CN113968780A - 白木香素a和b及其制备方法与其药物组合物和应用 - Google Patents
白木香素a和b及其制备方法与其药物组合物和应用 Download PDFInfo
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Abstract
本发明提供白木香素A(aquilarisinensin A,PES‑5a)和白木香素B(aquilarisinensin B,PES‑14)及其制备方法,以其为活性成分的药物组合物,以及PES‑5a和PES‑14在制备预防和治疗神经退行性疾病和抑郁症的药物中的应用。属于医药技术领域。本发明证实PES‑5a和PES‑14对皮质酮诱导的PC12细胞损伤有显著的保护作用,可以用于制备预防和治疗抑郁症的药物组合物或膳食补充组合物。
Description
技术领域:
本发明属于医药技术领域,尤其涉及白木香素A和B与其药物组合物及其制备方法,与其在制备预防和治疗神经退行性疾病的药物中的应用。
背景技术:
抑郁症(depression)又称抑郁障碍,是一种发病机制复杂多样的精神系统疾病,其典型的特征是高发病率、死亡率及致残率,严重威胁着人类的身心健康。近年来虽然人们从多方面揭示了抑郁症潜在的发生发展机制,但仍然没有一个统一的标准。现有治疗药物存在疗效出现比较缓慢的缺点,部分药物还有口渴、大便干结、血压升高等副作用[高贵元,黄捷,刘丹,张芳,张超群,张国利,陈丽华,邵迎新.抑郁症的发病机制及抗抑郁药物的研究进展.中国医药导报,2021,18(1):52-55]。因此,寻找新的治疗药物和方法,是抑郁症研究的热点和难点。
大鼠肾上腺嗜铬细胞瘤细胞系(pheochromocytoma cells,PC12 cells)起源于神经嵴,表达神经生长因子(NGF)受体。PC12细胞是一种儿茶酚胺细胞,能合成贮存并释放适量的儿茶酚胺(主要是多巴胺和去甲肾上腺素),具有典型的神经细胞特征,其作为体外模型被广泛用于研究多种神经系统疾病以及用于中药活性成分筛选[王秀力,陈东,刘佳梅.NGF诱导PC12细胞向神经元的分化.吉林大学学报(医学版),2007,33(5):827-830;嵇源源,楚小晶,王剑文.应用PC12细胞损伤模型筛选中药活性成分的研究进展.中成药,2013,35(6):1282-1288;Delavar MR,Baghi M,Safaeinejad Z,Kiani-Esfahani A,Ghaedi K,Nasr-Esfahani MH.Differential expression of miR-34a,miR-141,and miR-9in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease.Gene,2018,662:54-65;Shilo D,Cohen G,Blumenfeld A,Goren K,Hanhan S,Sharon S,Haze A,Deutsch D,Lazarovici P.Tuftelin is required for NGF-induced differentiationof PC12 cells.Journal of Molecular Neuroscience,2019,68(1):135-143]。
皮质酮诱导的PC12细胞损伤模型,是目前公认的抑郁症治疗药物的筛选模型[JiL-L,Wang X,Li J-J,Zhong X-J,Zhang B,Juan J,Shang X-Y.New iridoid derivativesfrom the fruits of Cornus officinalis and their neuroprotectiveactivities.Molecules,2019,24(3):625;Jiang B-P,Liu Y-M,Le L,Li Z-Y,Si J-Y,LiuX-M,Chang Q,Pan R-L.Cajaninstilbene acid prevents corticosterone-inducedapoptosis in PC12 cells by inhibiting the mitochondrial apoptoticpathway.Cellular Physiology and Biochemistry,2014,34(3):1015-1026]。
迄今为止,现有技术中未见有白木香素A和B的报道,以及其具有对神经退行性疾病和抑郁症的活性的报道。
发明内容:
本发明提供新化合物白木香素A和B与其药物组合物及其制备方法,及其在制备预防和治疗神经退行性疾病的药物中的应用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
如下结构式所示的白木香素A和白木香素B,
白木香素A和白木香素B在制备预防和治疗神经退行性疾病和抑郁症的药物中的应用。
白木香素A和白木香素B在制备预防神经退行性疾病和抑郁症的功能食品中的应用。
本发明同时提供了白木香素A和白木香素B的制备方法,该方法包括下述步骤:
干燥的中药沉香,即瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材,粉碎后,用10L的90%乙醇超声提取5次,每次30min,提取液减压蒸馏除去溶剂,得浸膏,然后将浸膏悬浮于1L水中,依次用等体积石油醚(5×1L)、乙酸乙酯(5×1L)和正丁醇(5×1L)萃取,回收溶剂得石油醚部分,乙酸乙酯部分,正丁醇部分,以及水部位(萃余部位);取正丁醇部分用80~100目硅胶拌样、装柱,以乙酸乙酯-甲醇(100:0→0:1,v/v)为洗脱剂进行梯度洗脱,薄层色谱检测合并相同馏分得5个部分Fr.1~Fr.5;Fr.2通过反相(RP)C18柱层析,以甲醇-水(5%→100%,v/v)进行梯度洗脱,经TLC检测后合并得到得Fr.2-1~Fr.2-13共13个部分;Fr.2-3用正相硅胶层析(300~400目),以二氯甲烷-甲醇为洗脱剂,进行梯度洗脱(50:1→1:1),得到5个组分(Fr.2-3-1~Fr.2-3-5);Fr.2-3-2由半制备高效液相色谱(Welch Ultimate AQ C18色谱柱,5μM,7.8×250mm;MeOH-H2O,20:80)纯化得到白木香素A(PES-5a)(tR=15.072min)和白木香素B(PES-14)(tR=22.831min)。
本发明还提供了一种药物组合物,其由治疗有效量的权利要求1所述的白木香素A和白木香素B任其一或组合,以及可药用载体所组成。
所述的药物组合物在制备预防和治疗神经退行性疾病和抑郁症的药物中的应用。
所述的药物组合物在制备预防神经退行性疾病和抑郁症的功能食品中的应用。
所述的药物组合物的制备方法,该方法包括下述步骤:
干燥的中药沉香,即瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材,粉碎后,用10L的90%乙醇超声提取5次,每次30min,提取液减压蒸馏除去溶剂,得浸膏,然后将浸膏悬浮于1L水中,依次用等体积石油醚(5×1L)、乙酸乙酯(5×1L)和正丁醇(5×1L)萃取,回收溶剂得石油醚部分,乙酸乙酯部分,正丁醇部分,以及水部位(萃余部位);取正丁醇部分用80~100目硅胶拌样、装柱,以乙酸乙酯-甲醇(100:0→0:1,v/v)为洗脱剂进行梯度洗脱,薄层色谱检测合并相同馏分得5个部分Fr.1~Fr.5;Fr.2通过反相(RP)C18柱层析,以甲醇-水(5%→100%,v/v)进行梯度洗脱,经TLC检测后合并得到得Fr.2-1~Fr.2-13共13个部分;Fr.2-3用正相硅胶层析(300~400目),以二氯甲烷-甲醇为洗脱剂,进行梯度洗脱(50:1→1:1),得到5个组分(Fr.2-3-1~Fr.2-3-5);Fr.2-3-2由半制备高效液相色谱(Welch Ultimate AQ C18色谱柱,5μM,7.8×250mm;MeOH-H2O,20:80)纯化得到白木香素A(PES-5a)(tR=15.072min)和白木香素B(PES-14)(tR=22.831min);然后再以白木香素A和/或白木香素B为活性成分,加入可药用载体。
此外,本发明提供了一种治疗神经系统疾病的药物,由以下重量百分比的组份所组成:白木香素A和/或白木香素B占20~80%,分散剂2~20%,崩解剂3~5%,乳化剂3~8%,粘结剂0.2~2%,润湿剂0.5~10%,其余为填料。
以及,一种膳食补充组合物,由以下的重量百分比的组份所组成:白木香素A和/或白木香素B占20~80%,常用食品辅料80~20%。
与现有相比,本发明具备如下的优益性:
1.首次从白木香含有树脂的心材中发现了新化合物白木香素A和B(PES-5a和PES-14)。提供了现有技术中未有的具有较好药用价值的新化合物,填补了技术空白。
2.本发明提供的新化合物白木香素A和B的制备方法简单易行,得率高,环保节料。
3.本发明提供的新化合物白木香素A和B具有较好的神经保护活性,其中,PES-5a在浓度为5μM、10μM、20μM和40μM时,对皮质酮诱导的PC12细胞损伤均具有显著的保护活性(P<0.001);化合物PES-14在20μM和40μM时,对皮质酮诱导的PC12细胞损伤均具有显著的保护活性(P<0.001)。
4.本发明提供了新化合物白木香素A和B的一个全新的药物应用,提供了新化合物白木香素A和B在预防和治疗神经退行性疾病和抑郁症的药物中的应用。
5.本发明提供了新化合物白木香素A和B的一个全新的药物应用,提供了新化合物白木香素A和B在预防神经退行性疾病和抑郁症的膳食补充组合物中的应用。
附图说明
图1:化合物PES-5a和PES-14的化学结构式示意图;
图2:化合物PES-5a和PES-14关键的二维核磁共振相关图;
图3:化合物PES-5a和PES-14实验的和计算的电子圆二色谱图。
具体实施方式:
下面用本发明的实施例来进一步说明本发明的实质性内容,但并不以此来限定本发明。
实施例1
白木香素A [aquilarisinensin A,(4S,5S,7S,8S,10S,13R)-7,8,13-dihydroxyrotunda-1,11-dien-3-one,PES-5a](化合物PES-5a)(图1)和白木香素B[aquilarisinensin B,(4S,5S,7S,8S,10S,13S)-7,8,13-Dihydroxyrotunda-1,11-dien-3-one,PES-14)(化合物PES-14(图1)的制备:
干燥的中药沉香,即瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材(2.9kg),粉碎后,用10L的90%乙醇超声提取5次,每次30min。提取液减压蒸馏除去溶剂,得浸膏(459.3g)。然后将浸膏悬浮于1L水中,依次用等体积石油醚(5×1L)、乙酸乙酯(5×1L)和正丁醇(5×1L)萃取,回收溶剂得石油醚部分0.7g,乙酸乙酯部分374.8g,正丁醇部分55.9g,以及水部位(萃余部位)6.9g。
取正丁醇部分(55.9g)用80~100目硅胶拌样、装柱,以乙酸乙酯-甲醇(100:0→0:1,v/v)为洗脱剂进行梯度洗脱,薄层色谱检测合并相同馏分得5个部分(Fr.1~Fr.5)。
Fr.2(16.7g)通过反相(RP)C18柱层析,以甲醇-水(5%→100%,v/v)进行梯度洗脱,经TLC检测后合并得到得Fr.2-1~Fr.2-13共13个部分。Fr.2-3(456.6mg)用正相硅胶层析(300~400目),以二氯甲烷-甲醇为洗脱剂,进行梯度洗脱(50:1→1:1),得到5个组分(Fr.2-3-1~Fr.2-3-5)。Fr.2-3-2(114.7mg)由半制备高效液相色谱(Welch Ultimate AQC18色谱柱,5μM,7.8×250mm;MeOH-H2O,20:80)纯化得到PES-5a(10.6mg,tR=15.072min)和PES-14(11.9mg,tR=22.831min)。
化合物PES-5a的波谱数据和结构鉴定:
白木香素A[aquilarisinensin A,(4S,5S,7S,8S,10S,13R)-7,8,13-dihydroxyrotunda-1,11-dien-3-one,PES-5a],浅黄色油状;[α]2D7-95.4(c=0.50,MeOH);UV(MeOH)λmax(logε)234(4.12)(3.81)nm;ECD(c 0.015,MeOH)λmax(Δε)246(+2.59),203(-13.63)nm;IRνmax(KBr)3416,2962,2932,2872,1686,1683,1600,1456,1384,1281,1196,1082,1044,1025,997,930cm-1;1H NMR和13C NMR数据见表1;ESIMS(negative)m/z299[M+Cl]-,309[M+HCOO-]+;ESIMS(positive)m/z 287[M+Na]+,551[2M+Na]+;HRESIMS(positive)m/z 287.1255[M+Na]+(calcd for C15H20NaO4,287.1259)。
根据化合物PES-5a的高分辨质谱(HRESIMS)及13C核磁共振(NMR)数据(表1),推测其分子式为C15H20O4。其1H和13C NMR数据(表1)表明,该化合物含有一个α,β-不饱和酮片段[δH 5.91(br s);δC 214.1,188.3,130.4],一个环外双键[δH 5.55(br s),5.36(br s);δC156.3,112.3],两个甲基[δH 1.29(s),1.14(d,J=7.4Hz);δC 25.2,15.4],一个亚甲基,四个次甲基,其中两个连氧的[δH 4.12(t,J=2.2Hz),3.88(dd,J=10.7,5.3Hz);δC 75.4,71.8],以及两个季碳(δC 77.3and 42.8)。PES-5a的NRR数据跟一个已知的倍半萜化合物(4R,5S,7R,8S,10S,13R)-8,13-Dihydroxyrotunda-1,11-dien-3-one非常接近[文献:WeiS-Y,Hu D-B,Xia M-Y,Luo J-F,Yan H,Yang J-H,Wang Y-S,Wang Y-H.Sesquiterpenoidsand 2-(2-phenylethyl)chromone derivatives from the resinous heartwood ofAquilaria sinensis.Natural Products and Bioprospecting,2021,11:545–555]。根据PES-5a二维NMR波谱中的COSY相关(图2),可以推断出两个片段,即C-15-C-4-C-5-C-6和C-8-C-9;根据二维NMR波谱中HMBC相关(图2),包括从H-2到C-4和C-5,从H3-15到C-3、C-4和C-5,从H2-6到C-1、C-8和C-11,从H2-12到C-7和C-13,以及从H3-14到C-1、C-9、C-10和C-13的相关,推测出PES-5a的平面结构为7,8,13-Trihydroxyrotunda-1,11-dien-3-one;根据二维NMR波谱中ROESY相关(图2),包括H3-15/H-5、H-5/H-9α、H-9β/H-13he和H-8/H-13,推测出PES-5a的相对立体构型如图2所示。最后,通过比较PES-5a实验的和计算的电子圆二色谱(ECD,图3),确定了PES-5a的绝对构型为(4S,5S,7S,8S,10S,13R)-7,8,13-Trihydroxyrotunda-1,11-dien-3-one,命名为白木香素A(aquilarisinensin A)。
表1化合物PES-5a的1H NMR和13C NMR数据(δin ppm,J in Hz)
化合物PES-14的波谱数据和结构鉴定:
白木香素B[aquilarisinensin B,(4S,5S,7S,8S,10S,13S)-7,8,13-Dihydroxyrotunda-1,11-dien-3-one,PES-14);浅黄色油状;(c=0.09,MeOH);UV(MeOH)λmax(logε)236(4.02)nm;ECD(c0.018,MeOH)λmax(Δε)258(+0.52),222(-6.96)nm;IRνmax(KBr)3425,2964,2927,2874,2852,1688,1633,1597,1456,1384,1284,1188,1073,1055,1028,982,928cm-1;1H NMR和13C NMR数据见表2;ESIMS(positive)m/z 287[M+Na]+,551[2M+Na]+;HRESIMS(positive)m/z 287.1253[M+Na]+(calcd for C15H20NaO4,287.1259)。
根据化合物PES-14的高分辨质谱(HRESIMS)及13C核磁共振(NMR)数据(表2),推测其分子式为C15H20O4,跟PES-5a一致,说明两个化合物是同分异构体。PES-14的13C NMR数据显示了15个碳原子信号,包括一个α,β-不饱和酮官能团(δC 214.1,191.5,and 128.5),一个环外双键(δC 156.3and 116.5),两个季碳(δC 77.1and 43.7),一个亚甲基,四个次甲基,其中两个连氧的(δC 78.5and 71.7),以及两个甲基(δC 24.5and 15.9)。根据PES-14二维NMR波谱中的COSY相关(图2),可以推断出两个片段,即C-15-C-4-C-5-C-6和C-8-C-9;根据二维NMR波谱中HMBC相关(图2),包括从H-2到C-4和C-5,从H3-15到C-3、C-4和C-5,从H2-6到C-1、C-8,和C-11,从H2-12到C-7和C-13,以及从H3-14到C-1、C-9、C-10和C-13的相关,推测出PES-14的平面结构为7,8,13-Trihydroxyrotunda-1,11-dien-3-one,跟PES-5a是一样的。化合物PES-14 1H NMR数据中,J8,9α(6.0Hz)和J8,9β(10.5Hz)的值,跟化合物PES-5a的这些值(J8,9α=5.3Hz and J8,9β=10.8Hz)非常接近,因此推测PES-14的H-8也是β-取向的。根据二维NMR波谱中ROESY相关(图2),包括H3-15/H-5、H-5/H-9α和H-2/H-13,推测出PES-14的相对立体构型如图3所示,它是PES-5a的C-13差向异构体。最后,通过比较PES-14实验的和计算的电子圆二色谱(ECD,图3),确定了PES-14的绝对构型为(4S,5S,7S,8S,10S,13S)-7,8,13-Trihydroxyrotunda-1,11-dien-3-one,命名为白木香素B(aquilarisinensin B)。
表2化合物PES-14的1H NMR和13C NMR数据(δin ppm,J in Hz)
实施例2:
化合物PES-5a和PES-14的神经保护活性测试方法如下:
1.PC12低分化细胞采用DMEM+10%FBS+100U/mL双抗的培养基进行培养,培养箱温度37℃,5%CO2;
2.当PC12低分化细胞长至合适数量时,取PC12低分化细胞,胰酶消化,制成细胞悬液;
3.将细胞悬液吸至15mL离心管中,800rpm,5min;
4.离心结束后,离心管用酒精消毒后拿进超净台,将上清倒入废液缸;
5.加入新的完全培养基5mL,用移液器吹打十次,尽量吹散细胞,但不能太用力;
6.取0.02mL细胞悬液,加入到细胞计数板中,上机计数;
7.将细胞浓度调整至1×105cells/mL,加入96孔板,每孔0.1mL,放入细胞培养箱培养;
8. 24小时后,将原培养基吸出,然后加入新的培养基,加入待测化合物;
9.实验设计:
空白组对照:不加皮质酮和Desipramine,只有细胞和终浓度为0.1%的DMSO;
模型组:含终浓度为150μM皮质酮和终浓度为0.1%的DMSO;
阳性对照组(desipramine):含终浓度为10μM Desipramine、终浓度为150μM皮质酮和终浓度为0.1%的DMSO;
PES-5a和PES14第一组至第五组:培养基分别加入终浓度为40、20、10、5和2.5μM的PES-5a和PES14,终浓度为150μM皮质酮和终浓度为0.1%的DMSO。
各组设计各做3个重复。
10.细胞放入细胞培养箱中继续培养;
11.每天观察细胞情况,在加入化合物48h后,用MTS法测吸光值,计算存活率(每个孔吸光值/空白组对照孔吸光值的平均值)。
实施例4:
化合物PES-5a和PES-14的神经保护活性的效果:
化合物PES-5a和PES-14的神经保护活性数据如表1所示。其中,PES-5a在浓度为5μM、10μM、20μM和40μM时,对皮质酮诱导的PC12细胞损伤均具有显著的保护活性(P<0.001);化合物PES-14在20μM和40μM时,对皮质酮诱导的PC12细胞损伤均具有显著的保护活性(P<0.001)。
表3.化合物PES-5a和PES-14对皮质酮诱导的PC12细胞损伤的保护作用
注释:跟模型组比较,***P<0.001。
实施例4:
制备治疗神经系统疾病的药物,按以下的重量百分比进行混合PES-5a或PES-14占20~80%,分散剂2~20%,崩解剂3~5%,乳化剂3~8%,粘结剂0.2~2%,润湿剂0.5~10%,其余为填料。然后按常规药物制备方法制得有效成分为PES-22的神经系统疾病的治疗药物。
实施例5:
口服液制剂的制备:
以PES-5a或PES-14为活性成分,按常规口服液制法制成口服液。
实施例6:
胶囊剂、颗粒剂、或冲剂的制备:
按PES-5a或PES-14与赋形剂重量比为5:1的比例加入赋形剂,制成胶囊或颗粒剂或冲剂。
实施例7:
膳食补充组合物的制备:按以下的重量百分比进行混合:PES-5a或PES-14占20~80%,常用食品辅料80~20%。
Claims (10)
2.权利要求1所述的白木香素A和白木香素B在制备预防和治疗神经退行性疾病和抑郁症的药物中的应用。
3.权利要求1所述的白木香素A和白木香素B在制备预防神经退行性疾病和抑郁症的功能食品中的应用。
4.权利要求1所述的白木香素A和白木香素B的制备方法,该方法包括下述步骤:
干燥的中药沉香,即瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材,粉碎后,用10L的90%乙醇超声提取5次,每次30min,提取液减压蒸馏除去溶剂,得浸膏,然后将浸膏悬浮于1L水中,依次用等体积石油醚(5×1L)、乙酸乙酯(5×1L)和正丁醇(5×1L)萃取,回收溶剂得石油醚部分,乙酸乙酯部分,正丁醇部分,以及水部位(萃余部位);取正丁醇部分用80~100目硅胶拌样、装柱,以乙酸乙酯-甲醇(100:0→0:1,v/v)为洗脱剂进行梯度洗脱,薄层色谱检测合并相同馏分得5个部分Fr.1~Fr.5;Fr.2通过反相(RP)C18柱层析,以甲醇-水(5%→100%,v/v)进行梯度洗脱,经TLC检测后合并得到得Fr.2-1~Fr.2-13共13个部分;Fr.2-3用正相硅胶层析(300~400目),以二氯甲烷-甲醇为洗脱剂,进行梯度洗脱(50:1→1:1),得到5个组分(Fr.2-3-1~Fr.2-3-5);Fr.2-3-2由半制备高效液相色谱(Welch Ultimate AQ C18色谱柱,5μM,7.8×250mm;MeOH-H2O,20:80)纯化得到白木香素A(PES-5a)(tR=15.072min)和白木香素B(PES-14)(tR=22.831min)。
5.由治疗有效量的权利要求1所述的白木香素A和白木香素B任其一或其组合,以及可药用载体所组成的药物组合物。
6.权利要求5所述的药物组合物在制备预防和治疗神经退行性疾病和抑郁症的药物中的应用。
7.权利要求5所述的药物组合物在制备预防神经退行性疾病和抑郁症的功能食品中的应用。
8.权利要求5所述的药物组合物的制备方法,该方法包括下述步骤:
干燥的中药沉香,即瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材,粉碎后,用10L的90%乙醇超声提取5次,每次30min,提取液减压蒸馏除去溶剂,得浸膏,然后将浸膏悬浮于1L水中,依次用等体积石油醚(5×1L)、乙酸乙酯(5×1L)和正丁醇(5×1L)萃取,回收溶剂得石油醚部分,乙酸乙酯部分,正丁醇部分,以及水部位(萃余部位);取正丁醇部分用80~100目硅胶拌样、装柱,以乙酸乙酯-甲醇(100:0→0:1,v/v)为洗脱剂进行梯度洗脱,薄层色谱检测合并相同馏分得5个部分Fr.1~Fr.5;Fr.2通过反相(RP)C18柱层析,以甲醇-水(5%→100%,v/v)进行梯度洗脱,经TLC检测后合并得到得Fr.2-1~Fr.2-13共13个部分;Fr.2-3用正相硅胶层析(300~400目),以二氯甲烷-甲醇为洗脱剂,进行梯度洗脱(50:1→1:1),得到5个组分(Fr.2-3-1~Fr.2-3-5);Fr.2-3-2由半制备高效液相色谱(Welch Ultimate AQ C18色谱柱,5μM,7.8×250mm;MeOH-H2O,20:80)纯化得到白木香素A(PES-5a)(tR=15.072min)和白木香素B(PES-14)(tR=22.831min);然后再以白木香素A和/或白木香素B为活性成分,加入可药用载体。
9.一种治疗神经系统疾病的药物,由以下重量百分比的组份所组成:白木香素A和/或白木香素B占20~80%,分散剂2~20%,崩解剂3~5%,乳化剂3~8%,粘结剂0.2~2%,润湿剂0.5~10%,其余为填料。
10.一种膳食补充组合物,由以下的重量百分比的组份所组成:白木香素A和/或白木香素B占20~80%,常用食品辅料80~20%。
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