CN113842405B - 构树根皮提取物在制备皮肤抗敏止痒药物中的应用 - Google Patents
构树根皮提取物在制备皮肤抗敏止痒药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种构树根皮提取物在制备皮肤抗敏止痒药物中的应用，本发明通过体外透明质酸酶抑制实验考察了不同浓度构树根皮正丁醇萃取物的抗过敏功效；并以构树根皮正丁醇萃取物为原料药制备成水凝胶制剂，并考察其在小鼠瘙痒模型上的疗效。研究结果表明，不同浓度的构树根皮正丁醇萃取物具有明显的透明质酸酶抑制功效，且对4‑氨基吡啶诱发的小鼠皮肤瘙痒模型有很好的防治作用。作为一种传统药材，构树根皮外用安全性高，有望成为抗敏止痒产品的有效活性成分，在外用止痒制剂中具广阔开发前景。
Description
技术领域
本发明涉及构树根皮提取物在制备皮肤抗敏止痒药物中的应用。
背景技术
瘙痒是一种不愉快的躯体感觉，是多种过敏性疾病的常见伴随症状。近年来，皮肤过敏、瘙痒的发生率呈上升趋势，这与气候环境变化、大量化学制品的应用、精神紧张、饮食结构改变等有关。瘙痒可使皮肤增厚、湿疹化，严重者可出现抓痕、血痂，显著影响患者的身心健康和生活质量。另一方面，瘙痒引起的搔抓行为不仅会破坏患者的皮肤屏障，还会使患者陷入“瘙痒-搔抓-严重瘙痒”的恶性循环，导致治疗成本不断增加。
透明质酸酶(Hyaluronidase)亦称扩散因子，是透明质酸的水解酶，主要存在于皮肤、关节、韧带、眼睛中，参与人体的许多病理生理活动，如胚胎发生、血管形成、血管重建、免疫逃逸及肿瘤进展。透明质酸酶是I型过敏反应的参与者，其过度活动会促进透明质酸降解，导致细胞外基质崩解、皮肤老化，从而引起皮肤过敏瘙痒，因此抑制透明质酸酶活性是研究抗过敏作用的靶点之一。
另一方面，瘙痒的产生涉及复杂的信号传导通路，主要包括组胺依赖性瘙痒和非组胺依赖性瘙痒2种机制。5-羟色胺(5-HT)是一种重要的内源性致痒物质，通过组胺依赖性通路传导激活感觉神经元而产生痒觉信号。研究显示，皮肤瘙痒症患者血清中5-HT水平显著增加。因此，寻找拮抗5-HT的有效物质对开发皮肤瘙痒相关治疗药物具有重要意义。
目前，临床针对皮肤过敏瘙痒的外用制剂主要包括糖皮质激素类药物、抗组胺类药物等。但是，长时间使用这些药物会带来很大的副作用。如，长期外用糖皮质激素类药物会导致皮肤萎缩，继发或加重感染的情况发生。因此，积极寻找和开发一种治疗皮肤瘙痒疗效好、副作用少且价格合适的外用制剂具有极大地临床价值和需求潜力。
构树(Broussonetiapapyrifera(L.)vent)，又名楮树、谷浆树等，为桑科(Moreceae)构树属。作为我国历版药典中的一种传统药材，构树根、叶、果实和树皮皆可入药。历史上对构树药性(味甘、性凉、无毒)的最早记载源于汉末陶氏的药学著作《名医别录》。《本草纲目》明确记载，构树根茎具有祛风止痒，治疗风疹之功效；其皮具有祛风湿之功效，外用可治神经性皮炎及癣症，这为构树皮提取物抗敏止痒功效的研究提供了依据。
发明内容
本发明根据《本草纲目》中关于构树根茎祛风止痒功效的记载，提供了构树根皮提取物在制备皮肤抗敏止痒药物中应用的可能和前景。
本发明采用体外透明质酸酶抑制实验考察了不同浓度构树根皮正丁醇萃取物溶液的抗过敏功效。同时，本发明以构树根皮正丁醇萃取物为原料制备水凝胶制剂，并考察其在小鼠急性瘙痒模型上的疗效。由于瘙痒反复发作、治疗周期长，水凝胶制剂可提高患者的用药顺应性。实验结果表明含药水凝胶制剂具有明显疗效，且给药更具有顺应性。
在体外实验中，本发明考察了不同浓度的BP-R-nBtOH对透明质酸酶的抑制作用。结果表明，不同浓度的BP-R-nBtOH对透明质酸酶有明显的抑制作用，且抑制作用随着浓度的升高不断增大。在体内实验中，本发明通过建立4-氨基吡啶(4-AP)致小鼠皮肤瘙痒模型，比较了复方醋酸地塞米松乳膏、构树根皮正丁醇萃取物(BP-R-nBtOH)、构树茎皮正丁醇萃取物(BP-S-nBtOH)治疗皮肤瘙痒的效果。实验结果显示，构树根皮正丁醇萃取物对4-AP所致皮肤瘙痒的疗效与复方地塞米松乳膏相当，且优于构树茎皮正丁醇萃取物。具体表现为构树根皮正丁醇萃取物可显著减少4-AP所致皮肤瘙痒小鼠的搔抓次数(P<0.05)。除此之外，其还能有效降低小鼠血清中5-HT水平(P<0.05)，这是与现有止痒中药提取物相关发明的最大不同之处。
本发明通过实验表明，在抗过敏方面，BP-R-nBtOH对透明质酸酶有明显的抑制作用；在止痒方面，BP-R-nBtOH对皮肤瘙痒的治疗效果与复方地塞米松乳膏相当，且优于BP-S-nBtOH的治疗效果。
综上所述，BP-R-nBtOH对皮肤瘙痒具有显著的抗敏止痒功效。
附图说明
图1为BP-S-nBtOH对透明质酸酶抑制率的影响；
图2为各组小鼠血清5-HT含量比较。
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，下面将对本发明实施方式作进一步地详细描述，但本发明的实施方式不限于此，对于未特别注明的工艺参数或条件，可参照常规技术进行。
实施例1构树根皮、茎皮提取物的制备
称取干燥粉碎后的构树根皮50g，按照料液比1:4加入95％的乙醇，75℃加热回流提取，一次1小时，共提取3次；合并提取液，过滤后得上清液①，进行旋转蒸发至上清液①体积的1/10，得到浓缩液；然后向浓缩液加入两倍体积的蒸馏水进行超声；充分分散后，进行离心取得上清液②，旋转蒸发至无醇味，然后加入等体积乙酸乙酯进行萃取，重复2-3次；取下层萃取液，再用等体积水饱和正丁醇进行萃取，重复2-3次，合并上层萃取液，得到正丁醇萃取液。最后将正丁醇萃取液浓缩至浸膏样，冷冻干燥，得到构树根皮正丁醇萃取物，保存备用。
构树茎皮的提取方法与上述提取方法相同。
实施例2构树根皮提取物的体外透明质酸酶实验
研究表明透明质酸酶与过敏密切相关，能够酶解体内的透明质酸，使其变为低分子量的酸性刺激源，诱导机体产生敏感症状。本发明采用透明质酸酶体外抑制实验测定BP-R-nBtOH对透明质酸酶活性抑制效果。实验浓度采用0.5mg/mL～2.5mg/mL。
所需溶液配制：
BP-R-nBtOH溶液：取实施例1中的BP-R-nBtOH，用去离子水配制成浓度为0.5mg/mL～2.5mg/mL的溶液。
醋酸缓冲溶液：量取1.155mL冰乙酸稀释至100mL混匀，取其中4.8mL为A溶液；称取2.72g乙酸钠结晶，加水溶解定容至100mL混匀，取其中45.2mL为B溶液；混合A、B溶液，以水定容至100mL，混匀。
透明质酸酶溶液：称取10mg透明质酸酶于烧杯中，加入4mL醋酸缓冲溶液。
透明质酸钠溶液：称取5mg透明质酸钠于烧杯中，加入10mL醋酸缓冲溶液。
埃尔利希试剂：称取0.8g对-二甲氨基苯甲醛，溶于15mL浓盐酸和15mL无水乙醇中。
乙酰丙酮溶液：取3.5mL乙酰丙酮，溶于50mL 1.0mol/L的碳酸钠溶液中，现配现用。
实验步骤：
取0.25mmol/L的CaCl2溶液0.1mL和透明质酸酶溶液0.5mL，37℃保温培养20min；加入不同浓度的BP-R-nBtOH溶液0.5mL，继续37℃保温培养20min；加入0.5mL透明质酸钠液37℃保温30min，常温放置5min；加入0.1mL 0.4mol/L的NaOH溶液和0.5mL乙酰丙酮溶液，沸水浴15min，立即用冰水冷却5min；加入埃尔利希试剂1.0mL，并用3.0mL无水乙醇进行稀释，室温放置20min，测定波长530nm处的吸光值。
样品对透明质酸酶抑制率的计算公式：
透明质酸酶抑制率(％)＝[(A1-A2)-(B1-B2)]/(A1-A2)×100％；
其中，A1为对照溶液ABS值(用醋酸缓冲溶液代替样品液)；A2为对照空白溶液ABS值(用醋酸缓冲溶液代替样品液及酶液)；B1为试样溶液ABS值；B2为试样空白溶液ABS值(用醋酸缓冲溶液代替酶液)。
实验结果：实施例1中得到的BP-R-nBtOH，其透明质酸酶抑制率结果见图1。如图1所示，随着BP-R-nBtOH浓度的增加，其对透明质酸酶活性的抑制效果逐渐增强。说明实施例1得到的BP-R-nBtOH能够有效抑制透明质酸酶活性，从而起到良好的抗敏作用。
实施例3构树根皮、茎皮水凝胶的制备
称量1g卡波姆940，将其撒于100mL水中溶胀过夜，用三乙醇胺调节凝胶pH至6.5。取构树根皮或茎皮正丁醇萃取物的干燥粉末1g(制备方法见实施例1)，用少量去离子水充分溶解，加入到调配好的凝胶基质中，搅拌均匀，用水补足凝胶至10g，混合均匀后得到10％构树根皮水凝胶制剂或10％茎皮正丁醇萃取物水凝胶制剂。
实施例4构树根皮、茎皮提取物对小鼠皮肤瘙痒模型的影响
实验动物：SPF级ICR小鼠，5～6周龄，体重20～25g，雌雄各半，由广东省实验动物中心提供。
实验分组：随机分成5组，包括正常组、模型组、阳性对照组(复方醋酸地塞米松乳膏)、BP-R-nBtOH、BP-S-nBtOH组。
实验方法：适应性饲养1周后，将所有小鼠背部毛用剪刀剪掉，再用脱毛膏洗干净使其露出皮肤，面积约为2cm×2cm，24h后给药。用实施例3中方法制备的凝胶给药，具体给药情况见表1。每天上午固定时间给药1次，连续七天。末次给药30min后，除正常组外，在所有小鼠背上脱毛部位中心皮下注射4-AP溶液0.01mL/g(先用生理盐水配制成0.5％的溶液，实验前再用生理盐水将其稀释成0.01％的溶液)，立即观察并记录小鼠在10min内的舔体次数(以小鼠连续舔体至出现短暂停顿，作为1次舔体计算)。
表l各组小鼠给药情况及给药量
| 组别 | 所给药物 | 每次给药量 |
| 正常组 | 生理盐水 | 0.2mL/只 |
| 模型组 | 水凝胶基质 | 0.2g/只 |
| 阳性对照组 | 复方醋酸地塞米松乳膏 | 0.2g/只 |
| BP-R-nBtOH组 | 10％BP-R-nBtOH水凝胶 | 0.2g/只 |
| BP-S-nBtOH组 | 10％BP-S-nBtOH水凝胶 | 0.2g/只 |
实验结果：
统计各组小鼠10min内的搔抓次数并作比较，见表2。由表2中结果可知，与正常组相比，模型组小鼠的搔抓次数明显增加(P<0.001)；与模型组比较，阳性对照组(复方醋酸地塞米松乳膏)、BP-R-nBtOH组均能减少4-AP所致急性瘙痒小鼠的抓挠次数(P<0.05)，且BP-R-nBtOH作用与复方醋酸地塞米松乳膏作用相当。根据记载，构树茎皮有治疗皮肤瘙痒的功效，但在实验中发现与BP-R-nBtOH组相比，BP-S-nBtOH组小鼠抹药后抓挠次数减少不明显，而BP-R-nBtOH的效果更好，表明构树根皮提取物的止痒效果优于茎皮部位。
表2各组小鼠10min内的搔抓次数比较
注：“***”表示与正常组比较，P<0.01；“+”与模型组比较，表示P<0.05。
统计各组小鼠血清5-HT含量并作比较，见图2。由图2中结果可知，与正常组相比，模型组小鼠血清5-HT含量明显增加(P<0.01)；与模型组比较，阳性对照组、BP-R-nBtOH组均能减少小鼠血清5-HT含量(P<0.05)。
相对于现有技术，本发明的区别在于：
1)提取部位：本研究发现，构树根皮提取物具有明显的透明质酸酶抑制作用及外用治疗皮肤瘙痒的效果，表明构树根皮部位含有抗过敏止痒相关有效成分。
2)组成成分：既往关于构树提取物止痒功效的研究，都是探讨含有构树提取物的组合物的总体止痒功效，本发明以含有构树根皮正丁醇萃取物这一成分的水凝胶制剂进行研究。
3)有益功效：本研究结果表明，在抗过敏方面，BP-R-nBtOH具有明显的透明质酸酶抑制作用；在治疗皮肤瘙痒方面，BP-R-nBtOH不仅有效减少了小鼠的搔抓次数，还能降低小鼠血清中5-HT水平。因此，本发明对临床上开发皮肤抗敏止痒药物具有重要意义。
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和应用本发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于这里的实施例，本领域技术人员根据本发明的揭示，对于本发明做出的改进和修改都应该在本发明的保护范围之内。
Claims (4)
1.构树根皮正丁醇萃取物在制备治疗组胺依赖型瘙痒药物中的应用，
构树根皮正丁醇萃取物的制备包括以下步骤：
取构树根皮干燥，粉碎过筛，得构树根皮粉末；
加入95%乙醇溶液，加热回流提取三次，合并提取液；
过滤上述提取液，得上清液①，将其旋转蒸发至原体积的1/10，得到浓缩液；
向浓缩液中加入两倍体积的蒸馏水超声分散，充分分散后离心，得上清液②，继续旋蒸直至无醇味，得到总提取液；
向总提取液中加入等体积乙酸乙酯进行萃取，重复2~3次；
收集下层液体，用等体积的水饱和正丁醇萃取，重复2~3次，合并上层萃取液，即为正丁醇萃取液；
将正丁醇萃取液浓缩至浸膏样，冷冻干燥，得构树根皮正丁醇萃取物。
2.如权利要求1所述的应用，其特征在于，构树根皮正丁醇萃取物以降低血清中5-HT含量水平发挥止痒作用。
3.如权利要求1所述的应用，其特征在于，所述药物制剂为外用制剂。
4.如权利要求3所述的应用，其特征在于，所述外用制剂的剂型为凝胶剂、软膏、乳膏、巴布剂、涂膜剂中的至少一种。
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