CN117357664A - 一种甲基-β-环糊精和阿苯达唑的包合物及其制备方法 - Google Patents
一种甲基-β-环糊精和阿苯达唑的包合物及其制备方法 Download PDFInfo
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- CN117357664A CN117357664A CN202311330799.6A CN202311330799A CN117357664A CN 117357664 A CN117357664 A CN 117357664A CN 202311330799 A CN202311330799 A CN 202311330799A CN 117357664 A CN117357664 A CN 117357664A
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- albendazole
- cyclodextrin
- methyl
- beta
- inclusion compound
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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Abstract
本发明公开了一种甲基‑β‑环糊精和阿苯达唑的包合物及其制备方法。所述甲基‑β‑环糊精和阿苯达唑的包合物包括如下成分:甲基‑β‑环糊精、阿苯达唑;所述甲基‑β‑环糊精和阿苯达唑的质量比为(1‑10):1。所述甲基‑β‑环糊精和阿苯达唑的包合物的制备方法包括如下步骤:将阿苯达唑溶液加入甲基‑β‑环糊精溶液中,反应后,除去溶剂,经纯化得到产物。本发明使阿苯达唑的水溶性从0.2μg/mL提高到30mg/mL,其水溶性提高了150000倍,阿苯达唑在最初10min内可释放70%,表明该包合物可作为一种新的高效口服抗线虫和抗肿瘤治疗制剂。
Description
技术领域
本发明属于医药技术领域,特别涉及一种甲基-β-环糊精和阿苯达唑的包合物及其制备方法。
背景技术
阿苯达唑由于其抗虫谱广,对人类和动物的蠕虫寄生虫有很强的杀虫作用,并且毒性低、安全性好,被世界卫生组织推荐为首选驱虫药。此外,阿苯达唑是一种微管解聚剂,在体外和体内对肝癌和结直肠癌细胞具有显著的活性。
阿苯达唑由于水溶性差(0.2mg/L)和高渗透性,在生物制药分类系统中属于第二类。阿苯达唑的肠道吸收率低、体内血药浓度低、生物利用度低,因此治疗全身性蠕虫感染需要大剂量;目前非肠道寄生虫病的临床治愈率仅为30%左右。使用IP或IV途径将药物用于癌症的临床应用需要更高的水溶性,通常为5-10mg/mL。这是因为低浓度的药物溶液需要非常大的用量才能达到所需的治疗剂量。这使得阿苯达唑的应用不切实际,严重影响了其作为抗癌药物的临床应用。
自1991年以来,为了提高阿苯达唑的溶解度从而增强其药效,人们进行了许多尝试,例如使用大豆油乳剂、表面活性剂、脂质体、聚乙烯吡咯烷酮、在酸中电离以及与环糊精复配。在这些方法中,与环糊精的络合比其他方法更好,因为阿苯达唑有三种同分异构体(图1为阿苯达唑的三种同分异构体结构式),环糊精可以与它们形成包合物,防止它们相互转化。其中,形式I和形式II是对映体相关的形式,市售的形式I在室温下易变,而形式II比较稳定。因此,与环糊精络合不仅可以增加溶解度,还可以稳定化合物。
据报道,β-环糊精包合物可稳定阿苯达唑,从而提高其水溶性和溶解速度。然而,由于β-环糊精的水溶性较低(18mg/mL),络合后的溶解度仅提高了53.4倍。并且,采用固体核磁共振光谱分析络合的固体产物后,在光谱中没有观察到阿苯达唑的信号。
有研究显示,阿苯达唑在与HP-β-环糊精的复合物中的溶解度增加了2到10000倍,溶解度高达1.9mg/mL。在HP-β-环糊精水溶液中加入柠檬酸、抗坏血酸、盐酸或醋酸,可将阿苯达唑的溶解度从0.2μm/mL提高到1.5mg/mL。将阿苯达唑与40%的磺丁基醚-β-环糊精在25℃和pH值为2.3的水中搅拌3天后,其水溶性达到8mg/mL。在相同条件下,HP-β-环糊精可使其水溶性达到6.4mg/mL。然而,阿苯达唑可溶于HCl溶液(0.4mg/mL),很难说8mg/mL的溶解度是由于酸性条件还是由于环糊精的增溶能力。
傅立叶变换红外光谱(FTIR)、二氯甲烷扫描光谱(DSC)、TAG、X射线和扫描电镜等多种技术已被用于确认固态复合物的形成。不过,水溶性的增加只能通过其在D2O中的质子核磁共振谱来确定。
当阿苯达唑在水中与40%的HP-β-环糊精、磺丁基醚-β-环糊精或甲基-β-环糊精一起处理时,其水溶性明显增加,分别从0.2μg/mL增加到0.79mg/mL、1.17mg/mL和1.52mg/mL,增加的水溶性通过D2O中的质子核磁共振谱得到证实。
还有研究通过喷雾干燥法合成柠檬酸酯-β-环糊精、伊他康酰-β-环糊精和琥珀酰-β-环糊精并与阿苯达唑络合。药物溶解速率和水溶性略有提高,并记录了它们在0.1NDCl和D2O中的质子核磁共振谱。由于阿苯达唑可溶于0.1HCl溶液(0.4mg/mL),因此复合物中阿苯达唑的化学位移不能完全支持药物的水溶性。
另外,在环糊精复合物中加入微量的水溶性聚合物(如聚乙烯吡咯烷酮K30)可增加药物的溶解度。
最近,在二甲基亚砜、丙酮和二氧化碳的混溶溶液中,采用超临界反溶剂技术将β-环糊精和阿苯达唑共沉淀,生成的沉淀物为微颗粒。通过光谱、热学和晶体学分析确定其特征后,发现这种新的固体形式含有阿苯达唑的同系物II。与单独的阿苯达唑相比,由于包合物的形成以及两种成分之间的协同作用,阿苯达唑的溶解速率提高了约4倍。不过,水溶性的增加并未得到测量和证实。有报道称,环糊精与阿苯达唑络合时的增溶能力可通过添加胆盐而增强。
总体而言,虽然现有研究在制备阿苯达唑/环糊精复合物方面付出了巨大努力,其水溶性仍未得到显著改善,与癌症治疗剂量所需的5-10mg/mL相去甚远。因此,有必要开发一种新的技术方案来提高阿苯达唑的水溶性,以解决现有技术中存在的问题。
发明内容
基于此,为解决现有技术中存在的缺陷和不足,本发明进一步研究了如何通过与环糊精形成包涵复合物来提高阿苯达唑的水溶性,提供了一种甲基-β-环糊精和阿苯达唑的包合物及其制备方法。本发明使阿苯达唑的水溶性从0.2μg/mL提高到30mg/mL,其水溶性提高了150000倍,阿苯达唑在最初10min内可释放70%,表明该包合物可作为一种新的高效口服抗线虫和抗肿瘤治疗制剂。
本发明的一个目的在于,提供一种甲基-β-环糊精和阿苯达唑的包合物,包括如下成分:甲基-β-环糊精、阿苯达唑。
进一步地,所述甲基-β-环糊精和阿苯达唑的质量比为(1-10):1。
进一步地,还包括助剂,所述助剂选自聚乙烯吡咯烷酮、水杨酸钠、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙二醇、十二烷基硫酸钠、溴化己二甲胺、三(羟甲基)氨基甲烷、乙酸钠或苯扎氯铵中的一种或多种。
本发明的另一个目的在于,提供上述甲基-β-环糊精和阿苯达唑的包合物的制备方法,包括如下步骤:
将阿苯达唑溶液加入甲基-β-环糊精溶液中,反应后,除去溶剂,经纯化得到产物。
进一步地,所述反应的方法选自超声法、溶液法、高压反应器法、微波反应器法、超临界CO2法中的一种或多种。
进一步地,所述超声法的反应条件为:20-30℃下,500-600W超声反应0.5-2h。
进一步地,所述溶液法的反应条件为:50-60℃下,以800-1200r/min搅拌反应5-10h。
进一步地,所述高压反应器法的反应条件为:在高压反应器中,110-130℃下,以800-1200r/min搅拌反应6-10h。
进一步地,所述微波反应器法的反应条件为:在微波反应器中,以200-400r/min搅拌反应0.5-2h,其中,每加热10min,停止反应5min。
进一步地,所述超临界CO2法的反应条件为:向甲基-β-环糊精和阿苯达唑混合溶液中加入液态CO2,在20-30℃下搅拌反应。
进一步地,所述纯化的方法包括洗涤、过滤、冷冻干燥。
本发明的有益效果如下:
本发明提供的甲基-β-环糊精和阿苯达唑的包合物,通过阿苯达唑与甲基-β-环糊精复配,使水溶性提高了150000倍,阿苯达唑在最初10min内可释放70%,这是目前最好的结果。在体内药代动力学研究中,活性代谢亚砜的Cmax和Tmax从3h的2.81提高到6h的10.2,AUC0-∞从50.72提高到119.95,T1/2从18.48h降低到3.04h,表明本发明的包合物可作为一种新的口服抗线虫和抗肿瘤治疗制剂,具有良好的应用前景。
附图说明
图1为阿苯达唑的三种同分异构体结构式。
图2示出了阿苯达唑在不同环糊精溶液中的溶解度。。
图3示出了阿苯达唑、甲基-β-环糊精及其物理混合物和包合物的傅立叶变换红外光谱图;
其中,
图3(a)为甲基-β-环糊精的傅立叶变换红外光谱图;
图3(b)为阿苯达唑的傅立叶变换红外光谱图;
图3(c)为物理混合物的傅立叶变换红外光谱图;
图3(d)为包合物的傅立叶变换红外光谱图。
图4示出了阿苯达唑、甲基-β-环糊精及其物理混合物和包合物的差示扫描量热曲线;
其中,
图4(a)为甲基-β-环糊精的差示扫描量热曲线;
图4(b)为阿苯达唑的差示扫描量热曲线;
图4(c)为物理混合物的差示扫描量热曲线;
图4(d)为包合物的差示扫描量热曲线。
图5示出了阿苯达唑在DMSOd6中的质子核磁共振谱、甲基-β-环糊精在D2O中的质子核磁共振谱以及包合物在D2O和DMSOd6中的质子核磁共振谱;
其中,
图5(a)为甲基-β-环糊精在D2O中的质子核磁共振谱;
图5(b)为包合物在D2O中的质子核磁共振谱;
图5(c)为阿苯达唑在DMSOd6中的质子核磁共振谱;
图5(d)为包合物在DMSOd6中的质子核磁共振谱。
图6示出了阿苯达唑/甲基-β-环糊精包合物在D2O中的Roesy光谱。
图7示出了阿苯达唑、阿苯达唑与甲基-β-环糊精的物理混合物以及包合物的溶解曲线。
图8示出了阿苯达唑、阿苯达唑砜和阿苯达唑亚砜的结构式;
其中,
Ⅰ为阿苯达唑;Ⅱ为阿苯达唑砜;Ⅲ为阿苯达唑亚砜。
图9示出了空白狗血浆中阿苯达唑、阿苯达唑砜和阿苯达唑亚砜的标准曲线;
其中,
图9(a)为阿苯达唑;
图9(b)为阿苯达唑砜;
图9(c)为阿苯达唑亚砜。
图10示出了空白狗血浆中的阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的高效液相色谱分析结果;
其中,
图10(A)为含有阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的样品;
图10(B)为空白狗血浆;
图10(C)为含有阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的血浆;
图10(D)为服用阿苯达唑的血浆;
图10(E)为服用阿苯达唑与甲基-β-环糊精复合物的血浆。
图11示出了阿苯达唑、阿苯达唑亚砜或阿苯达唑砜在狗血浆中的浓度与时间的关系曲线;
其中,
图11(a)为阿苯达唑;
图11(b)为阿苯达唑砜;
图11(c)为阿苯达唑亚砜。
具体实施方式
为了更清楚地说明本发明的技术方案,列举如下实施例。实施例中所出现的原料、反应和后处理手段,除非特别声明,均为市面上常见原料,以及本领域技术人员所熟知的技术手段。
本发明中的词语“优选的”、“优选地”、“更优选的”等是指,在某些情况下可提供某些有益效果的本发明实施方案。然而,在相同的情况下或其他情况下,其他实施方案也可能是优选的。此外,对一个或多个优选实施方案的表述并不暗示其他实施方案不可用,也并非旨在将其他实施方案排除在本发明的范围之外。
应当理解,除了在任何操作实例中,或者以其他方式指出的情况下,表示例如说明书和权利要求中使用的成分的量的所有数字应被理解为在所有情况下被术语“约”修饰。因此,除非相反指出,否则在以下说明书和所附权利要求中阐述的数值参数是根据本发明所要获得的期望性能而变化的近似值。
本发明实施例、测试例中:
甲基-β-环糊精(平均分子量:1303)、羟丙基-γ-环糊精、阿苯达唑、阿苯达唑亚砜标准品(98%)和阿苯达唑砜(98%)购自上海麦克林;柠檬酸、HP-β-环糊精和β-环糊精购自萨恩化学技术有限公司;无水醋酸钠购自西陇科学股份有限公司;狗取自广东省医学实验动物中心;空白狗血浆取自广州睿特生物科技有限公司,低脂狗粮取自广州睿特生物科技有限公司;低脂狗粮购自上海吉百创实业有限公司。
柠檬酸盐-β-环糊精采用文献“S.,Chaleawlert-umpon,O.,Nuchuchua,S.,Saesoo,P.,Gonil,U.R.Ruktanonchai,W.Sajomsang,N.Pimpha,Effect of citratespacer on mucoadhesive properties of a novel water-soluble cationicβ-cyclodextrin-conjugated chitosan,Carbohydr.Poly.,2011,84:186–194.”报道的方法制备。
本发明测试例中,统计分析方法为:每个实验都是一式三份,结果以平均值±标准偏差表示。统计分析采用单因素方差分析,然后使用DPS软件进行Tukey's诚实显著性差异检验。统计显著性定义为P<0.05。
实施例1
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)在醋酸(5mL)中的溶液加入甲基-β-环糊精(750mg)在水(10mL)中的溶液,在磁力搅拌器(RCT数字式,购自IKA)中搅拌均匀;然后将混合溶液在超声波反应器(宁波新芝生物科技有限公司JY92-IIN)中,25℃、520W下超声1h,并不时用冰水冷却,然后在4℃下冷藏6h,蒸发溶剂后,溶于水(15mL),用0.22μm滤膜过滤,冷冻干燥,得到凝块固体粉末。
实施例2
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)在醋酸(5mL)中的溶液加入甲基-β-环糊精(750mg)在水(10mL)中的溶液,将混合液在50℃、800r/min的条件下搅拌6h,然后在4℃下冷藏6h,蒸发溶剂后,溶于水(15mL),用0.22μm滤膜过滤,冷冻干燥,得到凝块固体粉末。
实施例3
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)和甲基-β-环糊精(750mg)在水和醋酸(30mL,67:33)中的混合溶液加入高温高压反应釜(上海贝加尔科技集团股份有限公司BZ-100ML/SC-L)中,在120℃、800r/min的条件下搅拌8h,蒸发溶剂后,加水、过滤,冷冻干燥,得到产品。
实施例4
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)在醋酸(5mL)中的溶液与甲基-β-环糊精(750mg)在水(10mL)中的溶液混合,然后将混合溶液在微电脑微波化学反应器(巩义裕华仪器有限公司WBFY-201)中以300r/min的速度搅拌1h;在反应过程中,每加热10min,然后静置5min;然后在4℃下冷藏,蒸发溶剂后,将残留物溶于水(15mL),过滤(0.22μm)并冷冻干燥,得到固体粉末。
实施例5
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)在冰醋酸(5mL)中的溶液与甲基-β-环糊精(750mg)在水(10mL)中的溶液混合,在反应器(上海贝加尔智能科技有限公司BZ-100ML/S0-L反应器)中注入液态CO2,并在25℃下搅拌,缓慢释放压力后,将溶液置于4℃的冰箱中保存;旋转蒸发除去溶剂后,将残留物溶于水(15mL),经0.22μm滤膜过滤和冷冻干燥后,得到固体粉末。
实施例6
一种甲基-β-环糊精和阿苯达唑的包合物,其制备方法包括如下步骤:
将阿苯达唑(150mg)在醋酸(5mL)中的溶液加入甲基-β-环糊精(750mg)在水(10mL)中的溶液,再加入5.6mg十二烷基硫酸钠(阿苯达唑的0.25%),搅拌30min后,将所得溶液在25℃、520W下超声40min,并不时用冰块冷却,然后在4℃下冷藏,蒸发溶剂,然后溶解于水(15mL)中,用0.22μm滤膜过滤,冷冻干燥,得到凝块固体粉末。
对比例
一种甲基-β-环糊精和阿苯达唑的混合物,其制备方法包括如下步骤:
将研磨好的阿苯达唑和甲基-β-环糊精混合(摩尔比为1:3),过80目筛,得到物理混合物。
测试例1
性能表征
1.阿苯达唑紫外最大吸光波长测定
将阿苯达唑(10mg)的乙酸溶液(5mL)用乙醇(95%,95mL)稀释,取5mL溶液用乙醇(95%,45mL)稀释,用紫外分光光度计(上海晶华科技仪器有限公司J51903001)在200-400nm范围内进行扫描。
2阿苯达唑高效液相色谱标准曲线的建立
阿苯达唑的一系列甲醇溶液浓度分别为0.01mg/mL、0.02mg/mL、0.04mg/mL、0.06mg/mL、0.08mg/mL和0.1mg/mL,采用Shim-pack VP-ODS C18色谱柱(250mm×4.6mm),以乙腈/水(30:70,V/V)为流动相、流速为1.0mL/min,紫外检测器(292nm)检测。根据高效液相色谱峰面积和浓度,得出线性回归方程和高效液相色谱标准曲线。
3.阿苯达唑在不同环糊精溶液中的溶解度
将过量的阿苯达唑加入浓度为5、10、15、20、25和30mmol/mL的β-环糊精、HP-β-环糊精、甲基-β-环糊精、柠檬酸-β-环糊精、γ-环糊精或HP-γ-环糊精水溶液中。每种溶液在室温下搅拌48h,过滤、用水稀释,然后用高效液相色谱分析。
4.傅立叶变换红外光谱研究
将阿苯达唑、甲基-β-环糊精、它们的物理混合物和包合物(与后文中的包合物均基于超声法制备)的干燥样品分别在VERTEX 70傅立叶变换红外光谱仪(购自Bruker公司)上用玛瑙研钵研磨,在红外灯下与光谱纯溴化钾混合,倒入压模中压制成KBr颗粒,用于400-4000cm-1范围内的傅立叶变换红外光谱分析。
5.差示扫描量热法研究
阿苯达唑、甲基-β-环糊精、它们的混合物和包合物的差示扫描量热曲线是在DSC214差示扫描量热仪(德国Netzsch公司)上记录的,方法是将它们置于铝坩埚中,在氮气环境下(150mL/min),以10℃/min的速率在25至300℃的扫描范围内加热。Al2O3用作参比。
6.质子核磁共振研究
在Bruker光谱仪(400MHz)上记录了甲基-β-环糊精溶液及其与阿苯达唑的包合物在D2O中的质子NMR光谱,以及阿苯达唑溶液及其包合物在DMSOd6中的质子NMR光谱,在D2O中记录的包合物的Roesy光谱在Bruker光谱仪(600MHz)上记录。
7.包合物中阿苯达唑含量的测定
将包合物(100mg)溶于水(1mL)中,搅拌2h,用水稀释至10μg/mL-100μg/mL(在此范围内建立了阿苯达唑HPLC标准曲线)。根据HPLC分析,通过回归方程计算包合物中的阿苯达唑含量。
8.阿苯达唑在包合物中的水溶性测定
将过量的包合物溶解于水(1mL)中2h,得到饱和水溶液,过滤后,样品即可用于HPLC分析。
9.包合率和包合产率的测定
包合率和包合产率的计算方法如下:
包合产率(%)=[阿苯达唑包合物(mg)/添加的阿苯达唑(mg)+甲基-β-环糊精(mg)]×100%;
包合率(%)=[包合物中的阿苯达唑(mg)/添加的阿苯达唑(mg)]×100%。
10.溶解率测定
采用《中国兽药典》2010年版Ⅰ的桨叶法,将阿苯达唑(50mg)、阿苯达唑包合物(含阿苯达唑50mg)、阿苯达唑与甲基-β-环糊精的物理混合物(含阿苯达唑50mg)分别置于脱气的0.1mol/L盐酸的物理混合物(900mL),在RC-3溶出度仪(天津市新天光分析仪器技术有限公司1号美国药典仪器篮)上以50r/min,在1、3、5、10、15、30、45、60和75min时,各取5mL混合物,然后在相同时间加入5mL相同的溶出培养基,经0.22μm微孔滤膜过滤30s后,在295nm波长下进行高效液相色谱分析,根据高效液相色谱数据得到溶出率曲线。
测试结果:
从200-400nm记录了阿苯达唑在乙醇(0.1mg/mL)和环糊精在水(1mg/mL)溶液中的紫外光谱,观察到阿苯达唑在292nm处有最大吸收。环糊精在此波长附近没有紫外线吸收,因此选择292nm波长进行阿苯达唑的HPLC分析。
对甲醇中浓度为0.01、0.02、0.04、0.06、0.08和0.1mg/ml的阿苯达唑溶液进行高效液相色谱分析,根据浓度和峰面积得出回归方程为Y=15598X+10.71(R2=0.9991,Y=浓度,X=峰面积)。
为避免出现系统误差,HPLC标准曲线和样品分析(包括血浆样品)均在同一台HPLC仪器上用同一根C-18色谱柱在短时间内完成,在HPLC分析前后,用HPLC检验了酮康唑标准溶液,以确认HPLC分析条件的稳定性。
图2示出了阿苯达唑在不同环糊精溶液中的溶解度。
研究发现,甲基-β-环糊精对阿苯达唑的增溶效果最好,根据Higuchi和Connors的描述,阿苯达唑与甲基-β-环糊精之间的线性关系属于AL型。
采用超声法、水溶液搅拌法、水热反应器法、微波法和CO2超临界法,将甲基-β-环糊精与阿苯达唑络合。所得溶液经高效液相色谱分析,发现超声法得到的络合物水溶性增加最大。
反应温度、反应时间、阿苯达唑与甲基-β-环糊精的比例以及超声功率都会影响络合效果。通过基于实验设计法的单因素和正交策略,在改变配比、超声功率、反应温度和反应时间的基础上,设计了多种与甲基-β-环糊精形成络合物的络合条件。经过高效液相色谱分析,发现提高溶解度的最佳条件如下:配比为1:3,反应时间为45min(每5s反应一次,间隔10s),超声波功率为80%,反应温度为25℃,偶尔用冰块冷却。最佳溶解度高达27mg/mL。
环糊精及其络合物通过自结合,可形成聚集体或胶束状结构,以非包合络合的方式增溶水不溶性药物,水溶性聚合物可增强环糊精的增溶作用。在阿苯达唑的络合反应中分别加入少量(0.25%)的十种水溶性聚合物或有机盐,经工作和高效液相色谱分析发现,加入十二烷基硫酸钠的络合物可使阿苯达唑的水溶性提高到30mg/mL,是单独使用药物的15万倍,是目前最好的结果。该包合物的包合率为16%,包合产率为86%,可用于包合物确认、体外和体内药代动力学研究。
络合物中只含有微量的十二烷基硫酸钠(按阿苯达唑用量计算为0.25%),因此络合物的傅立叶变换红外光谱、电热恒温光谱和核磁共振光谱无法显示其特征信号。
图3示出了阿苯达唑、甲基-β-环糊精及其物理混合物和包合物的傅立叶变换红外光谱图;
其中,
图3(a)为甲基-β-环糊精的傅立叶变换红外光谱图;
图3(b)为阿苯达唑的傅立叶变换红外光谱图;
图3(c)为物理混合物的傅立叶变换红外光谱图;
图3(d)为包合物的傅立叶变换红外光谱图。
根据图3可以看出,2647cm-1(咪唑中的-NH分子内振动)、1730cm-1(氨基甲酸酯中C=O键的弯曲振动)、1600cm-1(苯并咪唑中C=C芳香族和N-H的平面外弯曲)、1581cm-1(C=N基团的伸缩振动)、1491cm-1和1373cm-1(C-N和C-O伸缩振动)、1248cm-1、1123cm-1、1029cm-1(CH和NH平面内弯曲振动和CH变形)、1000-600cm-1(骨架振动、CH平面外弯曲、NH2摇摆和C-S伸缩振动),在阿苯达唑和甲基-β-环糊精的物理混合物(C)中明显可见,但在包合物(D)中略有减少。阿苯达唑特征峰的这些变化证实阿苯达唑与环糊精发生了络合。
图4示出了阿苯达唑、甲基-β-环糊精及其物理混合物和包合物的差示扫描量热曲线;
其中,
图4(a)为甲基-β-环糊精的差示扫描量热曲线;
图4(b)为阿苯达唑的差示扫描量热曲线;
图4(c)为物理混合物的差示扫描量热曲线;
图4(d)为包合物的差示扫描量热曲线。
根据图4可以看出,由于水分子从甲基-β-环糊精的空腔中蒸发,甲基-β-环糊精在50-125℃的曲线中出现了与脱水相对应的内热事件(A),阿苯达唑在225℃的曲线中出现了与熔化效应相对应的内热事件(B)、甲基-β-环糊精和阿苯达唑的物理混合物(C)在50-125℃范围内的甲基-β-环糊精脱水,阿苯达唑在225℃时没有与熔化相对应的内热现象,而在205℃时有内热现象,这表明物理混合物中的阿苯达唑和甲基-β-环糊精之间存在相互作用。包合物(D)的DSC曲线显示出与甲基-β-环糊精相同的热曲线,这可能是由于包合物中含有额外的甲基-β-环糊精,阿苯达唑在225℃时因被包裹而失去结晶结构,导致其特征性内热峰消失,这证实了阿苯达唑与甲基-β-环糊精之间的相互作用,并形成了一种新的相。
图5示出了阿苯达唑在DMSOd6中的质子核磁共振谱、甲基-β-环糊精在D2O中的质子核磁共振谱以及包合物在D2O和DMSOd6中的质子核磁共振谱;
其中,
图5(a)为甲基-β-环糊精在D2O中的质子核磁共振谱;
图5(b)为包合物在D2O中的质子核磁共振谱;
图5(c)为阿苯达唑在DMSOd6中的质子核磁共振谱;
图5(d)为包合物在DMSOd6中的质子核磁共振谱。
根据图5可以看出,D2O中包合物的质子核磁共振谱显示了阿苯达唑在7.61(1H,s)、7.56(1H,d,J1=8.0Hz)、7.33(1H,d,J1=8.0Hz)、2.91(2H,t,J1=8.0Hz)、1.54(2H,m)、1.06(3H,t,J1=8.0)处的信号。OCH3的信号与甲基-β-环糊精的信号重叠,范围在4.00ppm至3.50ppm之间。阿苯达唑在DMSOd6中的质子NMR光谱显示出7.46(1H,s)、7.34(1H,d,J1=8.0Hz)、7.11(1H,d,J1=8.0Hz)、3.76(3H,s,OCH3)、2.85(2H,d,J1=8.0Hz)、1.53(2H,d,J1=8.0Hz)和0.95(3H,d,J1=8.0Hz);DMSOd6中阿苯达唑包合物的质子NMR数据显示出7.42(1H,s)、7.34(2H,d,J1=8.0Hz)、7.10(2H,d,J1=8.0Hz)、2.65(2H,d,J1=8.0Hz)、1.54(2H,d,J1=8.0Hz)和0.95(3H,d,J1=8.0Hz)个信号。在DMSOd6中,阿苯达唑在包合物和单独药物之间的化学位移差异不能证明包合物的形成。
图6示出了阿苯达唑/甲基-β-环糊精包合物在D2O中的Roesy光谱。
根据图6可以看出,三个芳香质子、两个亚甲基质子和一个甲基质子的信号显示了与甲基-β-环糊精的相互作用,这证实了包合物的形成。
图7示出了阿苯达唑、阿苯达唑与甲基-β-环糊精的物理混合物以及包合物的溶解曲线。
根据图7可以看出,包合物中的阿苯达唑可在10min内释放70%,是单独阿苯达唑的14倍,是物理混合物的5倍。
测试例2
1.体内药代动力学研究
温州肯恩大学批准了本研究,伦理批件编号为WKULAEC2023-00。
阿苯达唑在肝脏中迅速代谢为阿苯达唑亚砜和阿苯达唑砜,阿苯达唑亚砜具有很好的驱虫活性,因此亚砜主要存在于血液中,这也是迄今为止进行的PK研究的主要特征。
将12只健康成年犬(雌雄各半,5±0.1kg)分为阿苯达唑组和复方组,称重、编号,在温暖通风的环境中以低脂食物和普通饮用水喂养1周,禁食1天,分别口服阿苯达唑或阿苯达唑复方(阿苯达唑25mg/kg)。
在服药0、0.25、0.5、0.75、1、1.5、2、3、4、6、8、12、24和48h后,通过前臂静脉采集血样(2mL),然后立即转移到肝素化试管中,在2000rpm转速下离心10min,然后保存在-20℃的冰箱中。
将解冻的血浆样本(0.5mL)移入离心管(2mL)中,加入硫代硫酸钠(200μg)和乙酸乙酯(1mL),涡旋5min,离心(13000r/min)10min,然后转移到试管中。反复涡旋和离心后,将试管中的上清液在40℃的氮气鼓风机中吹干,加入甲醇(0.5mL),涡旋5min,离心(13000r/min)10min,用0.22μm的微孔滤膜过滤,进行高效液相色谱分析。
2.血浆中阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的标准曲线
将塑料离心管中的空白血浆(0.5mL)加入浓度分别为5μg/mL、1μg/mL、0.5μg/mL、0.1μg/mL、0.05μg/mL和0.025μg/mL的阿苯达唑、阿苯达唑亚砜或阿苯达唑砜溶液中,涡旋振荡,用乙酸乙酯或二氯甲烷萃取,吹氮气,溶于甲醇(1mL),采用Shim-packVP-ODS C18色谱柱(250L×4.6mm),在295nm波长下进行高效液相色谱分析,得到标准曲线。
测试结果:
图8示出了阿苯达唑、阿苯达唑砜和阿苯达唑亚砜的结构式;
其中,
Ⅰ为阿苯达唑;Ⅱ为阿苯达唑砜;Ⅲ为阿苯达唑亚砜。
图9示出了空白狗血浆中阿苯达唑、阿苯达唑砜和阿苯达唑亚砜的标准曲线;
其中,
图9(a)为阿苯达唑;
图9(b)为阿苯达唑砜;
图9(c)为阿苯达唑亚砜。
用高效液相色谱法分析空白血浆中不同浓度的阿苯达唑、阿苯达唑砜和阿苯达唑亚砜的系列溶液,范围为0.1μg/mL至5μg/mL。阿苯达唑在高效液相色谱中的峰面积与血浆溶液中的阿苯达唑浓度呈线性关系,得到阿苯达唑的标准曲线方程为Y=36.185X+0.0942(判定系数R2=0.9983,Y=峰面积,X=浓度,S/N≥10,LLOD=0.054μg/mL,LLOQ=0.165μg/mL),阿苯达唑亚砜的标准曲线方程为:Y=42.51X-0.0942(判定系数R2=0.9983,Y=峰面积,X=浓度,S/N≥10):Y=42.51X-0.976(判定系数R2=0.9977,Y=峰面积,X=浓度,S/N≥10:LLOD=0.043μg/mL,LLOQ=0.141μg/mL),阿苯达唑砜的判定系数为:Y=37.706X-0.976,S/N≥10:LLOD=0.043μg/mL,LLOQ=0.141μg/mL:Y=37.706X-0.915(判定系数R2=0.9973,Y=峰面积,X=浓度,S/N≥10:LLOD=0.044μg/mL,LLOQ=0.147μg/mL)。
图10示出了空白狗血浆中的阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的高效液相色谱分析结果;
其中,
图10(A)为含有阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的样品;
图10(B)为空白狗血浆;
图10(C)为含有阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的血浆;
图10(D)为服用阿苯达唑的血浆;
图10(E)为服用阿苯达唑与甲基-β-环糊精复合物的血浆。
根据图10可以看出,在高效液相色谱条件下,空白狗血浆不干扰阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的检测。
浓度为2μg/mL、5μg/mL和10μg/mL的空白狗血浆中阿苯达唑、阿苯达唑亚砜和阿苯达唑砜的回收率和测定内变异系数如表1所示。
表1回收率和测定内变异系数
回收率 | 测定内变异系数 | |
阿苯达唑 | 90.2±6.1%-109.4±4.8% | 2.2%-3.62% |
阿苯达唑亚砜 | 89.8±3.6%-117.2±2.2% | 1.81%-2.24% |
阿苯达唑砜 | 93.9±4.1%-103.2±3.1% | 2.78%-5.49% |
图11示出了阿苯达唑、阿苯达唑亚砜或阿苯达唑砜在狗血浆中的浓度与时间的关系曲线;
其中,
图11(a)为阿苯达唑;
图11(b)为阿苯达唑砜;
图11(c)为阿苯达唑亚砜。
口服阿苯达唑后,部分代谢为阿苯达唑亚砜和阿苯达唑砜,其中阿苯达唑亚砜为抗虫活性物质。阿苯达唑亚砜在狗血浆中的Cmax和Tmax分别为:复方组在6.0h时为10.18μg/mL,阿苯达唑组在3.0h时为2.81μg/mL。复方组的T1/2从阿苯达唑组的18.48h变为3.04h,阿苯达唑亚砜的AUC0-∞从阿苯达唑组的50.72h·μg/mL变为复方组的119.95h·μg/mL,相对生物利用度为236%。不过,复方组阿苯达唑和阿苯达唑砜的Cmax、Tmax和AUC0-∞与阿苯达唑组相比没有显著差异。
药代动力学参数(平均值±标度)由Phoenix WinNonlin软件(8.3版)采用非室分析法计算,并汇总于表2。
表2阿苯达唑及其与甲基-β-环糊精包合物的药代动力学参数
通过与甲基-β-环糊精络合,活性物质阿苯达唑亚砜在体内的AUC0-∞增加了一倍,Cmax增加了两倍多,T1/2与单独使用阿苯达唑相比大大缩短,表明阿苯达唑与甲基-β-环糊精的包合物是迄今为止阿苯达唑作为潜在抗蠕虫药的最佳制剂。
综上所述,采用超声波法制备的阿苯达唑与甲基-β-环糊精的包合物中添加了微量的十二烷基硫酸钠,与单独制备阿苯达唑相比,阿苯达唑的水溶性提高了约15万倍,在其体内pk研究中,活性代谢物亚砜的Cmax和Tmax从2.81μg/mL提高到6h时的10.2μg/mL,AUC0-∞从50.72h·μg/mL提高到119.95h·μg/mL。
对于本领域技术人员而言,显然本发明不限于上述示范性实施例的细节,而且在不背离本发明的精神或基本特征的情况下,能够以其他的具体形式实现本发明。因此,无论从哪一点来看,均应将实施例看作是示范性的,而且是非限制性的,本发明的范围由所附权利要求而不是上述说明限定,因此旨在将落在权利要求的等同要件的含义和范围内的所有变化囊括在本发明内。
此外,应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
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Claims (10)
1.一种甲基-β-环糊精和阿苯达唑的包合物,其特征在于,包括如下成分:甲基-β-环糊精、阿苯达唑。
2.根据权利要求1所述甲基-β-环糊精和阿苯达唑的包合物,其特征在于,所述甲基-β-环糊精和阿苯达唑的质量比为(1-10):1。
3.根据权利要求1所述甲基-β-环糊精和阿苯达唑的包合物,其特征在于,还包括助剂,所述助剂选自聚乙烯吡咯烷酮、水杨酸钠、羟丙基甲基纤维素、羧甲基纤维素钠、聚乙二醇、十二烷基硫酸钠、溴化己二甲胺、三(羟甲基)氨基甲烷、乙酸钠或苯扎氯铵中的一种或多种。
4.权利要求1-3任一项所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,包括如下步骤:
将阿苯达唑溶液加入甲基-β-环糊精溶液中,反应后,除去溶剂,经纯化得到产物。
5.根据权利要求4所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述反应的方法选自超声法、溶液法、高压反应器法、微波反应器法、超临界CO2法中的一种或多种。
6.根据权利要求5所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述超声法的反应条件为:20-30℃下,500-600W超声反应0.5-2h。
7.根据权利要求5所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述溶液法的反应条件为:50-60℃下,以800-1200r/min搅拌反应5-10h。
8.根据权利要求5所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述高压反应器法的反应条件为:在高压反应器中,110-130℃下,以800-1200r/min搅拌反应6-10h。
9.根据权利要求5所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述微波反应器法的反应条件为:在微波反应器中,以200-400r/min搅拌反应0.5-2h,其中,每加热10min,停止反应5min。
10.根据权利要求5所述甲基-β-环糊精和阿苯达唑的包合物的制备方法,其特征在于,所述超临界CO2法的反应条件为:向甲基-β-环糊精和阿苯达唑混合溶液中加入液态CO2,在20-30℃下搅拌反应。
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