CN105294676B - 一种小檗碱复盐及其制备方法和用途 - Google Patents
一种小檗碱复盐及其制备方法和用途 Download PDFInfo
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- CN105294676B CN105294676B CN201510855954.5A CN201510855954A CN105294676B CN 105294676 B CN105294676 B CN 105294676B CN 201510855954 A CN201510855954 A CN 201510855954A CN 105294676 B CN105294676 B CN 105294676B
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- China
- Prior art keywords
- jamaicin
- oleanolic acid
- ursolic acid
- double salt
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- WITLAWYGGVAFLU-UHFFFAOYSA-N 3-(6-methoxy-1,3-benzodioxol-5-yl)-8,8-dimethylpyrano[2,3-f]chromen-4-one Chemical compound C1=CC(C)(C)OC2=CC=C(C(C(C3=CC=4OCOC=4C=C3OC)=CO3)=O)C3=C21 WITLAWYGGVAFLU-UHFFFAOYSA-N 0.000 title claims abstract description 114
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- -1 jamaicin oleanolic acid salt Chemical class 0.000 claims abstract description 44
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 claims abstract description 27
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 claims abstract description 27
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 claims abstract description 27
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- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 claims abstract description 21
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 claims abstract description 17
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明公开一种小檗碱复盐,具体为小檗碱齐墩果酸盐或小檗碱熊果酸盐,其制备方法是将齐墩果酸或熊果酸在乙醇溶液中与氢氧化钠作用,再与小檗碱盐水溶液反应而制得,小檗碱齐墩果酸盐、小檗碱熊果酸盐难溶于水,亲脂性、无苦味;小檗碱与齐墩果酸、熊果酸都是有重要药理活性的天然化学成分,两者结合成离子对化合物,可以发挥更大的疗效,尤适用于口腔,黏膜和小儿用药;本发明药源丰富,制备简单,成本低,毒副作用小;小檗碱齐墩果酸盐、小檗碱熊果酸盐分别具有如下的结构式:
Description
技术领域
本发明涉及医药保健技术领域,具体是指一种小檗碱复盐及其制备方法和用途。
背景技术
盐酸小檗碱(又名盐酸黄连素)主要用于肠道感染和炎症,目前临床上也用于降糖调脂,近若年来研究发现它有多种重要药理活性,如抗病原微生物,抗炎、保肝、抗心衰和心律失常、防治风湿性关节炎、防治阿尔兹海默病,特别是抗癌作用备受关注,但盐酸小檗碱口服吸收差,临床应用受到限制。小檗碱对多种口腔致病菌有抑制作用,可用于防治牙周炎、龋齿,牙尖炎等。小檗碱有促进牙周膜的增殖和生物合成作用,有抗口腔癌作用,对口腔溃疡,急慢性咽炎有效。加拿大研究指出,治疗牙周炎可以降低血糖水平。欧洲研究发现牙周病与心脏病有相关性。如果小檗碱局部口腔给药,效果非常显著。但是黄连和小檗碱的味极苦,患者难以依从,尤其是小儿。为了解决小檗碱味苦的问题,有人用载体包含物,还有人用离子交换树脂吸附等,但都难以实用。早年日本研制鞣酸小檗碱又称无味黄连素,用于肠道感染腹泻,现为我国法定药品。近年来有膜剂、凝胶剂、栓剂的专利申请,用于口腔溃疡,咽炎和妇科炎症。
齐墩果酸是广泛存在于天然植物中的五环三萜类化合物,现为我国法定药物,用于急慢性肝炎和肿瘤的辅助治疗。现代研究发现有抗HIV病毒、抗菌、抗原虫抗病毒,降糖调脂、抗心律失常、强心、护胃、抗炎、抗变态反应、免疫调节以及抗肿瘤的药理作用,毒副作用小。韩国和美国已批准用于保护胃黏膜,骨关节炎和类风湿关节炎(有机化学,2013,33,46~65)。
齐墩果酸和熊果酸是化学结构相同的同分异构体,具有基本相似的理化性质和药理活性。
鞣酸小檗碱虽然无苦味,但它不溶于水,也不具有脂溶性,口服不吸收,适用于肠道感染腹泻。但也存在某些缺陷,鞣酸化学组成复杂,在空气中易变色氧化,影响质量,鞣酸对胃黏膜有刺激,能与蛋白结合,易产生便秘。鞣酸仅有微弱的生理活性。口服完全不吸收,由于不良的理化性质,也导致黏膜吸收困难。而齐墩果酸抗伤寒杆菌,金葡菌的作用比氯霉素还强。对万霉素耐药肠球菌的最低抑菌浓(MIC)仅为8μg/ml杀菌浓度为16μg/ml。熊果酸为4μg/ml和8μg/ml。齐墩果酸和熊果酸对多种口腔致病菌有抑制作用,如熊果酸对牙龈卟啉菌,中间型普氏菌和福赛氏类杆菌的MIC值极小,仅为0.74μg/ml齐墩果酸和熊果酸有抗真菌作用,抗原虫特别是疟原虫的作用(齐墩果酸和熊果酸抗微生物和原虫药理研究进展,抗感染药学,2010,7(3))。显然齐墩果酸和熊果酸的药理活性远远大于鞣酸,对肠道感染效果和口腔疾患更为显著。但是,齐墩果酸难溶于水(0.002mg/ml)溶解速率低,细胞渗过率差,以及首过效应的影响,导致极低的生物利用度(约0.7%),口服的全身治疗作用受到严重制约。(中国药学杂志,2009,18(6))。
发明内容
有鉴于此,本发明的目的在于提出一种小檗碱复盐,其具有无苦味、安全性高,脂溶性好的特点,具有优良的临床应用前景。
基于上述目的,本发明提供一种小檗碱复盐,具有式I所示结构通式:
所述A-为齐墩果酸负离子或熊果酸负离子,所述齐墩果酸负离子和熊果酸负离子的结构分别如式II和式III所示:
所述齐墩果酸负离子与小檗碱正离子结合成齐墩果酸小檗碱化合物,其结构式如式IV结构所示,所述熊果酸负离子与小檗碱正离子结合成熊果酸小檗碱化合物,其结构式如式V结构所示。
所述小檗碱复盐的制备方法包括以下步骤:
将齐墩果酸盐溶液或熊果酸盐溶液分别和小檗碱盐溶液混合,得到齐墩果酸小檗碱或熊果酸小檗碱。
本发明还提供一种小檗碱复盐组合物,所述小檗碱复盐组合物由小檗碱复盐作为有效成分加入适当的辅料或载体制成临床上可以接受的药物制剂。
本发明还提供一种小檗碱复盐在制备一种抗病原微生物,保肝、降糖、降脂、抗炎、护胃、抗变态反应、抗肿瘤,免疫调节和防治风湿炎风湿性关节炎的药物中的应用。
本发明还提供一种小檗碱复盐在制备为一种防治牙周炎,牙尖炎,龋齿、口腔溃疡,咽炎,鼻炎和口腔癌的药物的应用。
本发明还提供一种小檗碱复盐在制备为一种祛头屑,止痒,防止脱发的保健用品及日用化妆品的应用。
本发明的小檗碱复盐无苦味,活性高,且具有适当溶解性。所述小檗碱复盐,具体是小檗碱齐墩果酸盐和小檗碱熊果酸盐。小檗碱齐墩果酸盐又称齐墩果酸小檗碱,小檗碱熊果酸盐又称熊果酸小檗碱。
本发明的小檗碱复盐的制备方法,具体的优选,包括下列步骤:在乙醇介质中齐墩果酸或熊果酸与氢氧化钠反应生成钠盐,也可以制成其他盐类,优选钠盐,再与小檗碱盐水溶液作用生成小檗碱齐墩果酸盐或小檗碱熊果酸盐。
本发明的小檗碱齐墩果酸盐为黄色固体,无臭,无苦味,难溶于水,易溶于乙醇,甲醇,可溶于三氯甲烷,正辛醇,具有良好的脂溶性。
本发明的小檗碱齐墩果酸盐和小檗碱熊果酸盐经质谱和核磁共振测定,确证二者的分子式为C50H65NO7,相对分子质量为792.1,结构式如IV和V所示。
本发明的小檗碱齐墩果酸盐为活性成分,制备含片和凝胶剂可用于口腔和皮肤黏膜给药。
本发明的小檗碱齐墩果酸盐的小鼠灌胃急性毒性试验,LD50为807.21mg/vg,小檗碱熊果酸盐为1019.6mg/vg,均大于盐酸小檗碱,安全性高。
从上面所述可以看出,本发明提供的小檗碱复盐具有以下有益效果:
(1)、解决了小檗碱味苦的问题,尤适合于口腔小儿用药,有利于口腔疾病的防治。
(2)、改善了盐酸小檗碱、齐墩果酸、熊果酸单一成分的理化性质,具亲脂性,增加透膜吸收,可用于黏膜给药,克服首过效应,提高生物利用度,发挥全身治疗作用。
(3)、由两种活性成分组成的化合物,发挥协同增效作用,比单一成分的药理作用强。对肠道感染的治疗效果更为显著。
(4)、与现有的鞣酸小檗碱相比,性质稳定,结构清楚,质量可控,应用广泛,药效增强。因此本发明既提供了一种小檗碱又同时提供了一种齐墩果酸或熊果酸药用盐的形式,具有优良临床应用前景。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白,以下结合具体实施例,对本发明进一步详细说明。
实施例1
小檗碱齐墩果酸盐的制备方法,取齐墩果酸9克加70%(v/v)乙醇500毫升,加氢氧化钠0.6克,在温水浴上加热振摇,使大部分的齐墩果酸溶解,停止加温,加酚酞指示液5滴,滴加1mol/L氢氧化钠液,边加边摇,溶液呈粉红色不褪,此时溶液澄明,过滤,得滤液1,另取硫酸小檗碱(不限于硫酸小檗碱,优选硫酸小檗碱)10克加水1500毫升振摇使溶解,过滤,得滤液2,将滤液1缓缓分次加入到滤液2中,不断搅拌,放置,析出黄色沉淀,过滤,水洗,抽干,干燥,40%(v/v)乙醇水溶液重结晶,即得,得率约为80%。
实施例2
小檗碱熊果酸盐的制备方法,同实施例1小檗碱齐墩果酸盐的制备方法。
实施例3
小檗碱齐墩果酸盐和小檗碱熊果酸盐的结构确证。
MS(m/z):正离子模式336.1[MBer]+,负离子模式455.5[MoA]-,455.5[MuA]-。
小檗碱正离子的NMR
氢谱
1H NMR(500MHz,acetone-D6)δ:6.65(1H,s,H-3),2.81(1H,J=15.3,4.2,dt,H-5),2.74(1H,J=15.3,9.6,4.8,ddd,H-5),3.32(2H,m,H-6),5.31(1H,s,H-8),6.83(1H,J=8.3,d,H-12),6.72(1H,J=8.3,d,H-13),5.95(1H,s,H-15),7.17(1H,s,H-18),3.83(3H,s,OCH3-10),3.81(3H,s,OCH3-11),5.98,5.96(2H,J=1.1,d,H-1’)。
碳谱
样品的碳核磁共振图和DEPT谱显示化合物分子中共有20个碳原子,其13C NMR如下:δ:147.6(C-1),148.2(C-2),108.5(C-3),129.9(C-4),30.9(C-5),48.1(C-6),55.1(C-8),124.5(C-9),144.6(C-10),150.9(C-11),113.1(C-12),119.2(C-13),129.0(C-14),95.9(C-15),139.2(C-16),126.5(C-17),104.7(C-18),60.6(C-10),56.3(C-11),102.0(C-1’)。
齐墩果酸负离子的NMR
氢谱
1H NMR(500MHz,acetone-D6)δ:1.57,0.97(2H,H-1),1.55(2H,H-2),3.13(1H,J=11.1,4.7,d,H-3),0.75(1H,o,H-5),1.53,1.39(2H,H-6),1.48,1.29(2H,H-7),1.58(1H,H-9),1.86(2H,H-11),5.16(1H,J=2.9,t,H-12),1.81,1.02(2H,H-15),1.97,1.58(2H,H-16),2.88(1H,H-18),1.67,1.10(2H,H-19),1.38,1.17(2H,H-21),1.74,1.51(2H,H-22),0.97(3H,s,H-23),0.77(3H,s,H-24),0.91(3H,s,H-25),0.78(3H,s,H-26),1.13(3H,s,H-27),0.89(3H,s,H-29),0.90(3H,s,H-30)。
碳谱
样品的碳核磁共振图和DEPT谱显示化合物分子中共有30个碳原子,其13C NMR如下:δ:39.3(C-1),28.1(C-2),78.6(C-3),39.5(C-4),56.2(C-5),19.1(C-6),33.6(C-7),40.2(C-8),48.5(C-9),37.8(C-10),24.1(C-11),123.0(C-12),145.0(C-13),42.5(C-14),28.5(C-15),23.8(C-16),46.6(C-17),42.2(C-18),46.9(C-19),31.3(C-20),34.5(C-21),33.2(C-22),28.7(C-23),16.7(C-24),15.8(C-25),17.6(C-26),26.3(C-27),179.1(C-28),33.2(C-29),23.9(C-30)。
熊果酸负离子的NMR
氢谱
1H NMR(500MHz,acetone-D6)δ:1.61,1.00(2H,H-1),1.59,1.54(2H,H-2),3.14(1H,J=11.1,4.9,dd,H-3),0.77(1H,o,H-5),1.54,1.38(2H,H-6),1.54,1.32(2H,H-7),1.55(1H,H-9),1.90(2H,H-11),5.18(1H,J=3.4,br.t,H-12),1.95,1.06(2H,H-15),2.03,1.65(2H,H-16),2.23(1H,d,H-18),1.38(1H,H-19),0.97(1H,H-20),1.48,1.33(2H,H-21),1.66(2H,H-22),0.98(3H,s,H-23),0.77(3H,s,H-24),0.94(3H,s,H-25),0.83(3H,s,H-26),1.11(3H,s,H-27),0.94(3H,o.d.,H-29),0.87(3H,d,H-30)。
碳谱
样品的碳核磁共振图和DEPT谱显示化合物分子中共有30个碳原子,其13C NMR如下:δ:39.3(C-1),27.9(C-2),78.5(C-3),39.1(C-4),55.9(C-5),18.8(C-6),33.8(C-7),40.0(C-8),48.2(C-9),37.5(C-10),23.8(C-11),126.1(C-12),139.0(C-13),42.7(C-14),28.6(C-15),24.8(C-16),47.8(C-17),53.7(C-18),39.7(C-19),39.7(C-20),31.2(C-21),37.4(C-22),28.5(C-23),16.1(C-24),15.8(C-25),17.5(C-26),23.8(C-27),178.4(C-28),21.2(C-29),17.3(C-30)。
实施例4
采用灌胃给药观察小檗碱齐墩果酸盐对小鼠的急性毒性作用,其半数致死剂量LD50为807.27mg/kg。
实施例5
采用灌胃给药法观察小檗碱熊果酸盐对小鼠的急性毒性试验,其半数致死剂量LD50为1019.6mg/kg。
实施例6
含片的制备
一、配方
二、制法:
小檗碱齐墩果酸盐或小檗碱熊果酸盐粉碎,过100目筛,加入木糖醇、麦芽糊精、甜菊糖苷,混合均匀,95%乙醇制软材,24目筛制粒,60℃干燥,24目筛整粒,加入薄荷脑与0.5%的硬脂酸镁,混合均匀,压片,制成约1000片(0.5g/片)。
实施例7
凝胶剂的制备
凝胶剂制备过程:将2.5g海藻酸钠撒入含50mL蒸馏水的烧杯中密闭放置过夜使其充分溶胀,在溶胀好的海藻酸钠溶液中加入甘油3g,尼泊金乙酯0.05g,搅拌均匀,制成海藻酸钠空白凝胶,用适量乙醇将2.5g檗碱齐墩果酸盐或小檗碱熊果酸盐溶解,缓慢加至海藻酸钠空白凝胶中,搅拌均匀即可。
所属领域的普通技术人员应当理解:以上任何实施例的讨论仅为示例性的,并非旨在暗示本公开的范围(包括权利要求)被限于这些例子;在本发明的思路下,以上实施例或者不同实施例中的技术特征之间也可以进行组合,步骤可以以任意顺序实现,并存在如上所述的本发明的不同方面的许多其它变化,为了简明它们没有在细节中提供。因此,凡在本发明的精神和原则之内,所做的任何省略、修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种小檗碱复盐,其特征在于,具有式I所示结构通式:
所述A-为齐墩果酸负离子或熊果酸负离子,所述齐墩果酸负离子和熊果酸负离子的结构分别如式II和式III所示:
所述齐墩果酸负离子与小檗碱正离子结合成齐墩果酸小檗碱,所述熊果酸负离子与小檗碱正离子结合成熊果酸小檗碱。
2.一种如权利要求1所述的小檗碱复盐的制备方法,其特征在于,包括以下步骤:
将齐墩果酸盐溶液或熊果酸盐溶液分别和小檗碱盐溶液混合,得到齐墩果酸小檗碱或熊果酸小檗碱。
3.一种小檗碱复盐组合物,其特征在于,所述小檗碱复盐组合物由小檗碱复盐作为有效成分加入适当的辅料和载体制成临床上可以接受的药物制剂。
4.一种如权利要求1所述的小檗碱复盐在制备一种抗病原微生物,保肝、降糖、降脂、抗炎、护胃、抗变态反应、抗肿瘤,免疫调节和防治风湿炎风湿性关节炎的药物中的应用。
5.一种如权利要求1所述的小檗碱复盐在制备为一种防治牙周炎,牙尖炎,龋齿、口腔溃疡,咽炎,鼻炎和口腔癌的药物的应用。
6.一种如权利要求1所述的小檗碱复盐在制备为一种祛头屑,止痒,防止脱发的保健用品及日用化妆品的应用。
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