WO2022161376A1 - 一种含有西洛他唑的组合物在脑血管病中的应用 - Google Patents

一种含有西洛他唑的组合物在脑血管病中的应用 Download PDF

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WO2022161376A1
WO2022161376A1 PCT/CN2022/073910 CN2022073910W WO2022161376A1 WO 2022161376 A1 WO2022161376 A1 WO 2022161376A1 CN 2022073910 W CN2022073910 W CN 2022073910W WO 2022161376 A1 WO2022161376 A1 WO 2022161376A1
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edaravone
cilostazol
component
composition
animals
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PCT/CN2022/073910
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English (en)
French (fr)
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华垚
王磊
张正平
陈荣
杨士豹
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南京宁丹新药技术有限公司
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Priority to AU2022212142A priority Critical patent/AU2022212142A1/en
Priority to US18/263,191 priority patent/US20240122917A1/en
Priority to EP22745250.5A priority patent/EP4285903A4/en
Priority to JP2023543219A priority patent/JP2024503490A/ja
Publication of WO2022161376A1 publication Critical patent/WO2022161376A1/zh

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of pharmacy, and relates to the application of a cilostazol and edaravone composition in preparing a medicine for treating cerebrovascular disease, especially ischemic cerebrovascular disease.
  • Cerebrovascular disease refers to the brain lesions caused by various cerebrovascular diseases. According to its pathogenesis, it can be divided into acute cerebrovascular disease (stroke) and chronic cerebrovascular disease.
  • Acute cerebrovascular disease includes transient ischemic attack, cerebral thrombosis, cerebral embolism, hypertensive encephalopathy, cerebral hemorrhage and subarachnoid hemorrhage; chronic cerebrovascular disease includes cerebral arteriosclerosis, cerebrovascular dementia, cerebral arterial Steal syndrome, Parkinson's disease, etc.
  • Ischemic stroke refers to the general term for brain tissue necrosis caused by stenosis or occlusion of the blood supply arteries (carotid artery and vertebral artery) and insufficient blood supply to the brain.
  • cerebral ischemia There are four types of cerebral ischemia, which are transient ischemic attack (TIA), reversible neurological impairment (RIND), progressive stroke (SIE) and complete stroke (CS).
  • TIA transient ischemic attack
  • RIND reversible neurological impairment
  • SIE progressive stroke
  • CS complete stroke
  • Cilostazol (vinpocetine) is an anti-platelet aggregation drug. It was first developed and synthesized by Japan's Otsuka Pharmaceutical Co., Ltd. and was listed in Japan in 1988. It was approved by the FDA in the United States in May 1999 and entered my country in 1996. Cilostazol is a selective phosphodiesterase 3 inhibitor (Phosphodiesterase 3, PDE3). The binding rate of cilostazol to plasma proteins is about 95%, and most of them exist in a relatively stable prototype. Cilostazol has broad-spectrum pharmacological activity and has clinical value in many diseases, such as peripheral thrombotic disease and intermittent claudication.
  • cilostazol has the functions of anti-platelet and vasodilation, which can prevent circulatory shock and the recurrence of coronary artery stenosis.
  • PDE3 can inhibit the degradation of cAMP in the circulatory system and increase the cAMP in platelets and vascular smooth muscle, inhibiting the formation of platelets and promoting the proliferation of vascular smooth muscle cells.
  • Cilostazol inhibits platelet degradation mainly by affecting the following various factors: arachidonic acid, adenosine diphosphate, epinephrine, collagen, fibrinase.
  • cilostazol can be recommended for patients with carotid artery thrombosis, which can treat or prevent cerebral ischemia.
  • PDE3 can inhibit the production of nitric oxide synthase (NOS), thereby reducing the production of nitric oxide (NO).
  • NOS nitric oxide synthase
  • Edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one) is a neuroprotective agent on the market (Yakugaku Zasshi. 2004, 124(3): 99- 111). Studies have shown that edaravone has antioxidant activity, which can significantly improve the symptoms of neurological deficits in animals with cerebral ischemia and reperfusion, reduce the infarct size, reduce the degree of brain damage, reduce brain edema, and inhibit lipid peroxidation in damaged brain tissue. .
  • the object of the present invention is to provide an application of a pharmaceutical composition in the preparation of a cerebrovascular drug, the pharmaceutical composition contains cilostazol or a pharmaceutically acceptable salt thereof and edaravone, further, this
  • the combined use of the drug combination can synergistically increase the efficacy of the treatment of cerebrovascular disease.
  • the present invention provides a composition comprising the following components:
  • Component (I) cilostazol, a derivative thereof, a pharmaceutically acceptable salt thereof, or a prodrug molecule thereof;
  • Component (II), edaravone, or a drug whose active ingredient is edaravone is Component (II), edaravone, or a drug whose active ingredient is edaravone.
  • the weight ratio of the component (I) to the component (II) is 1:10 to 10:1.
  • the weight ratio of the component (I) to the component (II) is 1:10 to 5:1.
  • the weight ratio of the component (I) to the component (II) is 1:5 to 10:1.
  • the weight ratio of the component (I) to the component (II) is 1:5 to 5:1.
  • the weight ratio of the component (I) to the component (II) is 1:2.5 ⁇ 2.5:1.
  • the weight ratio of the component (I) to the component (II) is 1:1 to 2.5:1.
  • the weight ratio of the component (I) to the component (II) is 1:1, 5:1, 2.5:1, 1:2.5 and/or 1:5 .
  • the present invention also provides a medicine, including the composition, and a pharmaceutically acceptable adjuvant.
  • the present invention also provides the application of the composition or the medicament in the preparation of a medicament for preventing and/or treating cerebrovascular disease;
  • the cerebrovascular disease includes ischemic cerebrovascular disease
  • the ischemic cerebrovascular disease includes ischemic stroke.
  • the pharmaceutical combination of the present invention can be applied to the preparation of cerebrovascular drugs.
  • the cerebrovascular disease is preferably ischemic cerebrovascular disease, and more preferably ischemic stroke.
  • the beneficial effects of the present invention are: the compatibility of cilostazol and edaravone, according to the results of the drug efficacy test of animals (rats, mice), for cerebrovascular disease, the two have the effect of synergistically increasing the drug efficacy .
  • test results of the present invention show that administration of 1-15 mg/kg cilostazol or 1.67-8.33 mg/kg edaravone to the tail vein of focal cerebral ischemia-reperfusion injury in rats can significantly improve the neurological deficits and neurological deficits in MCAO rats. Reduce the size of cerebral infarction; and the compound combination (cilostazol: edaravone mass ratio 1:5 to 5:1) within the above dose range can synergize. In mice with focal cerebral ischemia-reperfusion injury, administration of 3.33-16.67 mg/kg cilostazol or 3.33-16.67 mg/kg edaravone to the tail vein can significantly improve neurological deficits and reduce cerebral infarct size in MCAO mice.
  • the invention discloses the application of a composition containing cilostazol in cerebrovascular disease, and those skilled in the art can learn from the content of this article and appropriately improve process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • the raw materials and reagents used in the application of the cilostazol-containing composition provided by the present invention in cerebrovascular disease can be purchased from the market.
  • SD rats Sprague-Dawley rats, male, SPF grade, weighing 250-280 g.
  • the rat model of focal cerebral ischemia-reperfusion was established by the internal carotid artery suture method.
  • the rats under anesthesia were tied with rubber bands (the hind limbs were fixed above the knee joint, and the forelimbs were fixed below the wrist joint) and the head. Hair, alcohol to disinfect the skin.
  • a midline incision was made in the neck, and the subcutaneous tissue was bluntly dissected.
  • the thin layer of fascia on the surface of the anterior triangle of the neck is separated, and the lower edge of the lower edge of the clavicular hyoid muscle is pulled up.
  • the longitudinal pulsating artery parallel to this muscle can be seen, the arterial shell is opened, the right carotid artery bifurcation is exposed, and the right side is separated.
  • the common carotid artery, external carotid artery, and internal carotid artery were gently stripped off, and the external carotid artery was ligated and cut. Clip the proximal end of the common carotid artery, make an incision from the distal end of the ligature of the external carotid artery, insert the suture, enter the internal carotid artery through the bifurcation of the common carotid artery, and then insert it slowly until there is slight resistance (since the bifurcation). approximately 20 mm), blocking all blood supply to the middle cerebral artery.
  • the suture was slightly fixed under the external carotid artery incision with silk thread, the proximal end of the common carotid artery was loosened to clamp the silk thread, the wound surface was covered with gauze soaked with sterile saline, and the rat was placed on a thermal pad to keep warm. After 2.0 hours of right cerebral ischemia, the suture was gently pulled out, the blood supply was restored for reperfusion, the external carotid artery was ligated with silk thread fixing the suture, and the skin was sutured and sterilized. The rats were placed in clean feed, and their general conditions and breathing were observed until they woke up from anesthesia;
  • the animals were sacrificed with CO 2 , the brains were removed by decapitation, the olfactory bulb, cerebellum and lower brain stem were removed, the blood on the surface of the brain was rinsed with normal saline, the residual water on the surface was sucked off, and placed at -20 °C for 20 min. Immediately, a coronal section was made vertically downward at the intersection plane of the sight, and a slice was cut every 2 mm backward. The brain slice was incubated in 1% TTC staining solution (37 ° C for 30 min), the normal brain tissue was stained dark red, and the ischemic brain The tissue was pale white. After rinsing with normal saline, the brain slices were quickly arranged in a row from front to back, and the residual water on the surface was blotted and photographed.
  • Calculation of cerebral infarction area The photos were processed with Image J software, and the corresponding area of the left brain and the non-infarcted area of the right brain were calculated according to the formula, and the percentage of infarct area was calculated.
  • V t(A1+A2+A3+............+An)
  • t is the slice thickness
  • A is the infarct area
  • %I is the percentage of infarct volume
  • VC is the brain volume on the control side (left cerebral hemisphere)
  • VL is the non-infarcted area volume on the infarcted side (right cerebral hemisphere).
  • the effect on the scope of cerebral infarction is shown in Table 1.
  • the synergistic calculation result q 1.33, indicating that the combination of the two drugs has a synergistic effect.
  • SD rats Sprague-Dawley rats, male, SPF grade, weighing 250-280 g.
  • Cilostazol and edaravone are the same as in Example 1.
  • cilostazol group 5mg/kg
  • edaravone edaravone
  • Lavone 1:1:1:1:1:1:1:1, cilostazol 5mg/kg+edaravone 5mg/kg
  • model group a total of 4 groups.
  • mice were randomly assigned to each group in a single-blind manner. Animals were given intravenous administration once immediately after reperfusion, and animals in the model group were given an equal volume of normal saline. The animals were sacrificed 24 hours after cerebral ischemia, and the brain
  • SD rats Sprague-Dawley rats, male, SPF grade, weighing 250-280 g.
  • Cilostazol and edaravone are the same as in Example 1.
  • cilostazol group 15mg/kg
  • edaravone edaravone
  • Lavone 5:1
  • model group a total of 4 groups.
  • mice were randomly assigned to each group in a single-blind manner. Animals were given intravenous administration once immediately after reperfusion, and animals in the model group were given an equal volume of normal saline. The animals were sacrificed 24 hours after cerebral ischemia, and the brains were harvested, stained, and photographed
  • Example 4 The effect of cilostazol/edaravone (1:5, 1:2.5, 1:1) on focal cerebral ischemia-reperfusion injury
  • SD rats Sprague-Dawley rats, male, SPF grade, weighing 250-280 g.
  • Cilostazol and edaravone are the same as in Example 1.
  • the experimental animals were divided into a model group and three composition groups of cilostazol/edaravone (respectively: 1:5 group, cilostazol 1.67 mg/kg + edaravone 8.33 mg/kg; 1:2.5 group, Cilostazol 2.86mg/kg+edaravone 7.14mg/kg; 1:1 group, cilostazol 5mg/kg+edaravone 5mg/kg.
  • the total dose of each composition is 10mg/kg. ), a total of 4 groups.
  • Example 5 The effect of cilostazol/edaravone (1:1, 2.5:1, 5:1) on focal cerebral ischemia-reperfusion injury
  • SD rats Sprague-Dawley rats, male, SPF grade, weighing 250-280 g.
  • Cilostazol and edaravone are the same as in Example 1.
  • the experimental animals were divided into model group and cilostazol/edaravone three composition groups (1:1 group, cilostazol 5mg/kg + edaravone 5mg/kg; 2.5:1 group, cilostazol 5mg/kg + edaravone 5mg/kg; Stazol 7.14 mg/kg + edaravone 2.86 mg/kg; 5:1 group, cilostazol 8.33 mg/kg + edaravone 1.67 mg/kg.
  • the total dose of each composition is 10 mg/kg. ), a total of 4 groups.
  • Example 6 The effect of cilostazol/edaravone (1:5, 1:2.5, 1:1) on focal cerebral ischemia-reperfusion injury in mice
  • Cilostazol and edaravone are the same as in Example 1.
  • the experimental animals were divided into a model group and three composition groups of cilostazol/edaravone (respectively: 1:5 group, cilostazol 3.33 mg/kg + edaravone 16.67 mg/kg; 1:2.5 group, Cilostazol 5.71mg/kg + edaravone 14.29mg/kg; 1:1 group, cilostazol 10mg/kg + edaravone 10mg/kg.
  • the total dose of each composition is 20mg/kg. ), a total of 4 groups.
  • the mouse model of focal cerebral ischemia-reperfusion was established by the internal carotid artery suture method.
  • the anesthetized mice were fixed on the operating table in a supine position. A midline incision was made in the neck, and the subcutaneous tissue was bluntly dissected.
  • the right common carotid artery, external carotid artery, and internal carotid artery were separated. Insert the suture from the external carotid artery, enter the internal carotid artery through the bifurcation of the common carotid artery, and then insert it slowly until there is slight resistance (about 10mm from the bifurcation), blocking all blood supply of the middle cerebral artery. After 60 min of right cerebral ischemia, the suture was gently pulled out to restore blood supply for reperfusion. The mice were placed in clean feed, and their general condition and breathing were observed until they woke up from anesthesia;
  • Example 7 The effect of cilostazol/edaravone (1:1, 2.5:1, 5:1) on focal cerebral ischemia-reperfusion injury in mice
  • Cilostazol and edaravone are the same as in Example 1.
  • the experimental animals were divided into model group and cilostazol/edaravone three composition groups (1:1 group, cilostazol 10mg/kg + edaravone 10mg/kg; 2.5:1 group, cilostazol 10mg/kg + edaravone 10mg/kg; Stazol 14.29 mg/kg + edaravone 5.71 mg/kg; 5:1 group, cilostazol 16.67 mg/kg + edaravone 3.33 mg/kg.
  • the total dose of each composition is 20 mg/kg. ), a total of 4 groups.
  • Example 6 The preparation of the focal cerebral ischemia-reperfusion model is the same as that in Example 6, and the methods for measuring the extent of cerebral infarction and data statistics are the same as those in Example 1.
  • composition containing cilostazol provided by the present invention in cerebrovascular disease has been described in detail above.
  • the principles and implementations of the present invention are described herein by using specific examples, and the descriptions of the above embodiments are only used to help understand the method and the core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

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Abstract

一种含有西洛他唑或其在药学上可接受的盐和依达拉奉的组合物，在制备治疗脑血管病，特别是缺血性脑血管病的药物中的应用。试验结果表明，大鼠局灶性脑缺血再灌损伤尾静脉给予1～15mg/kg西洛他唑或1.67～8.33mg/kg依达拉奉能够显著改善MCAO大鼠神经功能缺陷和减少脑梗死面积；并且在上述剂量范围内进行复方组合(西洛他唑：依达拉奉质量比1:5～5:1)能够协同增效。小鼠局灶性脑缺血再灌损伤尾静脉给予3.33～16.67mg/kg西洛他唑或3.33～16.67mg/kg依达拉奉能够显著改善MCAO小鼠神经功能缺陷和减少脑梗死面积。

Description

一种含有西洛他唑的组合物在脑血管病中的应用
本申请要求于2021年01月29日提交中国专利局、申请号为202110122555.3、发明名称为“一种含有西洛他唑的组合物在脑血管病中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于制药领域，涉及西洛他唑和依达拉奉组合物在制备治疗脑血管病，特别是缺血性脑血管病药物中的应用。
背景技术
脑血管疾病(cerebrovascular disease,CVD)是指由于各种脑血管病变所引起的脑部病变，按其发病进程可分为急性脑血管病(中风)和慢性脑血管病两种。急性脑血管病包括短暂性脑缺血发作、脑血栓形成、脑栓塞、高血压脑病、脑出血和蛛网膜下腔出血等；慢性脑血管病包括脑动脉硬化、脑血管病性痴呆、脑动脉盗血综合症、帕金森氏病等。缺血性脑卒中(Stroke)是指由于脑的供血动脉(颈动脉和椎动脉)狭窄或闭塞、脑供血不足导致的脑组织坏死的总称。脑缺血包括四种类型，分比为短暂性脑缺血发作(TIA)、可逆性神经功能障碍(RIND)、进展性卒中(SIE)和完全性卒中(CS)。TIA无脑梗死存在，而RIND、SIE和CS有不同程度的脑梗死存在。
西洛他唑(vinpocetine)为抗血小板聚集药，最早由日本大冢制药有限公司研制合成，并于1988年在日本上市，1999年5月在美国获得FDA批准，1996年进入我国。西洛他唑是一种选择性磷酸二脂酶3抑制剂(Phosphodiesterase 3，PDE3)，西洛他唑与血浆蛋白的结合率约为95％，而且大多是以比较稳定的原型存在。西洛他唑具有广谱的药理学活性，对 于很多疾病，如外周血栓疾病和间歇性跛行等都有临床价值。而且西洛他唑具有抗血小板、舒张血管的功能，从而可以起到防止循环性休克和冠状动脉狭窄再发生的作用。研究表明PDE3可以抑制循环系统内cAMP的降解，并增加血小板和血管平滑肌中的cAMP，对血小板的形成有抑制作用并且有促进血管平滑肌细胞增生的作用。西洛他唑主要通过影响下列各种因素抑制血小板降解：花生四烯酸、二磷酸腺苷、肾上腺素、胶原蛋白、纤维蛋白酶。现在已经有专家认为可以对颈动脉血栓的患者建议行西洛他唑治疗，可以治疗或预防脑缺血。同时PDE3可以抑制一氧化氮合成酶(NOS)的生成，从而减少一氧化氮(NO)的产生。
西洛他唑的结构式如下：
Figure PCTCN2022073910-appb-000001
(分子式C 20H 27N 5O 2；分子量369.47)
依达拉奉(Edaravone)(化学名：3-甲基-1-苯基-2-吡唑啉-5-酮)是已上市脑神经保护剂(YakugakuZasshi.2004,124(3):99-111)。研究表明，依达拉奉具有抗氧化活性，能够显著地改善脑缺血再灌注动物的神经缺陷症状，缩小梗死面积，降低脑损伤程度，减轻脑水肿，抑制受损脑组织的脂质过氧化。
Figure PCTCN2022073910-appb-000002
(分子式C 10H 10N 2O，分子量174.20)
综上，提供西洛他唑和依达拉奉组合物用于制备治疗脑血管病，特别是缺血性脑血管病具有重要的现实意义。
发明内容
本发明目的是提供一种药物组合物在制备治疗脑血管药物中的应用，所述的药物组合物含有西洛他唑或其药学上可接受的盐和依达拉奉，更进一步地，此药物组合配合使用能协同性增加治疗脑血管病的药效。
为了实现上述发明目的，本发明提供以下技术方案：
第一方面，本发明提供了组合物，包括如下组分：
组分(I)、西洛他唑、其衍生物、其药学上可接受的盐、或其前药分子；和
组分(II)、依达拉奉、或有效成分为依达拉奉的药物。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：10～10：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：10～5：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：5～10：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：5～5：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：2.5～2.5：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的重量比为1：1～2.5：1。
在本发明的一些具体实施方案中，所述组分(I)与所述组分(II)的 重量比为1:1、5:1、2.5:1、1:2.5和/或1:5。
第二方面，本发明还提供了药物，包括所述的组合物，以及药学上可接受的辅料。
第三方面，本发明还提供了所述组合物或所述药物在制备预防和/或治疗脑血管病药物中的应用；
作为优选，所述脑血管病包括缺血性脑血管病；
作为优选，所述缺血性脑血管病包括缺血性脑卒中。
本发明的药物组合可以应用于制备脑血管的药物。其中，脑血管病优选缺血性脑血管病，进一步优选缺血性脑卒中。
本发明的有益效果是：西洛他唑和依达拉奉两者配伍，根据动物(大鼠、小鼠)药效试验结果，针对脑血管病，两者具有协同性地增加药效的作用。
本发明试验结果表明，大鼠局灶性脑缺血再灌损伤尾静脉给予1～15mg/kg西洛他唑或1.67～8.33mg/kg依达拉奉能够显著改善MCAO大鼠神经功能缺陷和减少脑梗死面积；并且在上述剂量范围内进行复方组合(西洛他唑：依达拉奉质量比1:5～5:1)能够协同增效。小鼠局灶性脑缺血再灌损伤尾静脉给予3.33～16.67mg/kg西洛他唑或3.33～16.67mg/kg依达拉奉能够显著改善MCAO小鼠神经功能缺陷和减少脑梗死面积。
具体实施方式
本发明公开了一种含有西洛他唑的组合物在脑血管病中的应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方 法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明提供的含有西洛他唑的组合物在脑血管病中的应用中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1西洛他唑和依达拉奉组合物对局灶性脑缺血再灌损伤的保护作用研究1
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，SPF级，体重250-280g。
1.2受试药品
Figure PCTCN2022073910-appb-000003
1.3实验方法
1.3.1动物分组与给药
实验动物分为西洛他唑组(1mg/kg)、依达拉奉组(5mg/kg)、西洛他唑与依达拉奉组合物组(6mg/kg，西洛他唑:依达拉奉＝1:5，西洛他唑1mg/kg+依达拉奉5mg/kg)及模型组，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给予等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
1.3.2局灶性脑缺血再灌模型的制备
采用颈内动脉线栓法制备大鼠局灶性脑缺血再灌模型。将处于麻醉状态的大鼠用皮筋束紧四肢(后肢固定膝关节以上，前肢固定腕关节以下)及头部，动物仰卧位固定于手术台上，以动物剃毛器自头端向胸部方向剃毛，酒精消毒皮肤。颈部正中切开，钝性分离皮下组织。分离颈前三角表面的薄层筋膜，拨起低边-锁骨舌骨肌下缘，可见与此肌肉平行的纵行搏动的动脉，打开动脉壳，暴露右侧颈动脉分叉，分离右侧颈总动脉、颈外动脉、颈内动脉，轻轻剥离迷走神经，结扎并剪断颈外动脉。夹闭颈总动脉近心端，从颈外动脉的结扎线的远端作一切口，插入栓线，经过颈总动脉分叉进入颈内动脉，然后徐徐插入至有轻微阻力为止(自分叉处约20mm)，阻断大脑中动脉的所有血供。以丝线在颈外动脉切口下方稍固定栓线，松开颈总动脉近心端夹闭丝线，将浸有消毒生理盐水的纱布覆盖于创面上，将大鼠放置在保温垫上保温。右侧脑缺血2.0h后，轻轻拔出栓线，恢复血供进行再灌注，用固定栓线的丝线结扎颈外动脉，缝合皮肤，消毒。将大鼠放置干净饲料中，观察一般情况和呼吸直至麻醉苏醒；加食进水，常规饲养。
1.3.3脑梗塞范围测定
动物神经缺陷症状评价完毕后以CO 2处死，断头取脑，去除嗅球、小脑和低位脑干，用生理盐水冲洗大脑表面血迹，吸去表面残留水迹，于-20℃放置20min，取出后立即于视线交叉平面垂直向下作冠状切面，并向后每隔2mm切一片，将脑片置于1％TTC染液中孵育(37℃30min)，正常脑组织染成深红色，缺血脑组织则呈苍白色，用生理盐水冲洗后，迅速将脑片从前向后按顺序排成一排，吸干表面残留水迹，拍照。
脑梗死面积的计算：照片用Image J软件处理，根据公式计算左脑相应面积以及右脑非梗死灶面积，求出梗死范围百分比。
梗死体积计算法：
V＝t(A1+A2+A3+………+An)
t为切片厚度，A为梗死面积。
％I＝100％×(VC-VL)/VC
％I为梗死体积百分比，VC为对照侧(左脑半球)脑体积，VL为梗死侧(右脑半球)非梗死区域体积。
1.3.4组合物协同性分析
根据金正均公式q＝E(a+b)/(Ea+Eb-Ea×Eb)评价组合物中西洛他唑与依达拉奉是否有协同作用。式中E(a+b)为合用药物的有效率，Ea、Eb分别为A药(西洛他唑)、B药(依达拉奉)单独用药的有效率。E给药组＝(X 模型-X 给药)/X 模型，X为脑梗塞范围值。若q值在0.85～1.15范围内，为两药合用单纯相加，q值>1.15为协同，q值<0.85则表示两药合用有拮抗作用。
1.4数据统计
实验数据以平均值±标准差(Mean±SD)表示。采用单因素方差分析各组之间差异，组间比较采用LSD法检验，P<0.05定义为差异显著。
2实验结果
对脑梗塞范围的影响见表1，实验结果表明，依达拉奉5mg/kg和组合物(西洛他唑1mg/kg+依达拉奉5mg/kg)给药能够显著减小动物脑梗塞范围(p＝0.012，p＝0.000)，西洛他唑1mg/kg给药有改善脑缺血损伤的趋势，但无统计学差异(p＝0.08)。协同性计算结果q＝1.33，表明两药联用具有协同作用。
表1西洛他唑与依达拉奉复方用药对脑梗范围的影响
Figure PCTCN2022073910-appb-000004
Figure PCTCN2022073910-appb-000005
均值±标准差，*p<0.05，***p<0.001，与模型组相比
实施例2西洛他唑和依达拉奉组合物对局灶性脑缺血再灌损伤的保护作用研究2
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，SPF级，体重250-280g。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为西洛他唑组(5mg/kg)、依达拉奉组(5mg/kg)、西洛他唑与依达拉奉组合物组(10mg/kg，西洛他唑:依达拉奉＝1:1，西洛他唑5mg/kg+依达拉奉5mg/kg)及模型组，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定、组合物协同性分析及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表2，实验结果表明，西洛他唑5mg/kg、依达拉奉5mg/kg和组合物(西洛他唑5mg/kg+依达拉奉5mg/kg)给药能够显著减小动物脑梗塞范围(p＝0.025，p＝0.008，p＝0.000)。协同性计算结果q＝1.47，表明两药联用具有协同作用。
表2西洛他唑与依达拉奉复方用药对脑梗范围的影响
Figure PCTCN2022073910-appb-000006
均值±标准差，*p<0.05，**p<0.01，***p<0.001，与模型组相比
实施例3西洛他唑和依达拉奉组合物对局灶性脑缺血再灌损伤的保护作用研究3
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，SPF级，体重250-280g。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为西洛他唑组(15mg/kg)、依达拉奉组(3mg/kg)、西洛他唑与依达拉奉组合物组(18mg/kg，西洛他唑:依达拉奉＝5:1，西洛他唑15mg/kg+依达拉奉3mg/kg)及模型组，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定、组合物协同性分析及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表3，实验结果表明，西洛他唑15mg/kg、依达拉奉3mg/kg和组合物(西洛他唑15mg/kg+依达拉奉3mg/kg)给药能够显著减小动物脑梗塞范围(p＝0.007，p＝0.029，p＝0.000)。协同性计算结果q＝1.38，表明两药联用具有协同作用。
表3西洛他唑与依达拉奉复方用药对脑梗范围的影响
Figure PCTCN2022073910-appb-000007
均值±标准差，*p<0.05，**p<0.01，***p<0.001，与模型组相比
实施例4西洛他唑/依达拉奉(1:5，1:2.5，1:1)对局灶性脑缺血再灌损伤的作用
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，SPF级，体重250-280g。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为模型组和西洛他唑/依达拉奉三个组合物组(分别为1:5组，西洛他唑1.67mg/kg+依达拉奉8.33mg/kg；1:2.5组，西洛他唑2.86mg/kg+依达拉奉7.14mg/kg；1:1组，西洛他唑5mg/kg+依达拉奉5mg/kg。各组合物给药总剂量均为10mg/kg。)，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表4，实验结果表明，西洛他唑/依达拉奉1:5、1:2.5和1:1组合给药均能显著减小动物脑梗塞范围(p<0.001)。
表4西洛他唑/依达拉奉组合物对脑梗范围的影响
Figure PCTCN2022073910-appb-000008
均值±标准差，***p<0.001，与模型组相比
实施例5西洛他唑/依达拉奉(1:1，2.5:1，5:1)对局灶性脑缺血再灌损伤的作用
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，SPF级，体重250-280g。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为模型组和西洛他唑/依达拉奉三个组合物组(分别为1:1组，西洛他唑5mg/kg+依达拉奉5mg/kg；2.5:1组，西洛他唑7.14mg/kg+依达拉奉2.86mg/kg；5:1组，西洛他唑8.33mg/kg+依达拉奉1.67mg/kg。各组合物给药总剂量均为10mg/kg。)，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备、脑梗塞范围测定及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表5，实验结果表明，西洛他唑/依达拉奉1:1、2.5:1和5:1组合给药均能显著减小动物脑梗塞范围(p＝0.000，p＝0.000，p＝0.001)。
表5西洛他唑/依达拉奉组合物对脑梗范围的影响
Figure PCTCN2022073910-appb-000009
均值±标准差，**p<0.01，***p<0.001，与模型组相比
实施例6西洛他唑/依达拉奉(1:5，1:2.5，1:1)对小鼠局灶性脑缺血再灌损伤的作用
1材料和方法
1.1实验动物
C57BL/6J小鼠，雄性，SPF级，8周龄。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为模型组和西洛他唑/依达拉奉三个组合物组(分别为1:5组，西洛他唑3.33mg/kg+依达拉奉16.67mg/kg；1:2.5组，西洛他唑5.71mg/kg+依达拉奉14.29mg/kg；1:1组，西洛他唑10mg/kg+依达拉奉10mg/kg。各组合物给药总剂量均为20mg/kg。)，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型制备：采用颈内动脉线栓法制备小鼠局灶性脑缺血再灌模型。将处于麻醉状态的小鼠仰卧位固定于手术台上。颈部正中切开，钝性分离皮下组织。分离右侧颈总动脉、颈外动脉、颈内动脉。从颈外动脉插入栓线，经过颈总动脉分叉进入颈内动脉，然后徐徐插入至有轻微阻力为止(自分叉处约10mm)，阻断大脑中动脉的所有血供。右侧脑缺血60min后，轻轻拔出栓线，恢复血供进行再灌注。将小鼠放置干净饲料中，观察一般情况和呼吸直至麻醉苏醒；加食进水，常规饲养。
脑梗塞范围测定及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表6，实验结果表明，西洛他唑/依达拉奉1:5、 1:2.5和1:1组合给药均能显著减小动物脑梗塞范围(p<0.001,p<0.012,p<0.001)。
表6西洛他唑/依达拉奉组合物对脑梗范围的影响
Figure PCTCN2022073910-appb-000010
均值±标准差，**p<0.01，***p<0.001，与模型组相比
实施例7西洛他唑/依达拉奉(1:1，2.5:1，5:1)对小鼠局灶性脑缺血再灌损伤的作用
1材料和方法
1.1实验动物
C57BL/6J小鼠，雄性，SPF级，8周龄。
1.2受试药品
西洛他唑和依达拉奉同实施例1。
1.3实验方法
实验动物分为模型组和西洛他唑/依达拉奉三个组合物组(分别为1:1组，西洛他唑10mg/kg+依达拉奉10mg/kg；2.5:1组，西洛他唑14.29mg/kg+依达拉奉5.71mg/kg；5:1组，西洛他唑16.67mg/kg+依达拉奉3.33mg/kg。各组合物给药总剂量均为20mg/kg。)，共4组。制备脑缺血模型后，将动物机率均等单盲分配至各组。动物于再灌注后立即静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时处死动物，取脑，染色，拍照测定脑梗塞范围。
局灶性脑缺血再灌模型的制备同实施例6，脑梗塞范围测定及数据统计方法同实施例1。
2实验结果
对脑梗塞范围的影响见表7，实验结果表明，西洛他唑/依达拉奉1:1、2.5:1和5:1组合给药均能显著减小动物脑梗塞范围(p<0.001)。
表7西洛他唑/依达拉奉组合物对脑梗范围的影响
Figure PCTCN2022073910-appb-000011
均值±标准差，***p<0.001，与模型组相比
以上对本发明所提供的含有西洛他唑的组合物在脑血管病中的应用进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 组合物，其特征在于，包括如下组分：
    组分(I)、西洛他唑、其衍生物、其药学上可接受的盐或其前药分子；和
    组分(II)、依达拉奉、或有效成分为依达拉奉的药物。
  2. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：10～10：1。
  3. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：10～5：1。
  4. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：5～10：1。
  5. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：5～5：1。
  6. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：2.5～2.5：1。
  7. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1：1～2.5：1。
  8. 如权利要求1所述的组合物，其特征在于，所述组分(I)与所述组分(II)的重量比为1:1、5:1、2.5:1、1:2.5和/或1:5。
  9. 药物，其特征在于，包括如权利要求1至8任一项所述的组合物，以及药学上可接受的辅料。
  10. 如权利要求1至8任一项所述的组合物或如权利要求9所述的药物在制备预防和/或治疗脑血管病药物中的应用；作为优选，所述脑血管病包括缺血性脑血管病；作为优选，所述缺血性脑血管病包括缺血性脑卒中。
PCT/CN2022/073910 2021-01-29 2022-01-26 一种含有西洛他唑的组合物在脑血管病中的应用 WO2022161376A1 (zh)

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