CN116785305A - 一种药物组合物及其用途 - Google Patents
一种药物组合物及其用途 Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 36
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 14
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims description 20
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims description 10
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
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- 229960001285 quercetin Drugs 0.000 claims description 10
- 235000005875 quercetin Nutrition 0.000 claims description 10
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- HCUDCIHFJUTKCF-UHFFFAOYSA-N gossypetin 8-O-beta-D-glucuronide Natural products OC1C(O)C(Oc2c(O)c(O)c(O)c3C(=O)C=C(Oc23)c4ccc(O)c(O)c4)OC(C1O)C(=O)O HCUDCIHFJUTKCF-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
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Abstract
本发明提供一种药物组合物,该药物组合物含有的金丝桃苷:异槲皮苷:杨梅素:槲皮素‑3'‑O‑葡萄糖苷:棉皮素‑8‑O‑β‑D‑葡萄糖醛酸苷的质量比为3.0‑20:4.0‑18:1.9‑6.0:6.0‑20:8‑12,具有良好的治疗糖尿病肾病的效果,副作用小,还具有治疗肺纤维化作用。
Description
技术领域
本发明涉及一种药物组合物,本发明还涉及该药物组合物的用途。
背景技术
黄酮类化合物广泛存在于带黄色的花朵、果实、叶片之中,研究证实黄酮类成分不仅对缺血导致心、脑、组织等损伤具有明显的保护作用。此外,众多文献报道表明,黄酮类化合物在抗炎、解热镇痛、保护心脑缺血损伤、降血糖、抗病毒等方面可能具有较好效果。
尽管生物类黄酮具有各种治疗作用,但是黄酮种类众多,目前主要可以分为7种不同的亚型,且不同的黄酮成分组成将具有不同的治疗作用。
黄酮类化合物棉皮素-8-O-β-D-葡萄糖醛酸苷(Gossypetin-8-O-β-D-glucuronide,Hibifolin)、金丝桃苷(Hyperoside)、异槲皮苷(Isoquercitrin)、杨梅素(Myricetin)、槲皮素(Quercetin)、槲皮素-3'-O-葡萄糖苷(quercetin-3'-O-β-D-glucoside)、槲皮素-3-洋槐糖苷存在于多种植物中,可以自植物中提取分离制备得到,也可通过化学方法制备得到。
棉皮素-8-O-β-D-葡萄糖醛酸苷、金丝桃苷、异槲皮苷、杨梅素、槲皮素、槲皮素-3'-O-葡萄糖苷、槲皮素-3-洋槐糖苷结构式分别如下:
黄葵胶囊用于治疗肾病已上市多年,具有较好的治疗肾病的临床效果,是黄蜀葵花提取物,含有多种黄酮成分,包括棉皮素-8-O-β-D-葡萄糖醛酸苷,金丝桃苷(Hyperoside)、异槲皮苷(Isoquercitrin)、杨梅素(Myricetin)、槲皮素-3'-O-葡萄糖苷等成分,但总黄酮在提取物中含量不高。
统计黄葵胶囊的不良反应病例发现,最近某一年度共收到关于黄葵胶囊不良反应194例,按照药物不良反应表现统计,出现次数超过10例次的有恶心、瘙痒、皮疹、呕吐、腹泻、上腹部胀满不适等,均为已知不良反应。最近出现新的不良反应表现表现有头晕、头痛、食欲下降等。另外,在已收到的严重不良反应中,有1例涉及到肝细胞损害,有可能是黄葵胶囊损害肝细胞的信号。因此,开发一种新的可以替代黄蜀葵花黄酮提取物以降低副作用且可用于治疗多种疾病的药物组合物具有重要的临床意义。
发明内容
本发明提供了一种药物组合物及其应用。发现其具有更好的肾病治疗活性,同时兼具良好的肺纤维化预防、治疗作用。
本发明的一个目的,提供一种要药物组合物,含有下列重量份的组分:
进一步地,所述的药物组合物,含有下列重量份的组分:
进一步地,所述的药物组合物,含有下列重量份的组分:
进一步地所述的药物组合物,含有下列重量份的组分:
跟更进一步地,所述的药物组合物,含有下列重量份的组分:
本发明所述的药物组合物,进一步地含有槲皮素,其中棉皮素-8-O-β-D-葡萄糖醛酸苷与槲皮素的重量比为9-11:1.0-10.0,优选为10:1.0-6.0,进一步优选为10:1.5-5.0,进一步优选为10:1.0-10.0。
本发明所述的药物组合物,进一步地含有槲皮素-3-O-洋槐糖苷,其中,棉皮素-8-O-β-D-葡萄糖醛酸苷与槲皮素-3-O-洋槐糖苷的重量比为9-11:0.05-2.5,10:0.1-0.9,优选为10:0.15-0.5,进一步优选为10:0.05-2.5。
本发明所述的药物组合物,所述组分作为药物活性成分其含量在60%以上,进一步为65%以上,更进一步为75%以上,优选所述棉皮素-8-O-β-D-葡萄糖醛酸苷的重份为9-11份,优选为10份。
本发明所述的药物组合物,进一步的含有药学上可接受的载体。
本发明的另一个目的,提供所述的药物组合物在制备肾病药物中的应用,所述肾病可选自糖尿病或所述的药物组合物在制备抗纤维化药物中的应用,所述纤维化可选自肺纤维化,进一步的为特异性肺纤维化。
本发明所述的药物组合物,按照特定比例进行组合具有良好的治疗糖尿病肾病的效果,副作用小,还具有治疗肺纤维化作用。
具体实施方式
实施例1药物组合物的制备
取金丝桃苷、异槲皮苷、hibifolin、杨梅素、槲皮素-3'-o-葡萄糖苷、槲皮素、槲皮素3-O-洋槐糖苷原料,按下表投料比例,称取各活性成分,混合,制备得到药物组合物。
实施例2药物组合物的制备
按下表投料比例,称取各活性成分,混合,制备得到药物组合物。
取金丝桃苷、异槲皮苷、hibifolin、杨梅素、槲皮素-3'-o-葡萄糖苷、槲皮素、槲皮素3-O-洋槐糖苷原料,按下表投料比例,称取各活性成分,混合,制备得到药物组合物。
实施例3糖尿病肾病实验
动物模型:db/db小鼠,16周龄,C57BL/6小鼠,16周龄。
给药方式:灌胃给药
实验造模:db/db小鼠饲养17周后,检测尿蛋白,出现尿蛋白、肾功能异常,则模型成功,用于后期实验。
实验分组:C57BL/6小鼠分为正常组,将db/db小鼠分为模型组,阳性药组(达格列净片,45.5mg/kg),实施例1药物组合物组(62.4mg/kg),每组15只,给药4周后检测尿蛋白及尿肌酐及每日摄食量,并观察小鼠状态。检测结果如下表12所示。
表1
组别 | 尿蛋白/mg | 尿蛋白/尿肌酐 |
正常组 | 17.21±10.07 | 0.29±0.16 |
模型组 | 61.97±32.17* | 2.68±1.03* |
阳性药组 | 15.09±10.27# | 1.17±1.26# |
实施例1组 | 19.38±14.67# | 1.31±1.28# |
注:*与正常对照组比较,P<0.05;#与模型对照组比较,P<0.05;
结果显示,实施例1的药物组合物组可降低尿蛋白和尿蛋白/尿肌酐(ACR)。仅1个动物出现腹泻/腹胀情形,具有较低的副作用反应。而在同期研究的不同黄酮成分的黄蜀葵花提取物的研究中发现,由与实施例1不同比例黄酮成分组成的黄蜀葵花提取物,动物呈现不同的副作用,含有本发明比例的黄酮成分的黄蜀葵花提取物具有较低副作用,比剂量更大的黄葵胶囊还显示出更低的副作用。
实施例4特发性肺纤维化作用实验
实验动物:昆明种小鼠60只,雌雄各半,体重18-22克,清洁级。
动物分组:随机分为5组,即正常组、模型组、对照药组(罗格列酮5mg/kg)、实施例1药物组合物组(70mg/kg)、实施例2药物组合物组(70mg/kg)、黄葵胶囊样品组(以提取物计180mg/kg),实施例2药物组合物组(70mg/kg)、每组小鼠10只。
实验造模:实验小鼠适应性饲养3天后,用4%的水合氯醛(0.01ml/g)腹腔注射麻醉。取仰卧固定位,常规消毒,行颈正中切口,钝性分离暴露气管,模型组,对照药组、治疗组于气管软骨环间隙穿刺缓慢注入博莱霉素(5mg/kg),正常对照组注入等体积生理盐水,注药后立即将小鼠直立旋转3-5min,使药液均匀分布于两侧肺内,然后缝合皮肤,并在缝合处消毒,待清醒后送清洁级观察室饲养。
给药方式:造模第二天开始给药,给药组按上述剂量给药,每天一次,正常组和模型组按同样的方法给予同等体积的蒸馏水10ml/kg,连续给药28天。
肺组织病理切片染色:给药结束后,取右肺,按常规病理学方法进行固定、包埋、切片、HE染色。将肺泡炎和肺纤维化的程度分为四级。
实验结果:
组别 | 肺泡炎程度 | 纤维化程度 |
正常组 | 0.43±0.58 | 0.29±0.38 |
模型组 | 1.69±0.66* | 1.87±0.69* |
对照药组 | 1.03±0.49# | 1.15±0.81# |
实施例1样品组 | 1.23±0.55# | 1.20±0.67# |
黄葵胶囊组 | 1.48±0.62# | 1.69±0.63# |
实施例2样品组 | 1.33±0.74# | 1.48±0.54# |
注:*与正常组比较,P<0.01;#与模型组比较,P<0.05
实验结果表明,模型组小鼠肺组织肺泡炎和肺纤维化程度显著加重,呈典型的肺纤维化实质病变。给药28天,各剂量组小鼠肺系数明显降低,肺组织肺泡炎及肺纤维化程度明显减轻。总黄酮有效部位可明显降低肺纤维化小鼠的肺泡炎和肺纤维化程度,对肺纤维化小鼠的肺部具有保护作用,可以减缓由纤维化对方肺部组织造成的损伤。
Claims (10)
1.一种药物组合物,含有下列重量份的组分:
2.根据权利要求1所述的药物组合物,含有下列重量份的组分:
3.根据权利要求1所述的药物组合物,含有下列重量份的组分:
4.根据权利要求1所述的药物组合物,含有下列重量份的组分:
5.根据权利要求1所述的药物组合物,含有下列重量份的组分:
6.根据权利要求1所述的药物组合物,含有槲皮素,其中棉皮素-8-O-β-D-葡萄糖醛酸苷与槲皮素的重量比为9-11:1.0-10.0,优选为10:1.0-6.0,进一步优选为10:1.5-5.0,特别地,为10:1.0-10.0。
7.根据权利要求1所述的药物组合物,含有槲皮素-3-O-洋槐糖苷,其中,棉皮素-8-O-β-D-葡萄糖醛酸苷与槲皮素-3-O-洋槐糖苷的重量比为9-11:0.05-2.5,10:0.1-0.9,优选为10:0.15-0.5,进一步优选为10:0.05-2.5。
8.权利要求1所述的药物组合物,所述组分作为药物活性成分其含量在60%以上,进一步为65%以上,更进一步为75%以上,优选所述棉皮素-8-O-β-D-葡萄糖醛酸苷的重量份为9-11份,优选为10份。
9.权利要求1所述的药物组合物在制备肾病药物中的应用,所述肾病可选自糖尿病或所述的药物组合物在制备抗纤维化药物中的应用,所述纤维化可选自肺纤维化,进一步的为特异性肺纤维化。
10.权利要求1所述的药物组合物,进一步的含有药学上可接受的载体。
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