CN106692976A - P‑糖蛋白抑制剂Gelucire44/14作为经口服的盐酸小檗碱吸收促进剂的应用 - Google Patents
P‑糖蛋白抑制剂Gelucire44/14作为经口服的盐酸小檗碱吸收促进剂的应用 Download PDFInfo
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Abstract
本发明公开了P‑糖蛋白抑制剂Gelucire44/14作为经口服的盐酸小檗碱吸收促进剂的应用。Gelucire44/14作为P‑糖蛋白抑制剂,能够抑制P‑糖蛋白药泵作用,从而增加难吸收药物盐酸小檗碱的吸收,提高其生物利用度;同时,毒性考察结果显示Gelucire44/14对口服吸收部位粘膜无明显损伤,由此可以推断,Gelucire44/14是安全的口服吸收促进剂,改善难吸收药物盐酸小檗碱口服生物利用度,可用于制备难吸收药物小檗科异喹啉类生物碱盐酸小檗碱口服给药制剂。
Description
技术领域
本发明涉及药物制剂技术领域,涉及改善盐酸小檗碱口服生物利用度。
背景技术
口服给药是药物治疗中最常采用的给药方式,其因给药方式简单,不直接损伤皮肤或粘膜,顺应性好,容易被患者接受,药品生产成本低等优点而得到广泛关注。但是该给药方式容易受到药物溶解度、渗透性、肠道P-糖蛋白外排以及胃肠道环境等众多因素影响,导致药物生物利用度低,药效发挥受到影响。
盐酸小檗碱(berberine,BBR)作为广谱抗菌药在治疗肠道细菌感染性疾病方面已有悠久的历史。近年来研究者研究发现BBR具有广泛的药理活性,除了传统研究的抑菌、抗炎、抗病毒等药理作用外,在治疗糖尿病、心血管疾病、肿瘤方面也有很好的治疗作用:宁光等人研究发现,BBR能够显著改善Ⅱ型糖尿病合并血脂水平异常患者的血糖、血脂和胰岛素抵抗水平,对代谢综合征也有一定的治疗作用;赵海英等人研究发现BBR能够降低血压,可能的机理为通过阻断血管平滑肌α受体,舒张小动脉及静脉血管平滑肌从而降低血压;丁世豪等人研究表明BBR能有效降低室颤发生率、缩短室颤持续时间、延长存活时间,从而起到对抗快速型室性心律失常的作用;李健等人在BBR对CT26皮下移植瘤组织中肿瘤相关巨噬细胞的影响研究中得出结论,BBR能够抑制肿瘤相关巨噬细胞的形成而发挥抗肿瘤作用,从而抑制皮下移植瘤生长。BBR在传统药理研究中不可取代的主导地位以及在治疗肿瘤、糖尿病、心脑血管系统疾病、消化系统疾病中表现出的显著的治疗效果受到广泛的关注而成为当前研究热点。另外,BBR具有疗效确切、价格低廉、副作用小等优点,因而新用途的开发具有巨大的市场潜力。但是由于较低的肠道吸收,使得BBR生物利用度低,临床应用受到限制。
近年来,为提高难吸收口服药物,如BBR的生物利用度,研究者提出了很多解决措施,例如开发新剂型或应用吸收促进剂等。而P-糖蛋白作为重要的口服药物吸收屏障,其抑制剂的研究和开发得到了国内外研究者的大量关注并取得了一定的成果:开发出三代抑制剂。第一代抑制剂多为P-糖蛋白底物,如环孢霉素、维拉帕米等,其缺点为专属性差,具有明显的药理活性,会产生较多的不良反应;第二代抑制剂为第一代抑制剂的同系物或其结构类似物,如右维拉帕米,其特点为毒性较低,但是具有抑制P450的作用,会影响其他药物的体内过程;第三代抑制剂如tariquidar(XR9576),其特点为对P-糖蛋白选择性高,抑制作用较前两者强且不良反应少,但是其仍然可能与任何含有P-糖蛋白的组织或器官发生作用。为了克服上述缺点,越来越多的研究者致力于研究和开发具有抑制P-糖蛋白作用的药用辅料。筛选出药理活性极低、抑制作用强且毒副作用小的抑制剂,提高口服难吸收药物,如BBR的生物利用度仍然是当前亟待解决的问题。
Gelucire44/14,也称聚乙二醇-32甘油月桂酸酯,是一种饱和多糖分解的C8-C18甘油酯,含20%的单、双、三甘油酯,72%的聚乙二醇单、双脂肪酸酯和8%的游离聚乙二醇;目前已经报道的关于Gelucire44/14的用途包括:控释制剂的骨架材料或固体分散体的材料。未见到其可作为P-糖蛋白抑制剂用以提高难吸收药物BBR的生物利用度的报道。
发明内容
本发明的一个目的在于提供Gelucire44/14作为口服吸收促进剂用于改善难吸收药物口服生物利用度的应用,一方面提高了口服难吸收药物BBR的生物利用度,另一方面对吸收部位的粘膜毒性小,无药理活性,甚至不被吸收,安全性能高。
本发明的另一个目的在于提供Gelucire44/14作为P-糖蛋白抑制剂用于促进P-糖蛋白底物药物BBR的吸收的应用。
本发明采用了以下技术方案:
Gelucire44/14作为经口服的盐酸小檗碱的吸收促进剂的应用。
所述Gelucire44/14作为P-糖蛋白抑制剂促进经口服的盐酸小檗碱的吸收的应用。
所述Gelucire44/14的浓度≥临界胶束浓度。
所述Gelucire44/14作为吸收促进剂改善盐酸小檗碱的口服生物利用度的应用。
Gelucire44/14在制备经口服的盐酸小檗碱的吸收促进剂中的应用。
Gelucire44/14在制备盐酸小檗碱口服给药制剂中的应用。
Gelucire44/14作为促进P-糖蛋白底物盐酸小檗碱口服吸收的P-糖蛋白抑制剂的应用。
本发明的有益效果体现在:
本发明基于Gelucire44/14促进药物体外肠道转运以及在体肠道吸收作用,提出了Gelucire44/14作为口服吸收促进剂用于改善诸如BBR等难吸收药物口服生物利用度的应用。所述的Gelucire44/14具有良好的吸收促进作用,也是较为理想的P-糖蛋白抑制剂。在体外扩散池实验中,除了促进吸收方向的药物转运量,还可很大程度的抑制分泌方向的药物转运量,从而实现药物吸收增加;同时,毒性考察结果显示,Gelucire44/14对药物口服吸收部位的粘膜无损伤;另外,Gelucire44/14作为P-糖蛋白抑制剂,在一定浓度范围内能够有效的抑制P-糖蛋白对药物分子的外排作用,综上所述,Gelucire44/14是安全且有效的P-糖蛋白抑制剂,可用于促进难吸收药物BBR的口服吸收,提高其生物利用度。
附图说明
图1为0.1%和1.0%的Gelucire44/14(G44)对BBR在大鼠小肠转运的Papp的影响;**p<0.01(与BBR组相比);m-s:从粘膜到浆膜方向(吸收方向)的BBR转运,s-m:从浆膜到粘膜方向(分泌方向)的BBR转运。
图2为Gelucire44/14(G44,0.1%,v/v)对BBR在大鼠回肠(A)、结肠(B)吸收的影响。
图3为Gelucire44/14(G44,0.1%,v/v)对大鼠肠吸收部位粘膜毒性评价结果;其中,(A)为蛋白释放量,(B)为乳酸脱氢酶(LDH)释放量;**p<0.01,n.s.为无显著差异(均与PBS组相比)。
具体实施方式
下面结合附图和实施例对本发明做进一步详细说明。所述实施例是对本发明的解释而非限定。
理想的吸收促进剂应具备吸收促进作用强,毒副作用小,不发挥药理活性,联合用药时与其他药物不存在相互作用,不与除给药部位以外的其他组织或器官发生作用,不会影响药物的正常分布等优点。
Gelucire44/14的脂肪酸分布如表1所示,可发现其较为安全且不具有药效;此外,Gelucire44/14作为药用辅料于1998年在欧洲药典中发布,近年来在药物制剂中得到了广泛的应用,在药用辅料的研究领域具有极大的发掘潜力;再者,Gelucire44/14的亲水亲油平衡值为14,是两亲性表面活性剂,遇水后可乳化形成乳剂(临界胶束浓度为0.001~0.01%),可增加药物溶解度。
表1 Gelucire44/14的脂肪酸组成
尽管Gelucire44/14显示出了作为口服吸收促进剂的一定优势,但是,口服吸收促进剂发挥作用的原因较为复杂,同一种口服吸收促进剂仅能够对有限种类的难吸收药物发挥作用,提高其口服生物利用度。
本发明结合Gelucire44/14促进药物肠道吸收的实验,证实Gelucire44/14可作为口服吸收促进剂用于改善BBR口服生物利用度,实验过程和结果如下。
1、Gelucire44/14促大鼠体外肠道转运
选取8~10周龄雄性SD大鼠(体重230~250克),实验前16小时禁食,可自由饮水。将大鼠戊巴比妥钠腹腔注射麻醉(40mg/kg)后,仰卧置于固定板,沿腹中线剪开,从回肠(或结肠)上端插管,用PBS溶液(pH7.4)冲洗肠段,腹主动脉脱血后分离回肠(或结肠)并置于Hepes-tris缓冲溶液(pH7.4)中,剪取3~4厘米长的肠段,迅速分离筋膜层并安于扩散池。分别精密量取一定体积的BBR母液、BBR母液和相应量的Gelucire44/14及一定量的Gelucire44/14,用Hepes-tris缓冲溶液稀释得到相应的药液、药物与Gelucire44/14混合溶液及Gelucire44/14溶液。对照组(即BBR组)及实验组吸收方向上,粘膜侧分别为药液及药物与Gelucire44/14混合溶液,浆膜侧均为Hepes-tris缓冲溶液;对照组及实验组分泌方向上,浆膜侧均为药液,粘膜侧分别为Hepes-tris缓冲溶液及Gelucire44/14溶液。在混合气体(95%O2和5%CO2)循环及37℃水浴保温中,分别于不同的时间间隔于底物接收侧取样0.1mL,同时及时补充0.1mL缓冲溶液。取样完毕后立即测定。采用上述体外肠道转运模型,以难吸收药物BBR为模型药物,考察不同浓度(0.001%、0.02%、0.1%、1.0%及5.0%,v/v)的Gelucire44/14对上述模型药物BBR在大鼠肠转运的影响,结果如表2、表3和图1所示。
表2.不同浓度Gelucire44/14(G44)对BBR在大鼠回肠转运的影响
注:与BBR组相比,*p<0.05,**p<0.01,***p<0.001,n.s.为无显著差异
如表2所示,浓度为0.001%的Gelucire44/14只对BBR吸收方向有促进作用,而对分泌方向无作用;当浓度为0.1%和1.0%时,Gelucire44/14一方面对BBR吸收方向有促进作用,另一方面对分泌方向有抑制作用。由此可得,当Gelucire44/14浓度低于临界胶束浓度时,其促进作用可能的机制与P-糖蛋白无关,而浓度高于临界胶束浓度时,其促进药物吸收的作用可能主要为P-糖蛋白抑制作用。
表3.不同浓度Gelucire44/14(G44)对BBR在大鼠结肠转运的影响
注:与BBR组相比,**p<0.01,***p<0.001,n.s.为无显著差异
如表3所示,除0.02%以外所有浓度的Gelucire44/14均对BBR吸收方向的转运有促进作用,该结果与对BBR在小肠转运的影响一致。而不同浓度的Gelucire44/14对回肠、结肠分泌方向的抑制作用存在差异,其原因可能与肠道不同部位P-糖蛋白的含量有关。
从图1可以得出,0.1%和1.0%的Gelucire44/14可以增加BBR吸收方向上的透过性,但是促进作用较经典的P-糖蛋白抑制剂维拉帕米(verapamil)弱;另一方面,0.1%和1.0%的Gelucire44/14能够降低BBR分泌方向上的透过性,且0.1%的抑制作用较verapamil强。由此推断,0.1%和1.0%的Gelucire44/14均可发挥P-糖蛋白抑制作用,两者比较发现0.1%的Gelucire44/14对P-糖蛋白的抑制作用更强。
2、Gelucire44/14促大鼠在体肠道吸收
选取8~10周龄雄性SD大鼠(体重230~250克),实验前禁食12小时以上,可自由饮水。将大鼠戊巴比妥钠腹腔注射麻醉(40mg/kg)后,仰卧置于固定板,沿腹中线剪开,从回肠(或结肠)上端插管,用PBS溶液(pH7.4)冲洗肠道后,从回肠(或结肠)末端插管并密封。分别精密量取一定体积的BBR母液及BBR母液和相应量的Gelucire44/14,用PBS缓冲溶液稀释得到相应的药液及药物与Gelucire44/14混合溶液。从肠段上端用注射器将药液或药物与Gelucire44/14混合溶液缓缓注入后密封,并缝合腹中线。剥离大鼠颈静脉,分别于不同的时间间隔取血0.25~0.3mL,置于肝素化的离心管中,12000rpm离心5分钟,分离0.1mL血浆于离心管内,置于冰盒内待测。采用上述在体肠道吸收模型,以难吸收药物BBR为模型药物,根据体外实验结果,选择考察0.1%的Gelucire44/14对上述模型药物BBR在大鼠肠道吸收的影响,结果如图2和表4所示。
图2(A)为0.1%的Gelucire44/14(G44)对BBR在大鼠回肠吸收的影响,如图2(A)所示,与单独使用BBR的对照组相比较,浓度为0.1%的Gelucire44/14显著提高药物吸收,但是其作用稍较经典的P-糖蛋白抑制剂verapamil作用弱。
图2(B)为0.1%的Gelucire44/14(G44)对BBR在大鼠结肠吸收的影响,从图2(B)中可以得到与Gelucire44/14对BBR在大鼠回肠吸收促进作用相似的结果,但是Gelucire44/14对结肠的作用较回肠弱。
表4.Gelucire44/14(G44)对BBR在大鼠肠道药动学参数的影响
注:与BBR组相比,*p<0.05,**p<0.01,n.s.为无显著差异
从表4中可见,0.3mM的verapamil和0.1%(v/v)的Gelucire44/14均能够显著提高BBR肠道吸收的Cmax和AUC,而对Tmax没有显著影响。
3、Gelucire44/14对大鼠肠道粘膜毒性评价
选取8~10周龄雄性SD大鼠(体重230~250克),采用上述在体肠道吸收模型,以浓度为0.1%的Gelucire44/14溶液给予大鼠肠道部位,给药12小时后,以PBS(pH7.4)冲洗给药部位肠段,以灌流液中总蛋白和乳酸脱氢酶(LDH)为检测指标,评价Gelucire44/14对吸收部位粘膜毒性,结果见图3。
从图3可见,与对照组(PBS溶液,pH7.4)相比,给药组Gelucire44/14(0.1%,v/v)各部位(结肠、回肠)的总蛋白含量和乳酸脱氢酶活性均无显著性差异,且与阳性对照组(Triton X-100,3%,v/v)具显著差异(P<0.01),表明给药浓度0.1%(v/v)的Gelucire44/14对肠道吸收部位粘膜没有显著损伤,在上述给药浓度可以安全应用。
经上述实验表明,Gelucire44/14作为P-糖蛋白抑制剂,能够抑制P-糖蛋白药泵作用,从而增加难吸收药物BBR的吸收,提高生物利用度;同时,毒性考察结果显示Gelucire44/14对口服吸收部位粘膜无明显损伤,由此可以推断,Gelucire44/14是安全的口服吸收促进剂及P-糖蛋白抑制剂,可用于制备难吸收药物小檗科异喹啉类生物碱BBR口服给药制剂,用于改善其口服生物利用度。
结论:Gelucire44/14能够应用于制备难吸收药物小檗科异喹啉类生物碱BBR口服给药制剂中。P-糖蛋白抑制剂Gelucire44/14可作为口服吸收促进剂用于改善盐酸小檗碱口服生物利用度。
Claims (7)
1.Gelucire44/14作为经口服的盐酸小檗碱的吸收促进剂的应用。
2.根据权利要求1所述的应用,其特征在于:所述Gelucire44/14作为P-糖蛋白抑制剂促进经口服的盐酸小檗碱的吸收的应用。
3.根据权利要求2所述的应用,其特征在于:所述Gelucire44/14的浓度≥临界胶束浓度。
4.根据权利要求1所述的应用,其特征在于:所述Gelucire44/14作为吸收促进剂改善盐酸小檗碱的口服生物利用度的应用。
5.Gelucire44/14在制备经口服的盐酸小檗碱的吸收促进剂中的应用。
6.Gelucire44/14在制备盐酸小檗碱口服给药制剂中的应用。
7.Gelucire44/14作为促进P-糖蛋白底物盐酸小檗碱口服吸收的P-糖蛋白抑制剂的应用。
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