CN108653304A - 一种紫檀芪纳米胶束外用凝胶及其制备方法 - Google Patents
一种紫檀芪纳米胶束外用凝胶及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种紫檀芪纳米胶束外用凝胶,特别是一种自行提供弱酸性环境的紫檀芪纳米胶束皮肤外用凝胶及其制备方法。本发明的紫檀芪外用凝胶含有如下浓度的主要成分:紫檀芪:2mg/ml~10mg/ml;瑞鲍迪苷A:30mg/ml~60mg/ml;甘草酸:5mg/ml~12mg/ml;透明质酸钠:1mg/ml~5mg/ml,卡波姆940:3mg/ml~10mg/ml。制备方法包括只需4个简单步骤即得本发明的紫檀芪纳米胶束外用凝胶剂。本发明的凝胶剂安全无毒无刺激性,药物与辅料形成胶束,提高了药物的溶解度和稳定性,紫檀芪更容易透过皮肤吸收,且制备方法简单,制备工艺能量消耗少,不使用有毒试剂溶剂,所用的瑞鲍迪苷A和甘草酸均为植物提取物,绿色环保,凝胶剂药物持久。
Description
技术领域
本发明涉及一种紫檀芪外用凝胶,特别涉及一种具有提供弱酸性胶束微环境的高稳定性高促进皮肤渗透吸收型紫檀芪外用凝胶及其制备方法。
背景技术
日常生活中,皮肤表面经常会受到伤害而产生伤口、划痕或者溃疡。特别是糖尿病病人,容易出现伤口不能及时修复会影响皮肤的美观,更重要的是,长时间暴露的伤口很容易感染而引起的各种疾病,进而影响健康。而目前的外用贴剂或者软膏使用后创面消毒效果以及促进皮肤修复效果较差。
糖尿病病人因免疫力受到破坏等原因,容易出现伤口不愈合、溃烂,长时间暴露的伤口很容易感染等问题,属于糖尿病的常见并发症,需要药物干预,但是目前临床应用的各种药物疗效不理想,因此研究新的促皮肤愈合药物有着广阔的应用前景。
紫檀芪(Pterostilbene,CAS号537-42-8),是一种来源于紫檀、蓝莓、葡萄和花榈木等植物的有效成分,具有抗癌、抗炎、抗氧化和镇痛剂的作用。目前大量研究表明紫檀芪在皮肤疾病的治疗和防护中有较好的作用,特别是在抗氧化等领域。最新的研究表明,因紫檀芪具有显著的抗氧化、抗炎、清除自由基等广泛的药理学活性,在促皮肤伤口愈合方面有疗效和临床价值,特别是针对糖尿病病人的皮肤伤口愈合作用。但是紫檀芪存在如下不足,严重影响其开发和利用:(1)水溶解性和脂溶性均差,紫檀芪在水相中20℃时,在水中溶解度约为0.03mg/ml,透皮吸收差;(2)分子结构不稳定,紫檀芪分子结构中含有酚羟基,而酚羟基极其不稳定,这就决定了紫檀芪的稳定性极差,尤其是在水溶液中极其不稳定,容易氧化;(3)半衰期短、透生物膜性能差,口服、透皮吸收等生物利用度极低。上述这些不足,严重限制了紫檀芪在临床中的应用,特别是在皮肤外用药物中的临床应用。因此,很有必要进一步探索既安全,又经济又有效的皮肤外用紫檀芪创新药物制剂。
发明内容
针对上述问题,本发明的目的是提供一种具有提供弱酸性胶束微环境的高稳定性高促进皮肤渗透吸收型紫檀芪外用凝胶。
本发明的另一个目的是提供上述凝胶的制备方法。
本发明技术构思与技术方案
按照本发明提供的技术方案,一种可自行提供弱酸性环境的紫檀芪纳米胶束外用凝胶剂,其以水凝胶为基质,含有如下浓度的主要成分:紫檀芪:2mg/ml~10mg/ml;瑞鲍迪苷A:30mg/ml~60mg/ml;甘草酸:5mg/ml~12mg/ml;透明质酸钠:1mg/ml~5mg/ml,卡波姆940:3mg/ml~10mg/ml。
本发明所述瑞鲍迪苷A(CAS登记号58543-16-1,分子式C44H70O23,分子量967.03)纯度≥98%,所述甘草酸(CAS登记号:1405-86-3,分子式:C42H62O16,分子量:822.93)纯度≥97%。
本发明还提供上述含有能自行提供弱酸性环境的紫檀芪纳米胶束外用凝胶的制备方法,包括如下步骤:
(1)先将紫檀芪充分溶解于乙醇中,再将瑞鲍迪苷A与甘草酸按比例混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取适量的卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的
紫檀芪纳米胶束外用凝胶剂。
本发明提供的技术方案的有益效果:紫檀芪不溶于水,分子中含有酚羟基,容易发生氧化反应而失活。瑞鲍迪苷A具有抗炎作用,瑞鲍迪苷A在水溶液环境下可自组装形成粒径在6~10nm胶束,可包封增溶难溶性药物,甘草酸在水溶液环境下也可自组装到形成胶束,与瑞鲍迪苷A形成混合胶束,减小胶束的粒径,提高药物的吸收效率,进一步提高增溶效果,并提高胶束的稳定性,此外,甘草酸呈弱酸性,赋予胶束弱酸性微环境,紫檀芪在弱酸性微环境条件下分子稳定性更好。甘草酸作为一种炎症因子抑制剂,可与紫檀芪协同发挥抗炎增效作用。紫檀芪本身难溶于水,皮肤、眼表等粘膜生物利用度低,直接药用很难发挥期望的药效,制备成为胶束后,以纳米胶束形态分散在水体系中,最大程度的发挥药效,同时胶束包封及胶束的弱酸性微环境提高了紫檀芪的稳定性,使其不易被氧化降解。在药效与药物协同增效方面,瑞鲍迪苷A和甘草酸均具有抗炎作用,两者对糖尿病引发的并发症具有良好的疗效,瑞鲍迪苷A和甘草酸协同增强紫檀芪的抗炎活性,二者在整个剂型中不仅发挥了胶束载体的作用,同时也与主药紫檀芪共同发挥药效,提高药物治疗的有效性。本发明人研究发现,甘草酸与瑞鲍迪苷A混合胶束包封的紫檀芪凝胶,对于糖尿病性皮肤溃疡等的疗效更好,显著优于紫檀芪凝胶、甘草酸胶束包封的紫檀芪凝胶、瑞鲍迪苷A胶束包封的紫檀芪凝胶。
本发明具有以下优点:本发明的凝胶剂安全无毒无刺激性,药物与辅料形成胶束,提高了药物的溶解度和稳定性,紫檀芪更容易透过皮肤吸收,且制备方法简单,制备工艺能量消耗少,不使用有毒试剂溶剂,所用的瑞鲍迪苷A和甘草酸均为植物提取物,绿色环保,凝胶剂药物持久。
具体实施方式
实施例1:
(1)先将100mg紫檀芪充分溶解于乙醇中,再将900mg瑞鲍迪苷A与120mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取100mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实施例2:
(1)先将40mg紫檀芪充分溶解于乙醇中,再将600mg瑞鲍迪苷A与100mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取60mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实施例3:
(1)先将40mg紫檀芪充分溶解于乙醇中,再将1200mg瑞鲍迪苷A与240mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取200mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实施例4:
(1)先将200mg紫檀芪充分溶解于乙醇中,再将600mg瑞鲍迪苷A与100mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取60mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实施例5:
(1)先将200mg紫檀芪充分溶解于乙醇中,再将1200mg瑞鲍迪苷A与240mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取200mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实施例6:
(1)先将100mg紫檀芪充分溶解于乙醇中,再将1200mg瑞鲍迪苷A与240mg甘草酸混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用20ml水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取200mg卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。该紫檀芪凝胶在室温条件下保存12个月,高效液相色谱法检测,紫檀芪从胶束中渗漏量与氧化降解的量小于10%。
实验效果例1:本发明的紫檀芪凝胶有效性实验。
实验药物:0.5%紫檀芪凝胶(实施例1制备,设为实验1组)。
对照药物:采用本发明专利实施例1制备方法,但是不加甘草酸,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验2组);不加瑞鲍迪苷A,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验3组);不加甘草酸和瑞鲍迪苷A,将紫檀芪先用少量乙醇溶解,直接加入透明质酸钠和卡波姆940凝胶中,配制0.5%紫檀芪溶液凝胶(设为实验4组);不加瑞鲍迪苷A和紫檀芪,其余制备过程一致,制备的空白的甘草酸凝胶(设为实验5组);不加甘草酸和紫檀芪,其余制备过程一致,制备的空白的瑞鲍迪苷A凝胶(设为实验6组),不加甘草酸、紫檀芪和瑞鲍迪苷A,其余制备过程一致,制备的空白的普通凝胶(设为实验7组)。
实验动物与实验方法:因STZ诱导的糖尿病小鼠作为较公认的类似于人糖尿病病变模型,本部分内容采用此模型进行研究。选用C57BL/6小鼠,雄性,6-8周龄,体重18~25克(购买自北京维通利华实验动物技术有限公司)。动物随机分为两组,一组采用新鲜配置的柠檬酸盐缓冲液(pH 4.5)配制STZ溶液后对小鼠进行腹腔注射,连续注射5天,在最后一次(第五次注射)后的第8天(一周后)对每只小鼠测量血糖,连续测量3天,STZ注射组血糖值大于300mg/dL(16.7mmol/L)认为Ⅰ型糖尿病模型成功。在12周实验取材时,对小鼠进行同样的体重和血糖监测,符合各参数指标和取组织材料的条件的小鼠用于实验。另一组注射不含STZ的柠檬酸缓冲液作为正常对照。实验结果表明,STZ腹腔注射建模的小鼠逐渐表现出多饮、多食、多尿、体重下降等糖尿病典型症状,其血糖稳定维持在较高水平,体重较正常小鼠偏低(表1),表明造模成功。
表1正常和糖尿病模型小鼠在取样点时体重及血糖检测(n=80)
小鼠糖尿病模型成模12周后,各组小鼠腹部剃毛。手术刀小心划尽可能相同的创口,分别将上述各组紫檀芪凝胶或空白凝胶涂抹于伤口处,包扎。一天涂抹三次,并在不同时间点观察创口修复程度。
另取同龄正常小鼠,各组小鼠腹部剃毛。手术刀小心划尽可能相同的创口,分别将上述各组紫檀芪凝胶涂抹于伤口处,包扎。一天涂抹三次,并在不同时间点观察创口修复程度。
结果发现:由伤口愈合的速度和恢复程度比较,在正常小组中,实验1组修复速度最快,伤口未见化脓红肿等并发症,其次是实验2组和实验3组,修复速度慢于实验1组,伤口红肿度也差于实验1组,而实验4组、实验5组、实验6组和实验7组四组修复速度相当,差于实验2组和实验3组,口红肿度也差于实验2组和实验3组。在糖尿病模型小鼠中,各实验组的修复速度和伤口愈合情况总体均慢于正常实验小鼠,实验1组修复速度最快,伤口未见化脓红肿等并发症,其次是实验2组和实验3组,修复速度慢于实验1组,伤口红肿度也差于实验1组,而实验4组、实验5组和实验6组三组修复速度相当,差于实验2组和实验3组,口红肿度也差于实验2组和实验3组,但是未见伤口化脓等现象,而实验7组,发现伤口红肿、化脓感染,出现皮肤溃烂。由此可见,本发明的瑞鲍迪苷A和甘草酸混合胶束增溶的紫檀芪凝胶,因瑞鲍迪苷A和甘草酸抗炎的协同效应,同时形成的纳米胶束所致的纳米效应,疗效优于瑞鲍迪苷A或甘草酸单独胶束包封紫檀芪的凝胶,更优于普通的紫檀芪凝胶。
实验效果例2:0.5%紫檀芪凝胶的刺激性实验。
实验药物:0.5%紫檀芪凝胶(实施例1制备,设为实验1组)。
对照药物:采用本发明专利实施例1制备方法,但是不加甘草酸,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验2组);不加甘草酸和瑞鲍迪苷A,将紫檀芪先用少量乙醇溶解,直接加入透明质酸钠和卡波姆940凝胶中,配制0.5%紫檀芪溶液凝胶(设为实验3组);不加瑞鲍迪苷A,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验4组);不加瑞鲍迪苷A和紫檀芪,其余制备过程一致,制备的空白的甘草酸凝胶(设为实验5组);不加甘草酸和紫檀芪,其余制备过程一致,制备的空白的瑞鲍迪苷A凝胶(设为实验6组),不加甘草酸、紫檀芪和瑞鲍迪苷A,其余制备过程一致,制备的空白的普通凝胶(设为实验7组)。
实验方法:各组大鼠腹部剃毛。手术刀小心划尽可能相同的创口,分别将上述各组紫檀芪凝胶涂抹于伤口处,观察大鼠是否出现不适、焦躁、甚至扭体反应等不同于控制组的。
结果显示:各组均未发现明显动物刺激性,初步判断各组凝胶均适用于皮肤表面创口的治疗。
实验效果例3:0.5%紫檀芪凝胶的贮存稳定性。
实验药物:0.5%紫檀芪凝胶(实施例1制备,设为实验1组)。
对照药物:采用本发明专利实施例1制备方法,但是不加甘草酸,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验2组);不加瑞鲍迪苷A,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验3组);不加甘草酸和瑞鲍迪苷A,将紫檀芪先用少量乙醇溶解,直接加入透明质酸钠和卡波姆940凝胶中,配制0.5%紫檀芪溶液凝胶(设为实验4组)。
实验方法:将上述各组凝胶分别封装于透明玻璃瓶中室温保存,12个月后取各组凝胶,先观察凝胶外观颜色等变化情况,然后用水稀释各组凝胶,甲醇溶解各组中的药物紫檀芪,经相同前处理后,高效液相色谱法测定处理前后溶液中的紫檀芪药物浓度,计算其贮存稳定性。
结果显示,实验1组12个月后凝胶的外观形态和颜色未见明显变化,凝胶中紫檀芪含量为初始浓度的95.6%。实验2组和实验3组在12个月后凝胶的颜色微变黄,凝胶中紫檀芪含量分别为初始浓度的61.9%和73.1%。实验4组在12个月后凝胶的颜色明显变黄变深,凝胶中紫檀芪含量仅为初始浓度的1.3%。这可解释为:实验1组由瑞鲍迪苷A和甘草酸混合胶束包封紫檀芪,包封药物能稳定,药物不易从胶束中渗漏析出,且甘草酸弱酸性,赋予混合胶束弱酸性微环境,而紫檀芪在弱酸性条件下分子更稳定,不易被氧化降解。而单独的瑞鲍迪苷A或甘草酸胶束,因形成的胶束结构没有混合胶束稳定性好,紫檀芪有一定量的析出与降解。而不进行纳米胶束包封的紫檀芪凝胶,紫檀芪绝大部分已经被氧化降解。
实验效果例4:0.5%紫檀芪凝胶的人体有效性。
实验药物:0.5%紫檀芪凝胶(实施例1制备,设为实验1组);采用本发明专利实施例1制备方法,但是不加甘草酸,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验2组);不加瑞鲍迪苷A,其余制备过程一致,制备的0.5%紫檀芪凝胶(设为实验3组);不加甘草酸和瑞鲍迪苷A,将紫檀芪先用少量乙醇溶解,直接加入透明质酸钠和卡波姆940凝胶中,配制0.5%紫檀芪溶液凝胶(设为实验4组)。
使用方法:选取40名皮肤有患处的志愿实验者,随机分为4组,皮肤伤患处每天早晚各涂抹上述各组实验一次,涂抹后轻轻按摩皮肤患处,唤醒皮肤感觉,以便更易被皮肤吸收,连续使用1周。
结果显示:连续使用实施例1制备的紫檀芪凝胶(实验1组)1周,试用人群皮肤伤口均有很大程度的改善,9名实验者伤口完全修复,1名实验伤口未完全修复,但是明显改善,伤口未见红肿、感染;实验2组和实验3组,试用人群皮肤伤口也均有很大程度的改善,两组均有7名实验者伤口完全修复,3名实验伤口未完全修复,但是明显改善,伤口略微红肿,未见感染;实验4组,试用人群皮肤伤口有一定程度的改善,有5名实验者伤口完全修复,5名实验伤口未完全修复,但是也有一定程度的改善,伤口略微红肿,但均未见感染。由此可见,瑞鲍迪苷A和甘草酸混合胶束包封紫檀芪药效最强。
上述实施例只为说明本发明的技术构思及特点,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围内。
Claims (3)
1.一种可自行提供弱酸性环境的紫檀芪纳米皮肤外用凝胶,包括紫檀芪为主药,其特征在于还包括瑞鲍迪苷A与甘草酸为药物辅料,卡波姆940为凝胶骨架,其特征在于还包括紫檀芪在凝胶中浓度为2mg/ml~10mg/ml,瑞鲍迪苷A在凝胶中浓度为30mg/ml~60mg/ml,甘草酸在凝胶中浓度为5mg/ml~12mg/ml,透明质酸钠在凝胶中浓度为1mg/ml~5mg/ml,卡波姆940在凝胶中浓度为3mg/ml~10mg/ml。
2.如权利要求1所述的高稳定型紫檀芪嫩肤水,其特征在于所述瑞鲍迪苷A(CAS登记号58543-16-1,分子式C44H70O23,分子量967.03)纯度≥98%,所述甘草酸(CAS登记号:1405-86-3,分子式:C42H62O16,分子量:822.93)纯度≥97%。
3.如权利要求1所述的紫檀芪皮肤凝胶的制备过程如下:
(1)先将紫檀芪充分溶解于乙醇中,再将瑞鲍迪苷A与甘草酸按比例混合溶解在上述溶解了紫檀芪的乙醇溶液中,旋干乙醇得固体粉末;
(2)取透明质酸钠用水浸泡过夜完全溶解,待用;
(3)将步骤(2)所得的透明质酸钠水溶液分成两等份,一份加入至步骤(1)所得固体粉末,搅拌至固体粉末完全溶解;另一份步骤(2)所得的透明质酸钠水溶液,取适量的卡波姆940加入,将卡波姆完全浸入溶液中后,静置过夜,使卡波姆完全溶胀;
(4)将步骤(3)所得两等份溶液混合,在减压脱气条件下,搅拌均匀,即得本发明的紫檀芪纳米胶束外用凝胶剂。
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