WO2017193573A1 - Composition pharmaceutique pour le traitement d'un accident ischémique cérébral, son procédé de préparation et son application - Google Patents

Composition pharmaceutique pour le traitement d'un accident ischémique cérébral, son procédé de préparation et son application Download PDF

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Publication number
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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PCT/CN2016/109005
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English (en)
Chinese (zh)
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秦正红
李梅
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重庆纳德福实业集团股份有限公司
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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

Definitions

  • 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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  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne une composition pharmaceutique pour le traitement d'un accident ischémique cérébral, son procédé de préparation et son application. La composition pharmaceutique comprend : de 3 à 12 parties en poids de NADPH, et de 0,5 à 8 parties en poids d'une acétovanillone.
PCT/CN2016/109005 2016-05-13 2016-12-08 Composition pharmaceutique pour le traitement d'un accident ischémique cérébral, son procédé de préparation et son application WO2017193573A1 (fr)

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CN201610318781.8 2016-05-13

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CN105998048A (zh) * 2016-05-13 2016-10-12 重庆纳德福实业集团股份有限公司 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

Citations (4)

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WO2007099151A1 (fr) * 2006-03-01 2007-09-07 Etren Procédé et agents permettant de réduire le stress oxydatif
CN102459291A (zh) * 2009-04-27 2012-05-16 Mcw研究基金会股份有限公司 神经保护性化合物和它们的应用
CN103340890A (zh) * 2013-06-08 2013-10-09 苏州人本药业有限公司 Nadph作为制备用于防治脑缺血性中风药物方面的应用
CN105998048A (zh) * 2016-05-13 2016-10-12 重庆纳德福实业集团股份有限公司 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

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AU2004216541A1 (en) * 2003-02-28 2004-09-10 Howard Florey Institute Of Experimental Physiology And Medicine Therapeutic compositions
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CN102459291A (zh) * 2009-04-27 2012-05-16 Mcw研究基金会股份有限公司 神经保护性化合物和它们的应用
CN103340890A (zh) * 2013-06-08 2013-10-09 苏州人本药业有限公司 Nadph作为制备用于防治脑缺血性中风药物方面的应用
CN105998048A (zh) * 2016-05-13 2016-10-12 重庆纳德福实业集团股份有限公司 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

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