CN112521322A - 氨基酸类化合物及组合物及其用于治疗牙周疾病的用途 - Google Patents
氨基酸类化合物及组合物及其用于治疗牙周疾病的用途 Download PDFInfo
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- CN112521322A CN112521322A CN202011466194.6A CN202011466194A CN112521322A CN 112521322 A CN112521322 A CN 112521322A CN 202011466194 A CN202011466194 A CN 202011466194A CN 112521322 A CN112521322 A CN 112521322A
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Abstract
Description
技术领域
本发明涉及牙周疾病治疗的技术领域,尤其涉及氨基酸类化合物及组合物用于治疗牙周疾病的用途。
背景技术
牙周炎(periodontitis)是一种微生物相关的、宿主介导的、多因素参与并导致牙周附着丧失的炎症性疾病。药物治疗是一种牙周炎的辅助治疗方式,目前最常用于临床的药物主要是一些抗生素类药物,如:甲硝唑、阿莫西林等,它们主要通过抑制某些特定种类的细菌及细菌复合物发挥其辅助治疗的效果。但近些年来,抗生素耐药性问题已经被认为是全球健康的主要风险,而且相关研究人员已经从感染的牙髓组织和牙周组织中分离出多种耐药菌株,这表明口腔很可能作为耐药菌菌库,限制抗生素在治疗身体其他部位的感染性疾病中的有效性。
烯丙基半胱氨酸(SAC,S-allycysteine)是大蒜中的天然有机硫化合物,是成熟大蒜提取物(Aged garlic extact)中的主要有效成分,由S-alk(en)yl cysteinesulfoxides(ACSs)降解获得。已有文献报道该化合物具有抗肿瘤、抗细菌和抗真菌的特性。
炔丙基半光氨酸(SPRC,S-propargyl-cysteine)与SAC(S-allycysteine)结构类似,具有相同的半胱氨酸结构。SPRC对心肌细胞缺氧损伤的保护作用和抗肿瘤的作用已有报道,但目前尚未见有关炔丙基半胱氨酸治疗牙周疾病方面的报道,尤其是其在治疗牙周炎方面的报道。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供氨基酸类化合物及药物组合物及其在制备预防、治疗牙周病产品中的用途,用于解决现有技术中的问题。
为实现上述目的,本发明第一方面提供一种用于治疗牙周疾病的氨基酸类化合物及其盐,其特征在于,所述化合物结构如式I所示
其中R1为H或C1-6烷基,n为1-6的整数。
进一步的,所述式I化合物为炔丙基半胱氨酸(S-propargyl-cysteine)。
本发明第二方面提供一种用于治疗牙周疾病的产品,其特征在于,所述产品包含作为活性成分的所述的式I化合物及其盐,所述产品为药物、保健品或食品。
进一步的,所述式I为
其中R1为H或C1-6烷基,n为1-6的整数。
更进一步的,所述式I化合物为炔丙基半胱氨酸(S-propargyl-cysteine)。
更进一步的,所述产品为药物,所述药物包含作为活性成分的式I化合物及其盐,以及药学上可接受的载体或赋形剂。
再进一步的,所述药物组合物为片剂、粉剂、注射剂、胶囊、混悬剂、糊剂、凝胶、软膏、含漱剂、冲洗剂、涂布剂、药膜剂、缓释剂或微球。
本发明的第三方面提供前述的氨基酸类化合物及其盐以及相应产品在制备治疗或预防牙周疾病的产品中的用途,所述产品为药物、保健品或食品。
进一步的,所述氨基酸类化合物为式I所示的化合物
其中R1为H或C1-6烷基,n为1-6的整数。
更进一步的,所述式I化合物为炔丙基半胱氨酸(S-propargyl-cysteine)。
更进一步的,所述产品为药物,所述药物包含作为活性成分的式I化合物及其盐,以及药学上可接受的载体或赋形剂。
再进一步的,所述药物组合物为片剂、粉剂、注射剂、胶囊、混悬剂、糊剂、凝胶、软膏、含漱剂、冲洗剂、涂布剂、药膜剂、缓释剂或微球。
更进一步的,所述牙周疾病包括牙龈病和牙周炎。
更进一步的,所述牙周炎包括各期各级牙周炎、坏死性牙周病和反映全身疾病的牙周炎。
本发明的第四方面提供炔丙基半胱氨酸(S-propargyl-cysteine)用于制备预防或治疗牙周疾病产品中的用途。
进一步的,所述产品为药物、保健品或食品,所述牙周疾病包括牙龈病和牙周炎,所述牙周炎包括各期各级牙周炎、坏死性牙周病和反映全身疾病的牙周炎。
本发明中,“药学上可接受的”是指当分子本体和组合物适当地给予动物或人时,它们不会产生不利的、过敏的或其它不良反应。
更进一步的,所述药学上可接受的药物载体包含肠溶衣制剂、胶囊、微球/囊、脂质体、微乳液、复乳液、纳米颗粒、磁颗粒、明胶或凝胶中的一种或一种以上。
更进一步的,药学上可接受的辅料应当与所述有效成分相容,即能与其共混而不会在通常情况下大幅度降低药物的效果。可作为药学上可接受的载体或辅料的一些物质的具体例子是糖类,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和土豆淀粉;纤维素及其衍生物,如甲基纤维素钠、乙基纤维素和甲基纤维素;西黄蓍胶粉末;麦芽;明胶;滑石;固体润滑剂,如硬脂酸和硬脂酸镁;硫酸钙;植物油,如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可油;多元醇,如丙二醇、甘油、山梨糖醇、甘露糖醇和聚乙二醇;海藻酸;乳化剂,如Tween;润湿剂,如月桂基硫酸钠;着色剂;调味剂;压片剂、稳定剂;抗氧化剂;防腐剂;无热原水;等渗盐溶液;和磷酸盐缓冲液等。这些物质根据需要用于帮助配方的稳定性或有助于提高活性或它的生物有效性或在口服的情况下产生可接受的口感或气味。
本发明中,除非特别说明,药物剂型并无特别限定,可以被制成片剂、粉剂、注射剂、胶囊、混悬剂、糊剂、凝胶、软膏、含漱剂、冲洗剂、涂布剂、药膜剂、缓释剂或微球等剂型,可通过常规方法进行制备。药物剂型的选择应与给药方式相匹配。
本发明中,所述牙周疾病是指发生在牙周支持组织(包括牙龈、牙周膜、牙槽骨和牙骨质)的各种疾病。牙周疾病包括牙龈病和牙周炎。所述牙周炎为一种微生物相关的、宿主介导的、多因素参与并导致牙周附着丧失的炎症性疾病。具体的,按照2018年牙周病和植体周病国际新分类,牙周炎包括坏死性牙周病、反映全身疾病的牙周炎以及各期各级牙周炎。其中,各期各级牙周炎分期包括四期分别为:I期、II期、III期、IV期,分级包括三级分别为:慢速进展、中速进展和快速进展。
附图说明:
图1亚甲蓝染色及H&E评估SPRC对牙槽骨吸收的影响。
图2 Micro-CT评价SPRC对牙槽骨吸收的影响。
图3采用免疫组织化学定位、Westernblot和RT-PCR方法检测IL-17A、IL-6、IL-10和TGF-β1,评价SPRC对Th17/Treg相关细胞因子表达的影响。
具体实施方式
下面结合具体的实施例对本发明作进一步地说明,以更好地理解本发明。
1、构建大鼠牙周炎模型,给予SPRC治疗处理
雄性SD大鼠(200-230g)是饲养在同济大学沪北校区SPF级实验室,牙周炎模型建立:用水合氯醛(25mg/kg)麻醉,用伤寒沙门氏菌LPS 2μl(10μg/μl)在上颌骨两侧第一磨牙和第二磨牙之间的牙间乳头之间注射诱导牙周炎。
实验组分组
-LPS组:大鼠按上述方法接受LPS诱导的牙周炎,每24h腹腔注射2mL生理盐水,持续21天(N=10)。
-LPS+25SPRC组:大鼠按上述方法接受LPS诱导的牙周炎,每24h腹腔注射一次SPRC(25mg/Kg),持续21天(N=10)。
-LPS+50SPRC组:大鼠按上述方法接受LPS诱导的牙周炎,每24h腹腔注射一次SPRC(50mg/Kg),持续21天(N=10)。
control组:大鼠假手术处理,给予生理盐水龈内注射,每24h腹腔注射2mL生理盐水持续21天(N=10)。
2、采用micro-CT,HE染色和亚甲蓝染色析评估牙槽骨吸收情况;
3、免疫组化检测Th17/Treg相关炎症相关因子(IL-6,IL-17,IL-10,TGF-β1)的表达;
4、RT-PCR检测牙龈组织中相关炎症相关因子(IL-6,IL-17,IL-10,TGF-β1),表达水平;
5、Western blot分析牙龈组织中相关炎症相关因子(IL-6,IL-17,IL-10,TGF-β1)的表达。
实施例1SPRC对牙槽骨吸收的影响
如图1所示、亚甲蓝染色及H&E评估SPRC对牙槽骨吸收的影响:SPRC治疗三周后我们测量了从牙本质界CEJ到牙槽嵴ABC的距离,以定量牙周骨丢失。与control组大鼠相比,LPS组大鼠的CEJ与ABC之间的平均距离增加,牙周骨严重丢失。用SPRC治疗3周后,LPS25SPRC组和LPS50SPRC组与LPS组相比,CEJ与ABC之间的平均距离明显减小,SPRC可抑制LPS诱导的牙周骨吸收,其中,Control是正常对照组,LPS是炎症模型组,用药组分别是SPRC的25和50mg/Kg两个浓度处理组,*P<0.05。
如图2所示、通过Micro-CT评价SPRC对牙槽骨吸收的影响:与control组相比,LPS组大鼠的CEJ与ABC之间的平均距离增加,LPS大鼠的Bone volume/totalvolume(BV/TV)明显低于对照组,LPS大鼠的Trabecular separation(TbSp)明显高于对照组,说明炎症引起牙周骨严重丢失。而给予SPRC治疗后发现,LPS25SPRC组和LPS50SPRC组与LPS组相比,CEJ与ABC之间的平均距离明显减小,(BV/TV)明显高于于LPS组,LPS大鼠的Trabecularseparation(TbSp)明显低于LPS组,SPRC可抑制LPS诱导的牙周骨吸收,其中,Control是正常对照组,LPS是炎症模型组,用药组分别是SPRC的25和50mg/Kg两个浓度处理组,*P<0.05。
实施例2SPRC对Th17/Treg细胞相关细胞因子的影响
如图3所示,采用免疫组织化学定位、Westernblot和RT-PCR方法检测IL-17A、IL-6、IL-10和TGF-β1,进一步探讨SPRC对Th17/Treg相关细胞因子表达的影响。免疫组织化学定位分析显示,龈内LPS注射后三周,LPS组大鼠IL-17A、IL-6表达明显增加。每日用SPRC治疗三周。与LPS组相比,LPS25SPRC和LPS50SPRC组能显著降低牙龈组织中IL-17A、IL-6的表达。与对照组相比,LPS组IL-10和TGF-β的表达无差异。与LPS组相比,LPS25SPRC和LPS50SPRC组能显著增加牙龈组织中IL-10和TGF-β1的表达。Western blot显示相同的结果。RT-PCR分析表明,在龈内LPS注射三周后,LPS组大鼠IL-17Am RNA和IL-6m RNA表达明显增加。每日用SPRC治疗三周。与LPS组相比,LPS25SPRC和LPS50SPRC组能显著降低牙龈组织中IL-17AmRNA和IL-6mRNA的表达。与对照组相比,LPS组IL-10m RNA和TGF-β1mRNA的表达增加。与LPS组相比,LPS25SPRC和LPS50SPRC组能显著增加牙龈组织中IL-10mRNA和TGF-β1mRNA的表达,说明SPRC能显著的抑制促炎因子IL-17A和IL-6的表达,抑制Th17细胞的功能,促进抗炎因子IL-10和TGF-β1的表达,促进Treg细胞的功能,其中,Control是正常对照组,LPS是炎症模型组,用药组分别是SPRC的25和50mg/Kg两个浓度处理组,*P<0.05。
根据以上结果可知,SPRC可抑制LPS诱导的牙周骨吸收,能显著的抑制促炎因子IL-17A和IL-6的表达,抑制Th17细胞的功能,促进抗炎因子IL-10和TGF-β1的表达,促进Treg细胞的功能,因此SPRC及其类似物能够用于制备预防或治疗牙周疾病(尤其是牙周炎)的药物。
以上对本发明的具体实施例进行了详细描述,但其只是作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (10)
2.根据权利要求1所述的一种用于治疗牙周疾病的氨基酸类化合物及其盐,其特征在于,所述式I化合物为炔丙基半胱氨酸(S-propargyl-cysteine)。
3.一种用于治疗牙周疾病的产品,其特征在于,所述产品包含作为活性成分的权利要求1或2所述的式I化合物及其盐,所述产品为药物、保健品或食品。
4.根据权利要求3所述的一种用于治疗牙周疾病的产品,其特征在于,所述产品为药物,所述药物包含作为活性成分的权利要求1或2所述的式I化合物及其盐,以及药学上可接受的载体或赋形剂。
5.根据权利要求4所述的一种用于治疗牙周疾病的产品,其特征在于,所述药物组合物为片剂、粉剂、注射剂、胶囊、混悬剂、糊剂、凝胶、软膏、含漱剂、冲洗剂、涂布剂、药膜剂、缓释剂或微球。
6.权利要求1-2中任一项所述的氨基酸类化合物及其盐以及权利要求3-5中任意一项所述的产品在制备治疗或预防牙周疾病的产品中的用途,所述产品为药物、保健品或食品。
7.根据权利要求6所述的制备治疗或预防牙周疾病的产品中的用途,其特征在于,所述牙周疾病包括牙龈病和牙周炎。
8.根据权利要求7所述的制备治疗或预防牙周疾病的产品中的用途,其特征在于,所述牙周炎包括各期各级牙周炎、坏死性牙周病和反映全身疾病的牙周炎。
9.炔丙基半胱氨酸(S-propargyl-cysteine)用于制备预防或治疗牙周疾病产品中的用途。
10.根据权利要求9所述的用途,其特征在于,所述产品为药物、保健品或食品,所述牙周疾病包括牙龈病和牙周炎,所述牙周炎包括各期各级牙周炎、坏死性牙周病和反映全身疾病的牙周炎。
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