CN113563493A - 疏水化多糖及其制备方法与应用 - Google Patents
疏水化多糖及其制备方法与应用 Download PDFInfo
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- CN113563493A CN113563493A CN202110744511.4A CN202110744511A CN113563493A CN 113563493 A CN113563493 A CN 113563493A CN 202110744511 A CN202110744511 A CN 202110744511A CN 113563493 A CN113563493 A CN 113563493A
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- Prior art keywords
- polysaccharide
- hydrophobized
- water
- glucan
- acid
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Abstract
本发明提供一种疏水化多糖及其制备方法与应用。所述疏水化多糖的结构通式为G‑P‑O;其中,G为多糖或二糖,P为氨基酸与二酸缩合而成的两端带有羧基的连接分子,O为胆固醇;G和P之间通过酯键与多糖或二糖上的羟基连接,P和O之间通过酯键连接。本发明的疏水化多糖具有免疫调节性能,可与柴胡提取物共同发挥免疫调节作用。本发明疏水化多糖合成所用原料,皆安全、无毒,可用于食品、药品领域。疏水化多糖无毒,可在自然界全分解,无毒性。本发明的疏水化多糖修饰物,属于新型的高效药物递送载体,所制备的药液,药理活性高,强于现有的药物递送系统,微量药液就起显著药理作用,由于属于免疫调节性药物,具有一次治愈不复发的特性。
Description
技术领域
本发明涉及生物医药领域,具体地说,涉及一种疏水化多糖及其制备方法与应用。
背景技术
目前免疫调节剂的代表性药物为左旋咪唑和梯洛龙,主要通过诱导机体产生干扰素发挥抗病毒作用。它们属于化学合成的小分子药物,由于毒副作用大,限制了临床应用。多糖的胆固醇修饰物,由于具有低毒性、细胞靶向性,作为功能性乳化剂被广泛用于疫苗装载、药物递送以及氨基酸和肽类的递送体系,作为免疫调节剂的研究却鲜见报道。
发明内容
本发明的目的是提供一种新型的疏水化多糖及其制备方法与应用。
为了实现本发明目的,第一方面,本发明提供一种疏水化多糖,结构通式如下:G-P-O;
其中,G为多糖或二糖,P为氨基酸与二酸缩合而成的两端带有羧基的连接分子,O为胆固醇;G和P之间通过酯键与多糖或二糖上的羟基连接,P和O之间通过酯键连接。
所述多糖为水溶性多糖,所述多糖可选自透明质酸、硫酸软骨素、硫酸皮肤素、肝素、水溶性淀粉、水溶性菊糖、水溶性壳聚糖、水溶性葡聚糖、水溶性普鲁兰多糖、水溶性甘露糖、水溶性海藻多糖、水溶性淀粉、水溶性羟乙基右旋糖酐、水溶性果聚糖、水溶性木葡聚糖、水溶性纤维素、各类水溶性聚糖以及具有生理活性的多羟基化合物(如唾液酸)。
所述二糖可选自蔗糖、果糖或乳糖等。
所述氨基酸可选自甘氨酸、谷氨酸、L-赖氨酸、L-半胱氨酸、DL-丙氨酸、DL-蛋氨酸、L-鸟氨酸、γ-氨基丁酸、L-天门冬氨酸、L-茶氨酸、L-精氨酸、β丙氨酸、L-瓜氨酸、L-组氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、谷氨酰胺、天冬酰胺、组氨酸等中的至少一种,以及任意的合成的氨基酸,也可以选自各种氨基酸缩合而成的短肽(如双甘肽)。
所述二酸可选自乙二酸、丙二酸、丁二酸、乙二胺N,N二乙酸和N,N二羧基乙二胺。以及任意的化学合成的二酸,也可以选自带有两个羧基的氨基酸例如谷氨酸、天门冬氨酸等,以及化学合成的带有两个端羧基的氨基酸。
所述胆固醇可以是任意来源的胆固醇或者胆甾醇类化合物,例如各种动物来源的胆固醇或具有环戊烷多氢菲母核的胆甾醇类。
第二方面,本发明提供所述疏水化多糖的制备方法,包括以下步骤:
1)胆固醇与连接分子发生酯化反应生成中间体;
2)多糖或二糖与上述中间体发生缩合反应生成疏水化多糖。
第三方面,本发明提供一种疏水化葡聚糖,所述疏水化葡聚糖的结构如式(I)所示:
第四方面,本发明提供所述疏水化葡聚糖的制备方法,包括以下步骤:
①在有机溶剂中使丁二酸与羧基保护的甘氨酸反应,加入适量催化剂和脱水剂,反应温度0~60℃,反应时间1~96h,得到双乙酸基丁二酰胺;
②将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将上述双乙酸基丁二酰胺加入氢氧化钠水溶液中水解,再用盐酸水溶液中和,双乙酸基丁二酰胺的羧基迅速游离出,减压干燥除水后,复溶于有机溶剂,加入适量催化剂和脱水剂,于0~300℃反应1~96h;然后向上述反应体系中加入胆固醇,进行酯化反应,于0~300℃反应1~96h,加水终止反应,沉淀物精制干燥得到中间体;
③将步骤②所得中间体复溶于有机溶剂,加入葡聚糖,加入适量催化剂和脱水剂,于0~300℃反应1~96h,反应结束后,将反应体系进行过滤,向滤液中加入醇类溶剂,收集沉淀,干燥即得疏水化葡聚糖。
前述的方法,步骤①、②所述催化剂选自DMAP(4-二甲氨基吡啶)、DCC、吡啶、浓硫酸中的至少一种,所述脱水剂选自五氧化二磷、DCC(二环己基碳二亚胺)、分子筛、氯化钙、氯化锌、硫酸镁等无机盐类,它们的用量为适量。
步骤③所述醇类溶剂可以是无水乙醇或甲醇等,所述醇类溶剂的用量为适量。
优选地,所述葡聚糖、丁二酸、甘氨酸和胆固醇的摩尔比为1-2:1-2:2-4:1-2,优选1:1:2:1或2:1:4:1。
前述的方法,步骤③中反应体系经过滤,收集滤渣,干燥后,可回收利用DMAP及副产物二环己基脲(DCU)。
第五方面,本发明提供所述疏水化多糖,或所述疏水化葡聚糖的以下任一应用:
a.作为药物递送载体;
b.用于制备抗菌剂;
c.单独或与其它活性成分联合用于制药。例如,可将该药物用于瘙痒和脚气的治疗,用于流行性感冒(流感病毒)的治疗等。
其中,所述活性成分可选自中药、西药、生物药中的至少一种。
本发明的疏水化多糖可作为抗炎、抗菌、抗病毒、抗肿瘤药、氨基酸、肽类的载体,与各种抗炎药、各种抗菌药、各种抗病毒药、各种抗肿瘤药、各种氨基酸、各种肽类一起使用,用于各种类免疫性疾病的治疗。例如各类炎症、各种菌类感染、各种类病毒感染、各种类肿瘤的治疗、糖尿病的治疗、多发性硬化症的治疗,也包括重症肌无力等免疫性疾病的治疗。以及作为护肤品用于保湿除皱和作为护发品用保持发质健康。
其中,各种抗炎药、各种抗菌药、各种抗病毒药、各种抗肿瘤药既可以是中药,可以是西药,也可以是生物药。
其中,各种类炎症性疾病例如牙神经炎、胃炎、肠炎、结肠炎、肝炎、脊柱炎、关节炎、红斑狼疮、阴道炎、尿道炎、过敏性炎症如鼻粘膜充血性炎症、免疫因子风暴引发的肺部炎症、湿疹、螨虫、蚊虫叮咬引发的瘙痒等。
其中,各种菌类感染性疾病例如细菌、放线菌、螺旋体、支原体、衣原体、立克次体感染性疾病。真菌类感染性疾病例如脚气、手气、牛皮癣、接触性皮炎等。
其中,所述菌包括肠管出血性大肠菌等病原性大肠菌、黄色葡萄球菌、髓膜炎菌、绿脓杆菌、虫齿连锁球菌、Cholera菌、Typhus菌、Chlamydophilafelis赤痢菌、肺炎球菌、百日咳菌、Corynebacteriumdiphtheriae菌、破伤风菌、Influenza菌、pestis菌、botulinum菌、Bacillusanthracis炭疽菌、野兔病菌、Salmonella菌、VRE(肠球菌)、结核菌、赤痢菌、SalmonellaTyphi肠菌、SalmonellaParatyphiA菌、Chlamydophilafelis菌、Ameba赤痢、Legionella菌、Lymeborreliosis菌、brucellosis病(波状热)菌等病原性细菌;CoxiellaburnetiiQ热、Chlamydia等Rickettsia;malaria病原虫、CryptosporidiumTyzzer等原虫类;cryptococcosis·aspergillosis等真菌等。
其中,各种类病毒感染性疾病例如新冠病毒、HPV病毒、流感病毒、比如InfluenzaA型、InfluenzaB型、C型肝炎病毒、A型肝炎病毒、B型肝炎病毒、Rotavirus病毒、Cytomegalovirus:CMV病毒、RS病毒、咽头结膜热、HIV病毒、水痘带状疱疹病毒、单纯herpes病毒1型·2型、ATL(成人型T细胞白血病)病毒、Coxsackie病毒、entero病毒、突发性发疹病毒、麻疹病毒、风疹病毒、流行性耳下腺炎病毒、急性灰白髓炎病毒、日本脑炎病毒、狂犬病病毒、C型肝炎病毒、Norwalk病毒、狂犬病病毒、RS病毒、Cytomegalovirus病毒、口蹄疫病毒、传染性胃肠炎病毒、风疹病毒、ATL病毒、adeno病毒、Echovirus、Herpes病毒、天然痘病毒、denguefever热病毒、黄热病毒、WestNilevirus、SARS(病毒)、埃博拉出血热病毒、Marburghemorrhagicfever、Lassafever病毒、Hantavirus、Nipahvirusinfection等病原性病毒等各类病毒感染性疾病。
其中,各种类肿瘤的治疗包括各种细胞类型的肺癌、鼻咽癌、肠癌、皮肤癌、口腔癌、乳腺癌、头颈部癌症、胰腺癌等各种肿瘤性疾病。
其中,各种氨基酸可以是动物来源的氨基酸,也可以是植物来源的氨基酸。肽类可以是任何微生物来源的肽类、化学合成的肽类,生物提取而来的肽类。
进一步地,所述疏水化多糖作为活性成分的载体;其中包括与其它常用药物的载体或药用乳化剂联用。
进一步地,所述疏水化多糖用于制药或抗菌、袪痱止痒剂。
其中,所述活性成分包括柴胡提物具体包括柴胡皂苷和柴胡多糖。
第六方面,本发明提供一种含有所述疏水化多糖,或所述疏水化葡聚糖的药物或组合物。
优选地,所述药物或组合物中包含柴胡提取物;或者,所述药物或组合物的活性成分包含柴胡总皂苷和柴胡多糖。
更优选地,疏水化多糖或疏水化葡聚糖与柴胡提取物的重量比为500:1-1:500,优选100:1-1:100。
第七方面,本发明提供一种柴胡水乳液,所述柴胡水乳液是将所述疏水化葡聚糖、油酸酯化葡聚糖和柴胡提取物按比例混合溶于水中,使用探头乳化器或超声波处理得到的水乳液。
其中,疏水化葡聚糖、油酸酯化葡聚糖、柴胡提取物和水的重量比为1-0.01:0.01-1:0.01-1:97-99.97,优选0.1:0.1:0.1:99.7。
所述油酸酯化葡聚糖的结构如式(II)所示:
所述柴胡水乳液的平均粒径大小为0~1000nm。
第八方面,本发明提供所述柴胡水乳液的以下任一应用:
(1)用于制备抗炎药;
(2)用于制备抗菌药;
(3)用于制备抗病毒药;
(4)用于制备抗肿瘤药;
(5)用于制备免疫性疾病治疗药物;
(6)用于制备糖尿病治疗药物;
(7)用于制备多发性硬化症治疗药物;
(8)用于制备洗护用品。
借由上述技术方案,本发明至少具有下列优点及有益效果:
(一)本发明提供的疏水化多糖具有免疫调节性能,可与柴胡提取物(柴胡皂苷和柴胡多糖)共同发挥免疫调节作用。
(二)本发明疏水化多糖合成所用原料,皆安全、无毒,可用于食品、药品领域。疏水化多糖无毒,可在自然界全分解,无急性毒性,亦无远期毒性。
(三)本发明的疏水化多糖修饰物,属于新型的高效药物递送载体,所制备的药液,药理活性高,强于现有的药物递送系统,微量药液就起显著药理作用,由于属于免疫调节性药物,具有一次治愈不复发的特性。
附图说明
图1为本发明较佳实施例中制备的疏水化葡聚糖修饰物的核磁检测结果。
图2~图4分别为本发明较佳实施例中空白对照组、模型组和给药组的肺病理情况。
具体实施方式
本发明提供一种新型的疏水化多糖及其制备方法以及作为免疫调节物质在药物制剂方面的应用。此类疏水化多糖(也称疏水化多糖修饰物)具有多种生理活性,例如抗免疫、增强免疫活性。可作为抗炎、抗菌、抗病毒、抗肿瘤药、氨基酸、肽类的载体,与各种抗炎药、各种抗菌药、各种抗病毒药、各种抗肿瘤药、各种氨基酸、各种肽类一起使用,用于各种类免疫性疾病的治疗。例如各种类炎症、各种菌类感染、各种类病毒感染、各种类肿瘤的治疗、糖尿病的治疗、多发性硬化症的治疗,也包括重症肌无力等免疫性疾病的治疗;以及作为护肤品用于保湿除皱和作为护发用品保护发质健康。亦可单独使用,用于各种类免疫性疾病的治疗。例如各类炎症、各种菌类感染、各种类病毒感染、各种类肿瘤的治疗、糖尿病的治疗、多发性硬化症的治疗,也包括重症肌无力等免疫性疾病的治疗;以及作为护肤品用于保湿除皱和作为护发品用保持发质健康。
本发明采用如下技术方案:
本发明提供的疏水化多糖的分子通式为:G-P-O,由三部分构成:
(1)水溶性多糖;
(1)氨基酸与二酸缩合而成的两端带有羧基的连接分子(连接臂);
(3)胆固醇。
其中,G为多糖或二糖(作为亲水性基团),P为由二酸与两个氨基酸缩合而成的两端为羧基的分子片段(作为连接臂),O为胆固醇(作为疏水性基团);优选地,G为葡聚糖,P为双乙酸基丁二酰胺。G和P之间通过酯键与多糖上的羟基连接,P和O之间通过酯键连接。
所述连接臂为任意由氨基酸类与二酸类缩合成的分子片段。所述氨基酸选自甘氨酸、谷氨酸、L-赖氨酸、L-半胱氨酸、DL-丙氨酸、DL-蛋氨酸、L-鸟氨酸、γ-氨基丁酸、L-天门冬氨酸、L-茶氨酸、L-精氨酸、β丙氨酸、L-瓜氨酸、L-组氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、谷氨酰胺、天冬酰胺、组氨酸等中的至少一种,以及任意的合成的氨基酸,也可以选自各种氨基酸缩合而成的短肽。所述二酸类选自乙二酸、丙二酸、丁二酸、乙二胺N,N二乙酸和N,N二羧基乙二胺,以及任意的化学合成的二酸,也可以选自带有两个羧基的氨基酸例如谷氨酸、天门冬氨酸等,以及化学合成的带有两个端羧基的氨基酸。
所述疏水化多糖修饰物是葡聚糖与所述胆固醇酯化物中间体通过缩合反应,制备以葡聚糖为亲水性基团,以胆固醇为疏水性基团,以双乙酸基丁二酰胺(连接臂)为装载性基团的功能性多糖。
本发明中,所述多糖选自透明质酸、硫酸软骨素、硫酸皮肤素、肝素、水溶性淀粉、水溶性菊糖、水溶性壳聚糖、水溶性葡聚糖、水溶性普鲁兰多糖、水溶性甘露糖、水溶性海藻多糖、水溶性淀粉、水溶性羟乙基右旋糖酐、水溶性果聚糖、水溶性木葡聚糖、水溶性纤维素以及各类水溶性聚糖等中的至少一种,也可以是具有生理活性的多羟基化合物(如唾液酸)。
所述二糖为蔗糖、果糖或乳糖。
优选地,通式G-P-O中,G为葡聚糖,P为双乙酸基丁二酰胺,所述疏水化多糖的结构如式(I)所示。所述疏水化多糖是胆固醇的羟基与双乙酸基丁二酰氨的一端羧基反应,先制备乙酸基丁二酰氨胆固醇酯,再与葡聚糖反应,使得连接臂的另一端羧基与葡聚糖酯化,得疏水化葡聚糖修饰物(疏水化葡聚糖)。
本发明还提供所述疏水化多糖修饰物的制备方法,包括以下步骤:
1)二酸与氨基酸缩合生成带有端羧基的分子片段作为连接臂;
2)胆固醇的羟基与连接臂一端羧基进行酯化反应生成胆固醇酯化的连接臂;
3)多糖上的羟基与胆固醇酯化的连接臂上的端羧基通过酯键缩合。
式(1)所示疏水化多糖的制备方法如下:
①在有机溶剂中使丁二酸与羧基保护的甘氨酸反应,加入适量催化剂和脱水剂,反应温度0~60℃,反应时间1~96h,得到双乙酸基丁二酰胺;
②将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将上述双乙酸基丁二酰胺加入氢氧化钠水溶液中水解,再用盐酸水溶液中和,双乙酸基丁二酰胺的羧基迅速游离出,减压干燥除水后,复溶于有机溶剂,加入适量催化剂、脱水剂,于0~300℃反应1~96h,加胆固醇,进行酯化反应,于0~300℃反应1~96h,加水终止反应,沉出物精制干燥备用;
③将步骤②所得上述精制产物复溶于有机溶剂,加入葡聚糖,加入适量催化剂、脱水剂,于0~300℃反应1~96h,反应结束后,将反应体系进行过滤,向滤液中加入醇类溶剂,收集沉淀,干燥即得疏水化葡聚糖修饰物。
前述的方法,步骤①所述有机溶剂选自甲苯、二甲苯、二甲基甲酰胺、二甲基亚砜或二氯甲烷等中的至少一种。
前述的方法,步骤①、②所述催化剂为DMAP(4-二甲氨基吡啶)和DCC(二环己基碳二亚胺),脱水剂为DCC,它们的用量为适量。此外,催化剂也可选择吡啶、浓硫酸;脱水剂可选择五氧化二磷、分子筛、氯化钙、氯化锌、硫酸镁等无机盐类。
前述的方法,步骤③所述醇类溶剂为无水乙醇或甲醇,所述醇类溶剂的用量为适量。
前述的方法,所述葡聚糖、丁二酸、甘氨酸和胆固醇的摩尔比为1-2:1-2:2-4:1-2,优选1:1:2:1或2:1:4:1。
前述的方法,步骤③中反应体系经过滤,收集滤渣,干燥后,可回收利用DMAP及副产物二环己基脲(DCU)。
本发明还提供所述疏水化多糖修饰物,或按照上述方法制备的疏水化多糖修饰物的以下任一应用:
a.作为活性成分与免疫调节性药物联合使用;
b.单独作为免疫调节剂药物;
其中,所述活性成分包括中药药物、西药药物和生物药。
本发明提供的疏水化多糖修饰物可与其他药物复配使用。
本发明还提供含有所述疏水化多糖修饰物,或按照上述方法制备的疏水化多糖修饰物以及至少一种活性成分的药物或组合物。
优选地,所述活性成分为柴胡总皂苷和柴胡多糖。
所述疏水化多糖修饰物与柴胡总皂苷和柴胡多糖的重量比为100:1-1:100,优选10:4-10:50。
更优选地,所述药物或组合物的剂型为水乳剂,平均粒径大小为0~1000nm,优选500nm以下。所述疏水化多糖与柴胡总皂苷和柴胡多糖的重量比为10:1-10:100,优选10:4-10:50。
更优选地,所述药物或组合物的剂型为水溶液。
本发明还提供所述药物或组合物的制备方法,所述方法包括:将疏水化多糖修饰物溶于水中,然后加入柴胡总皂苷和柴胡多糖,完全溶解后使用探头乳化器或超声波处理直至形成稳定的水乳剂或溶液,即得。
本发明还提供由所述疏水化多糖修饰物与柴胡总皂苷和柴胡多糖制备的水乳液在蚊虫叮咬止痒和脚气、手气、接触性皮炎治疗方面的应用。
以下实施例用于说明本发明,但不用来限制本发明的范围。若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段,所用原料均为市售商品。
以下实施例中的柴胡提取物的成分为柴胡总皂苷和柴胡多糖,该柴胡提取物按照文献(张国松,封传华、罗晓键等.柴胡总皂苷提取工艺的优化[J].中国实验方剂学杂志.2011(12):17-20)方法制备:柴胡粉末加入8倍量80%乙醇,调pH8,于80℃加热回流提取2次,每次1小时,减压蒸馏去除溶剂得到柴胡总皂苷。将药渣复溶于水,50℃浸泡1小时,减压浓缩干燥得到柴胡多糖。
实施例1疏水化葡聚糖修饰物及其制备方法
本实施例制备的疏水化多糖是先合成双乙酸基丁二酰胺连接臂,然后胆固醇的羟基与连接臂一端羧基反应,制备胆固醇酯化双乙酸基丁二酰胺,再与葡聚糖反应,得疏水化葡聚糖修饰物。具体制备方法如下:
1、将100g(0.01mol)丁二酸溶解在2L甲苯中,加0.02mol羧基保护的甘氨酸,加催化剂DMAP 1g和脱水剂DCC 10g,室温反应48h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇2L,得到白色沉淀物即为双乙酸基丁二酰胺。
2、将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将双乙酸基丁二酰胺100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双乙酸基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于2L甲苯中,加催化剂DMAP 0.5g和脱水剂DCC 5g,加0.01mol胆固醇于室温反应48h,加水终止反应,沉出物精制干燥备用。
3、将2所得上述精制产物100g复溶于2L甲苯溶液中,加入0.01mol葡聚糖,加催化剂DMAP 0.25g和脱水剂DCC 2.5g,于室温反应48h,反应结束后,将反应体系进行过滤,向滤液中加入无水乙醇2L类溶剂,收集沉淀,干燥即得疏水化多葡聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
实施例2疏水化葡聚糖修饰物及其制备方法
具体制备方法如下:
1、将100g(0.02mol)丁二酸溶解在4L甲苯中,加0.04mol羧基保护的甘氨酸,加催化剂DMAP 2g和脱水剂DCC 20g,40℃反应24h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇4L,得到白色沉淀物即为双乙酸基丁二酰胺。
2、将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将双乙酸基丁二酰胺100g加入1N的NaOH水溶液1L于室温反应2h,再加入1N的HCl水溶液50mL中和剩余的氢氧化钠,使双乙酸基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于4L甲苯中,加催化剂DMAP 1g和脱水剂DCC 10g,加0.02mol胆固醇于40℃反应24h,加水终止反应,沉出物精制干燥备用。
3、将2所得上述精制产物100g复溶于4L甲苯溶液中,加入0.01mol葡聚糖,加催化剂DMAP 0.5g和脱水剂DCC 5g,于40℃反应24h,反应结束后,将反应体系进行过滤,向滤液中加无水乙醇4L溶剂,收集沉淀,干燥即得疏水化多葡聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
实施例3疏水化葡聚糖修饰物及其制备方法
具体制备方法如下:
1、将100g(0.015mol)丁二酸溶解在1L甲苯中,加0.03mol羧基保护的甘氨酸,加催化剂DMAP 0.5g和脱水剂DCC 5g,50℃反应12h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇1L,得到白色沉淀物即为双乙酸基丁二酰胺。
2、将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将双乙酸基丁二酰胺100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双乙酸基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于1L甲苯中,加催化剂DMAP 0.25g和脱水剂DCC2.5g,加0.015mol胆固醇于50℃反应12h,加水终止反应,沉出物精制干燥备用。
3、将2所得上述精制产物100g复溶于1L甲苯溶液中,加入0.01mol葡聚糖,加催化剂DMAP 0.13g和脱水剂DCC 1.3g,于50℃反应12h,反应结束后,将反应体系进行过滤,向滤液中加入无水乙醇1L类溶剂,收集沉淀,干燥即得疏水化多葡聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
实施例1~3中制备的疏水化葡聚糖修饰物的核磁检测数据如下;
1HNMR(400MHz,D2O)1.25,1.40,1.45ppm(胆固醇),2.73,2.86,3.02ppm(琥珀酸),3.44~5.35ppm(葡聚糖和甘氨酸),具体为:1.25ppm,1.40ppm,1.45ppm的吸收峰来自于胆固醇,2.73ppm,2.86ppm,3.02ppm的吸收峰来自于丁二酸,3.44~5.35ppm的吸收峰来自于葡聚糖和甘氨酸(图1)。
实施例4柴胡水乳液及其制备方法
将油酸酯化葡聚糖(即ZL201910418160.0说明书实施例1中的疏水化葡聚糖)10g溶于水1L中,然后加入柴胡提取物10g,使用探头乳化器或超声波处理直至形成多分散的水乳剂,再将实施例1制备的疏水化葡聚糖修饰物10g溶于水3L中待完全溶解,将两种溶液混合即为柴胡水乳液。
实施例5柴胡水乳液及其制备方法
将油酸酯化葡聚糖(即ZL201910418160.0说明书实施例1中的疏水化葡聚糖)10g溶于水1L中,然后加入柴胡提取物10g,使用探头乳化器或超声波处理直至形成多分散的水乳剂,再将实施例1制备的疏水化葡聚糖修饰物10g溶于水4L中待完全溶解,将两种溶液混合即为柴胡水乳液。
实施例6柴胡水乳液及其制备方法
将油酸酯化葡聚糖(即ZL201910418160.0说明书实施例1中的疏水化葡聚糖)5g溶于水2L中,然后加入柴胡提取物5g,使用探头乳化器或超声波处理直至形成多分散的水乳剂,再将实施例1制备的疏水化葡聚糖修饰物20g溶于水2L中待完全溶解,将两种溶液混合即为柴胡水乳液。
实施例4~6中,将油酸酯化葡聚糖与柴胡提取物的水乳剂、疏水化葡聚糖修饰物水溶液混合均匀,超声处理5分钟,用0.22微米滤膜过滤,紫外线灭菌处理后灌装。在实施例4~6的柴胡水乳液的制备中,先将油酸酯化葡聚糖与柴胡提取物乳化使柴胡总皂苷充分溶解乳化,再与疏水化葡聚糖修饰物水溶液混合。这样可以避免柴胡提物对疏水化葡聚糖修饰物药效的干扰,可提高疗效同时降低成本。
柴胡水乳液的稳定性考察结果如下:
取3批样品各10ml于(40±2)℃,(25±2)℃,(-20±2)℃温度中分别放置3个月,性状、含量、微生物限度检查均无明显变化。
柴胡水乳液的鼻腔刺激性试验如下:
选择键康大鼠10只,体质量300±20g,雌雄各半,蚌埠医学院实验动物中心提供。于密封箱内用雾化机进行药液雾化吸入30分钟,大鼠无任何不适或过敏症状发生。
实施例7柴胡水乳液对瘙痒的治疗作用
1、用药与评价方法
用药与评价方法参照文献进行(姜辉,徐兴亚.醋酸地塞米松搽剂质量控制及疗效观察[J].实用药物与临床.2010,13(1):36-38)。从药店、医院和学校召集的21例由于蚊虫叮咬引起瘙痒的志愿者,均给予柴胡水乳液与疏水化葡聚糖溶液涂抹进行治疗。只用药1次,每次用药1.5mg。对其进行三分钟内止痒效果观察,一周内疗效调查。志愿者的疗效检定标准分为痊愈、显效、有效和无效四种。痊愈:志愿者的瘙痒治愈,皮肤红肿消失;显效:志愿者瘙痒治愈,皮肤红肿部分消退;有效:志愿者瘙痒减轻,皮肤红肿部分消退;无效:志愿者瘙痒未减轻,皮肤红肿部分未消退。
2、结果
通过对10例蚊虫叮咬引起瘙痒的志愿者用柴胡水乳液一次性涂抹治疗之后,有6例志愿者痊愈,占60%;4例患者治疗显效,40%;总有效率为100%。总有效率=[痊愈十显效+有效]÷10×100%。志愿者年龄最大56岁,最小20岁,疗效与年龄无明显关联(表1)。
表1柴胡水乳液对瘙痒治疗效果资料
10名志愿者一次性涂抹药液后无一例出现不良反应(表2)。
表2柴胡水乳液安全性评价
实施例8疏水化葡聚糖水溶液单独用药对瘙痒的治疗作用
1、疏水化葡聚糖水溶液单独用药对瘙痒的治疗作用其评价方法按照实施例7进行。疏水化葡聚糖水溶液浓度与实施例7的柴胡水乳液浓度相同,即疏水化葡聚糖含量比与柴胡水乳液中所含柴胡提取物、油酸酯化葡聚糖、疏水化葡聚糖重量之和的含量相同,数值为3mg/mL。
2、结果
通过对11例蚊虫叮咬引起瘙痒的志愿者用疏水化葡聚糖一次性涂抹治疗之后,有9例志愿者痊愈,占81.8%;2例患者治疗显效,占18.2%;总有效率为100%。总有效率=[痊愈十显效+有效]÷11×100%。志愿者年龄最大60岁,最小20岁,疗效与年龄无明显关联(表3)。
表3疏水化葡聚糖对瘙痒治疗效果资料
11名志愿者一次性涂抹药液后无一例出现不良反应(表4)。
表4疏水化葡聚糖安全性评价
实施例9柴胡水乳液对脚气、手气、接触性皮炎的治疗作用
1、用药与评价方法
用药与评价方法参照文献进行(蔡贵山.醋酸地塞米松搽剂的质量控制与临床疗效分析[J].中国医药指南.2013,11(32):180-181)。从药店、医院和学校召集12例脚气、手气、接触性皮炎患者均给予柴胡水乳液涂抹进行治疗。只用药1次,每次用药1.5mg。对其进行三分钟内止痒效果观察,一周内疗效调查。脚气、手气、接触性皮炎患者的疗效检定标准分为痊愈、显效、有效和无效四种。痊愈:患者的皮损现象完全消退,瘙痒治愈;显效:患者皮损消退在70%以上,瘙痒改善;有效:思者皮损梢退在30%-69%,瘙痒减轻;无效:患者皮损消退在30%以下,或者其症状改善不明显,瘙痒未减轻。
2、结果
通过对12例脚气、手气、接触性皮炎患者用柴胡水乳液一次性涂抹治疗之后,有9例患者痊愈,占75%;1例患者治疗显效,8.3%,;1例患者治疗有效,8.3%;1例患者无效,8.3%;总有效率为91.7%。总有效率=[痊愈十显效+有效]÷12×100%。志愿者年龄最大56岁,最小21岁,疗效与年龄无明显关联(表5)。
表5柴胡水乳液对脚气、手气、接触性皮炎的治疗作用
12例患者一次性涂抹柴胡水乳液后无一例出现不良反应(表6)。
表6柴胡水乳液安全性评价
本发明的柴胡水乳液对瘙痒和脚气的治疗,与临床常用激素类药物地塞米松相比,具有明显的优势。在用药时间方面,柴胡水乳液只用药一次用药量1.5mg,而地塞米松用药一周总用药量3.0mg。在疗效方面,柴胡水乳液治愈率和总有效率明显高于地塞米松治疗组,且具有痊愈后不复发的优点。在安全性方面,柴胡水乳液中的柴胡提取液,配合物油酸酯化葡聚糖和配合物疏水化葡聚糖修饰物为食品、药品级化合物,安全性有保障,一次性用药起效,不存在对长期用药风险的顾虑。而地塞米松在长期用药的情况下会出现严重不良反应(表7)。
表7柴胡水乳液治疗组、疏水化葡聚糖治疗组与地塞米松治疗对照组疗效比较(例,%)
治疗组与对照组总有效率差异有统计学意义(P<0.01)。
实施例10柴胡水乳液对风寒感冒模型小鼠的经鼻治疗作用
雌性小鼠36只,体重(20±2)g。小鼠购买于蚌埠医学院动物中心,寄养于蚌埠医学院药学院动物房,自由进食和饮水,观察检疫、适应性喂养3天后,称重,随机分为3组,即空白对照组、模型组、柴胡水乳液治疗组(每次每只给药1.5mg),每组12只。小鼠染毒箱(聚苯乙烯材质,规格330mm×215mm×200mm),制备二氧化硫药品:浓硫酸和亚硫酸氢钠。每日上午10点,对模型组和给药组小鼠染毒,其余时间小鼠自由进食饮水。
具体染毒方法:
实验中采取静式染毒的方式,SO2浓度为(28±2)mg/m3。将小鼠分组置于小鼠染毒箱(330mm×215mm×200mm)中,染毒箱除气孔外其他部位均为密封状态。每次取2.5g亚硫酸氢钠放入浓硫酸中反应,自然封住气孔,待SO2在染毒箱中扩散五分钟后再开启气孔,同时取出小鼠。染毒在通风厨中进行。模型组和中药治疗组自染毒两周后,第14天起,模型组和给药组小鼠开始腹腔注射苯甲酸雌二醇稀释溶液2mg/kg,至第21天止,共注射7天,最后3天注射后于18℃冷风下吹5分钟,制成小鼠感冒模型。
动物处死及取材:
染毒处理后第21天结束之后,动物禁食、自由饮水20小时,于次日早上8点,称重后以脱颈椎法处死空白对照组和模型组小鼠。立即打开小鼠胸腔,肉眼观察双肺的形态、质地、颜色及有无明显的肺纤维化结节等改变。以5mL冰冷生理盐水从右心室处注入,通过肺循环灌洗肺脏,反复几次,至双肺呈白色,立即将肺脏采出,称重。取小鼠左侧肺脏制作肺部病理切片。药液治疗组在治疗结束之后以相同方法制作肺部切片。
结果:
用24只昆明小白鼠造模,去除造模失败中途死亡8只,16只造模成功。但随即出现病死小鼠,于是将模型组小鼠全部处死,取血白细胞计数。给药组小鼠每隔一天,柴胡水乳液雾化吸入10分钟,连续两周,给药结束后将正常组(8只)和给药组小鼠(6只)全部脱颈处死,取血白细胞计数,取肺作病理。正常组小鼠和给药组小鼠白细胞计数大致相同,模型组小鼠白细胞数明显偏高。肺病理如图2~图4所示。正常组小鼠肺组织偏小,肺泡正常。模型组小鼠肺组织偏大,肺泡稍大,说明SO2所致急性炎症造模成功。给药组小鼠肺组织明显偏大,肺泡也明显偏大,说明毛细血管炎症导致小鼠肺气肿,导致肺泡增大,但给药治疗可以延长给药组小鼠生存期。
目前治疗免疫性疾病的药物多为小分子药物,例如治疗脚气选用达克宁霜等抗真菌药,止痒效果差易复发。本发明的柴胡水乳液具有确切的蚊虫叮咬迅速止痒作用、治疗脚气、手气和接触性皮炎作用。且具有一次性治愈不复发的特点。
目前对于流行性感冒(流感病毒)的治疗,也缺少特效药物,例如治疗感冒鼻塞用的滴鼻净,疗效很差。本发明的柴胡水乳液,具有抗流感病毒的药理作用。现存治疗感冒病例一例,痊愈病例一例(F30),经鼻腔滴注迅速治疗鼻塞,减轻感冒症状,缩短病程。
按照本发明提供的疏水化葡聚糖制备方法,进行了如下化合物的合成,具体见实施例11~14。
实施例11疏水化壳聚糖修饰物及其制备方法
本实施例制备的疏水化壳聚糖是先合成双乙酸基丁二酰胺连接臂,然后胆固醇的羟基与连接臂一端羧基反应,制备胆固醇酯化双乙酸基丁二酰胺,再与壳聚糖反应,得疏水化壳聚糖修饰物。具体制备方法如下:
1、将100g(0.01mol)丁二酸溶解在2L甲苯中,加0.02mol羧基保护的甘氨酸,加催化剂DMAP 1g和脱水剂DCC 10g,室温反应48h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇2L,得到白色沉淀物即为双乙酸基丁二酰胺。
2、将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将双乙酸基丁二酰胺100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双乙酸基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于2L甲苯中,加催化剂DMAP 0.5g和脱水剂DCC 5g,加0.01mol胆固醇于室温反应48h,加水终止反应,沉出物精制干燥备用。
3、将步骤2所得上述精制产物100g复溶于2L甲苯溶液中,加入0.01mol壳聚糖,加催化剂DMAP 0.25g和脱水剂DCC 2.5g,于室温反应48h,反应结束后,将反应体系进行过滤,向滤液中加入无水乙醇2L,收集沉淀,干燥即得疏水化壳聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
合成的疏水化壳聚糖修饰物的结构如下:
实施例12疏水化唾液酸修饰物及其制备方法
本实施例制备的疏水化唾液酸是先合成双乙酸基丁二酰胺连接臂,然后胆固醇的羟基与连接臂一端羧基反应,制备胆固醇酯化双乙酸基丁二酰胺,再与唾液酸反应,得疏水化唾液酸修饰物。具体制备方法如下:
1、将100g(0.01mol)丁二酸溶解在2L甲苯中,加0.02mol羧基保护的甘氨酸,加催化剂DMAP 1g和脱水剂DCC 10g,室温反应48h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇2L,得到白色沉淀物即为双乙酸基丁二酰胺。
2、将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将双乙酸基丁二酰胺100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双乙酸基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于2L甲苯中,加催化剂DMAP 0.5g和脱水剂DCC 5g,加0.01mol胆固醇于室温反应48h,加水终止反应,沉淀物精制干燥备用。
3、将步骤2所得上述精制产物100g复溶于2L甲苯溶液中,加入0.01mol唾液酸,加催化剂DMAP 0.25g和脱水剂DCC 2.5g,于室温反应48h,反应结束后,将反应体系进行过滤,向滤液中加入水2L,过滤去除沉淀,向体系加入无水乙醇收集沉淀,干燥即得疏水化唾液酸修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
合成的疏水化唾液酸修饰物的结构如下:
实施例13疏水化葡聚糖修饰物及其制备方法
本实施例制备的疏水化葡聚糖是先合成双甘肽基丁二酸酯连接臂,然后胆固醇的羟基与连接臂一端羧基反应,制备胆固醇酯化双甘肽基丁二酸酯,再与葡聚糖反应,得疏水化葡聚糖修饰物。具体制备方法如下:
1、将100g(0.01mol)丁二酸溶解在2L甲苯中,加0.02mol羧基保护的双甘肽,加催化剂DMAP 1g和脱水剂DCC 10g,室温反应48h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇2L,得到白色沉淀物即为双甘肽基丁二酸酯。
2、将双甘肽基丁二酸酯的羧基保护脱除,具体方法为:将双甘肽基丁二酸酯100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双甘肽基丁二酰胺的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于2L甲苯中,加催化剂DMAP 0.5g和脱水剂DCC 5g,加0.01mol胆固醇于室温反应48h,加水终止反应,沉淀物精制干燥备用。
3、将步骤2所得上述精制产物100g复溶于2L甲苯溶液中,加入0.01mol葡聚糖,加催化剂DMAP 0.25g和脱水剂DCC 2.5g,于室温反应48h,反应结束后,将反应体系进行过滤,向滤液中加入无水乙醇2L类溶剂,收集沉淀,干燥即得疏水化葡聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
合成的疏水化葡聚糖修饰物的结构如下:
实施例14疏水化葡聚糖修饰物及其制备方法
本实施例制备的疏水化葡聚糖是先合成双甘氨酸基乙二胺N,N二乙酸酯连接臂,然后胆固醇的羟基与连接臂一端羧基反应,制备胆固醇酯化双甘氨酸基乙二胺N,N二乙酸酯,再与葡聚糖反应,得疏水化葡聚糖修饰物。具体制备方法如下:
1、将100g(0.01mol)乙二胺N,N二乙酸溶解在2L甲苯中,加0.02mol羧基保护的甘氨酸,加催化剂DMAP 1g和脱水剂DCC 10g,室温反应48h,过滤去除副产物二环己基脲,滤液加水少量终止反应,加入无水乙醇2L,得到白色沉淀物即为双甘氨酸基乙二胺N,N二乙酸酯。
2、将双甘氨酸基乙二胺N,N二乙酸酯的羧基保护脱除,具体方法为:将双甘氨酸基乙二胺N,N二乙酸酯100g加入1N的NAOH水溶液1L于室温反应2h,再加入50mL,1N HCl中和剩余的氢氧化钠,使双甘氨酸基乙二胺N,N二乙酸酯的羧基游离出来,将反应体系减压蒸馏去除水分后,复溶于2L甲苯中,加催化剂DMAP 0.5g和脱水剂DCC 5g,加0.01mol胆固醇于室温反应48h,加水终止反应,沉淀物精制干燥备用。
3、将步骤2所得上述精制产物100g复溶于2L甲苯溶液中,加入0.01mol葡聚糖,加催化剂DMAP 0.25g和脱水剂DCC 2.5g,于室温反应48h,反应结束后,将反应体系进行过滤,向滤液中加入无水乙醇2L类溶剂,收集沉淀,干燥即得疏水化葡聚糖修饰物。
步骤2、3中反应体系经过滤收集的滤渣为副产物二环己基脲(DCU),干燥后,可回收利用。
合成的疏水化葡聚糖修饰物的结构如下:
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之做一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (10)
1.疏水化多糖,其特征在于,结构通式如下:G-P-O;
其中,G为多糖或二糖,P为氨基酸与二酸缩合而成的两端带有羧基的连接分子,O为胆固醇;G和P之间通过酯键与多糖或二糖上的羟基连接,P和O之间通过酯键连接。
2.根据权利要求1所述的疏水化多糖,其特征在于,所述多糖为水溶性多糖,所述多糖选自透明质酸、硫酸软骨素、硫酸皮肤素、肝素、水溶性淀粉、水溶性菊糖、水溶性壳聚糖、水溶性葡聚糖、水溶性普鲁兰多糖、水溶性甘露糖、水溶性海藻多糖、水溶性淀粉、水溶性羟乙基右旋糖酐、水溶性果聚糖、水溶性木葡聚糖、水溶性纤维素;以及具有生理活性的多羟基化合物(如唾液酸);和/或
所述二糖选自蔗糖、果糖或乳糖;和/或
所述氨基酸选自甘氨酸、谷氨酸、L-赖氨酸、L-半胱氨酸、DL-丙氨酸、DL-蛋氨酸、L-鸟氨酸、γ-氨基丁酸、L-天门冬氨酸、L-茶氨酸、L-精氨酸、β丙氨酸、L-瓜氨酸、L-组氨酸、亮氨酸、异亮氨酸、缬氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、谷氨酰胺、天冬酰胺、组氨酸,或者由各种氨基酸缩合而成的短肽中的至少一种;和/或
所述二酸选自乙二酸、丙二酸、丁二酸、谷氨酸、天门冬氨酸、乙二胺N,N二乙酸和N,N二羧基乙二胺。
3.权利要求1或2所述疏水化多糖的制备方法,其特征在于,包括以下步骤:
1)胆固醇与连接分子发生酯化反应生成中间体;
2)多糖或二糖与上述中间体发生缩合反应生成疏水化多糖。
5.权利要求4所述疏水化葡聚糖的制备方法,其特征在于,包括以下步骤:
①在有机溶剂中使丁二酸与羧基保护的甘氨酸反应,加入适量催化剂和脱水剂,反应温度0~60℃,反应时间1~96h,得到双乙酸基丁二酰胺;
②将双乙酸基丁二酰胺的羧基保护脱除,具体方法为:将上述双乙酸基丁二酰胺加入氢氧化钠水溶液中水解,再用盐酸水溶液中和,双乙酸基丁二酰胺的羧基迅速游离出,减压干燥除水后,复溶于有机溶剂,加入适量催化剂和脱水剂,于0~300℃反应1~96h;然后向上述反应体系中加入胆固醇,进行酯化反应,于0~300℃反应1~96h,加水终止反应,沉淀物精制干燥得到中间体;
③将步骤②所得中间体复溶于有机溶剂,加入葡聚糖,加入适量催化剂和脱水剂,于0~300℃反应1~96h,反应结束后,将反应体系进行过滤,向滤液中加入醇类溶剂,收集沉淀,干燥即得疏水化葡聚糖。
6.根据权利要求5所述的方法,其特征在于,步骤①、②所述催化剂选自DMAP、DCC、吡啶、浓硫酸中的至少一种,所述脱水剂选自五氧化二磷、DCC、分子筛、氯化钙、氯化锌、硫酸镁;和/或
步骤③所述醇类溶剂为无水乙醇或甲醇;
优选地,所述葡聚糖、丁二酸、甘氨酸和胆固醇的摩尔比为1-2:1-2:2-4:1-2,优选1:1:2:1或2:1:4:1。
7.权利要求1或2所述疏水化多糖,或权利要求4所述疏水化葡聚糖的以下任一应用:
a.作为药物递送载体;
b.用于制备抗菌剂;
c.单独或与其它活性成分联合用于制药;
其中,所述活性成分选自中药、西药、生物药中的至少一种。
8.含有权利要求1或2所述疏水化多糖,或权利要求4所述疏水化葡聚糖的药物或组合物;
优选地,所述药物或组合物中包含柴胡提取物;
更优选地,疏水化多糖或疏水化葡聚糖与柴胡提取物的重量比为500:1-1:500,优选100:1-1:100。
10.权利要求9所述柴胡水乳液的以下任一应用:
(1)用于制备抗炎药;
(2)用于制备抗菌药;
(3)用于制备抗病毒药;
(4)用于制备抗肿瘤药;
(5)用于制备免疫性疾病治疗药物;
(6)用于制备糖尿病治疗药物;
(7)用于制备多发性硬化症治疗药物;
(8)用于制备洗护用品。
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