CN112791189B - 高水溶性5-氨基水杨酸药物组合物及制剂、制备和应用 - Google Patents
高水溶性5-氨基水杨酸药物组合物及制剂、制备和应用 Download PDFInfo
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Abstract
本发明提供一种高水溶性5‑氨基水杨酸药物组合物及其制剂、其制备方法和应用,属于药物技术领域。本发明提供的一种高水溶性的5‑氨基水杨酸药物组合物包括组分5‑氨基水杨酸和第四代树形高分子聚酰胺‑胺,所述第四代树形高分子聚酰胺‑胺具有氨基末端。所述组合物中5‑氨基水杨酸与树形高分子聚酰胺‑胺的摩尔比为1:20~1:30。本发明还提供了包含上述组合物的制剂及制备方法和应用。本发明提供的药物组合物及其制剂能够大大提高难溶性药物5‑氨基水杨酸在水中的溶解度,大幅度提升5‑氨基水杨酸在用于治疗葡聚糖硫酸钠诱导的溃疡性结肠炎的药物利用度,提高其体内应用治疗效果。
Description
技术领域
本发明属于药物技术领域,具体涉及一种高水溶性的5-氨基水杨酸药物组合物及其制剂、其制备方法和应用。
背景技术
炎性肠疾病是一种特发在肠道的炎症性疾病,主要包括克罗氏病(CD)和溃疡性结肠炎(UC),而溃疡性结肠炎的发病率较高且发病地区较多。溃疡性结肠炎是一种累及结肠、直肠,具有腹痛、腹泻、血便等临床表现的慢性非特异性肠道疾病,在发生溃疡性结肠炎时,肠道免疫系统处于被破坏的状态,而且复发性很强,并发结肠癌危险性高,病程20年的癌发率达5%~10%。据报道,溃疡性结肠炎在欧美国家年发病率最高可达8-246例/100,000人,我国发病率较欧美低,且轻型病例较多,但近年来发病率呈上升趋势。轻、中度的UC患者通常经口服用药缓解疾病症状及提升生活质量,5-氨基水杨酸(5-ASA)是治疗溃疡性结肠炎临床上应用最多的药物之一。
5-氨基水杨酸又称为美沙拉嗪(Mesalamine),其化学式:C7H7NO3,相对分子质量153.14,熔点279~281℃,白色至粉红色结晶,熔点约280℃(分解),微溶于水,20℃在水中的溶解度仅为0.84g/L,37℃水中的溶解度也仅为1.41g/L,水溶液偏酸性,25℃饱和溶液的pH为4.1,极微溶于无水乙醇、丙酮和甲醇,几乎不溶于氯仿、乙酸乙酯和正己烷。因此,5-氨基水杨酸的溶解性很差,无论是水溶性,还是在常用的有机溶剂中,其溶解度都很低。
另一方面,5-氨基水杨酸的抗炎作用是局部的,其只有在与大肠大肠粘膜接触和络合时才能发挥作用,而不是进入血液循环后发挥作用。如果将5-氨基水杨酸直接口服,会被胃和小肠迅速吸收,这样不能有足够量的药物到达结肠,无法起到有效的抗炎作用。
上述两方面的原因,导致了5-氨基水杨酸存在药物溶解性差、药物利用度低的问题。将5-氨基水杨酸制成普通制剂进行给药的效果并不理想,口服时药物会在胃肠道上部被吸收而代谢失活,不能达到治疗效果;直肠给药灌肠会使药物在结肠分布不均匀,个体差异大,药物只限在直肠和乙状结肠,到达不了横结肠和升结肠,同时增加病人痛苦和医务人员负担;栓剂只能用于直肠疾病或全身治疗,无法达到结肠靶向的给药目的。
因此,5-氨基水杨酸相关制剂必须要经过特殊设计,以减少其在上肠道的吸收,使其靶向到末端回肠或结肠释放药物,才能保持病变肠段有效的药物浓度,提高药物利用率。虽然目前很多研究报道了口服制剂、灌肠剂或各类型水凝胶可作为5-ASA载体治疗肠炎,但是肠内释放的5-ASA仍然具有难溶特性,从而仅使少量溶解于消化液的5-ASA能够穿透肠内壁黏膜在局部发挥抗炎作用。同时,在以往介质载药研究中,因5-ASA局部内停留时间短,5-ASA负载量低导致药物利用率低,未从根本上解决5-ASA增溶的问题。
为了改善5-氨基水杨酸溶解性差和生物利用度低的缺点,国内外研究者进行了大量5-氨基水杨酸药物递送和释放的研究。
Silveira[1]报道了将5-ASA与脂类增溶剂混合后在80℃下加热1h进行溶解,发现选用的三种脂类物质十六醇、十六硬脂酸酯和十六烷酸鲸蜡醇酯与5-ASA按用量比4:1时分别在45min、30min和15min后使药物溶解,而低于4:1的用量比时在60min之后才使药物溶解。虽然该研究表明这三类脂溶性物质能够溶解5-ASA,但是需要在加热条件下经过较长时间才能溶解,未从根本上解决5-ASA水溶性差的问题。
Tenjarla[2]对六种市售美沙拉胺制剂在pH值与人类胃肠道常见pH值相似的条件下5-ASA的体外释放进行了研究,结果表明在pH值1.0和6.4时,每种美沙拉明制剂的5-ASA释放率均为1%,各制剂之间的5-ASA溶出率变化不大。从上述研究结果可以看出,虽然目前市售的各种美沙拉胺制剂通过包衣能够较好实现5-ASA的药物递送和靶向缓释,但现有药物并未从根本上解决5-ASA溶解度差的问题,仍只有少量的药物释放来发挥作用。
C.Mura[3]提出用带环糊精(CD)和不带环糊精的nss-壳聚糖经冻干制备三维非晶态基质用于5-ASA结肠递送,特别考察了5-ASA:CD:ns-壳聚糖在4:1:20摩尔比条件下对药物释放的影响。结果表明,在基质中引入这些环状低聚糖对5-ASA结肠递送没有任何有利的结果。
C.Mura[4]进一步制备了用于结肠中5-氨基水杨酸(5-ASA)转运的ns-壳聚糖微粒子,5-ASA负载的壳聚糖微粒子可以扩散到大面积的结肠,提高了药物的负载量,并能够提高药物释放率,使5-ASA的局部疗效更显著,但是对于5-ASA的溶解度并无本质上的改善。
Suet Li Chew[5]采用3D打印技术制备了载药聚乙烯醇纤维丝,采用极性溶剂DMSO、EtOH和MeOH增加极性来制备载药纤维丝,但得到的5-ASA-EtOH载药丝的载药量仅为0.1%,5-ASA-MeOH的载药量为0.17%。在体外溶出介质中,增加PVA浓度,测定5-ASA在pH6.8磷酸盐缓冲液中的饱和溶解度为2.98mg/mL,该方法获得的5-ASA在酸性环境下的溶解度仍然不高,而且并不能增加其水溶性。
Saboktakin[6]报道了采用水溶性的树状大分子来进行5-ASA的溶解和给药,其方法是先将树状大分子PAMAM采用过量的乙酸酐进行乙酰化,将5-氨基水杨酸溶于二甲基甲酰胺中,然后得到壳聚糖与药物溶液的混合溶液,将壳聚糖药物溶液滴加于含不同浓度戊二醛饱和甲苯的氯化钠-饱和三盐酸缓冲液中,进行固化后分离,用0.05M Tris-HCl缓冲液洗涤后真空干燥,得到Ac-PAMAM-CS水凝胶,然后将5-ASA溶于甲醇中与Ac-PAMAM-CS水凝胶混合,混合物在黑暗条件下搅拌24小时,然后旋转蒸发除去甲醇,再向其中加入去离子水,黑暗条件下搅拌24小时,才使得5-ASA完全溶解,其制备得到的CS-PAMAM(G4)-(5-ASA)纳米复合材料用于5-ASA的药物递送。上述方法并不能直接增加5-ASA在水中的溶解度,并且需要对树状大分子进行乙酰化改性,且大量使用有机溶剂,工艺过程复杂,后处理麻烦。
大量文献表明,虽然有大量的增溶剂报道能够对某些难溶性物质起到一定增溶效果,但是目前对于5-氨基水杨酸未能提供一种有效的药物形式,即使是采用增溶手段,将其给药到靶向部位,但其在体内释放和治疗的效果仍不佳,仍然存在药物利用度不高的问题。因此,在能够显著增加5-氨基水杨酸在水中的溶解度的同时,如何提供一种有效的药物剂型,以提高其药物利用度,提高该药物在溃疡性结肠炎中的治疗效果,成为亟待解决的技术问题。
参考文献如下:
[1]Silveira.Loading of 5-aminosalicylic in solid lipid microparticles(SLM)Solubility screening of lipid excipients and physicochemicalcharacterization[J].JOURNAL OF THERMAL ANALYSIS AND CALORIMETRY.2020.
[2]Tenjarla.Dissolution of Commercially Available MesalamineFormulations atVarious pH Levels[J].DRUGS IN R&D.2015.
[3]C.Mura.In vitro study of N-succinyl chitosan for targeted deliveryof 5-aminoslicylic acid to colon,Carbohydr.Polym.85(2011)578-583.
[4]C.Mura.Design,characterization and in vitro evaluation of5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colonspecific delivery[J].Colloids and Surfaces B:Biointerfaces 94(2012)199-205.
[5]Suet Li Chew.3D-Printed Solid Dispersion Drug Products[J].pharmaceutics.2019.
[6]Saboktakin.Synthesis and Characterization of Chitosan HydrogelsContaining 5-Aminosalicylic Acid Nanopendents for Colon:Specific DrugDelivery[J].JOURNAL OF PHARMACEUTICAL SCIENCES.2010.
发明内容
本发明的目的就是为了解决上述技术问题,而提供一种高水溶性的5-氨基水杨酸药物组合物及其制剂、其制备方法和应用。本发明提供的药物组合物能够大大提高难溶性药物5-氨基水杨酸在水中的溶解度,其提升幅度可达25.62倍以上,且并不需要通过复杂的反应和大量有机溶剂的助溶即可获得高浓度的5-氨基水杨酸水溶液。该组合物除了能够从根本上提升5-氨基水杨酸的水溶性之外,还能够大大增加对5-氨基水杨酸的药物负载量。在本发明的药物组合物的基础上制备的各种制剂,发现其在给药后在体内的释放和利用效果要显著优于现有其它增溶后的药物制剂,从根本上改善了5-氨基水杨酸的体内利用问题,因此本发明的药物组合物作为制剂后用于治疗葡聚糖硫酸钠诱导的溃疡性结肠炎方面具有很好的疗效,其药物利用度大大提高,提升了现有制剂的治疗水平。
本发明的目的之一是提供一种高水溶性的5-氨基水杨酸药物组合物,所述药物组合物包括组分5-氨基水杨酸和第四代树形高分子聚酰胺-胺,所述第四代树形高分子聚酰胺-胺具有氨基末端。
本发明提供的上述药物组合物,经申请人研究发现,二者组合之后直接能够使得5-氨基水杨酸的悬浮液变得透明,其中的树形高分子聚酰胺-胺能够将5-氨基水杨酸的溶解度显著提高25.62倍以上,并且大幅度增加了难溶性药物5-氨基水杨酸的药物利用度。进一步经体外研究发现,该药物组合物在酸性微环境中,还具有药物响应性释放特性。因此本发明的药物组合物可以显著提高5-氨基水杨酸溶解性和利用度,从而大大提高了难溶性药物5-氨基水杨酸在溃疡性结肠炎中的治疗效果。
另一方面,本发明的上述组合物中,因组分之一第四代树形高分子聚酰胺-胺高度支化的树枝状结构及多链末端的功能性基团,能够为5-氨基水杨酸提供充足位点,可以直接高量负载脂溶性药物5-氨基水杨酸。第四代树形高分子聚酰胺-胺能够高效负载5-氨基水杨酸,大幅度提高其溶解性,并能在肠道局部缓释抗炎性5-氨基水杨酸用于治疗葡聚糖硫酸钠诱导的溃疡性结肠炎。第四代树形高分子聚酰胺-胺在水溶液中具有良好的溶解能力,经过第四代树形高分子聚酰胺-胺修饰的5-氨基水杨酸组合物同时提高了疏水性5-氨基水杨酸的水溶解度,可使5-氨基水杨酸稳定长期停留在肠液或肠泌粘液,同时二者形成的纳米颗粒组合物更容易穿越肠粘膜上皮细胞分泌的黏液化学屏障,直接接触肠上皮细胞,释放5-氨基水杨酸分子发挥抗炎作用。
进一步的是,所述药物组合物中5-氨基水杨酸与第四代树形高分子聚酰胺-胺的摩尔比为1:20~1:30。经申请人研究发现,在该摩尔比范围内能够最佳程度发挥该药物组合物的作用,起到最佳的体内抗炎效果。
进一步的是,所述药物组合物还包括溶剂,所述溶剂包括水、有机溶剂或有机溶剂的水溶液,优选的,所述有机溶剂包括二甲基亚砜。
本发明的目的之二是提供一种高水溶性的5-氨基水杨酸药物组合物的制备方法,其包括以下步骤:将第四代树形高分子聚酰胺-胺溶解于溶剂中,然后向其中加入5-氨基水杨酸,将混合液超声形成澄清的溶液,选择性除去或不除去溶剂。
本发明的目的之三是提供一种高水溶性的5-氨基水杨酸的药物制剂,所述药物制剂包括如上所述的药物组合物。
进一步的是,所述制剂的形式为药学上可接受的任意剂型,包括胶囊、片剂、丸剂、水剂、注射制剂(葡萄糖或氯化钠等)或栓剂。
本发明的目的之四是提供一种高水溶性的5-氨基水杨酸药物组合物的应用,其包含如上所述的药物组合物,该应用是将该药物组合物用于制备治疗肠道性炎症方面的药物。
进一步的,所述肠道性炎症包括溃疡性结肠炎,具体包括由葡聚糖硫酸钠诱导的溃疡性结肠炎。具体应用时,所述药物组合物制备成的制剂是通过在体内靶向缓释5-氨基水杨酸用于肠道性炎症如溃疡性结肠炎的治疗。
本发明的有益效果如下:
本发明的药物组合物不仅解决了5-氨基水杨酸水溶性差的根本问题,显著增加了5-氨基水杨酸的水溶性,同时该组合物还从根本上解决了5-氨基水杨酸在体内的利用问题,很好解决了5-氨基水杨酸在口服和直肠用药中由于水溶性差带来的药物利用度不高的根本问题。本发明的组合物可通过提高疏水性5-氨基水杨酸溶解度和负载量显著提升葡聚糖硫酸钠诱导的溃疡性结肠炎的治疗效果,显著提高了5-氨基水杨酸的利用率。
附图说明
图1为本发明的组合物中两种组分形成纳米复合物的过程示意图;
图2为G4和G4-ASA的TEM结果;
图3:(a)G4和G4-ASA的电势电位;(b)G4和G4-ASA的粒子大小;
图4为G4,5-ASA及G4-ASA复合物的UV-Vis吸收光谱;
图5为G4的肉眼观高溶解性:图中浑浊的5-ASA悬浮液(a)转变为了透明的G4-ASA溶液(b);
图6为不同浓度的G4以5-ASA作为模型药物时G4-ASA的载药特性;图7在pH 7.4环境下测定5-ASA分别从5-ASA溶液和G4-ASA溶液的释放情况。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例对本发明进行具体描述,有必要指出的是,以下实施例仅仅用于对本发明进行解释和说明,并不用于限定本发明。本领域技术人员根据上述发明内容所做出的一些非本质的改进和调整,仍属于本发明的保护范围。
以下实施例中的部分缩略词的含义如下:
G4:具有氨基末端的第四代树形高分子聚酰胺-胺;5-ASA:5-氨基水杨酸;G4-ASA:具有氨基末端的第四代树形高分子聚酰胺-胺与5-氨基水杨酸形成的纳米颗粒复合物。
实施例1
选择具有氨基末端的第四代树形高分子聚酰胺-胺(简记为G4,含有64个表面氨基,其分子量为14215g/mol,由Aldrich Company(UK)生产,其合成路线参照西南石油大学硕士学位论文《改性树枝状聚酰胺-胺的合成及其在破乳中的应用》,黄华平,2014),将G4溶解于去离子水中后再溶解不同浓度的5-氨基水杨酸(5-ASA),将混合液超声2h形成稳定的纳米颗粒复合物,记为G4-ASA。为了评估本发明组合物的药物溶解能力,称取3mg的5-ASA与100mL的不同浓度的G4水溶液混合后超声2h,10000rpm离心5分钟去除沉淀,取上清液,通过光谱仪(UV-vis spectrometer)测量上清液中5-ASA的溶解度(浓度)。
对照例1
将3mg的5-ASA直接溶于100mL的去离子水中混合后得到5-ASA悬浮液,超声2h并在10000rpm下离心5分钟去除沉淀,取上清液,通过光谱仪(UV-vis spectrometer)测量上清液中5-ASA的溶解度(浓度),即测定在未添加G4时5-ASA的溶解度。
测试例1
(一)外观形貌表征
用相机在宏观角度记录G4-ASA复合物和5-ASA悬浮液的外观。G4和G4-ASA纳米颗粒形态与电势电位和粒径大小分别通过TEM(Transmission Election Microscopy)和动态光散射(Dynamic light scattering)来测定和观察。G4-ASA复合物通过光谱仪(UV-visspectrometer)测定吸收光谱以确认G4-ASA复合物形成。
(二)相关溶液的物理化学特性
通过平衡渗透实验法测定5-ASA从G4中和水溶液中的释放率。将相应溶液转至透析袋中(摩尔分子量低于3500Da)后,透析袋两端封闭后沉浸入45mL的PBS溶液。通过工作力良好的摇床在37℃下不断晃动透析袋外PBS溶液。在特定的时间点收集透析袋外PBS液1mL后再补充等量的新鲜PBS溶液。5-ASA累积释放量通过HPLC(High Performance LiquidChromatography)进行测定。
结果例1
(一)总体特点和G4-ASA的高溶解性
图1为G4包裹5-ASA后的复合物形成示意图。TEM结果显示G4 PAMAM和G4-ASA复合物的粒径微小,呈圆点状散布,并呈现聚集现象(图2)。通过动态光散射(dynamic lightscattering)量化G4和G4-ASA的大小和电势电位,证明复合物G4-ASA与G4相比具有更大的电势电位和粒径大小(图3a,3b)。
UV-VIs吸收值表现出G4-ASA具备完整的,介于G4波和5-ASA波之间的独立波,表明5-ASA吸收入G4后形成了独立的G4-ASA复合物,使溶液波长从300nm(5-ASA)变为330nm(G4-ASA)(图4)。
肉眼观将G4加入5-ASA悬浮液后将白色浑浊悬浮液明显地转变为透明水溶液,因此G4显著提高了5-ASA在去离子水中的溶解度(图5)。经测试,不同浓度的G4溶液中5-ASA的饱和溶解度见表1,可见,5-ASA在无G4加入的情况下(5-ASA悬浮液)的水溶解度仅为0.901mg/mL,随着G4加入浓度增加5-ASA溶解度呈直线式上涨,直到G4浓度30mg/mL(即水溶液中G4的浓度,相当于1mL水中含有30mg G4)时达23.132mg/mL(图6)。由此可以看出,仅30mg/mL浓度的G4即可有效地提升5-ASA水溶解度25.62倍,这表明G4-ASA在应用于结肠炎的治疗过程中出色的载药能力。
表1不同浓度G4溶液中5-ASA的饱和溶解度
(二)药物释放结果
本实验中探究了抗炎试剂5-ASA在不同条件下从复合物中的释放行为及影响因素。比较了5-ASA溶液和G4-ASA溶液对5-ASA的释放(图7)。24h时,5-ASA溶液几乎将所有的5-ASA药物以释放完毕,相比而言G4-ASA溶液展现出更低的累积释放量和更低的释放速率。这可能是由于G4将疏水性5-ASA包裹于内部疏水空腔,延缓了5-ASA的释放速度,达到缓释5-ASA的效果。显然G4-ASA在缓释药物方面优于传统的5-ASA溶液。
对比例1
以增溶剂SDS(十二烷基硫酸钠)替换本发明中的G4,与5-ASA悬浮液混合,发现当向5-ASA悬浮液中加入30mg/mL的SDS时,对于5-ASA的水溶解度提升倍数仅为5.14倍。
对比例2
以“Saboktakin.Synthesis and Characterization of Chitosan HydrogelsContaining 5-Aminosalicylic Acid Nanopendents for Colon:Specific DrugDelivery[J].JOURNAL OF PHARMACEUTICAL SCIENCES.2010.”中的方法作为对照,分别取乙酰化改性的Ac-PAMAM和壳聚糖改性的Ac-PAMAM-CS溶液与5-ASA悬浮液混合,在使用浓度均为30mg/mL时,得出这两种物质对于5-ASA的水溶解度提升倍数分别为13.21倍和15.96倍。
对比例3
将本发明中的G4替换为端基为—OH修饰的PAMAM-OH,发现PAMAM-OH(4代)的添加浓度为30mg/mL时,对5-ASA的水溶解度提升倍数为12.35倍。
对比例4
将本发明中的G4替换为G3和G5(即分别为第三代和第五代树形高分子聚酰聚酰胺-胺),与5-ASA组成组合物,在相同的用量配比下,用于由葡聚糖硫酸钠诱导的溃疡性结肠炎的治疗,试验结果表明这两种组合与本发明的组合相比,用于小鼠模型的治疗,治疗效果表明本发明组合物的疗效最佳,而替换后的组合物效果不如本发明。
Claims (9)
1.一种高水溶性的5-氨基水杨酸药物组合物,其特征在于,所述药物组合物包括组分5-氨基水杨酸和第四代树形高分子聚酰胺-胺,所述第四代树形高分子聚酰胺-胺具有氨基末端;所述5-氨基水杨酸和第四代树形高分子聚酰胺-胺形成纳米颗粒;所述药物组合物中5-氨基水杨酸与第四代树形高分子聚酰胺-胺的摩尔比为1:20~1:30。
2.根据权利要求1所述的高水溶性的5-氨基水杨酸药物组合物,其特征在于,所述药物组合物还包括溶剂,所述溶剂包括水、有机溶剂或有机溶剂的水溶液。
3.根据权利要求1所述的高水溶性的5-氨基水杨酸药物组合物,其特征在于,所述有机溶剂包括二甲基亚砜。
4.一种如权利要求1-3任一项所述高水溶性的5-氨基水杨酸药物组合物的制备方法,其特征在于,包括以下步骤:将第四代树形高分子聚酰胺-胺溶解于溶剂中,然后向其中加入5-氨基水杨酸,将混合液超声形成澄清的溶液,除去或不除去溶剂。
5.一种高水溶性的5-氨基水杨酸药物制剂,其特征在于,所述药物制剂包括权利要求1-3任一项所述的药物组合物。
6.根据权利要求5所述的药物制剂,其特征在于,所述制剂的形式为药学上可接受的任意剂型,包括胶囊、片剂、丸剂、水剂、注射制剂或栓剂。
7.一种如权利要求1-3任一项所述的高水溶性的5-氨基水杨酸药物组合物的应用,其特征在于,所述应用包括将该药物组合物用于制备治疗肠道性炎症方面的药物。
8.根据权利要求7所述的应用,其特征在于,所述肠道性炎症包括溃疡性结肠炎。
9.根据权利要求7或8所述的应用,其特征在于,所述溃疡性结肠炎包括由葡聚糖硫酸钠诱导的溃疡性结肠炎。
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