CN116350746A - 沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用 - Google Patents
沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用 Download PDFInfo
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Abstract
本发明提供了沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用，所述沙丁鱼肽组合物为沙丁鱼二肽至五肽的混合物，其中多种肽段间生物活性协同作用，具有抑制鼻腔炎症发作，预防鼻腔毛细血管充血的作用；还可改善过敏性鼻炎引起的鼻痒、打喷嚏、鼻溢、鼻塞，和伴有腭、喉、耳和眼部发痒以及眼发红、肿胀以及水样分泌物的多项症状。同时，所述沙丁鱼肽组合物对于鼻黏膜敏感的患者也无刺激感，未观察到局部副作用、困倦等全身性副作用，具有优异的有效性和安全性。
Description
技术领域
本发明属于生物医药技术领域，特别涉及沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用。
背景技术
变应性鼻炎又称过敏性鼻炎(allergic rhinitis，AR)是一种免疫球蛋白E(immunoglobulin E，IgE)介导的炎症性鼻腔疾病，发病者约占人群的10％，由敏感个体暴露于变应原引起。肥大细胞、嗜酸性粒细胞、CD4+T淋巴细胞和B淋巴细胞都是参与其中的主要炎性细胞。其中肥大细胞脱颗粒释放各种递质导致微血管通透性增加，鼻粘膜水肿，分泌亢进，且能释放多种细胞因子，这是过敏性鼻炎发生时组织损伤的重要机制。
AngⅡ(AngiotensinII，AngⅡ)作为肾素-血管紧张素系统(RAS)重要组成部分，AngⅡ大部分的功效是由AT1介导产生的，两者结合可引起血管收缩、血压升高、对白细胞、内皮细胞和血管平滑肌细胞产生促炎症效应。血管紧张素转换酶(angiotensinconvertingenzyme，ACE)是一种锌金属蛋白酶，主要存在于肺血管内皮细胞，也可见于子宫、胎盘、心脏、血管、肾、大脑、肾上腺皮质等大多数组织。ACE将AngⅠ转换为AngⅡ(血管收缩剂)和降解缓激肽(血管舒张药)，在体内调节血压和心血管平衡。AngⅡ可通过诱导肥大细胞脱颗粒而增加血管通透性。
肥大细胞(mastcell，MC)脱颗粒为过敏反应中的重要环节，MC脱颗粒起因于钙内流调节和钙信号通路的激活。现行过敏性鼻炎药物色甘酸二钠(DSCG)因其限制了具有调节细胞体积功能的氯离子通道，防止细胞外钙离子流入肥大细胞胞质，从而防止肥大细胞脱颗粒。DSCG可以限制鼻腔对变应原的反应，成为预防症状发作的最佳选择之一。研究发现，VY即Val-Tyr也具有钙离子通道抑制功能，能抑制细胞外钙离子内流。
过敏性鼻炎为复发性疾病，需要连续使用药物，目前如何有效治疗过敏性鼻炎仍是医学领域的难题。现有的鼻喷雾用甾类药物会存在鼻内刺激感、干燥感、鼻灼热感、鼻出血等。抗组胺药物可以抑制过敏反应，但也存在鼻黏膜干燥、发困等缺点。因此，提供一种可有效治疗过敏性鼻炎的药物具有重要的现实意义。
发明内容
本发明提出了沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用，研究证实所述沙丁鱼肽组合物作为过敏性鼻炎治疗剂具有优异的有效性和安全性，可明显改善鼻炎、特别是过敏性鼻炎的相关症状。
沙丁鱼肽为沙丁鱼肌肉经处理制备获得的低聚肽的混合物，分子量在200-900道尔顿。目前已有将沙丁鱼肽添加在食品和保健食品中，用于维持正常的血压水平。沙丁鱼肽内含有的低聚肽，具有较高的生物活性，按照功能分为抗过敏活性短肽、ACE抑制活性短肽和L-型钙离子通道抑制的活性肽。因此发明人针对每种活性肽的功能进行了进一步研究发现，抗炎活性肽可以通过减少促炎细胞因子释放，抑制或干预TNF-α诱导的炎症途径、NF-κB和MAPK信号通路达到预防和治疗炎症的目的。ACE抑制短肽通过抑制ACE活性，抑制AngⅡ产生，从而起到抑制炎症的目的。L-型钙离子通道抑制的活性肽可以抑制细胞L-型钙通道活性，从而抑制钙离子内流，防止肥大细胞脱颗粒。这些生物活性多肽的生理机制支持了沙丁鱼肽在治疗过敏性鼻炎或症状改善方面的作用。基于此，发明人进一步研究发现，混合多肽的吸收效率高于单一多肽的吸收效率，且多肽间的生物活性具有协同效应，混合多肽的生物活性高于单一多肽生物活性。
有鉴于此，发明人提供了本发明的如下方案。
为了实现上述发明目的，本发明的第一方面提供了沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用。
进一步的，所述沙丁鱼肽组合物是由沙丁鱼经包括微生物发酵法、酸法、碱法、电法、人工嫁接法、基因表达法、酶解法在内的方法制备而成，只要具有生物活性，则不特别限定；优选为酶解法制得沙丁鱼肽组合物。
进一步的，所述沙丁鱼肽组合物为沙丁鱼二肽至至五肽的混合物；其中，沙丁鱼二肽包括Ala-Leu、Lys-Trp、Ala-Trp、Met-Leu、Arg-Tyr、Met-Phe、Gly-Trp、Met-Tyr、Gly-Tyr、Phe-Leu、Ile-Phe、Thr-Tyr、Ile-Trp、Tyr-Leu、Ile-Tyr、Val-Phe、Leu-Trp、Val-Trp、Leu-Tyr、Val-Tyr；沙丁鱼三肽包括Ala-Asn-Pro、Ala-Lys-Lys、Arg-Phe-His、Arg-Val-Tyr、Gly-Arg-Pro、Ile-Val-Tyr、Trp-Ile-Thr、Tyr-Val-Pro、Val-Val-Phe；沙丁鱼四肽为Gly-Trp-Ala-Pro；沙丁鱼五肽为Asn-Val-Pro-Ile-Tyr。
进一步的，所述沙丁鱼肽组合物在患病机体中的有效剂量为0.01～0.03mg/kg。
本发明的第二方面提供了一种防治过敏性鼻炎的组合物，所述组合物中包含沙丁鱼肽组合物和药学上可接受的辅料。
进一步的，所述沙丁鱼肽组合物为沙丁鱼二肽至五肽的混合物；其中，沙丁鱼二肽包括Ala-Leu、Lys-Trp、Ala-Trp、Met-Leu、Arg-Tyr、Met-Phe、Gly-Trp、Met-Tyr、Gly-Tyr、Phe-Leu、Ile-Phe、Thr-Tyr、Ile-Trp、Tyr-Leu、Ile-Tyr、Val-Phe、Leu-Trp、Val-Trp、Leu-Tyr、Val-Tyr；沙丁鱼三肽包括Ala-Asn-Pro、Ala-Lys-Lys、Arg-Phe-His、Arg-Val-Tyr、Gly-Arg-Pro、Ile-Val-Tyr、Trp-Ile-Thr、Tyr-Val-Pro、Val-Val-Phe；沙丁鱼四肽为Gly-Trp-Ala-Pro；沙丁鱼五肽为Asn-Val-Pro-Ile-Tyr。
进一步的，组合物中所述沙丁鱼肽组合物的质量浓度可以考虑到症状、年龄、剂型等来适当选择，具体来说，对于滴鼻剂来说，沙丁鱼肽组合物的质量浓度为0.01％～50％，优选0.15％～10％(w/w)。
所述组合物的使用次数和使用时间根据症状、年龄、剂型等不同而定，但是标准为1天2-3次，使用时间为7-14天。
进一步的，所述组合物的给药途径，可以根据患者、症状使用包括粘膜给药制剂、胃肠道给药制剂、呼吸道给药制剂、皮肤给药制剂、腔道给药制剂、注射给药制剂。具体地说，可以为滴鼻剂、凝胶剂、软膏剂、乳膏剂、洗剂、喷雾剂、液体制剂、鼻喷雾剂、贴剂、气雾剂、胶冻剂、巴布剂、贴剂、硬膏剂、悬浮剂、乳剂、注射剂、片剂、丸剂、胶囊剂、颗粒剂、粉末剂等。通过选择适当的溶剂，也可以液体制剂的方式使用。任意一种制剂都可以通过公知的方法制备。
进一步的，所述粘膜给药制剂优选鼻制剂或舌下片剂，所述鼻制剂包含软膏剂、凝胶剂、乳膏剂、洗剂、液体制剂、粉末剂、油喷剂或喷雾剂的鼻制剂；特别优选为油喷剂。
本发明的滴鼻剂，可以为液体制剂或粉末剂等干燥制品，可以含有载体或赋形剂、表面活性剂、助悬剂、渗透压调节剂等。可以使用氯化钠、甘油、亚硫酸氢钠、苯扎氯氨、果糖、柠檬酸、柠檬酸钠、结晶磷酸二氢钠、氢氧化钠、山梨醇液、烟酰胺、浓甘油、丙二醇、苯甲醇、硼酸、硼砂、聚乙二醇4000、氢氧化钠、磷酸、磷酸二氢钠、磷酸二氢钾。作为助悬剂，可以使用结晶纤维素、羧甲基纤维素钠和羟丙基纤维素。
液体制剂为将有效成分沙丁鱼肽组合物溶解在作为基质的乙醇、甘油、丙二醇、聚乙二醇、水、脂肪油中而成。优选为包含将所述沙丁鱼肽组合物溶解在生理盐水中而制成的水溶液的液体制剂。水溶液除了生理盐水外，还可以少量混合乙醇、甘油、丙二醇、聚乙二醇、二甲基亚枫等有机溶剂。
液体制剂，除了上述水溶液制剂外，还可以形成水性或油性的溶液、混悬剂、乳剂等。此外也可以在使用前通过水或适当的介质再溶解的干燥药物组合物方式提供。
喷雾剂为将沙丁鱼肽组合物制成水溶液、油溶液、乳剂或混悬剂。
在制备本发明的鼻炎治疗剂时，可以任意组合、配合各种的基质、保湿剂、醇类、螯合剂、pH调节剂、防腐剂、增稠剂、着色剂、香料、填充剂、赋性剂、崩解剂、增量剂、粘合剂、涂抹剂、增溶剂、助悬剂、缓冲剂、稳定剂、抑菌剂、表面活性剂、抗氧剂、乳化剂、助溶剂等。除了作为有效成分的沙丁鱼肽外，还可以根据需要适当配合各种药剂，如维生素类、杀菌消毒剂等。
进一步的，所述过敏性鼻炎又称变应性鼻炎(Allergic Rhinitis，AR)，包括为季节性过敏性鼻炎和常年性过敏性鼻炎。
本发明的优点和有益效果是：
1、本发明所述沙丁鱼肽组合物内含有多种短肽，具有较高的生物活性，按照功能分为抗过敏活性短肽、ACE抑制活性短肽和L-型钙离子通道抑制的活性肽；其中，抗炎活性肽可以通过减少促炎细胞因子释放，抑制或干预TNF-α诱导的炎症途径、NF-κB和MAPK信号通路达到预防和治疗炎症的目的。ACE抑制短肽通过抑制ACE活性，抑制AngⅡ产生，从而起到抑制炎症的目的。L-型钙离子通道抑制的活性肽可以抑制细胞L-型钙通道活性，从而抑制钙离子内流，防止肥大细胞脱颗粒。所述沙丁鱼肽组合物中上述不同短肽相互配合、发挥各自功效，从而使得组合物在治疗、改善过敏性鼻炎相关症状中作用效果显著。
2、本发明的沙丁鱼肽组合物在治疗过敏性鼻炎或症状改善方面具有较好的效果，可制成多种剂型给药。
3、利用本发明所述沙丁鱼肽组合物制备得到的鼻制剂，不仅改善鼻腔毛细血管充血的作用，还可改善过敏性鼻炎引起的鼻痒、打喷嚏、鼻溢和鼻塞、和伴有腭、喉、耳和眼部发痒以及眼发红、肿胀以及水样分泌物等具有效果。进一步地，对于鼻黏膜敏感的患者也无刺激感，未观察到局部副作用、困倦等全身性副作用。
具体实施方式
以下实施例中，在没有特别说明的情况下，涉及到的实验仪器及原料均为市售产品。
原料，见表1。
表1
| 原料名称 | 级别 | 来源 |
| 沙丁鱼肽组合物(Valtyron) | 食品级 | 日本仙味公司 |
| 环糊精 | 食品级 | 四川华源盛泰生物科技有限公司 |
| 磷酸氢二钾 | 食品级 | 四川康百瑞生物科技有限公司 |
| 磷酸二氢钾 | 食品级 | 四川康百瑞生物科技有限公司 |
| 氯化钠 | 试剂级 | 中科瑞泰(北京)生物科技有限公司 |
| 苯扎氯铵 | 药用级 | 西安天正药用辅料有限公司 |
| 维生素E | 食品级 | 浙江新和成股份有限公司 |
| 精制芝麻油 | 食品级 | CrodaInc. |
| 大豆卵磷脂 | 食品级 | 沈阳天峰生物制药有限公司 |
| 大豆油 | 药用口服级 | 山西锦洋药用辅料有限公司 |
经测定，日本仙味公司的沙丁鱼肽组合物Valtyron是经酶解法制备得到，为沙丁鱼二肽至五肽的混合物；其中，沙丁鱼二肽为Ala-Leu、Lys-Trp、Ala-Trp、Met-Leu、Arg-Tyr、Met-Phe、Gly-Trp、Met-Tyr、Gly-Tyr、Phe-Leu、Ile-Phe、Thr-Tyr、Ile-Trp、Tyr-Leu、Ile-Tyr、Val-Phe、Leu-Trp、Val-Trp、Leu-Tyr、Val-Tyr的组合。沙丁鱼三肽为Ala-Asn-Pro、Ala-Lys-Lys、Arg-Phe-His、Arg-Val-Tyr、Gly-Arg-Pro、Ile-Val-Tyr、Trp-Ile-Thr、Tyr-Val-Pro、Val-Val-Phe的组合。沙丁鱼四肽为Gly-Trp-Ala-Pro。沙丁鱼五肽为Asn-Val-Pro-Ile-Tyr。
实验仪器，见表2。
表2
实施例1——沙丁鱼肽鼻喷雾剂(水溶液)
本实施例提供了一种水溶液型的沙丁鱼肽鼻喷雾剂，其中包含沙丁鱼肽组合物和相关辅料，所述鼻喷雾剂中各物料的含量如表3所示。
表3
本实施例所述沙丁鱼肽鼻喷雾剂的制备方法包括以下步骤：
首先根据表3所示的用量精确称取各物料，将各物料分别溶于适量的注射用水中，待物料完全溶解后，将各组分充分混匀，并加入注射用水至所需配置量。测定溶液pH值达到5.5～6.5，使用0.22μm微孔滤膜过滤，得到混合水溶液。将所述混合水溶液罐装于30ml定量式喷雾容器，即制成所述水溶液型的沙丁鱼肽鼻喷雾剂。该鼻喷剂1次的喷雾量为50μl。
实施例2——沙丁鱼肽鼻喷雾剂(油溶液)
本实施例提供了一种油溶液型的沙丁鱼肽鼻喷雾剂，其中包含沙丁鱼肽组合物和相关辅料，所述鼻喷雾剂中各物料的含量如表4所示。
表4
本实施例所述沙丁鱼肽鼻喷雾剂的制备方法包括以下步骤：
根据表4所示的用量精确称取沙丁鱼肽组合物和维生素E，先将维生素E溶于芝麻油中，待其完全溶解后，再将沙丁鱼肽组合物混悬于芝麻油溶液中，从而配置成所述油溶液型的沙丁鱼肽鼻喷雾剂。
在摇匀致无沉淀物状态下，将所述沙丁鱼肽鼻喷雾剂罐装入20ml定量鼻用喷雾器中，喷雾器每喷剂量约为45μl。
实施例3——沙丁鱼肽鼻喷雾剂(乳剂)
本实施例提供了一种乳剂型的沙丁鱼肽鼻喷雾剂，其中包含沙丁鱼肽组合物和相关辅料，所述鼻喷雾剂中各物料的含量如表5所示。
表5
本实施例所述沙丁鱼肽鼻喷雾剂的制备方法包括以下步骤：
首先根据表5所示的用量精确称取各物料，将沙丁鱼肽组合物溶于纯化水中，形成水相溶液。再将维生素E、大豆卵磷脂和大豆油搅拌混合均匀，得到油相溶液。
然后，将水相溶液倒入油相溶液，利用高速剪切乳化机1000rmp的转速下乳化，得粗乳；再利用高压均质机在70℃，1000bar的压力下乳化，制得油包水型乳剂——乳剂型的沙丁鱼肽鼻喷雾剂。
将乳剂罐装于30ml定量鼻用喷雾器，制成1次的喷雾量为45μl。
测试例
将实施例1、2、3制备得到的水溶液型、油溶液型及乳剂型的沙丁鱼肽鼻喷雾剂，给予过敏性鼻炎的患者，每天使用2～3次，在连续使用7天后统计患者的反映情况。
参与的受试者共18人，随机分为3组，每组6人。
第一组6位受试者使用实施例1制备得到的水溶液型的沙丁鱼肽鼻喷雾剂，每日早晚各对鼻腔喷1-2喷，或外界环境刺激情形导致鼻塞时1-2喷，喷药时，应让喷头指向鼻腔外侧。
第二组6位受试者使用实施例2制备得到的油溶液型的沙丁鱼肽鼻喷雾剂，在使用前上下摇动喷瓶20次或观察瓶底无沉淀，受测者每日早晚各对鼻腔喷1-2喷，或外界环境刺激导致鼻塞时1-2喷，喷药时，应让喷头指向鼻腔外侧。
第三组6位受试者使用实施例3制备得到的乳剂型的沙丁鱼肽鼻喷雾剂。受测者每日早晚各对鼻腔喷1-2喷，或外界环境刺激导致鼻塞时1-2喷，喷药时，应让喷头指向鼻腔外侧。
连续使用7天后，效果参见表6。
表6
最后应说明的是，以上仅用以说明本发明的技术方案而非限制，尽管参照较佳布置方案对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围。
Claims (10)
1.沙丁鱼肽组合物在治疗过敏性鼻炎的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述沙丁鱼肽组合物是由沙丁鱼经包括微生物发酵法、酸法、碱法、电法、人工嫁接法、基因表达法、酶解法在内的方法制备而成。
3.根据权利要求1或2所述的应用，其特征在于，所述沙丁鱼肽组合物为沙丁鱼二肽至五肽的混合物。
4.根据权利要求3所述的应用，其特征在于，所述沙丁鱼肽组合物中，沙丁鱼二肽包括Ala-Leu、Lys-Trp、Ala-Trp、Met-Leu、Arg-Tyr、Met-Phe、Gly-Trp、Met-Tyr、Gly-Tyr、Phe-Leu、Ile-Phe、Thr-Tyr、Ile-Trp、Tyr-Leu、Ile-Tyr、Val-Phe、Leu-Trp、Val-Trp、Leu-Tyr、Val-Tyr；沙丁鱼三肽包括Ala-Asn-Pro、Ala-Lys-Lys、Arg-Phe-His、Arg-Val-Tyr、Gly-Arg-Pro、Ile-Val-Tyr、Trp-Ile-Thr、Tyr-Val-Pro、Val-Val-Phe；沙丁鱼四肽为Gly-Trp-Ala-Pro；沙丁鱼五肽为Asn-Val-Pro-Ile-Tyr。
5.根据权利要求1所述的应用，其特征在于，所述沙丁鱼肽组合物在患病机体中的有效剂量为0.01～0.03mg/kg。
6.一种防治过敏性鼻炎的组合物，其特征在于，所述组合物中包含沙丁鱼肽组合物和药学上可接受的辅料。
7.根据权利要求6所述防治过敏性鼻炎的组合物，其特征在于，所述沙丁鱼肽组合物为沙丁鱼二肽至五肽的混合物；其中，沙丁鱼二肽包括Ala-Leu、Lys-Trp、Ala-Trp、Met-Leu、Arg-Tyr、Met-Phe、Gly-Trp、Met-Tyr、Gly-Tyr、Phe-Leu、Ile-Phe、Thr-Tyr、Ile-Trp、Tyr-Leu、Ile-Tyr、Val-Phe、Leu-Trp、Val-Trp、Leu-Tyr、Val-Tyr；沙丁鱼三肽包括Ala-Asn-Pro、Ala-Lys-Lys、Arg-Phe-His、Arg-Val-Tyr、Gly-Arg-Pro、Ile-Val-Tyr、Trp-Ile-Thr、Tyr-Val-Pro、Val-Val-Phe；沙丁鱼四肽为Gly-Trp-Ala-Pro；沙丁鱼五肽为Asn-Val-Pro-Ile-Tyr。
8.根据权利要求6所述防治过敏性鼻炎的组合物，其特征在于，组合物中所述沙丁鱼肽组合物的质量浓度为0.01％～50％。
9.根据权利要求6所述防治过敏性鼻炎的组合物，其特征在于，所述组合物的剂型包括粘膜给药制剂、胃肠道给药制剂、呼吸道给药制剂、皮肤给药制剂、腔道给药制剂、注射给药制剂。
10.根据权利要求6所述防治过敏性鼻炎的组合物，其特征在于，所述过敏性鼻炎包括季节性过敏性鼻炎和常年性过敏性鼻炎。
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