饰胆汁酸的口服治疗组合物,包载的药经颗粒主要通过肠肝循环来吸收到体内。这些组合物包括阳离子复合物和含胆汁酸的阴离子复合物,它们通过静电相互作用耦合形成颗粒。这种颗粒内包药物外修饰胆汁酸。或者带有胆汁酸-磷脂复合物插入到包裹的颗粒表面形成胆汁酸修饰的颗粒。药物包裹的颗粒可以是脂质体,胶束,乳剂,微球,纳米粒等。这些组合物包含的治疗药物,如基因、蛋白质,多肽,抗体,小分子药物。
背景技术
很多治疗药物口服给药后受到多种因素的限制,包括肠道通透性差,导致生物利用度低,对pH或温度不稳定导致药物的分解,有的药物被蛋白酶降解等,都阻碍了药物口服给药。一些慢性治疗药物如糖尿病药,抗癌药,神经病等药需要长期口服,如果制成注射剂会带来很多付作用和不方便。因此,急需开发一种可提高生物利用度,降低用药剂量,减少毒副作用,既经济又实惠的口服药物制剂。
发明内容
本发明提供了一种口服药物颗粒组合物,其中包含药物和胆汁酸或与阴离子聚合物共价结合的胆汁酸共轭物。核心复合物具有带正电荷,胆汁酸结合的阴离子聚合物具有带负电荷。阴离子聚合物和阳离子复合物通过静电耦合形成颗粒。本发明包括带有胆汁酸-磷脂复合物插入到含药物包裹的脂质体表面形成胆汁酸修饰的脂质体,载药物的颗粒可以是脂质体,胶束,乳剂,微球,纳米粒等组合物。
附图说明:
图1.是构成口服颗粒的成分和组合物的示意图。
图2.胆汁酸-磷脂复合物插入颗粒中形成胆汁酸修饰颗粒
图3.胆汁酸表面修饰基因包载的颗粒
图4.胆汁酸表面修饰质粒包载的颗粒
图5.牛磺胆汁酸修饰硫酸软骨素的反应式
图6.硫酸软骨素和(左)硫酸软骨素与牛磺胆酸共价结合(右)的质子核磁共振谱。
图7.电镜下阳离子复合物(左),阴离子胆汁酸聚合物包裹颗粒(右)
图8.牛磺胆汁酸修饰磷脂的反应式
图9.电镜下脂质体(左),胆汁酸-磷脂包裹的脂质体颗粒
图10.颗粒大小随肝素-胆汁酸与质粒复合物比列变化而变化
图11.颗粒电位随肝素-胆汁酸与质粒复合物比列变化而变化
图12.口服和静脉Exendin-4胆汁酸包裹颗粒后的血药浓度
图13.口服pGLP颗粒后体内血糖浓度
图14.静脉注射pGLP颗粒后体内血糖浓度
图15.口服pGLP颗粒后体重变化
图16.静脉注射pGLP颗粒后体重变化
图17.口服胆汁酸软骨素包裹的阿霉素颗粒给药后(10mg/kg),肿瘤体积变化
图18.口服胆汁酸肝素包裹的阿霉素颗粒给药后(10mg/kg),肿瘤体积变化
图19.口服胆汁酸肝素包裹的阿霉素颗粒给药后(10mg/kg),相对体重变化
图20.口服含胰岛素的胆汁酸修饰脂质体后胰岛素的血药浓度
图21.口服含胰岛素的胆汁酸修饰脂质体后胰岛素的血糖浓度
具体实施方式
口服药物疗效低的主要原因是药物在肠壁上吸收差。胆汁酸转运蛋白是治疗药物吸收的重要载体,肝分泌的胆汁酸通过肠上皮细胞从回肠吸收,经门静脉,转运于肝。因此,表面修饰胆汁酸的载药颗粒,在体内具有较高的吸收。因为回肠末端的胆汁酸转运蛋白的作用下,促进药物颗粒吸收入血。
牛磺胆酸(Taurocholicacid,TCA)是一种丰富的胆汁酸,约占人体肠道液的45%。TCA可作为治疗药物的载体,主要表现在回肠末端,通过末端胆汁酸转运蛋白使肠道细胞吸收最大化。因此,药物从回肠末端转运到门静脉并进入全身循环,可由胆酸载体牛磺胆酸来促进药物吸收。
本发明公开了药物组合物,其中包含药物和阳离子基团的复合物,与共价结合的胆汁酸阴离子聚合物静电结合,形成包载药物的表面修饰胆汁酸的颗粒。形成的颗粒大小在10纳米到10微米之间,这些颗粒在回肠部位吸收入血液中。所阐述的治疗组合物至少含一胆汁酸结合的阴离子结构,而且通过阳离子基团与该阴离子基团静电作用结合,并且至少包含一种药物。所阐述的治疗组合物中包含胆汁酸-磷脂复合物,以便修饰脂质体插入磷脂双层中。
组合物中胆汁酸的修饰使药物生物利用度得到了增加,为目前不能口服的药物,如阿霉素,顺铂,和紫杉醇等抗癌药物提供了口服的可能性。还为一些药物包括DNA、RNA、基因,寡核苷酸,蛋白质,多肽、疫苗、载体,病毒药物,开创了口服的可能性。本发明的组合物提供了一种口服技术平台。为肠道吸收差、不稳定,以及酶降解而不能口服的药,提供了口服给药的技术和方法。
描述了药物治疗性组合物,包含包载药制成的核心复合物,其外表面具有正电荷。该组合物还含有胆汁酸或胆汁酸共轭物,其共价结合在阴离子聚合物上。该阴离子聚合物具有负电荷。在图一中得到了说明。
这种药物可以是任何类型的药,包括核酸、基因、蛋白质、肽、病毒或小分子药物。在下面的实施例中,药物是基因、线性DNA、质粒DNA、RNA、RNAi或mRNA。治疗药物可能是一种蛋白质,如胰岛素、生长激素或促红细胞生成素,也可能是一种肽。也可能是一种小分子药物,如抗癌药物,包括阿霉素,顺铂或紫杉醇。也许可能是一种病毒,如流感病毒或肿瘤学腺病毒。
核心复合物可包括单一阳离子药物或多种阳离子药物,或者包括两个或多个与此相关联的基团,使得该外表面具有正电荷。核心复合物可能包括阳离子聚合物如聚乙烯亚胺、鱼精蛋白和聚(赖氨酸)等如(图三和图四)。在实施例中,核心复合物包括阳离子脂质体和胆汁酸-磷脂修饰的脂质体(图二)。
阴离子聚合物是一种高分子,在中性pH值的条件下带负电荷,如包括至少一个磺酸、羧酸聚合物、磷酸盐或磺胺类。天然阴离子聚合物如多糖包括葡聚糖硫酸酯、肝素、硫酸软骨素、透明质酸、褐藻酸;核酸或DNA包括RNA,siRNA部分mRNA和ODN;或蛋白质如白蛋白。合成的阴离子聚合物如聚砜,聚(2-acylamido-2-methyl-1-propane磺酸(polyamps),聚(丙烯酸),聚(甲基丙烯酸),聚(乙基丙烯酸),聚(丙基丙烯酸酸),聚(苯乙烯磺酸盐)、聚(磺),聚(聚(2-甲基丙烯酰氧乙基磷酰胆碱磷酸),或任何混合物或共聚物的上述聚合物。聚合物可以是直连的、块状的、枝连的聚合物。聚阴离子也可能是一个天然的或合成的聚合物的混合物,或两个或两个以上的任何类型的聚合物混合物。
颗粒修饰部分可以胆汁酸或胆汁酸的共轭物,初级胆汁酸如胆酸、鹅去氧胆酸、次级胆汁酸如脱氧胆酸,石胆酸,熊去氧胆酸,鹅去氧胆酸或,或任何类型的胆汁酸盐。在实施例中,胆汁酸是牛磺胆酸,甘氨胆酸、去氧胆酸、甘氨脱氧胆酸、牛磺鹅去氧胆酸,甘氨鹅脱氧胆酸钠,或任何修饰的胆汁酸结合到参与胆汁酸转运蛋白,如蛋白。
图三所示。左部分可以是质粒DNA,形成具有外部阳离子表面的核心复合体。核心的复合物的静电与阴离子聚合物共价结合成颗粒。在图中,右部分的一部分是BPEI,质粒DNA,如peegfp-n1,pglp-1,或pexendin-4,和胆汁酸的共轭基团的聚阴离子TCA是肝素。在图一中,详细描述了该制剂的各种成分,包括以胆汁酸或胆汁酸缀合物共价结合到阴离子聚合物上的核心复合体。
胆汁酸或胆汁酸结合物和阴离子聚合物是通过共价键链接的。一种胆汁酸牛磺胆酸和阴离子聚合物是硫酸软骨素作为阴离子聚合物供价链接的。合成路线如图五所示。
基因治疗组合物,包含一个基因与聚乙烯亚胺和肝素复合物。该组合物的外表面装饰了肝素-牛磺胆,含基因颗粒提高了口服吸收,主要是通过胆汁酸转运蛋白如(图三)。
Exendin-4是治疗2型糖尿病的小肽是胰高血糖素样肽1(GLP-1)的激动剂。用Exendin-4基因进行了研究,测定了尾静脉和口服后血浆中Exendin-4的水平。
这些基因与支连聚乙烯亚胺(BPEI)复合,具有正电荷。该复合物包裹阴离子聚合物肝素-牛磺胆酸。如图一所示。药物可以是质粒DNA,如pEeGFP-N1、pGLP-1或Pex-4。聚阴离子-胆汁酸结合物可以是肝素-胆汁酸,可以是胆汁酸,例如胆酸或脱氧胆酸,也可以是胆酸结合物,如牛磺胆酸或甘胆酸。在图一中详细描述了各种成分,包括与胆酸或胆酸共价结合到阴离子聚合物上的核心配合物(这里,阴离子聚合物是肝素,胆汁酸结合物是牛磺胆酸)。
肝素-胆汁酸合成。零度下在圆底烧瓶中加入1摩尔牛磺胆汁酸钠盐溶解在4.6mlDMF,然后再加入5摩尔4-NPC。该溶液在相同的条件下反应1小时,然后在室温下搅拌6小时。然后将溶液离心,在分液漏斗中用无水乙醇(EtOH)(20毫升)和去离子水(20毫升),这个过程重复三次。分离后的溶液被放置在一个旋转蒸发器中蒸发有机溶剂,最后冷冻干燥48小时,得到一个粉末。这粉末(1mol)溶于DMF(5毫升)和4-mmp(2mol)加入。反应持续50℃,1小时后,滴入溶液中的EDA(100摩尔),室温下继续搅拌16小时。结晶部分过滤后用真空干燥器干燥。合成的肝素-胆汁酸共轭物。1摩尔的肝素溶于蒸馏水,加入0.1M HCl pH保持在5.5–6范围内。EDC(5摩尔)加入到肝素溶液中,搅拌5分钟,然后加入NHS(7摩尔),再次搅拌30分钟。耦合修饰的肝素-牛磺胆汁酸(Heparine-TCA)经透析纯化得产品。
图6左表明硫酸软骨素的质子核磁共振谱。图6右显示产品透析后的硫酸软骨素和tca-nh2反应后的产品质子谱核磁共振谱,确定结构。
阳离子复合物的(BPEI/pDNA)图7左,肝素-牛磺胆汁酸包裹的组合物图右,电子显微镜下大小。该正电复合物的大小约为90纳米,包裹的组合物约为180纳米。
本发明中包括胆汁酸-磷脂复合物,以便制备制备胆汁酸包裹的脂质体。牛磺胆汁酸修饰硫酸软骨素的反应式如图8,将1摩尔的二油酰磷脂酰乙醇胺DOPE溶解在3ml氯仿-甲醇(1:3)中溶解,羧基牛磺胆汁酸溶解水溶液中溶解,两液体混合再加入EDC和NHS,60度氮气条件下搅拌过夜,粗品纯化冻干得产品。胆固醇:卵磷脂(3:7)磷脂中加入5%的牛磺胆汁酸-磷脂后制得的脂质体电镜下图,脂质体(图9左),胆汁酸磷脂包附的脂质体颗粒(图9右)。
负电荷EGFP基因与带正电荷的bPEI在HEPES缓冲液中溶解时,由于阳离子聚合物与阴离子基因之间的静电吸引,通过电荷-电荷相互作用而相互接触。复合物的大小取决于基因(N)和bPEI(P)的N/P比值。通过大小分布分析和凝胶电泳证实了该基因与聚合物之间的复合物形成。
对阳离子(bPEI/PDNA)配合物的表征表明,N/P比为5/1和10/1的阳离子表面具有相似的Zeta值和大小,其大小约为15mV,直径约为91nm。选择N/P比为5/1的配合物用于阴离子肝素-TCA包裹。图10和11是阳离子(bPEI/PDNA-N1)络合胆汁酸偶联肝素的粒径和Zeta电位随比例变化的图形。颗粒大小随肝素-胆汁酸与质粒复合物(bPEI-N1Plasmid)比列变大而增加,而ZETA电位随肝素-胆汁酸与质粒复合物(bPEI-N1Plasmid)比列变大而变小。肝素-胆汁酸包裹(BPEI/EGFP)复合物的口服处方比例均为1/0.2(w/w)。
Exendin-4和BPEI以5/1比率混合,孵育30分钟,使它们形成一个复合物。然后用肝素-胆汁酸以1/0.2的比例包裹该复合物。30分钟,在室温孵育后,冻干两天。粉末溶解在10毫米HEPES缓冲液(200μ)中,室温孵育30分钟,使分散均匀。口服和静脉注射12,24和36小时后采集尾静脉血,测血药浓度和血糖浓度。
图12显示药物Exendin 4口服和静脉给药后血药浓度。相同剂量静脉注射后,血药浓度开始上升很高,24小时后浓度下降很大。然而口服给药血药浓度逐渐上升,72小时时超过静脉给药的血药浓度。该图表明口服后血药浓度平稳上升,避免了静脉给药血药浓度过高引起副作用,还有浓度快速下降药物无效现象。
pglp-1制剂给药后血糖监测II型糖尿病模型。GLP-1基因与BPEI混合(氮磷比为5/1),孵育30min后,通过静电作用形成复合物。复合物溶解在含阴离子肝素-胆汁酸的HEPES缓冲液中,室温孵育30分钟,然后冷冻干燥2天,给药时再溶解在HEPES缓冲液中。
用链激酶处理BALB/c小鼠,以破坏其胰腺β细胞在胰腺中的作用。将小鼠置于笼中,自由进食物和水,并连续监测。用链激酶处理2周后,其血糖水平增加到约300μg/dL。将小鼠分成两组,口服(7只小鼠)和IV(7只小鼠),肝素-胆汁酸包裹的PGLP-1制剂(提供100μg的PGLP-1基因的量)口服和静脉给药。
图13肝素-胆汁酸包裹的PGLP-1组合物制剂口服BALB/c小鼠后血糖水平。血糖水平在约100和约200mg/dl之间。图14显示了在给予肝素-胆汁酸包裹的PGLP-1组合物制剂静脉给药后血糖水平,浓度在约150和约250mg/dl之间。从图中看出口服后控制血糖浓度比静脉给药效果好。口服给药后体重维持比较稳定(图15),但是静脉给药后体重稍微下降(图16)。
很多药物不能口服给药,包括阿霉素(DOX)在内,是因为这些药物在胃肠道内吸收差,导致口服生物利用度低。药物口服吸收需要考虑其溶解性、稳定性、溶解率,在胃肠道(GI)中的吸收性能。所有这些因素都会影响药物口服生物利用度。
阿霉素是一种广泛用于治疗淋巴瘤、肉瘤、乳腺癌、卵巢癌和肺癌的抗癌药物。但口服生物利用度低(约5%),所以很难口服给药。静脉给药阿霉素由于其氧化等生成的副作用,产生肾毒性、骨髓抑制等。心脏毒性是阿霉素临床上最大副作用。因此,改善其肠道吸收性,提高口服生物利用度,才能临床上口服安全使用。
牛磺胆汁酸可作为载体通过共价键连接到阴离子聚合物。附在颗粒的表面能与小肠的胆汁酸转运蛋白相互作用,提高药物的肠道吸收性,改善药物生物利用度。
肝素(H)和硫酸软骨素(CS)作为典型的阴离子聚合物与牛磺胆汁酸(TCA)共价结合,具有良好的生物相容性、水溶性和生物降解性。作为天然的多糖聚合物,具有很好的生物相容性。肝素-TCA和软骨素-TCA可在颗粒表面,增加颗粒的稳定性,在胃肠道(GI)道中,保护药物从颗粒中泄漏,或不稳定分解。颗粒大小在此公开的范围为从10纳米到1微米。
载小分子阿霉素的口服颗粒是通过与阴离子软骨素-胆汁酸,或肝素-胆汁酸通过静电耦合而形成。具体的来说软骨素-胆汁酸直接与阿霉素以1:2的比例混合(w/w)而成颗粒。
肿瘤动物模型制备。将HepG2细胞(5×10 6个细胞/mL)皮下注射到小鼠的背部。当肿瘤大小达到约100-150mm 3时,4mg/kg DOX每三天一次口服给药。对照组中静脉给药等量的阿霉素。每三天用游标卡尺测量肿瘤,并使用下面显示的公式计算肿瘤体积。肿瘤体积=长度×宽度^2/2
图17-18显示了药物制剂的抗肿瘤效果。所有治疗组肿瘤体积随着时间的推移增加。然而,根据颗粒的组成不同,抑制肿瘤生长的速率和总体肿瘤体积变化有着显着差异。图17显示了用硫酸软骨素-胆汁酸来制备的颗粒制剂,在小鼠中的肿瘤体积随时间的变化百分比。口服DOX硫酸软骨素-胆汁酸抑制肿瘤效果比对照组,游离DOX口服,及硫酸软骨素都好。同样的结果在肝素-胆汁酸中得到(图18)。
如图19所示,在肿瘤治疗中,PBS组和阿霉素对照组以及阿霉素硫酸软骨素(DOX/CS)组,显示没有显着的体重减轻,小鼠体重变化很小,这表明治疗药物没有严重的毒性。动物数据表明,胆汁酸包裹不仅减少了阿霉素的毒性,而且增强了其在肠道中的吸收,特别是在回肠中。这些表明胆汁酸包裹的阿霉素组合物,通过肠肝循环吸收药物颗粒,提高了DOX血浆水平,结果增加了口服生物利用度,抑制了肿瘤生长。
修饰胆汁酸和/或胆汁酸缀合物的脂质体治疗组合物。本文公开的治疗组合物,其表面具有胆汁酸或胆汁酸缀合物,核心复合物包含了脂质或脂质层如脂质体。脂质体可以形成核心复合物,并且可以是阳离子或中性的脂质体。因此,本发明的组合物可以是阳离子脂质体在内的所有脂质体,载药形成核心复合物。这种脂质体核心复合物可以与共价结合胆汁酸或胆汁酸缀合物的阴离子聚合物,静电相互作用,也可以是磷脂-胆汁酸镶嵌在脂质体中形成胆汁酸修饰的脂质体。图二说明了这种脂质体组合物的一个实施方案,磷脂是阳离子脂质体组合物,可以是单一阳离子脂质,或中性和阳离子脂质的混合物,或中性脂质;治疗药物包括蛋白质,肽,DNA,基因或小分子药物;外表用阴离子聚合物共价结合的胆汁酸或胆汁酸缀合物修饰,或磷脂-胆汁酸镶嵌脂质中(图2)。
将用二甲基双十八烷基溴化铵和脱氧胆酸二者制备的胰岛素的脂质体与牛磺胆酸(CS-TCA,20mg/mL)共价结合的硫酸软骨素,制成CS-TCA修饰的胰岛素脂质体。
用1IU/20g胰岛素的剂量口服小鼠,胰岛素血药浓度(图20)。用CS包裹脂质体治疗的小鼠血清葡萄糖水平(图21),最初在第一小时内降低至约150mg/dL,但在接下来的3小时内回升至接近300mg/dL再次降低至约150mg/dL,随后逐渐升高至约200mg/dL至24小时。没有CS修饰的脂质体的血清葡萄糖水平维持在约250-300mg/dL之间。
将脂质体溶液和多柔比星(DOX)溶液混合并在60℃温育,加入硫酸铵形成铵离子和氨气梯度。通过透析(MWCO 1000)除去过量的游离DOX。最终的将载DOX的脂质体冻干。在490nm下通过UV-Vis的测量来计算DOX浓度,并且使用以下等式计算加载效率:包封效率(%)=100×(存在于颗粒中的DOX的重量)%(使用DOX的重量)
口服阿霉素制剂,在60℃下将载有DOX的脂质体溶解于含有PBS的聚氧乙烯(40mg/mL)中。通过100nm膜的脂质体挤出机。样品通过膜挤出10次。挤出后,脂质体用硫酸软骨素-胆汁酸CS-TCA(1:1.5w/w%)修饰,用于口服给药。
动物肿瘤治疗作用。游离DOX,不含胆汁酸包衣的阳离子DOX负载脂质体和负载DOX的脂质体与CS-TCA包裹的脂质体,体内抑制肿瘤评价。将4T1细胞(每只小鼠1×10 7个细胞)皮下注射到NOD/SCID小鼠的背部(n=3)。当肿瘤大小达到约100-150mm 3时,每只小鼠接受口服给予PBS,10mg/kg游离DOX,DOX-脂质体组合物中10mg/kg DOX或DOX-脂质体-牛磺胆汁酸10mg/kg DOX组成,每三天给药一次。每3天测量肿瘤大小和体重。用游标卡尺测量肿瘤体积,并使用下面显示的公式计算肿瘤体积。
肿瘤体积=(长度×宽度2)/2每种治疗的肿瘤体积的变化示于图17和18中。这些结果表明游离口服DOX在肿瘤体积生长最快。DOX的脂质体与牛磺软骨素-胆汁酸包裹的肿瘤体积的百分比抑制肿瘤生长最强,仅次于静脉给药,说明胆汁酸包裹的脂质体口服吸收能达到治疗效果。图19显示了治疗动物的相对体重的变化。游离DOX组,口服脂质体组合静脉给药组的体重在18天内似乎略有下降,但口服脂质体牛磺胆汁酸包裹的组没有明显的减少体积。
本文公开的实验包括通过口服增强型绿色荧光蛋白(eGFP),Exendin-4和GLP-1的质粒DNA。质粒DNA首先与阳离子支链聚乙烯亚胺(bPEI)复合,产生阳离子复合物。然后与肝素共价结合成牛磺胆酸(TCA)复合物,提供大小在约50和约500nm之间的颗粒。公开了含有DNA的口服颗粒。
除DNA之外,阳离子颗粒可以由蛋白质例如胰岛素与阳离子聚合物例如鱼精蛋白偶联形成。阳离子颗粒可以用肝素-TCA包裹,以产生纳米或微米大小的颗粒。这样的纳米颗粒可以用于降低血糖。
小分子药物如阿霉素(口服给药后生物可利用度低)的口服递送,可通过用胆汁酸包裹成颗粒来实现。将阿霉素与硫酸软骨素复合形成的阴离子颗粒再用ε-聚(L-赖氨酸)包裹,产生阳离子复合物。然后再用肝素-TCA包裹成颗粒。口服给药的颗粒在肿瘤小鼠中显示出明显的抑制肿瘤效果。
Claims (10)
1.治疗组合物,包含治疗药物的带正电荷核心复合物,和与带阴离子聚合物共价结合的胆汁酸或胆汁酸复合物,其中阴离子聚合物具有负电荷。带阴离子的聚合物胆汁酸与带正电的核心复合物静电耦合形成颗粒。或者是带有胆汁酸-磷脂复合物,可插入到包裹的颗粒表面形成胆汁酸修饰的颗粒,药物包裹的颗粒可以是脂质体,胶束,乳剂,微球,纳米粒等。
2.如权利要求1所述的组合物,其中所述治疗剂包含核酸。
3.如权利要求2所述的组合物,其中所述核酸包含基因。
4.权利要求3的组合物,其中所述基因编码GLP-1或Exendin 4。
5.权利要求1的组合物,其中所述治疗剂包含肽、或、和、小分子、或、和、疫苗、或、和、病毒。
肽是胰岛素、或、胰高血糖素样肽-1(GLP-1),或、艾塞那肽(exenatide)为胰高血糖素样肽-1(GLP-1)类似物Exendin 4,或胰岛素的一种药物;
小分子是阿霉素,顺铂,紫杉醇和多稀紫杉醇。
治疗剂包含疫苗或病毒。
6.根据前述权利要求中任一项所述的组合物,其中所述核心复合物包含阳离子聚合物。
7.根据前述权利要求1-6中任一项所述组合物,其中所述阳离子聚合物选自聚乙烯亚胺,鱼精蛋白或聚赖氨酸中的至少一种。
8.根据前述权利要求1-7中任一项所述的组合物,其中所述核心复合物包含阳离子脂质体。
或,其中所述阳离子脂质体包含阳离子脂质。
或,其中所述阴离子聚合物包含透明质酸,硫酸软骨素或肝素。
9.根据前述权利要求1-8中任一项所述所述的组合物,其中所述胆汁酸或胆汁酸缀合物包含胆酸,或、和、其中所述胆酸是牛磺胆酸。
10.一种治疗癌症的方法,所述方法包括将权利要求1-9中任一项所述的治疗组合物口服给予受试者,其中所述治疗药剂为抗癌药。
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