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 PDFInfo
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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
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Classifications
-
- 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
Description
Claims (10)
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
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US18/263,191 US20240122917A1 (en) | 2021-01-29 | 2022-01-26 | Use of composition containing cilostazol in cerebrovascular diseases |
EP22745250.5A EP4285903A4 (en) | 2021-01-29 | 2022-01-26 | USE OF A COMPOSITION CONTAINING VINPOCETIN IN CEREBROVASCULAR DISEASES |
JP2023543219A JP2024503490A (ja) | 2021-01-29 | 2022-01-26 | シロスタゾールを含む組成物の脳血管疾患への応用 |
AU2022212142A AU2022212142A1 (en) | 2021-01-29 | 2022-01-26 | Use of composition containing vinpocetine in cerebrovascular diseases |
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Non-Patent Citations (7)
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IKEDA SATOSHI, HARADA KATSUHIRO, OHWATASHI AKIHIKO, KAMIKAWA YURIE: "Effects of Edaravone, a Free Radical Scavenger, on Photochemically Induced Cerebral Infarction in a Rat Hemiplegic Model", THE SCIENTIFIC WORLD JOURNAL, vol. 2013, 1 January 2013 (2013-01-01), pages 1 - 5, XP055954621, DOI: 10.1155/2013/175280 * |
KIMURA TERUO, TUCKER ADAM, SUGIMURA TOSHIHIDE, SEKI TOSHITAKA, FUKUDA SHIN, TAKEUCHI SATORU, MIYATA SHIRO, FUJITA TSUTOMU, HASHIZU: "Ultra-Early Combination Antiplatelet Therapy with Cilostazol for the Prevention of Branch Atheromatous Disease: A Multicenter Prospective Study", CEREBROVASCULAR DISEASES EXTRA, vol. 6, no. 3, 12 October 2016 (2016-10-12), pages 84 - 95, XP055954618, DOI: 10.1159/000450835 * |
OHTA YASUYUKI, TAKAMATSU KAZUHIRO, FUKUSHIMA TOMOKO, IKEGAMI SATOMI, TAKEDA IKUKO, OTA TAISEI, GOTO KATSUYA, ABE KOJI: "Efficacy of the Free Radical Scavenger, Edaravone, for Motor Palsy of Acute Lacunar Infarction", INTERNAL MEDICINE (TOKYO, 1992), THE JAPANESE SOCIETY OF INTERNAL MEDICINE, JAPAN, 1 January 2009 (2009-01-01), Japan, pages 593 - 596, XP055954617, Retrieved from the Internet <URL:https://www.jstage.jst.go.jp/article/internalmedicine/48/8/48_8_593/_pdf/-char/en> DOI: 10.2169/internalmedicine.48.1871 * |
See also references of EP4285903A4 |
WU YUN, WANG XIAO-KUN,LIANG QING-CHENG,ET AL.: "Protection of Cilostazol on Cultured Brain Microvascular Endothelial Cells Deprived of Oxygen and Glucose in Rats", ZHONGFENG YU SHENJING JIBING ZAZHI = JOURNAL OF APOPLEXY AND NERVOUS DISEASES, JILIN DAXUE BAIQIUEN DI-1 YIYUAN ZHUANHUA YIXUE YANJIUYUAN, CN, vol. 27, no. 10, 31 October 2010 (2010-10-31), CN , pages 898 - 901, XP055954623, ISSN: 1003-2754, DOI: 10.19845/j.cnki.zfysjjbzz.2010.10.009 * |
YAKUGAKU ZASSHI, vol. 124, no. 3, 2004, pages 99 - 111 |
YASUMASA YAMAMOTO; TOMOYUKI OHARA; RYOTARO ISHII; EIJIRO TANAKA; TOMOHIKO MURAI; FUKIKO MORII; AIKO TAMURA; RYO OOHARA;: "A Combined Treatment for Acute Larger Lacunar-Type Infarction", JOURNAL OF STROKE AND CEREBROVASCULAR DISEASES, DEMOS PUBLICATIONS, NEW YORK, NY, US, vol. 20, no. 5, 13 February 2010 (2010-02-13), US , pages 387 - 394, XP028284624, ISSN: 1052-3057, DOI: 10.1016/j.jstrokecerebrovasdis.2010.02.007 * |
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CN114796217A (zh) | 2022-07-29 |
US20240122917A1 (en) | 2024-04-18 |
AU2022212142A1 (en) | 2023-08-03 |
EP4285903A1 (en) | 2023-12-06 |
JP2024503490A (ja) | 2024-01-25 |
EP4285903A4 (en) | 2024-04-17 |
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