CN112312919A - 用于预防、改善或治疗炎症性疾病的包含β-葡聚糖-肽复合物及抗生素的组合物 - Google Patents
用于预防、改善或治疗炎症性疾病的包含β-葡聚糖-肽复合物及抗生素的组合物 Download PDFInfo
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- CN112312919A CN112312919A CN201980041019.1A CN201980041019A CN112312919A CN 112312919 A CN112312919 A CN 112312919A CN 201980041019 A CN201980041019 A CN 201980041019A CN 112312919 A CN112312919 A CN 112312919A
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Abstract
本发明涉及包含β‑1,3‑葡聚糖及由序列号4的氨基酸序列组成的肽的用于预防、改善或治疗炎症性疾病的组合物以及抗炎用组合物。本发明还涉及包含β‑1,3‑葡聚糖(β‑1,3‑glucan)、由序列号4的氨基酸序列组成的肽及抗生素的针对引起败血症的细菌的抗菌用组合物。本发明还涉及包括向患者给药β‑1,3‑葡聚糖(β‑1,3‑glucan)及由序列号4的氨基酸序列组成的肽的步骤的炎症性疾病的预防或治疗方法。因此，当包含本发明的β‑1,3‑葡聚糖(β‑1,3‑glucan)及由序列号4的氨基酸序列组成的肽时，可降低败血症小鼠的活性氧、引起败血症的细菌或炎性细胞因子的水平，并显著提高败血症小鼠的存活率，因此对于用于预防、改善或治疗如败血症等的炎症性疾病的组合物或用于预防或治疗的方法是有效的。尤其，可显著减少因吞噬细胞引起的活性氧，并且当与抗生素联合使用时，可显著提高活性氧、引起败血症的细菌或炎性细胞因子的表达水平或存活率，因此效果更好。
Description
技术领域
本申请要求于2018年06月20日提交韩国专利厅、申请号为10-2018-0070846的韩国专利申请的优选权，其全部内容为本申请的参考文献。
本发明涉及用于预防、改善或治疗炎症性疾病的包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的组合物或抗炎用组合物。
本发明还涉及包含β-1,3-葡聚糖(β-1,3-glucan)、由序列号4的氨基酸序列组成的肽及抗生素的针对引起败血症的细菌的抗菌用组合物。
本发明还涉及包括向患者给药β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的步骤的炎症性疾病的预防或治疗方法。
背景技术
因细胞中的活性氧(reactive oxygen species；ROS)引起的过渡炎症反应有可能导致包括败血症在内的各种炎症性疾病。败血症是由于当致病性革兰氏阴性细菌被活体感染时作为细胞壁成分的脂多醣(lipopolysaccharide；LPS)充当毒素而使活体的免疫体系被过渡激活而引起的炎症反应，在全身感染或症状严重时可能会伴随休克。最近，已经弄清楚c-Src介导的急性炎症反应在与败血症相关的急性肺损伤中的重要性。
体内产生ROS的主要原因有两个，包括线粒体的呼吸过程及吞噬细胞(phagocyte)的吞噬过程。
通过吞噬细胞的吞噬作用吸收的物质的分解是通过蛋白质酶来实现，蛋白质酶由所谓的氧化爆发(oxidative burst)促进。这伴随着ROS及氧化氮(nitric oxide；NO)的产生。吞噬细胞膜中存在的烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶(Nicotinamideadenine dinucleotide phosphate oxidase；NOX)将氧(O2)还原为超氧阴离子(superoxide anion；O2 -)。这导致通过芬顿反应(Fenton reaction)或髓过氧化物酶(myeloperoxidase)的次氯酸盐(hypochlorite)合成而诱导过氧化氢(H2O2)的形成及高反应性羟基自由基的形成。并且，ROS与NO反应而产生的过氧亚硝酸盐(peroxynitrite)是与次氯酸盐非常有效的抗菌剂。这些反应性物质称为活性氧或氮物质。
线粒体的呼吸引起的ROS(mtROS)在各种先天性免疫信号传导通路中起着重要作用。它们将NOX或NLRP3炎性体激活，还参与到炎性细胞因子的合成中。另外，已知mtROS还可增加巨噬细胞的吞噬细胞作用。mtROS的产生受到如NO和一氧化碳(CO)等的双原子气体介体的调节。
NOX为由黄细胞色素b(flavocytochrome b)成分(gp91phox/NOX2和p22phox)及吞噬细胞的4种细胞液蛋白(p47phox、p67phox、p40phox及Rac1/2)组成的复合物。存在于多个丝氨酸残基中的p47phox的磷酸化对于NOX复合物的激活至关重要。此外，需要p22phox与多个调控伙伴之间的结合，但作为调节伙伴，具有与p47phox相同的NOX organizer 1(NOXO1)、与p67phox相同的NOX activator 1(NOXA1)及Rac1 GTPase等。对在ROS的产生中起到重要作用的NOX进行特异性靶向，可在致命性疾病中具有治疗作用。研究这种信号传导物质有助于特异性靶向治疗(specific targeted therapeutic)的研究。部分NOX的小型化学(非肽)抑制剂(二亚苯基碘(diphenylene iodonium)、4-羟基-3-甲氧基苯乙酮取代(4-hydroxy-3-methoxyacetophenonesubstituted)、氧化苯砷(phenylarsine oxide)及4-(2-氨基乙基)-苯磺酰氟(4-(2-aminoethyl)-benzenesulfonyl fluoride)等)用于抑制ROS的产生。但是，它们没有特异性，因此它们甚至还抑制与NOX相似或无关的酶。
从裂褶菌(Schizophyllum commune)的可溶性β-葡聚糖获得的裂褶多糖(Shizophyllan；SPG)为β-(1-3)-葡聚糖类型的多糖。它在中性溶液中形成三重螺旋。SPG的碱性溶液被中和时，变形为单链，并通过疏水性相互作用及氢键返回到原来的三重螺旋。
在发生这种物理化学作用期间，作为两种主链葡萄糖的β-(1-3)-葡聚糖与一个寡核苷酸(oilgonucleotide；ODN)碱基或肽结合形成化学计量的复合物(stoichiometriccomplex)。使用这种复合物，基于SPG的药物传递系统被设计为可向靶向细胞传递功能性ODN。
韩国公开专利第10-2016-0140472号涉及通过微生物发酵及酶处理生物转化工序进行生物转化的青花椒生物转化产品，所述微生物可以为裂褶菌，当包含所述青花椒生物转化产品作为有效成分时，可用于预防或治疗败血症的药物组合物。但是，尚未对结合了裂褶多糖等的β-葡聚糖和肽的复合物及其与抗生素联合使用的方法等进行过研究。
发明内容
技术问题
对此，本发明人试图通过特异性地靶向在活性氧的产生中起重要作用的NADPH氧化酶，来提供针对如败血症等的炎症性疾病的有效组合物，其结果，当结合了作为β-葡聚糖的种类的裂褶多糖和特定的肽的β-葡聚糖-肽复合物及与其与抗生素联合使用时，通过阑尾结扎穿孔(Cecal ligation and puncture；CLP)方法，可显著增加诱导败血症的小鼠的存活率，降低活性氧、引起败血症的细菌或炎性细胞因子的水平的效果，因此确认到可用于如败血症等的炎症性疾病的预防、改善或治疗中，从而完成了本发明。
因此，本发明的目的在于，提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的用于预防、改善或治疗炎症性疾病的组合物或抗炎用组合物。
本发明的再一目的在于，提供包含β-1,3-葡聚糖(β-1,3-glucan)、由序列号4的氨基酸序列组成的肽及抗生素的针对引起败血症的细菌的抗菌用组合物。
本发明的另一目的在于，提供包括向患者给药β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的步骤的炎症性疾病的预防或治疗方法。
技术方案
为了实现上述的目的，本发明可提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的用于预防或治疗炎症性疾病的药物组合物或炎症性疾病的预防或治疗方法。
根据本发明一优选实施例，所述β-1,3-葡聚糖和所述肽可通过间隔子(spacer)连接。
根据本发明一优选实施例，所述间隔子可以为包含GGGG氨基酸序列的肽。
根据本发明一优选实施例，所述β-1,3-葡聚糖可以为裂褶多糖(schizophyllan；SPG)。
根据本发明一优选实施例，所述组合物还可包含抗生素。
根据本发明一优选实施例，所述抗生素可以为选自由头孢霉菌素(cephalosporin)系列、β-内酰胺(beta-lactam)系列、β-内酰胺/β-内酰胺酶(beta-lactamse)抑制剂系列、喹诺酮(Quinolone)系列、糖肽(glycopeptide)系列、碳青霉烯(carbapenem)系列、氨基糖苷(aminoglycoside)系列、大环内酯(macrolide)系列、单环菌素(monobactam)系列、磺胺(sulfa drug)系列、克林达霉素(clindamycin)、替加环素(tigecycline)、粘杆菌素甲基磺酸钠(colistin sodium methanesulfonate)、甲硝唑(metronidazole)及螺旋霉素(spiramycin)组成的组中的一种以上。
根据本发明一优选实施例，所述头孢霉菌素(cephalosporin)系列的抗生素可以为选自由头孢唑啉(cefazolin)、头孢卡品酯(cefcapene pivoxil)、头孢泊肟酯(cefpodoxime proxetil)、头孢拉定(cephradine)、头孢曲松(ceftriaxone)、头孢拉宗(cefbuperazone)、头孢噻肟(cefotaxime)、头孢米诺(cefminox)、头孢他啶(ceftazidime)、头孢匹罗(cefpirome)、头孢克肟(cefixime)、头孢氨苄(cephalexin)、头孢地尼(cefdinir)、头孢沙定(cefroxadine)、头孢呋辛(cefuroxime)、头孢羟氨苄(cefadroxil)、头孢西丁(cefoxitin)、头孢他美酯(cefetamet pivoxil)、头孢唑肟(ceftizoxime)、头孢孟多酯钠(cefamandole nafate)、头孢西酮(cefazedone)、头孢特仑酯(cefteram pivoxil)、头孢替唑(ceftezole)、头孢丙烯(cefprozil)、头孢替坦(cefotetan)、头孢甲肟(cefmenoxime)、头孢妥仑匹酯(cefditoren pivoxil)、头孢曲嗪丙二醇(cefatrizine proplyen glycol)、头孢替安(cefotiam)、盐酸头孢替安(cefotiamhexetyl hcl)、头孢布烯(ceftibuten)、头孢克洛(cefaclor)、头孢哌酮(cefoperazone)、头孢匹胺(cefpiramide)、头孢噻吩(cephalothin)、头孢地嗪(cefodizime)、头孢尼西(cefonicid)、头孢美唑(cefmetazole)及头孢吡肟(cefepime)组成的组中的一种以上。
所述β-内酰胺(beta-lactam)系列的抗生素为选自由乙氧萘青霉素(nafcillin)、氧哌嗪青霉素(piperacillin)及氨苄青霉素(ampicillin)组成的组中的一种以上。
所述β-内酰胺酶(beta-lactamse)抑制剂系列的抗生素为选自由舒巴坦(sulbactam)、他唑巴坦(tazobactam)、对甲苯磺酸舒他西林(sultamicillintosylate)、阿莫西林(amoxicillin)、克拉维酸钾(potassium clavulanate)、替卡西林(ticarcillin)及舒巴坦匹酯(pivoxyl sulbactam)组成的组中的一种以上。
所述奎诺酮(Quinolone)系列的抗生素为选自由环丙氟哌酸(ciprofloxacin)、莫西沙星(moxifloxacin)、左氧氟沙星(levofloxacin)及洛美沙星(lomefloxacin)组成的组中的一种以上。
所述糖肽(glycopeptide)系列的抗生素为选自由万古霉素(vancomycin)、利奈唑胺(linezolid)及替考拉宁(teicoplanin)组成的组中的一种以上。
所述碳青霉烯(carbapenem)系列的抗生素为选自由美罗培南(meropenem)，多利培南一水合物(doripenem monohydrate)，西司他丁(cilastatin)及亚胺培南一水合物(imipenem monohydrate)组成的组中的一种以上。
所述氨基糖苷(aminoglycoside)系列的抗生素为丁胺卡那霉素(amikacin)、妥布霉素(tobramycin)、奈替米星(netilmicin)、西索米星(sisomicin)、异帕米星(isepamicin)、磷霉素(fosfomycin)及庆大霉素(gentamicin)组成的组中的一种以上。
所述大环内酯(macrolide)系列的抗生素为克拉霉素(clarithromycin)、罗红霉素(roxithromycin)及阿奇霉素(azithromycin)组成的组中的一种以上。
所述磺胺(sulfa drug)系列的抗生素可以为磺胺甲恶唑(sulfamethoxazole)及甲氧苄啶(trimethoprim)组成的组中的一种以上。
根据本发明一优选实施例，所述组合物可使选自由巨噬细胞、树突状细胞、单核细胞、肥大细胞及嗜中性粒细胞组成的组中的一种以上的吞噬细胞的活性氧的产量减少。
根据本发明一优选实施例，所述炎症性疾病可以为败血症(sepsis)、败血性休克、炎性肠病(Inflammatory bowel disease，IBD)、腹膜炎、肾炎、急性支气管炎、慢性支气管炎、骨关节炎、肠病脊柱炎、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)、类风湿性关节炎(rheumatoid arthritis)、急性肺损伤(acute lung injury)及支气管肺发育不良(broncho-pulmonary dysplasia)组成的组中的一种以上。
根据本发明一优选实施例，所述方法还包括向患者给药抗生素的步骤。
本发明还可提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的用于预防或改善炎症性疾病的保健功能食品组合物。
本发明还可提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的抗炎用组合物。
本发明还可提供包含β-1,3-葡聚糖(β-1,3-glucan)、由序列号4的氨基酸序列组成的肽及抗生素的针对引起败血症的细菌的抗菌用组合物。
以下，进一步详细说明本发明。
如上所述，在现有技术中，使用了NADHP氧化酶(NOX)的抑制剂来抑制ROS，但这些抑制剂均缺少特异性而无法有效地抑制ROS。因此，需要研究出特异性地靶向NOX并可提高针对除ROS以外的诸如败血症等的炎症性疾病的治疗效果的组合物，但是对于增加特异性和抗炎效果的有效结构的研究仍然是微不足道的。
根据本发明的包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的组合物使感染炎症性疾病的个体存活率显著增加，降低了活性氧、引起败血症的细菌或炎性细胞因子的表达水平，因此当组合使用抗生素时，其水平进一步显著提高，因此作为预防、改善或治疗炎症性疾病的用途方面上是有效的。
因此，本发明提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的用于预防或治疗炎症性疾病的药物组合物。
向CLP小鼠进行腹膜内给药本发明的所述药物组合物以验证了其抗炎症效果。具体地，向所述CLP小鼠进行腹膜内给药硫喷妥钠(pentothal sodium，50mg/kg)，使得所述CLP小鼠被麻醉之后，切开腹部以暴露了阑尾。阑尾的回盲瓣(ileocecal valve)下结扎，用22号针刺两次之后，放回腹部并关闭。
所述序列号4的氨基酸序列是基于c-Src序列上与作为NADPH氧化酶的结构要素的p67phox及p47phox相关的SH3-1及SH3-2序列制备的(图1)。研究并组合及导出了可起到最高的抗炎症相关效果的序列而不仅仅与SH3-1序列和SH3-2序列连接。
优选地，本发明的所述β-1,3-葡聚糖和所述肽通过间隔子(spacer)连接，但不限定于此。所述间隔子为将SPG序列和SH3肽序列连接成一个序列的部分，优选地，为包含1个至10个氨基酸序列的肽。更优选地，为3个至7个氨基酸序列，最优选地，为4个至5个氨基酸序列。
优选地，所述间隔子的氨基酸序列以重复相同氨基酸的方式形成，最优选地，重复甘氨酸(G)。
优选地，本发明的所述β-1,3-葡聚糖为裂褶多糖(schizophyllan；SPG)。优选地，所述裂褶多糖从裂褶菌获得，但不限定于此。
本发明的所述组合物还可包含抗生素。所述抗生素可包含一种以上，当包含两种以上时，能够以相同比例包含各个抗生素。
引起败血症的感染通常是因革兰氏阳性菌或革兰氏阴性细菌导致的细菌性感染，但可通过真菌或病毒来引起感染。优选地，本发明的所述抗生素为选自由头孢霉菌素(cephalosporin)系列、β-内酰胺(beta-lactam)系列、β-内酰胺/β-内酰胺酶(beta-lactamse)抑制剂系列、喹诺酮(Quinolone)系列、糖肽(glycopeptide)系列、碳青霉烯(carbapenem)系列、氨基糖苷(aminoglycoside)系列、大环内酯(macrolide)系列、磺胺(sulfa drug)系列、氨曲南(aztreonam)、克林达霉素(clindamycin)、替加环素(tigecycline)、粘杆菌素甲基磺酸钠(colistin sodium methanesulfonate)、甲硝唑(metronidazole)及螺旋霉素(spiramycin)组成的组中的一种以上，最优选地，为选自头孢霉菌素系列及氨基糖苷系列。
所述头孢霉菌素(cephalosporin)系列的抗生素为选自由头孢唑啉(cefazolin)、头孢卡品酯(cefcapene pivoxil)、头孢泊肟酯(cefpodoxime proxetil)、头孢拉定(cephradine)、头孢曲松(ceftriaxone)、头孢拉宗(cefbuperazone)、头孢噻肟(cefotaxime)、头孢米诺(cefminox)、头孢他啶(ceftazidime)、头孢匹罗(cefpirome)、头孢克肟(cefixime)、头孢氨苄(cephalexin)、头孢地尼(cefdinir)、头孢沙定(cefroxadine)、头孢呋辛(cefuroxime)、头孢羟氨苄(cefadroxil)、头孢西丁(cefoxitin)、头孢他美酯(cefetamet pivoxil)、头孢唑肟(ceftizoxime)、头孢孟多酯钠(cefamandole nafate)、头孢西酮(cefazedone)、头孢特仑酯(cefteram pivoxil)、头孢替唑(ceftezole)、头孢丙烯(cefprozil)、头孢替坦(cefotetan)、头孢甲肟(cefmenoxime)、头孢妥仑匹酯(cefditoren pivoxil)、头孢曲嗪丙二醇(cefatrizine proplyen glycol)、头孢替安(cefotiam)、盐酸头孢替安(cefotiam hexetyl hcl)、头孢布烯(ceftibuten)、头孢克洛(cefaclor)、头孢哌酮(cefoperazone)、头孢匹胺(cefpiramide)、头孢噻吩(cephalothin)、头孢地嗪(cefodizime)、头孢尼西(cefonicid)、头孢美唑(cefmetazole)及头孢吡肟(cefepime)组成的组中的一种以上。
所述β-内酰胺(beta-lactam)系列的抗生素为选自由乙氧萘青霉素(nafcillin)、氧哌嗪青霉素(piperacillin)及氨苄青霉素(ampicillin)组成的组中的一种以上。
所述β-内酰胺酶(beta-lactamse)抑制剂系列的抗生素为选自由舒巴坦(sulbactam)、他唑巴坦(tazobactam)、对甲苯磺酸舒他西林(sultamicillintosylate)、阿莫西林(amoxicillin)、克拉维酸钾(potassium clavulanate)、替卡西林(ticarcillin)及舒巴坦匹酯(pivoxyl sulbactam)组成的组中的一种以上。
所述奎诺酮(Quinolone)系列的抗生素为选自由环丙氟哌酸(ciprofloxacin)、莫西沙星(moxifloxacin)、左氧氟沙星(levofloxacin)及洛美沙星(lomefloxacin)组成的组中的一种以上。
所述糖肽(glycopeptide)系列的抗生素为选自由万古霉素(vancomycin)、利奈唑胺(linezolid)及替考拉宁(teicoplanin)组成的组中的一种以上。
所述碳青霉烯(carbapenem)系列的抗生素为选自由美罗培南(meropenem)、多利培南一水合物(doripenem monohydrate)、西司他丁(cilastatin)及亚胺培南一水合物(imipenem monohydrate)组成的组中的一种以上。
所述氨基糖苷(aminoglycoside)系列的抗生素为选自由丁胺卡那霉素(amikacin)、妥布霉素(tobramycin)、奈替米星(netilmicin)、西索米星(sisomicin)、异帕米星(isepamicin)、磷霉素(fosfomycin)及庆大霉素(gentamicin)组成的组中的一种以上。
所述大环内酯(macrolide)系列的抗生素为选自由克拉霉素(clarithromycin)、罗红霉素(roxithromycin)及阿奇霉素(azithromycin)组成的组中的一种以上。
所述氨曲南(aztreonam)为单环菌素(Monobactam)系列。
所述磺胺(sulfa drug)系列的抗生素可以为选自由磺胺甲恶唑(sulfamethoxazole)及甲氧苄啶(trimethoprim)组成的组中的一种以上，但不限定于此。
所述抗生素可与选自由钠(sodium)、盐酸(HCl)、氯化钠(NaCl)，硫酸盐(sulfate)及磷酸盐(phosphate)组成的组中的一种以上的物质结合一次以上来使用。
本发明的所述组合物可使感染炎症性疾病时所产生的活性氧减少，已知活性氧大致在线粒体的呼吸过程和吞噬细胞的吞噬作用时产生。在本发明的β-葡聚糖-肽复合物及其与抗生素联合使用的情况下，尤其，可特异性减少因吞噬细胞而产生的活性氧。因此，可以更清楚地说明通过抑制吞噬细胞引起的活性氧而不是由线粒体引起的活性氧的炎症抑制效果。所述吞噬细胞可以为选自由巨噬细胞、树突状细胞、单核细胞、肥大细胞及嗜中性粒细胞组成的组中的一种以上，更优选地，可以为巨噬细胞、树突状细胞及嗜中性粒细胞，最优选地，可以为巨噬细胞，但不限定于此。
除活性氧以外，本发明的所述组合物显著降低炎性细胞因子的表达水平(图5)，并且用CLP诱导败血症的大鼠的存活率(图4)及对败血症细菌的抗菌效果(图6)显著上升，因此可表现出对于诸如败血症等的炎症性疾病的预防或治疗效果。
优选地，本发明的所述炎症性疾病为选自由败血症(sepsis)、败血性休克、炎性肠病(Inflammatory bowel disease，IBD)、腹膜炎、肾炎、急性支气管炎、慢性支气管炎、骨关节炎、肠病脊柱炎、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)、类风湿性关节炎(rheumatoid arthritis)、急性肺损伤(acute lung injury)及支气管肺发育不良(broncho-pulmonary dysplasia)组成的组中的一种以上，更优选地，可以为败血症、败血性休克、慢性阻塞性肺病、急性肺损伤及支气管肺发育不良，最优选地，可以为败血症。
并且，本发明提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的用于预防或改善炎症性疾病的保健功能食品组合物。所述β-1,3-葡聚糖和由序列号4的氨基酸序列组成的肽与所述药物组合物中所使用的那些相同，因此由上述的记载来替代。
根据本发明的食品组合物可根据本发明领域公知的常规方法以各种形式制备。在普通食品中不限定于此，但可将饮料(包括酒精饮料)、水果及其加工食品(例如水果罐头、瓶罐头、果酱、酸果酱等)、鱼类、肉类及其加工食品(例如火腿、香肠、玉米牛肉等)、面包类及面食类(例如乌冬面、荞麦面、拉面、意大利面、通心粉等)、果汁、各种饮品、饼干、糖浆、乳制品(例如黄油、奶酪等)、植物性油脂、人造黄油、植物蛋白、干馏食品，冷冻食品，各种调味料(例如大酱、酱油、调味酱等)等中添加本发明的β-葡聚糖-肽复合物来制备。并且，作为营养补品，可通过将本发明的β-葡聚糖-肽复合物添加到胶囊、片剂、丸剂等中来制备，但不限于此。并且，作为保健功能食品，不限定于此，但例如对本发明的β-葡聚糖-肽复合物进行液化、颗粒化、胶囊化及粉末化来进行摄取，以便将本发明的β-葡聚糖-肽复合物本身制备成茶、果汁及饮料的形式来饮用(健康饮料)。并且，为了将本发明的β-葡聚糖-肽复合物以食品添加剂的形式使用，可制备成粉末或浓缩液的形式来使用。并且，将本发明的β-葡聚糖-肽复合物与被公知为对预防及改善炎症性疾病具有效果的活性成分一同混合以组合物的形式制备。
当将本发明的β-葡聚糖-肽复合物用作健康饮料时，所述健康饮料组合物可与常规饮料一同包含各种调味剂或天然碳水化合物等来作为附加成分。上述的天然碳水化合物可以为单糖，例如葡萄糖、果糖；二糖，例如麦芽糖、蔗糖；多糖，例如糊精、环糊精；糖醇，例如木糖醇、山梨糖醇和赤藓糖醇等。甜味剂可使用天然甜味剂，例如牛磺酸甜蛋白，甜叶菊提取物；以及合成甜味剂，例如糖精，阿斯巴甜代糖。每100mL的本发明的组合物，所述天然碳水化合物的比例通常为约0.01～0.04g，优选地，为约0.02～0.03g。
并且，本发明的β-葡聚糖-肽复合物可作为用于预防及改善炎症性疾病的食品组合物的有效成分来被包含，其量为在实现炎症性疾病的预防及改善作用方面上的有效量，因此不做特别限定，但优选地，相对于组合物总重量，其量为0.01重量％至100重量％。本发明的食品组合物可通过将β-葡聚糖-肽复合物与已知在用于预防及改善炎症性疾病的组合物中具有效果的其他活性成分混合来制备。
除了上述的内容以外，本发明的健康食品可包含各种营养素、维生素、电解质、调味剂、着色剂、果胶酸、果胶盐、藻酸、藻酸盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精或碳酸等。另外，本发明的健康食品可包含用于制备天然果汁、果汁饮料或蔬菜饮料的果肉。这种成分可单独使用或组合使用。这种添加剂的比例不是关键的，但通常选自每100重量份的本发明的组合物在0.01～0.1重量份的范围内。
并且，本发明提供包含β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的抗炎用组合物。所述β-1,3-葡聚糖和由序列号4的氨基酸序列组成的肽与所述药物组合物中所使用的那些相同，因此由上述的记载来替代。
所述组合物可以为选自由食品组合物、化妆品组合物及药物组合物组成的组中的一种以上，但不限定于此。
并且，本发明提供包含β-1,3-葡聚糖(β-1,3-glucan)、由序列号4的氨基酸序列组成的肽及抗生素的针对引起败血症的细菌的抗菌用组合物。所述β-1,3-葡聚糖，由序列号4的氨基酸序列组成的肽及抗生素与所述药物组合物中所使用的那些相同，因此由上述的记载来替代。
所述引起败血症的细菌可以为链球菌、金黄色葡萄球菌、大肠菌、肺炎菌、铜绿假单胞菌或真菌等，但只要是可引起败血症症状的菌体、细菌、病毒、或真菌等微生物，就不限定于此。
并且，本发明提供包括向患者给药β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的步骤的炎症性疾病的预防或治疗方法。所述β-1,3-葡聚糖、由序列号4的氨基酸序列组成的肽与所述药物组合物中所使用的那些相同，因此由上述的记载来替代。所述炎症性疾病与所述药物组合物的对象相同，因此由上述的记载来替代。
所述方法还可包括向患者给药抗生素的步骤。所述抗生素的给药包括与β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽同时给药或依次给药。
有益效果
因此，当包含本发明的β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽时，可降低败血症小鼠的活性氧、引起败血症的细菌或炎性细胞因子的水平，显著增加存活率，因此作为用于预防、改善或治疗诸如败血症等的炎症性疾病的组合物以及预防或治疗方法而言是有效的。尤其，可显著减少因吞噬细胞引起的活性氧，当与抗生素联合使用时，显著增加活性氧、引起败血症的细菌以及炎性细胞因子的表达水平以及存活率，因此效果更优异。
附图说明
图1示出c-Src的序列及可由此获得的SH3-1序列和SH3-2序列、p67phox及p47phox序列。
图2示出在RAW2647细胞中处理LPS，按照各个浓度(1，5或10μg/mL)来分别处理SH3-1、SH3-2、SH3(SH3-1+SH3-2)或SC之后，测量NADPH氧化酶的活性或线粒体ROS(MitoSOX)水平的结果。对照组未进行任何处理。可确认到NADPH氧化酶活性水平在处理SH3时最低，并且可确认到线粒体ROS水平无关于处理物质而生产类似水平的ROS。
图3示出在CLP小鼠中用SPG-SC、SPG-SH3、抗生素以及SPG-SH3和抗生素联合处理，并在CLP小鼠的脾脏中测得的NADPH氧化酶活性、总ROS及线粒体ROS的水平。对照组未进行任何处理。可确认到NADPH氧化酶活性水平及总ROS水平在SPG-SH3及SPG-SH3与抗生素联合处理的情况下显著减少，但线粒体ROS水平无关于处理物质而生产类似水平的ROS。
图4示出在CLP小鼠中用SPG-SC、SPG-SH3、抗生素以及SPG-SH3与抗生素联合处理之后7天内确认到的所述CLP小鼠的存活率的结果。在SPG-SH3与抗生素联合处理的情况下，作为协同效应，可确认到约90％的CLP小鼠以协同效应而存活。
图5示出在CLP小鼠中用SPG-SC，SPG-SH3、抗生素以及SPG-SH3与抗生素联合处理之后的TNF-α、IL-6、IL-1β及IL-18的炎性细胞因子的表达水平。可确认到在SPG-SH3及SPG-SH3与抗生素联合处理的情况下显著减少。
图6为在CLP小鼠中用SPG-SC，SPG-SH3、抗生素以及SPG-SH3与抗生素联合处理之后，测量外周血至腹膜液中的引起败血症的细菌的水平以表示抗菌效果。在SPG-SH3与抗生素联合处理的情况下，可确认到引起败血症的细菌显著减少。
具体实施方式
实施例1
实验准备
〈1-1〉细胞及CLP小鼠
作为小鼠巨噬细胞细胞株(macrophage cell line)的RAW2647(美国菌种保藏中心，ATCCTIB-71；American Type Culture Collection)细胞利用包含10％的胎牛血清(fetal bovine serum，FBS；Invitrogen)、丙酮酸钠(sodium pyruvate)、非必需氨基酸、青霉素G(100IU/ml)、链霉素(streptomycin，100ug/ml)的DMEM培养基(Invitrogen)来进行了培养。
使用6周龄(6-week-old)的C57BL/6雌性小鼠(Samtako，Korea)准备了由阑尾结扎穿孔(cecal ligation and puncture；CLP)诱导的败血症小鼠模型。所有与动物相关的程序均经韩国汉阳大学动物保护机构和使用委员会批准。在给CLP小鼠腹腔中施用(3小时、6小时及12小时)了3次以下表1所列的给药物质。SPG-SC为具有随机混合SPG-SH3的序列的序列的肽复合物，抗生素(antibiotic)混合使用了庆大霉素(gentamycin)和头孢霉菌素(cephalosporin)。
表1
〈1-2〉SPG-SH3的制备
从源自c-Src的序列的SH3-1序列和SH3-2序列制备了SH3肽序列。SC(scramble)序列通过在SH3-1序列和SH3-2序列中不包含在SH3序列中的氨基酸进行了制备。各个序列如下表2所示。
SPG-SH3的复合物将β-1,3-葡聚糖(β-1,3-glucan)溶解于有机溶剂中，并添加了环状酸酐(cycliccyclic anhydride)以将β-1,3-葡聚糖的羟基转换为羧基(-COOH基)。然后，分别使羧基与SH3-1、SH3-2或与SH3肽的胺基结合，以制备了β-葡聚糖-肽复合物SPG-SH3。
表2
实施例2
SPG-SH3的ROS生成抑制效果(体外(in vitro))
目的在于确认在RAW2647细胞中分别处理SPG-SH1、SPG-SH2以及SPG-SH3的情况下是否抑制ROS的生成。尤其，分别确认了NADPH氧化酶(NADPH oxidase；NOX)活性及线粒体ROS水平。
具体地，用LPS刺激RAW2647细胞之后，将SPG-SH1、SPG-SH2以及SPG-SH3分别处理为1μg/mL、5μg/mL及10μg/mL的浓度。NADPH氧化酶活性为通过光泽精(lucigenin；bis-N-methylacridinium nitrate)-ECL方法来测量所述RAW2647细胞中的超氧化物(superoxide)的生成以进行了验证。线粒体ROS的生成是在所述RAW2647细胞中用5μM的MitoSOX染色30分钟之后用FACS分析测量了平均荧光强度(mean fluorescenceintensity；MFI)。
其结果，如图2所示，NADPH氧化酶活性与处理SPG-SH3的情况相比最低，但可确认到线粒体的ROS无关于给药物质的种类以类似的水平继续生产ROS。
实施例3
SPG-SH3及抗生素的ROS生成抑制效果(体内(in vivo))
目的在于，在CLP小鼠中联合处理SPG-SH3及抗生素的情况下，确认是否抑制ROS的生成。尤其，分别确认了NADPH氧化酶(NADPH oxidase；NOX)活性，总ROS(Total ROS)及线粒体ROS水平。
具体地，准备了施用了与所述实施例1-1相同的给药物质的CLP小鼠(n＝5)。NADPH氧化酶活性的测量通过获得CLP小鼠的脾脏(spleen)并进行压碎之后以如同所述实施例2的方法进行了测量及验证。就总ROS而言，获得及压碎CLP小鼠的脾脏，将5μM的总ROS活性测定试剂盒(Total ROS Activity Assay kit，CA-R900)的试剂处理60分钟之后，在490nm/525nm下测量了Ex/Em(激发波长/发光波长)。就线粒体ROS的生成而言，获得及压碎CLP小鼠的脾脏之后，以如同所示实施例2的方法进行了测量及验证。或者，获得及压碎CLP小鼠的脾脏，将线粒体ROS活性测定试剂盒(Mitochondrial ROS Activity Assay Kit，CA-R933))的试剂5μM处理60分钟之后，在490nm/525nm下测量了(激发波长/发光波长)。对照组(UN)对正常小鼠进行了空白(vehicle)处理。
其结果，如图3所示，可确认到NADPH氧化酶活性以及总ROS水平在SPG-SH3或在SPG-SH3与抗生素联合处理的情况下显著减少。反之，可确认到线粒体无关于给药物质的种类以类似的水平继续生产ROS。
即，所述实施例2及实施例3的各个结果表明，本发明的SPG-SH3在ROS生成原因中靶向除了线粒体以外的巨噬细胞、树突状细胞或嗜中性粒细胞等的吞噬细胞以使ROS生成减少。
实施例4
SPG-SH3及抗生素的的保护效果
目的在于，在本发明的SPG-SH3及将其与抗生素联合使用的情况下，通过死亡率测量来确认对于由CLP诱导的具有系统性败血症的小鼠是否具有保护效果。
具体地，施用了与所述实施例1-1相同的给药物质的CLP小鼠(n＝7，2次；总共14)之后，监测了7天。
其结果，如图4所示，小鼠中处理了CLP之后经过约60小时，此时仅处理SPG-SH3的组示出了约70％的存活率，仅处理抗生素的组示出了约40％的存活率。反之，确认到SPG-SH3和抗生素联合施用的组出现上升效果并示出了90％的最高存活率。
实施例5
SPG-SH3及抗生素的抗炎效果
目的在于，在向CLP小鼠进行SPG-SH3及抗生素的联合使用的情况下，确认是否抑制促炎性细胞因子(pro-inflammatory cytokine)。
具体地，向CLP小鼠施用了与所述实施例1-1相同的给药物质的20小时之后，获得了外周血(pheripheral blood)。利用ELISA试剂盒(BD Biosciences)测量了所述血液内的TNF-α、IL-6、IL-1β及IL-18的浓度。
其结果，如图5所示，可确认到在SPG-SH3或在SPG-SH3与抗生素联合处理的情况下，TNF-α、IL-6、IL-1β及IL-18的浓度显著减少。
实施例6
SPG-SH3及抗生素的抗菌效果
由CLP引发的败血症与外周血(pheripheral blood)以及腹膜液(peritonealfluid)中的细菌相关。对此，目的在于，在向CLP小鼠联合使用SPG-SH3及抗生素的情况下，确认对于细菌的抗菌效果。
具体地，在施用了与所述实施例1-1相同的给药物质的CLP小鼠给药后20小时之后获得了外周血和腹膜液。将外周血及腹膜液分别在血琼脂(Blood agar)平板上点(spotting)5μL之后，在37℃培养箱中培养了18小时之后，测量了单位菌落数(colony-forming units；CFU)。
其结果，如图6所示，确认到了外周血以及腹膜液中细菌菌落总数(CFU)显著减少。尤其，在腹膜液中SPG-SH3和抗生素联合处理的情况下的抗菌效果最为优异。
工业可用性
本发明所提供的β-1,3-葡聚糖(β-1,3-glucan)及由序列号4的氨基酸序列组成的肽的ROS生成抑制效果或抗炎症效果优异，针对败血症模型的保护效果或针对败血症菌的抗菌效果优异，因此在用于预防、改善或治疗炎症性疾病的组合物或抗炎用组合物、抗菌用组合物、炎症性疾病的预防或治疗方法中可有效利用，因此具有高工业可用性。
序列目录自由文本
序列号1是c-Src的序列，其是62个氨基酸序列。
序列号2是SH3-1的序列，其是18个氨基酸序列。
序列号3是SH3-2的序列，其是20个氨基酸序列。
序列号4是SH3的序列，其是19个氨基酸序列。
序列号5是SC(Scramble)的序列，其是19个氨基酸序列。
序列表
<110> 株式会社贵真生物技术
<120> 用于预防、改善或治疗炎症性疾病的包含β-葡聚糖-肽复合物及抗生素的组合物
<130> SOP115432CN
<150> PCT/KR2019/007374
<151> 2019-06-19
<160> 5
<170> PatentIn version 3.2
<210> 1
<211> 62
<212> PRT
<213> 人工序列
<220>
<223> c-Src
<400> 1
Gly Gly Val Thr Thr Phe Val Ala Leu Tyr Asp Thr Glu Ser Arg Thr
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Glu Thr Asp Leu Ser Phe Lys Lys Gly Glu Arg Leu Gln Ile Val Asn
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Asn Thr Glu Gly Asp Trp Trp Leu Ala His Ser Leu Ser Thr Gly Gln
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Thr Gly Tyr Ile Pro Ser Asn Tyr Val Ala Pro Ser Asp Ser
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<210> 2
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<212> PRT
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<211> 20
<212> PRT
<213> 人工序列
<220>
<223> SH3-2
<400> 3
Trp Trp Leu Ala His Ser Leu Ser Thr Gly Gln Thr Gly Tyr Ile Pro
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<211> 19
<212> PRT
<213> 人工序列
<220>
<223> SH3
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Ala Leu Leu Ser Phe Lys Lys Gly Gly Gln Thr Gly Tyr Ile Pro Ser
1 5 10 15
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<213> 人工序列
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Claims (20)
1.一种用于预防或治疗炎症性疾病的药物组合物，其特征在于，包含β-1,3-葡聚糖及由序列号4的氨基酸序列组成的肽。
2.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述β-1,3-葡聚糖和所述肽通过间隔子连接。
3.根据权利要求2所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述间隔子为包含GGGG氨基酸序列的肽。
4.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述β-1,3-葡聚糖为裂褶多糖。
5.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述组合物还包含抗生素。
6.根据权利要求5所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述抗生素为选自由头孢霉菌素系列、β-内酰胺系列、β-内酰胺/β-内酰胺酶抑制剂系列、喹诺酮系列、糖肽系列、碳青霉烯系列、氨基糖苷系列、大环内酯系列、磺胺系列、氨曲南、克林达霉素、替加环素、粘杆菌素甲基磺酸钠、甲硝唑及螺旋霉素组成的组中的一种以上。
7.根据权利要求6所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述头孢霉菌素系列的抗生素为选自由头孢唑啉、头孢卡品酯、头孢泊肟酯、头孢拉定、头孢曲松、头孢拉宗、头孢噻肟、头孢米诺、头孢他啶、头孢匹罗、头孢克肟、头孢氨苄、头孢地尼、头孢沙定、头孢呋辛、头孢羟氨苄、头孢西丁、头孢他美酯、头孢唑肟、头孢孟多酯钠、头孢西酮、头孢特仑酯、头孢替唑、头孢丙烯、头孢替坦、头孢甲肟、头孢妥仑匹酯、头孢曲嗪丙二醇、头孢替安、盐酸头孢替安、头孢布烯、头孢克洛、头孢哌酮、头孢匹胺、头孢噻吩、头孢地嗪、头孢尼西、头孢美唑及头孢吡肟组成的组中的一种以上；
所述β-内酰胺系列的抗生素为选自由乙氧萘青霉素、氧哌嗪青霉素及氨苄青霉素组成的组中的一种以上；
所述β-内酰胺酶抑制剂系列的抗生素为选自由舒巴坦、他唑巴坦、对甲苯磺酸舒他西林、阿莫西林、克拉维酸钾、替卡西林及舒巴坦匹酯组成的组中的一种以上；
所述奎诺酮系列的抗生素为选自由环丙氟哌酸、莫西沙星、左氧氟沙星及洛美沙星组成的组中的一种以上；
所述糖肽系列的抗生素为选自由万古霉素、利奈唑胺及替考拉宁组成的组中的一种以上；
所述碳青霉烯系列的抗生素为选自由美罗培南、多利培南一水合物、西司他丁及亚胺培南一水合物组成的组中的一种以上；
所述氨基糖苷系列的抗生素为选自由丁胺卡那霉素、妥布霉素、奈替米星、西索米星、异帕米星、磷霉素及庆大霉素组成的组中的一种以上；
所述大环内酯系列的抗生素为选自由克拉霉素、罗红霉素及阿奇霉素组成的组中的一种以上；以及
所述磺胺系列的抗生素为选自由磺胺甲恶唑及甲氧苄啶组成的组中的一种以上。
8.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述组合物使选自由巨噬细胞、树突状细胞、单核细胞、肥大细胞及嗜中性粒细胞组成的组中的一种以上的吞噬细胞的活性氧的产量减少。
9.根据权利要求1所述的用于预防或治疗炎症性疾病的药物组合物，其特征在于，所述炎症性疾病为选自由败血症，败血性休克，炎性肠病、腹膜炎、肾炎、急性支气管炎、慢性支气管炎、骨关节炎、肠病脊柱炎、慢性阻塞性肺病、类风湿性关节炎、急性肺损伤及支气管肺发育不良组成的组中的一种以上。
10.一种用于预防或改善炎症性疾病的保健功能食品组合物，其特征在于，包含β-1,3-葡聚糖及由序列号4的氨基酸序列组成的肽。
11.一种抗炎用组合物，其特征在于，包含β-1,3-葡聚糖及由序列号4的氨基酸序列组成的肽。
12.一种针对引起败血症的细菌的抗菌用组合物，其特征在于，包含β-1,3-葡聚糖、由序列号4的氨基酸序列组成的肽及抗生素。
13.一种炎症性疾病的预防或治疗方法，其特征在于，包括向患者给药β-1,3-葡聚糖及由序列号4的氨基酸序列组成的肽的步骤。
14.根据权利要求13所述的炎症性疾病的预防或治疗方法，其特征在于，所述β-1,3-葡聚糖和所述肽通过间隔子连接。
15.根据权利要求14所述的炎症性疾病的预防或治疗方法，其特征在于，所述间隔子为包含GGGG氨基酸序列的肽。
16.根据权利要求13所述的炎症性疾病的预防或治疗方法，其特征在于，所述β-1,3-葡聚糖为裂褶多糖。
17.根据权利要求13所述的炎症性疾病的预防或治疗方法，其特征在于，所述方法还包括向患者给药抗生素的步骤。
18.根据权利要求17所述的炎症性疾病的预防或治疗方法，其特征在于，所述抗生素为选自由头孢霉菌素系列、β-内酰胺系列、β-内酰胺/β-内酰胺酶抑制剂系列、喹诺酮系列、糖肽系列、碳青霉烯系列、氨基糖苷系列、大环内酯系列、磺胺系列、氨曲南、克林达霉素、替加环素、粘杆菌素甲基磺酸钠、甲硝唑及螺旋霉素组成的组中的一种以上。
19.根据权利要求18所述的炎症性疾病的预防或治疗方法，其特征在于，所述头孢霉菌素系列的抗生素为选自由头孢唑啉、头孢卡品酯、头孢泊肟酯、头孢拉定、头孢曲松、头孢拉宗、头孢噻肟、头孢米诺、头孢他啶、头孢匹罗、头孢克肟、头孢氨苄、头孢地尼、头孢沙定、头孢呋辛、头孢羟氨苄、头孢西丁、头孢他美酯、头孢唑肟、头孢孟多酯钠、头孢西酮、头孢特仑酯、头孢替唑、头孢丙烯，头孢替坦、头孢甲肟、头孢妥仑匹酯、头孢曲嗪丙二醇、头孢替安、盐酸头孢替安、头孢布烯、头孢克洛、头孢哌酮、头孢匹胺、头孢噻吩、头孢地嗪、头孢尼西、头孢美唑及头孢吡肟组成的组中的一种以上；
所述β-内酰胺系列的抗生素为选自由乙氧萘青霉素、氧哌嗪青霉素及氨苄青霉素组成的组中的一种以上；
所述β-内酰胺酶抑制剂系列的抗生素为选自由舒巴坦、他唑巴坦、对甲苯磺酸舒他西林、阿莫西林、克拉维酸钾、替卡西林及舒巴坦匹酯组成的组中的一种以上；
所述奎诺酮系列的抗生素为选自由环丙氟哌酸、莫西沙星、左氧氟沙星及洛美沙星组成的组中的一种以上；
所述糖肽系列的抗生素为选自由万古霉素、利奈唑胺及替考拉宁组成的组中的一种以上；
所述碳青霉烯系列的抗生素为选自由美罗培南、多利培南一水合物、西司他丁及亚胺培南一水合物组成的组中的一种以上；
所述氨基糖苷系列的抗生素为选自由丁胺卡那霉素、妥布霉素、奈替米星、西索米星、异帕米星、磷霉素及庆大霉素组成的组中的一种以上；
所述大环内酯系列的抗生素为选自由克拉霉素、罗红霉素及阿奇霉素组成的组中的一种以上；以及
所述磺胺系列的抗生素为选自由磺胺甲恶唑及甲氧苄啶组成的组中的一种以上。
20.根据权利要求13所述的炎症性疾病的预防或治疗方法，其特征在于，所述炎症性疾病为选自由败血症、败血性休克、炎性肠病、腹膜炎、肾炎、急性支气管炎、慢性支气管炎、骨关节炎、肠病脊柱炎、慢性阻塞性肺病、类风湿性关节炎、急性肺损伤及支气管肺发育不良组成的组中的一种以上。
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| CN105683372A (zh) * | 2013-09-20 | 2016-06-15 | 国立研究开发法人医疗基盘健康荣养研究所 | 具有免疫增强活性的包含寡核苷酸的复合体及其用途 |
| CN107405389A (zh) * | 2014-12-10 | 2017-11-28 | 建国大学全球本土化产学合作基金会 | 含有adk蛋白作为活性成分的抗菌组合物，或用于预防或治疗败血症的组合物 |
| KR20170089766A (ko) * | 2016-01-26 | 2017-08-04 | 한양대학교 에리카산학협력단 | 베타글루칸-펩타이드 복합체, 이의 제조방법 및 이를 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물 |
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| US11311599B2 (en) | 2022-04-26 |
| KR102191491B1 (ko) | 2020-12-15 |
| WO2019245275A1 (ko) | 2019-12-26 |
| US20210268060A1 (en) | 2021-09-02 |
| JP2021529216A (ja) | 2021-10-28 |
| KR20190143193A (ko) | 2019-12-30 |
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