WO2017193573A1 - 一种治疗缺血性脑中风的药物组合物及其制备方法与用途 - Google Patents

一种治疗缺血性脑中风的药物组合物及其制备方法与用途 Download PDF

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WO2017193573A1
WO2017193573A1 PCT/CN2016/109005 CN2016109005W WO2017193573A1 WO 2017193573 A1 WO2017193573 A1 WO 2017193573A1 CN 2016109005 W CN2016109005 W CN 2016109005W WO 2017193573 A1 WO2017193573 A1 WO 2017193573A1
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nadph
oleandrin
pharmaceutical composition
weight
mice
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秦正红
李梅
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Chongqing Nadph Industry Group Co Ltd
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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
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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
    • A61K31/12—Ketones

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  • the invention belongs to the field of medicines, and particularly relates to a pharmaceutical composition for treating ischemic stroke and a preparation method and use thereof.
  • Stroke also known as stroke or cerebrovascular accident, is a sudden onset of cerebral blood circulation disorders, one of the three major diseases that threaten human health, with high incidence and high mortality. High residual rate and high recurrence rate. Stroke refers to patients with cerebrovascular disease, caused by various predisposing factors, such as cerebral artery stenosis, occlusion or rupture, resulting in acute cerebral circulation disorder, clinical manifestations of transient or permanent brain dysfunction symptoms and Signs. Stroke is divided into ischemic stroke and hemorrhagic stroke. In recent years, the number of patients with cerebrovascular diseases in China has increased year by year, with ischemic cerebrovascular disease the most common, accounting for 20-25%. At present, China has a new stroke of 300-3.5 million strokes per year, with a high mortality rate, and about 75% of the survivors are disabled. The 5-year recurrence rate is as high as 41%.
  • Chinese patent document CN103340890A discloses the use of NADPH as a medicament for the preparation of a medicament for preventing and treating cerebral ischemic stroke.
  • NADPH oleandrin
  • the present invention proposes a pharmaceutical composition for treating ischemic stroke.
  • the invention provides a pharmaceutical composition for treating ischemic stroke, the raw material composition comprising:
  • the pharmaceutical composition for treating ischemic stroke according to the present invention has a raw material composition comprising:
  • the pharmaceutical composition for treating ischemic stroke according to the present invention has a raw material composition comprising:
  • NADPH 7.5 parts by weight, 2.5 parts by weight of oleander
  • the invention also provides a preparation method of the above pharmaceutical composition for treating ischemic stroke, comprising the following steps:
  • NADPH and oleandrin were separately mixed and uniformly mixed to prepare a mixture preparation, or two preparations were separately prepared and different administration methods were employed.
  • the present invention also provides a preparation comprising the above pharmaceutical composition for treating ischemic stroke, or a preparation comprising the pharmaceutical composition prepared by the above preparation method,
  • the pharmaceutical composition is added to a conventional auxiliary material, and is prepared into a clinically acceptable tablet, capsule, powder, mixture, pill, granule, solution, syrup, ointment, plaster, suppository, gas according to a conventional process.
  • the pharmaceutically acceptable excipients are: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, matrices, and the like.
  • Filling agents include: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.
  • disintegrating agents include: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, Cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.
  • lubricants include: magnesium stearate, sodium lauryl sulfate, talc, silica, etc.
  • suspending agent Including: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc.
  • binders include: starch syrup, polyvinylpyrroli
  • the present invention also provides the use of the above pharmaceutical composition, the pharmaceutical composition prepared by the above preparation method, or the preparation of the above pharmaceutical composition for the preparation of a medicament for treating ischemic stroke.
  • NADPH itself has a certain role in the treatment of stroke
  • NADPH may also be used by NADPH oxidase to produce oxidative free radicals to reduce the efficacy of NADPH in the treatment of stroke
  • oleandrin itself plays a role in reducing ROS production by inhibiting NADPH oxidase.
  • the role of stroke treatment but it does not inhibit the ROS that have been produced and ROS produced by other pathways (such as mitochondria and succinate dehydrogenase), so there are limitations in the treatment of stroke.
  • the invention combines NADPH and oleandrin, and the two work together in a specific ratio, and acts on different targets, both ROS can be eliminated and ROS can be inhibited.
  • the pharmaceutical composition can reduce the volume of cerebral infarction under the condition of suitable administration route for clinical application, significantly improve the behavior disorder of mice with cerebral ischemia, reduce brain edema, improve the long-term survival ability of mice and enhance the recovery of nerve function; Moreover, the therapeutic effect of the pharmaceutical composition on ischemic stroke is significantly better than the therapeutic effect of the two drugs alone on ischemic stroke, and the combined administration of NADPH and oleandrin has a synergistic effect. This indicates that the pharmaceutical composition has an effect of treating ischemic stroke and can be used as a potential drug for treating ischemic stroke.
  • Figure 1 (a), 1 (b) is the effect of NADPH combined with Apocynin lateral ventricle injection and intravenous administration on the volume of cerebral infarction in mice with ischemic stroke, where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01 , *** indicates p ⁇ 0.001, ## indicates p ⁇ 0.01, ICV indicates intracerebroventricular administration, and IV indicates intravenous administration;
  • Figure 2 (a), 2 (b) is the effect of intravenous administration of NADPH combined with Apocynin on the volume of cerebral infarction in mice with ischemic stroke, where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, *** Indicates p ⁇ 0.001, ⁇ means p ⁇ 0.05;
  • Figure 3 is the effect of intravenous administration of NADPH combined with Apocynin on neurological symptoms in mice with ischemic stroke, where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, *** indicates p ⁇ 0.001, and ⁇ indicates p ⁇ 0.05;
  • Figure 4 is the effect of intravenous administration of NADPH combined with Apocynin on cerebral edema in mice with ischemic stroke, wherein * indicates p ⁇ 0.05, *** indicates p ⁇ 0.001, ### indicates p ⁇ 0.001;
  • Figure 5 is the effect of intravenous administration of NADPH combined with Apocynin on long-term survival of mice with ischemic stroke, wherein * indicates p ⁇ 0.05, # indicates p ⁇ 0.05;
  • Figure 6 is the effect of intravenous administration of NADPH combined with Apocynin on balance exercise in mice with ischemic stroke, where * indicates p ⁇ 0.05, *** indicates p ⁇ 0.001, ### indicates p ⁇ 0.001, and ⁇ indicates p ⁇ 0.05;
  • Figure 7 is the effect of intravenous administration of NADPH combined with Apocynin on learning and memory ability in mice with ischemic stroke.
  • ** means p ⁇ 0.01
  • *** means p ⁇ 0.001
  • ### means p ⁇ 0.001
  • ⁇ Indicates p ⁇ 0.05, ⁇ represents p ⁇ 0.01;
  • Figure 8 is the effect of intravenous administration of NADPH combined with Apocynin on ROS levels in the ischemic cerebral cortex of mice with ischemic stroke. *** indicates p ⁇ 0.001, ### indicates p ⁇ 0.001, and ⁇ indicates p ⁇ 0.05;
  • Figure 9 (a), 9 (b), 9 (c), 9 (d), 9 (e), 9 (f) is the intravenous administration of NADPH combined with Apocynin for ischemic stroke in mice with cerebral cortex ischemia
  • the effect of NOX2 and NOX4 protein levels in the region where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, *** indicates p ⁇ 0.001, ## indicates p ⁇ 0.01, ### indicates p ⁇ 0.001, and ⁇ indicates p ⁇ 0.05, ⁇ ⁇ indicates p ⁇ 0.01;
  • Figure 10 (a), 10 (b), 10 (c), 10 (d), 10 (e), 10 (f), 10 (g), 10 (h), 10 (i), 10 (j) , 10(k), 10(l), 10(m), 10(n), 10(o), 10(p) is an intravenous administration of NADPH combined with Apocynin for ischemic stroke in mice with cerebral cortex ischemia
  • the effect of the region NALP3 inflammation complex pathway protein level where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, # indicates p ⁇ 0.05, ## indicates p ⁇ 0.01, ### indicates p ⁇ 0.001, and ⁇ indicates p ⁇ 0.05, ⁇ ⁇ indicates p ⁇ 0.01;
  • Apocynin is represented by: oleandrin.
  • the pharmaceutical composition for treating ischemic stroke in the present embodiment has a raw material composition of: NADPH 7.5 g, and oleandrin 2.5 g;
  • the preparation method comprises the steps of: separately taking a selected part by weight of NADPH and oleandrin, and mixing uniformly, that is, obtaining.
  • the pharmaceutical composition for treating ischemic stroke according to the present embodiment, is: NADPH 6g, oleandrin 4g;
  • the preparation method comprises the steps of: separately taking a selected part by weight of NADPH and oleandrin, and mixing uniformly, that is, obtaining.
  • the pharmaceutical composition for treating ischemic stroke in the present embodiment is: NADPH 9g, oleandrin 1g;
  • the preparation method comprises the steps of: separately taking a selected part by weight of NADPH and oleandrin, and mixing uniformly, that is, obtaining.
  • the pharmaceutical composition for treating ischemic stroke in the present embodiment is: NADPH 8g, oleandrin 2g;
  • the preparation method comprises the steps of: separately taking a selected part by weight of NADPH and oleandrin, and mixing uniformly, that is, obtaining.
  • the pharmaceutical composition for treating ischemic stroke in the present embodiment is: NADPH 1g, oleandrin 4g;
  • the preparation method comprises the steps of: separately taking a selected part by weight of NADPH and oleandrin, and mixing uniformly, that is, obtaining.
  • Apocynin is represented by: oleandrin.
  • the source of exogenous NADPH and oleandrin drugs can be obtained by artificial synthesis, semi-synthesis, and biological extraction.
  • the mouse MCAO model was prepared with a slight improvement of the internal carotid artery suture method.
  • the mice were anesthetized with 4% chloral hydrate (400 mg/kg).
  • the internal carotid artery, the ligature and the total proximal end of the neck, the line plug (6023, Doccol Corporation, Redlands, USA) was inserted from the outside of the neck until the anterior end of the cerebral artery, blocking the blood supply to the middle cerebral artery. After blocking the blood flow for 2 hours, the plug was pulled out to achieve reperfusion.
  • the sham-operated mice were the same as the ischemic group and the treatment group except that the mice were not inserted.
  • the room temperature was maintained at 22-25 °C throughout the operation, and the temperature of the mouse was controlled at 37 ⁇ 0.5 °C using an automatic temperature-controlled heating pad. After the operation, the animals were placed in a feeding box with clean litter, and they were allowed to drink water and eat freely.
  • mice After 24 hours of cerebral ischemia-reperfusion, the mice were decapitated and placed in the refrigerator (-20 ° C) for several minutes to remove the olfactory bulb, cerebellum and lower brain stem. The coronary cut 4 knives were divided into 5 slices (2 mm), and the brain slices were red.
  • tetrazolium (TTC) staining staining solution consisting of: 1.5mL1% TTC, 0.1mL1mol / LK 2 HPO 4, 3.4mL saline, 37 [deg.] C dark staining 30min, normal tissue red, white infarcted tissue.
  • the liquid infiltrated with the filter paper and then the cerebral infarcted tissue was taken out, and the percentage of the infarcted brain tissue to the total brain weight was used as an indicator of the infarct volume.
  • the percentage of cerebral infarction area was calculated using Sigma Pro 5.0 software.
  • mice After 24 hours of cerebral ischemia-reperfusion in mice, the neurobehavioral scores of the mice were scored according to the five-point scale by an observer who did not understand the grouping: 0 points: no neurological deficit symptoms; 1 point: not fully extended Side forelimb; 2 points: Rotating to the opposite side while walking, there is a phenomenon of "tail-catching"; 3 points: standing unstable, dumping to the opposite side; 4 points: unable to self-issue, consciousness disorder.
  • mice weighing 23-28 g were selected for cerebral ischemia 2h reperfusion.
  • the animal model has a long cerebral ischemia time and a high mortality rate, and pay attention to the number of animals in time.
  • Rota-rod test balancing on the rotor bar requires proprioception, positional awareness, and fine-tuning. This test requires the mouse to maintain a balance on the uniform rotating rod and record its movement time on the rotating rod and the falling time to rotate the rod. The slow acceleration in the test limits the differences in performance between individuals.
  • the required instruments and materials include: (1) Instrument: The diameter of the roller shaft is about 5cm. It is made of sturdy plastic and is covered with gray rubber foam. The tube is about 5cm wide. This instrument can be used. Accelerate from 4 rpm to 40 rpm in 300 s; (2) stopwatch; (3) 50% alcohol; (4) paper towel.
  • mice were placed in their own cages and allowed to acclimate for 15 min in the test room (adapted to the environmental phase).
  • the entire test consisted of three trials at intervals of 15 min. There is no training phase before the test phase. It can be operated directly on the next batch of mice in the same experiment.
  • the instrument was set to accelerate from 4 rpm to 40 rpm in 300 s. The instrument was operated at a constant speed of 4 rpm before starting.
  • the bottom is the power grid. Only the light at the end of one arm emits light. At this time, the current at the bottom of the arm has no current, which is the safe area; the lights of the other two arms are not. Light, the bottom grid is energized (about 50V), which is a non-safe area; the safe area and the non-safe area are randomly changed.
  • the animal was placed in any arm of the maze for 2 to 3 minutes; then the signal of any other arm was turned on as a conditional stimulus, and after 1 s delay, the two arms of the lamp were not energized (unconditioned stimulus).
  • the animal evades the electric shock to the safe area, the light is on for 15s, then the light is turned off and rested for 45s, that is, one operation is completed and the time used is recorded; then the next operation is started.
  • both the NADPH group and the oleandrin group significantly reduced the volume of cerebral infarction after 24 hours of cerebral ischemia-reperfusion in mice (p ⁇ 0.01); NADPH The combined oleandrin group further reduced the volume of cerebral infarction in mice (p ⁇ 0.001); there was a significant difference (p ⁇ 0.05) between the combination group and the drug alone group. This indicates that NADPH, oleandrin and the combination of the two can reduce the volume of cerebral infarction in mice with cerebral ischemic stroke, and the combined effect of the two drugs is better than that of the single use.
  • the NADPH group and the oleandrin group significantly reduced the brain water content after 24 hours of cerebral ischemia-reperfusion in mice (p ⁇ 0.05); the combination of the two was further reduced.
  • the brain water content of the mice p ⁇ 0.01. This indicates that NADPH, oleandrin and the combination of both can reduce brain edema in mice with cerebral ischemic stroke.
  • the combination of the two drugs is better than the single use.
  • the NADPH group, the oleandrin group, and the two-drug combination group significantly improved the survival rate after 28 days of cerebral ischemia-reperfusion in mice (p ⁇ 0.05). This indicates that NADPH, oleandrin and the combination of both can improve the survival rate of mice, and the combined effect of the two drugs is better than that of the single use.
  • the NADPH and oleandrin groups significantly enhanced the balance exercise ability of mice surviving 28 days after cerebral ischemia-reperfusion (p ⁇ 0.05), NADPH combined with oleandrin
  • the group significantly enhanced the balance exercise ability of the surviving mice at 28 days after cerebral ischemia-reperfusion (p ⁇ 0.001); there was a significant difference (p ⁇ 0.05) between the combination group and the drug alone group. This indicates that NADPH, oleandrin and the combination of both can improve the balance exercise ability of mice, and the combined effect of the two drugs is better than that of the single use.
  • the NADPH and oleandrin groups significantly enhanced the learning and memory ability of the surviving mice 28 days after cerebral ischemia-reperfusion (p ⁇ 0.01), NADPH combined with oleandrin
  • the group significantly improved the learning and memory ability of the surviving mice 28 days after cerebral ischemia-reperfusion (p ⁇ 0.001); there was a significant difference (p ⁇ 0.05) between the combination group and the single-drug group. This indicates that NADPH combined with oleandrin can improve the learning and memory ability of mice more effectively.
  • Activation oxygen fluorescence assay kit detection that is, observation under a fluorescence microscope (qualitative detection): excitation wavelength 490nm, emission wavelength 530nm, enhanced fluorescence, indicating high reactive oxygen species (ROS) content.
  • the model group significantly increased ROS levels after 3 hours of cerebral ischemia-reperfusion (p ⁇ 0.001); after applying NADPH, oleandrin, and Model group
  • the levels of ROS in the cerebral cortex of mice with ischemic stroke were significantly inhibited (p ⁇ 0.001).
  • the combination of NADPH and oleandrin significantly inhibited the brain of ischemic stroke mice.
  • Cortical ROS levels increased (p ⁇ 0.001).
  • the combined effect of the two drugs is better than the single use.
  • the NC film was placed in TBS containing 5% skim milk powder for 2 h at room temperature;
  • the sham operation group has lower NLRP3 protein expression, while the I/R group lacks mice.
  • Blood side brain tissue The protein levels of NLRP3, ASC, precursor caspase-1, and il-1b, il-18 were significantly increased at 8h and 16h. The above results indicate that ischemia-induced inflammatory body protein, IL-1 increase, and IL-18 inflammatory factor expression are increased.
  • NADPH, oleandrin, and combination administration NADPH, oleandrin, and combination administration reduced NLRP3, ASC, and precursor caspase-1 cleavage of caspase-1 to varying degrees compared with the model group.
  • the combination of the two drugs is superior to the single use.
  • the present invention combines NADPH and oleandrin in a specific ratio, and the pharmaceutical composition can reduce the volume of cerebral infarction and significantly improve the behavioral disorder and alleviate the behavioral disorder in mice with cerebral ischemia. Cerebral edema, improve the ability of mice to survive for a long time and enhance the recovery of neurological function; Moreover, the therapeutic effect of the pharmaceutical composition on ischemic stroke is significantly better than that of the two drugs alone for ischemic stroke, NADPH The combined administration with oleandrin has a synergistic effect. This indicates that the pharmaceutical composition has an effect of treating ischemic stroke and can be used as a potential drug for treating ischemic stroke.

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Abstract

一种治疗缺血性脑中风的药物组合物、制备方法及其用途，其原料组成包括：NADPH 3-12重量份、夹竹桃麻素0.5-8重量份。

Description

一种治疗缺血性脑中风的药物组合物及其制备方法与用途 技术领域
本发明属于药物领域，具体涉及一种治疗缺血性脑中风的药物组合物及其制备方法与用途。
背景技术
脑卒中(Stroke)，又称脑中风或脑血管意外，是一种突然起病的脑血液循环障碍性疾病，是威胁人类健康的三大疾病之一，具有发病率高、死亡率高、致残率高、复发率高的特点。脑卒中是指在脑血管疾病的病人，因各种诱发因素引起脑内动脉狭窄，闭塞或破裂，而造成急性脑血液循环障碍，临床上表现为一过性或永久性脑功能障碍的症状和体征。脑卒中分为缺血性脑卒中和出血性脑卒中。近年来，我国的脑血管疾病患者逐年上升，以缺血性脑血管病最多见，约占20-25％。目前，我国每年新发脑中风300-350万人，死亡率高，存活者中约75％致残，5年复发率高达41％。
目前，我国已进入老年化社会，脑中风的发病率将有进一步增加的趋势。因此，研究脑中风尤其是缺血性脑中风的病理机制及治疗防护一直是医药界的重要任务。理论上，针对急性缺血或缺血再灌后细胞损伤的药物(神经保护剂)可保护脑细胞，提高对缺血缺氧损伤的耐受性，从目前的研究结果看，大多数在动物实验中具有疗效的药物，在临床试验中往往以失败告终。
中国专利文献CN103340890A公开了NADPH作为制备用于防治脑缺血性中风药物方面的应用。然而，未见NADPH和夹竹桃麻素联合应用治疗脑缺血性中风的报道。
因此，研究新型的治疗脑缺血性疾病的药物具有重要意义。
发明内容
为此，本发明提出一种治疗缺血性脑中风的药物组合物。
为解决上述技术问题，本发明是通过以下技术方案来实现的：
本发明提供一种治疗缺血性脑中风的药物组合物，其原料组成包括：
NADPH 3～12重量份，夹竹桃麻素0.5～8重量份。
优选地，本发明上述治疗缺血性脑中风的药物组合物，其原料组成包括：
NADPH 6～9重量份，夹竹桃麻素1～4重量份。
进一步优选地，本发明上述治疗缺血性脑中风的药物组合物，其原料组成包括：
NADPH 7.5重量份，夹竹桃麻素2.5重量份；或者
NADPH 6重量份，夹竹桃麻素4重量份；或者
NADPH 9重量份，夹竹桃麻素1重量份；或者
NADPH 8重量份，夹竹桃麻素2重量份。
本发明还提供一种上述治疗缺血性脑中风的药物组合物的制备方法，包括以下步骤：
分别取选定重量份的NADPH和夹竹桃麻素，混合均匀制成混合制剂，或分别制成2种制剂和采用不同的给药方式。
本发明还提供包括上述治疗缺血性脑中风的药物组合物的制剂、或者包括上述制备方法制备得到的药物组合物的制剂，
所述药物组合物加入常规辅料，按照常规工艺，制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、溶液剂、糖浆剂、煎膏剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
所述药学上可接受的辅料为：填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素纳等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000、PEG4000、虫蜡等。
本发明还提供上述药物组合物、上述制备方法制备得到的药物组合物、或上述药物组合物的制剂在制备治疗缺血性脑中风的药物中的应用。
本发明的上述技术方案相比现有技术具有以下优点：
NADPH本身虽有一定的治疗脑卒中的作用，但是NADPH也可能被NADPH氧化酶利用产生氧化自由基而降低NADPH治疗脑卒中的疗效；夹竹桃麻素本身通过抑制NADPH氧化酶降低ROS产生而发挥治疗脑卒中的作用，但是它对已经产生的ROS以及由其它途径产生的ROS(如线粒体和琥珀酸脱氢酶)没有抑制作用，因此治疗脑卒中时也有局限性。
本发明通过将NADPH和夹竹桃麻素联合给药，二者在特定的配比下共同作用，且作用于不同的靶点，既能清除ROS又能抑制ROS的产生。该药物组合物在采用适合于临床应用的给药途径条件下，能降低脑梗死体积，显著改善脑缺血小鼠行为障碍，减轻脑水肿，提高小鼠长期生存的能力和增强神经功能康复；而且，该药物组合物对缺血性脑中风的治疗效果显著优于二者单独给药对缺血性脑中风的治疗效果，NADPH和夹竹桃麻素联合给药具有协同增效的作用。这表明，该药物组合物具有治疗缺血性脑中风的作用，可以作为潜在的治疗缺血性脑中风的药物。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中：
图1(a)、1(b)是NADPH联合Apocynin侧脑室注射和静脉注射给药对缺血性脑中风小鼠脑梗死体积的影响，其中，*表示p<0.05，**表示p<0.01，***表示p<0.001，##表示p<0.01，I.C.V表示侧脑室注射给药，I.V表示静脉注射给药；
图2(a)、2(b)是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠脑梗死体积的影响，其中，*表示p<0.05，**表示p<0.01，***表示p<0.001，△表示p<0.05；
图3是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠神经症状的影响，其中，*表示p<0.05，**表示p<0.01，***表示p<0.001，△表示p<0.05；
图4是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠脑水肿的影响，其中，*表示p<0.05，***表示p<0.001，###表示p<0.001；
图5是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠长期存活的影响，其中，*表示p<0.05，#表示p<0.05；
图6是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠平衡运动的影响，其中，*表示p<0.05，***表示p<0.001，###表示p<0.001，△表示p<0.05；
图7是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠学习记忆能力的影响，其中，**表示p<0.01，***表示p<0.001，###表示p<0.001，△表示p<0.05，△△表示p<0.01；
图8是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区ROS水平的影响，其中，***表示p<0.001，###表示p<0.001，△表示p<0.05；
图9(a)、9(b)、9(c)、9(d)、9(e)、9(f)是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区NOX2、NOX4蛋白水平的影响，其中，*表示p<0.05，**表示p<0.01，***表示p<0.001，##表示p<0.01，###表示p<0.001，△表示p<0.05，△△表示p<0.01；
图10(a)、10(b)、10(c)、10(d)、10(e)、10(f)、10(g)、10(h)、10(i)、10(j)、10(k)、10(l)、10(m)、10(n)、10(o)、10(p)是NADPH联合Apocynin静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区NALP3炎症复合体通路蛋白水平的影响，其中，*表示p<0.05，**表示p<0.01，#表示p<0.05，##表示p<0.01，###表示p<0.001，△表示p<0.05，△△表示p<0.01；
图1-图10中，Apocynin表示的为：夹竹桃麻素。
具体实施方式
实施例1
本实施例治疗缺血性脑中风的药物组合物，其原料组成为：NADPH7.5g，夹竹桃麻素2.5g；
其制备方法，包括以下步骤：分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
实施例2
本实施例治疗缺血性脑中风的药物组合物，其原料组成为：NADPH 6g，夹竹桃麻素4g；
其制备方法，包括以下步骤：分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
实施例3
本实施例治疗缺血性脑中风的药物组合物，其原料组成为：NADPH 9g，夹竹桃麻素1g；
其制备方法，包括以下步骤：分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
实施例4
本实施例治疗缺血性脑中风的药物组合物，其原料组成为：NADPH 8g，夹竹桃麻素2g；
其制备方法，包括以下步骤：分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
对比例1
本实施例治疗缺血性脑中风的药物组合物，其原料组成为：NADPH 1g，夹竹桃麻素4g；
其制备方法，包括以下步骤：分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
实验例
下述各实验例证明本发明所述的技术效果。
本发明以下实验例中，Apocynin表示的为：夹竹桃麻素。
实验例1NADPH联合夹竹桃麻素对小鼠脑缺血再灌注损伤的保护作用
(1)实验材料
清洁级雄性ICR小鼠，质量23～28g，苏州大学实验动物中心提供，实验动物生产许可证号：XCYK(苏)2002-2008，实验动物使用许可证号：SYXK(苏)2002-0037。
室温22℃，湿度50-60％，通风良好，人工昼夜(12h/12h)，自由摄食摄水。实验前，将雄小鼠在饲养环境中适应2d。
分6组：假手术组、模型组、NADPH组(7.5mg/kg)、夹竹桃麻素组(2.5mg/kg)、NADPH+夹竹桃麻素组(7.5mg+2.5mg/kg)，NADPH+夹竹桃麻素组(1mg+4mg/kg)。
外源性NADPH和夹竹桃麻素药物的来源可以通过人工合成、半合成、生物提取获得。
(2)实验方案
1)小鼠短暂性大脑中动脉阻塞模型建立
采用颈内动脉线栓法，稍加改进制备小鼠MCAO模型，小鼠以4％水合氯醛(400mg/kg)腹腔注射麻醉，我们采用线栓法制备缺血模型，分离颈总、颈外和颈内动脉，结扎劲外和颈总近心端，线栓(6023，Doccol Corporation,Redlands，USA)从颈外插入直到大脑前动脉起始端，阻断大脑中动脉供血。阻断血流2h后，拔出线栓实现再灌注。假手术组小鼠除不插线外，其余步骤均与缺血组和治疗组相同。整个手术过程中室温保持在22～25℃，采用自动控温加热垫将小鼠肛温控制在37±0.5℃。术后将动物置于放有清洁垫料的饲养盒中，自由饮水、进食。
2)脑梗死体积测定
脑缺血再灌注24h后将小鼠断头取脑，置冰箱(-20℃)数分钟，去掉嗅球、小脑和低位脑干，冠状切4刀分为5片(2mm)，脑片用红四氮唑(TTC)染色，染色液组成为：1.5mL1％TTC，0.1mL1mol/L K2HPO4，3.4mL生理盐水，37℃避光染色30min，正常组织呈红色，梗死组织为白色。
4％甲醛固定两天后，用滤纸吸干液体再取出脑梗死组织，以梗死脑组织重量占总大脑重量的百分比作为脑梗死体积的指标。用Sigma Pro5.0软件计算脑梗塞面积所占百分比。
3)神经症状评分
小鼠脑缺血再灌注24h后，由一不了解分组情况的观察者按照五分制评分标准对小鼠进行神经行为障碍评分：0分：无神经功能缺损症状；1分：不能完全伸展对侧前肢；2分：行走时向对侧旋转，出现“追尾”现象；3分：站立不稳，向对侧倾倒；4分：不能自发行走，意识障碍。
4)大脑含水量测定
脑缺血再灌注24h后将小鼠断头取脑，去掉嗅球、小脑和低位脑干，称取大脑湿重，107℃烘烤48h后称干重，大脑含水量百分比＝(湿重-干重)/湿重×100％。
5)神经功能测试
I、动物模型的制作
选取体重在23-28g的雄性ICR小鼠，作脑缺血2h再灌注手术。该动物模型脑缺血时间长，死亡率高，注意及时补足动物数。
II、运动功能试验
转子杆测试(Rota-rod test)在转子杆上保持平衡需要本体觉、位置觉及微调运动能力。该测试要求小鼠在匀速旋转杆上保持平衡，并记录其在转棒上的运动时间及跌落时间得转棒旋转速度。测试中缓慢的加速限制了个体间表现的差异性。
所需仪器与材料包括：(1)仪器：滚轮轴心的直径为5cm左右，由坚固的塑料制作而成，外面包裹灰色的橡胶泡沫，管宽约5cm，这个仪器可以 在300s内从4转/min加速到40转/min；(2)秒表；(3)50％酒精；(4)纸巾。
在测验的时候，把小鼠放在他们自己的笼子里，让它们在测试房间内适应15min(适应环境阶段)。整个测试是由间隔15min的三次试验组成。在测验阶段前没有训练阶段。它可以在同一次试验时直接对下一批小鼠进行操作。仪器设定为在300s内从4转/min加速到40转/min。仪器在开始前以4转/min的恒速运转。
III、学习记忆的行为学试验—习迷宫实验(Y-maze test)
Y型电迷宫3条臂的尽头均有l灯，底部是电网，其中只有1条臂尽头的灯发出亮光，此时该臂底部电网无电流通过，即为安全区；另两臂的灯不亮，底部电网通电(约50V)，为非安全区；安全区与非安全区随机改变。
实验开始时，将动物放入迷宫中任一臂中适应2～3min；然后将其他任一臂的信号灯打开作为条件刺激，经l s延迟后，灯不亮的两臂通电(非条件刺激)；当动物逃避电击至安全区后，灯亮持续15s，然后熄灯休息45s，即完成1次操作并记录所用时间；然后再开始下一次操作。
6)数据统计与分析
数据均以均数±SD(Mean±SD)表示，统计分析采用单因素方差分析(one-way ANOVA)，p<0.05为统计学差异有显著性。
(4)实验结果NADPH联合夹竹桃麻素侧脑室注射和静脉注射给药对缺血性脑中风小鼠脑梗死体积的影响如图1(a)、1(b)所示。
由图1(a)、1(b)可知，与模型组相比，侧脑室注射NADPH(1mg/kg)联合夹竹桃麻素(4mg/kg)用药组显著降低了小鼠脑缺血再灌注24h后脑梗死体积(p<0.05)；和静脉注射NADPH(1mg/kg)联合夹竹桃麻素(4mg/kg)NADPH联合夹竹桃麻素用药组都明显著降低了小鼠脑缺血再灌注24h后脑梗死体积(p<0.05，p<0.01)；静脉注射NADPH(7.5mg/kg)联合 夹竹桃麻素(2.5mg/kg)用药组也显著降低了小鼠脑缺血再灌注24h后脑梗死体积(p<0.001)。但是相互比较三组的结果可以发现，静脉注射NADPH(1mg/kg)联合夹竹桃麻素(4mg/kg)产生的效果比脑室注射的差，差异有显著性(p<0.05)；静脉注射NADPH(7.5mg/kg)联合夹竹桃麻素(2.5mg/kg)产生的效果比静脉注射NADPH(1mg/kg)联合夹竹桃麻素(4mg/kg)产生的效果好，差异有显著性(p<0.01)。因此，单独静脉注射NADPH(1mg/kg)没有显著降低脑梗死体积的作用，单独静脉注射夹竹桃麻素(2.5mg/kg)只有轻微的治疗效果，所以静脉注射NADPH(7.5mg/kg)联合夹竹桃麻素(2.5mg/kg)效果更有临床应用价值。
夹竹桃麻素夹竹桃麻素夹竹桃麻素NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠脑梗死体积的影响如图2(a)、2(b)所示。
由图2(a)、2(b)可知，与模型组相比，NADPH组和夹竹桃麻素组都明显降低了小鼠脑缺血再灌注24h后脑梗死体积(p<0.01)；NADPH联合夹竹桃麻素组进一步降低小鼠脑梗死体积(p<0.001)；与单独用药组相比，联合用药组有显著性差异(p<0.05)。这表明，NADPH、夹竹桃麻素以及两者联合用药均可降低脑缺血性中风小鼠脑梗死体积，两药合用的效果优于单独使用。
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠神经症状的影响如图3所示。
由图3可知，与模型组相比，NADPH组和夹竹桃麻素组明显降低小鼠脑缺血再灌注24h后神经症状评(p<0.05)；两者联合应用则进一步降低了小鼠神经症状评分(p<0.01)；与单独用药组相比，联合用药组有显著性差异(p<0.05)。这表明，NADPH、夹竹桃麻素以及两者联合应用均可改善脑缺血性中风小鼠的神经症状，两药合用的效果优于单独使用。
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠脑水肿的影响如图4所示。
由图4可知，与模型组相比，NADPH组和夹竹桃麻素组明显降低了小鼠脑缺血再灌注24h后的大脑含水量(p<0.05)；两者联合应用则进一步降低了小鼠的大脑含水量(p<0.01)。这表明，NADPH,夹竹桃麻素以及两者联合应用均可降低脑缺血性中风小鼠的脑水肿，两药合用的效果优于单独使用。
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠长期生存的影响如图5所示。
由图5可知，与模型组相比，NADPH组和夹竹桃麻素组以及两药合用组明显提高了小鼠脑缺血再灌注后28天存活率(p<0.05)。这表明，NADPH、夹竹桃麻素以及两者联合应用均可提高小鼠生存率，两药合用的效果优于单独使用。
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠平衡运动的影响如图6所示。
由图6可知，与模型组相比，NADPH、夹竹桃麻素组明显增强了脑缺血再灌注后28天存活小鼠的平衡运动能力(p<0.05)，NADPH联合夹竹桃麻素组更显著增强了脑缺血再灌注后28天存活小鼠的平衡运动能力(p<0.001)；与单独用药组相比，联合用药组有显著性差异(p<0.05)。这表明，NADPH、夹竹桃麻素以及两者合用均可提高小鼠平衡运动能力，两药合用的效果优于单独使用。
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠学习记忆能力的影响如图7所示。
由图7可知，与模型组相比，NADPH，夹竹桃麻素组明显增强了脑缺血再灌注后28天存活小鼠的学习记忆能力(p<0.01)，NADPH联合夹竹桃麻素组更显著提高了脑缺血再灌注后28天存活小鼠的学习记忆能力(p<0.001)；与单独用药组相比，联合用药组有显著性差异(p<0.05)。这表明，NADPH联合夹竹桃麻素可更有效地提高小鼠学习记忆能力。
实验例2NADPH联合夹竹桃麻素对缺血性脑中风小鼠大脑皮层缺血区ROS水平的影响
(1)实验材料
同实验例1。
(2)实验方案
1)小鼠短暂性大脑中动脉阻塞模型建立
同实验例1。
2)ROS的测定
小鼠缺血再灌后3h，深度麻醉后断头取脑，去掉嗅球、小脑和低位脑干，冰冻切片机切片，厚10μm贴片于明胶处理过的载玻片上，然后用冰冻切片氧化应激活性氧荧光测定试剂盒检测，即在荧光显微镜下观察(定性检测)：激发波长490nm，散发波长530nm，荧光增强，表明活性氧族(ROS)含量高。
(3)实验结果
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区ROS水平的影响如图8所示。
由图8可知，与假手术(sham)组相比，Model组小鼠脑缺血再灌注3h后显著提高了ROS水平(p<0.001)；应用NADPH，夹竹桃麻素后，与Model组相比，均明显地抑制了缺血性脑中风小鼠大脑皮层ROS水平的升高(p<0.001)，联合应用NADPH和夹竹桃麻素更显著地抑制了缺血性脑中风小鼠大脑皮层ROS水平的升高(p<0.001)。结果提示NADPH，夹竹桃麻素,以及两者联合用药，均可降低缺血性脑中风小鼠大脑皮层缺血区ROS水平，两药合用的效果优于单独使用。
实验例3NADPH联合夹竹桃麻素对缺血性脑中风小鼠大脑皮层缺血区NOX水平的影响
(1)实验材料
同实验例1。
(2)实验方案
1)小鼠短暂性大脑中动脉阻塞模型建立
同实验例1。
2)Western blot方法
a.配制12％SDS-PAGE，上样，电压积层胶90V、分离胶110V，电泳；
b.电泳结束后采用湿转法将样品转移至NC膜，10％的胶恒流0.5A，1.5h；14％的胶恒流0.3A，45min；
c.转膜结束后，将NC膜放入含有5％脱脂奶粉的TBS中室温下封闭2h；
d.加入含有5％脱脂奶粉和0.1％叠氮钠的TBS配置的一抗，4℃过夜。e.TBS-T漂洗15min×3次，TBS漂洗15min×1次；
f.加入用含有5％脱脂奶粉TBS配置的二抗，室温2h；
g.TBS-T漂洗15min×3次，TBS漂洗15min×1次，将膜置于ECL显色液中(临用前A、B液等体积混匀)，室温1min，压片、曝光、显影。
(3)实验结果
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区NOX2、NOX4蛋白水平的影响如图9(a)、9(b)、9(c)、9(d)、9(e)、9(f)所示。
由图9(a)、9(b)、9(c)、9(d)、9(e)、9(f)可知，假手术组NOX2和NOX4的表达较低，而缺血再灌注8h、16h,NOX2蛋白表达明显升高(p<0.01)，而NOX4蛋白表达是在16h显著升高(p<0.001)。给予NADPH、夹竹桃麻素,以及联合给药，与Model组相比，NADPH，夹竹桃麻素及联合给药都不同程度的抑制了NOX2和NOX4的表达。这表明，NADPH，夹竹桃麻素,以及两者联合用药，均可抑制NOX2和NOX4的表达上调，两药合用的效果优于单独使用。
实验例4NADPH联合夹竹桃麻素对缺血性脑中风小鼠大脑皮层缺血区NALP3炎症复合体相关组件及炎症因子蛋白水平的影响
(1)实验材料
同实验例1。
(2)实验方案
1)小鼠短暂性大脑中动脉阻塞模型建立
同实验例1。
2)Western blot方法
同实验例2。
(3)实验结果
NADPH联合夹竹桃麻素静脉注射给药对缺血性脑中风小鼠大脑皮层缺血区NALP3炎症复合体通路蛋白水平的影响如图10(a)、10(b)、10(c)、10(d)、10(e)、10(f)、10(g)、10(h)、10(i)、10(j)、10(k)、10(l)、10(m)、10(n)、10(o)、10(p)所示。
由图10(a)、10(b)、10(c)、10(d)、10(e)、10(f)、10(g)、10(h)、10(i)、10(j)、10(k)、10(l)、10(m)、10(n)、10(o)、10(p)可知，假手术组NLRP3蛋白表达较低，而I/R组小鼠缺血侧脑组织中 NLRP3、ASC、前体caspase-1，和il-1b、il-18的蛋白水平在8h和16h都有显著增加。以上结果说明，缺血诱发炎症小体蛋白、IL-1增、IL-18炎症因子的表达增加。给予NADPH，夹竹桃麻素，以及联合给药，与model组相比，NADPH、夹竹桃麻素以及联合给药不同程度的降低了NLRP3、ASC、前体caspase-1裂解caspase-1和il-1b、il-18的蛋白水平。这表明，NADPH，夹竹桃麻素,以及联合给药均能抑制NLRP3炎症复合物通路的激活及炎症因子的产生，两药合用的效果优于单独使用。
综上，本发明通过将NADPH和夹竹桃麻素联合给药，二者在特定的配比下共同作用，该药物组合物能降低脑梗死体积，显著改善脑缺血小鼠行为障碍，减轻脑水肿，提高小鼠长期生存的能力和增强神经功能康复；而且，该药物组合物对缺血性脑中风的治疗效果显著优于二者单独给药对缺血性脑中风的治疗效果，NADPH和夹竹桃麻素联合给药具有协同增效的作用。这表明，该药物组合物具有治疗缺血性脑中风的作用，可以作为潜在的治疗缺血性脑中风的药物。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (6)

  1. 一种药物组合物，其特征在于，其原料组成包括：
    NADPH3～12重量份，夹竹桃麻素0.5～8重量份。
  2. 根据权利要求1所述的药物组合物，其特征在于，其原料组成包括：
    NADPH6～9重量份，夹竹桃麻素1～4重量份。
  3. 根据权利要求2所述的药物组合物，其特征在于，其原料组成包括：
    NADPH7.5重量份，夹竹桃麻素2.5重量份；或者
    NADPH6重量份，夹竹桃麻素4重量份；或者
    NADPH9重量份，夹竹桃麻素1重量份；或者
    NADPH8重量份，夹竹桃麻素2重量份。
  4. 一种权利要求1-3任一项所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    分别取选定重量份的NADPH和夹竹桃麻素，混合均匀，即得。
  5. 包括权利要求1-3任一项所述的药物组合物的制剂、或者包括权利要求4所述的制备方法制备得到的药物组合物的制剂，其特征在于，
    所述药物组合物加入常规辅料，按照常规工艺，制成临床上可接受的片剂、胶囊剂、散剂、合剂、丸剂、颗粒剂、溶液剂、糖浆剂、煎膏剂、贴膏剂、栓剂、气雾剂、软膏剂或注射剂。
  6. 权利要求1-3任一项所述的药物组合物、权利要求4所述的制备方法制备得到的药物组合物、或权利要求5所述的药物组合物的制剂在制备治疗缺血性脑中风的药物中的应用。
PCT/CN2016/109005 2016-05-13 2016-12-08 一种治疗缺血性脑中风的药物组合物及其制备方法与用途 Ceased WO2017193573A1 (zh)

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