WO2018090358A1 - 匹诺塞林在制备抗脑出血药物中的应用 - Google Patents

匹诺塞林在制备抗脑出血药物中的应用 Download PDF

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WO2018090358A1
WO2018090358A1 PCT/CN2016/106556 CN2016106556W WO2018090358A1 WO 2018090358 A1 WO2018090358 A1 WO 2018090358A1 CN 2016106556 W CN2016106556 W CN 2016106556W WO 2018090358 A1 WO2018090358 A1 WO 2018090358A1
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hemorrhage
cerebral
use according
caused
thrombolytic
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PCT/CN2016/106556
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English (en)
French (fr)
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杜冠华
马寅仲
宋俊科
李莉
牛子冉
吴松
吕扬
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中国医学科学院药物研究所
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

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  • the invention relates to a novel application of pinoserine compound in the preparation of medicine, mainly relates to the application of pinocelin in the preparation of hemorrhagic stroke and the side effects of cerebral hemorrhage caused by thrombolytic drugs, in particular to the preparation of pinocerin Hemorrhagic transformation after cerebral embolism and application of cerebrovascular accident drugs caused by thrombolytic drugs.
  • Cerebral embolism refers to cerebral vascular obstruction of blood vessels due to various factors such as various emboli in the blood (such as wall thrombus in the heart, atherosclerotic plaque, etc.) with blood flow into the cerebral artery or due to embolization of the blood vessel. It causes avascular necrosis of the brain tissue in the blood supply area of the artery, and then a focal nerve defect occurs.
  • various emboli in the blood such as wall thrombus in the heart, atherosclerotic plaque, etc.
  • thrombolytic therapy has become a key link in the clinical treatment of acute stroke.
  • drugs approved for clinical application are very limited.
  • the US FDA approved the use of recombinant tissue plasminogen activator (t-PA) for thrombolytic therapy in acute cerebral infarction in 1996. So far, t-PA has been dissolved. Suppository therapy is still the only internationally recognized drug treatment.
  • Thrombolytic therapy is a major breakthrough in the treatment of acute cerebral ischemia, effectively reducing the incidence of morbidity and saving the lives of patients with acute cerebral ischemia.
  • tPA treatment clinically, it is easy to show strong side effects, namely hemorrhagic transformation (HT).
  • HT hemorrhagic transformation
  • Clinical studies have found that the incidence of spontaneous HT caused by embolic migration after acute cerebral infarction is 24% to 71%. After tPA or streptokinase thrombolysis, the probability will increase by 2-3 times. The occurrence of HT will directly endanger the life of the patient.
  • finding drugs that reduce cerebral hemorrhage by reducing reperfusion injury to blood vessels is a drug development direction for relieving cerebrovascular accidents, improving the prognosis of stroke patients, and treating ischemic stroke and hemorrhagic stroke.
  • Pinoserine is a natural product of flavonoids derived from propolis. It is based on the theory of multi-target network and neurovascular unit integration function, and is based on high-throughput screening technology in tens of thousands. The active compound screened out of the compounds.
  • the National Drug Screening Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences uses high-throughput screening technology to screen pinocrine in tens of thousands of compounds.
  • the chemical structure is as follows:
  • Pinoserine is currently undergoing Phase II clinical trials for the treatment of ischemic stroke as an indication.
  • Preclinical studies have shown that pinoserine promotes cerebral ischemia, transient cerebral ischemia, and lack of major targets such as phosphorylation of cyclic adenosine response element binding proteins, AGER receptors, and vascular endothelial cells.
  • Blood reperfusion, chronic cerebral ischemia, acute global brain ischemia, whole brain diffuse cerebral ischemia and other animal models of cerebral ischemia have shown good anti-cerebral ischemia.
  • it can improve the blood perfusion of the ischemic brain area and improve the behavioral symptoms and learning and memory ability, and exert comprehensive brain protection on the neurovascular unit and various components after acute cerebral ischemia.
  • pinocelin in the preparation of anti-cerebral hemorrhage drugs has not been reported so far.
  • the technical problem solved by the invention is to provide the application of pinoserine in the preparation of anti-cerebral hemorrhage drugs, in particular for the preparation of hemorrhagic transformation after the onset of cerebral embolism and brain microvascular hemorrhage caused by factors such as thrombolytic drugs, thereby Thrombolytic therapy for cerebral embolism provides a solution to reduce the risk of HT, improve patient survival and improve prognosis.
  • the invention provides the use of pinocelin in the preparation of anti-cerebral hemorrhage drugs.
  • the pinocrine and the pharmaceutically acceptable carrier are prepared into anti-cerebral hemorrhage drugs of various dosage forms according to a conventional preparation method
  • the pinocrine and the pharmaceutically acceptable carrier are prepared into an injection type anti-cerebral hemorrhage drug according to a conventional preparation method, and used in combination with a thrombolytic drug.
  • the invention therefore also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the compound of the present invention is usually contained in the pharmaceutical composition in an amount of from 0.1 to 95% by weight.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low-
  • the tablet may further be formed into a coated tablet, such as a sugar coated tablet, a film coated tablet, Enteric coated tablets, or double-layered tablets and multilayer tablets.
  • a coated tablet such as a sugar coated tablet, a film coated tablet, Enteric coated tablets, or double-layered tablets and multilayer tablets.
  • the active ingredient compound of the present invention may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrants, glidants of the formulations used to prepare the tablets of the present invention are also useful in the preparation of capsules of the compounds of the invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added.
  • the solubilizing agent or co-solvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulating agent may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 250 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the beneficial effects of the invention are: using an intravascular thrombus acute stroke model in rats, anti-cerebral hemorrhage of pinoserine, especially preventing hemorrhagic transformation after cerebral embolism and brain micro-vessels caused by factors such as thrombolytic drugs Hemorrhagic effects were examined and the results showed that, in combination with tPA, pinocelin significantly reduced vascular injury during tPA thrombolysis in a rat model of acute stroke in rats, reducing Evans blue and hemoglobin The amount of exudation in ischemic brain tissue.
  • the effective time window is narrow, generally 3-4.5 hours.
  • the reason why the time window is narrow is not the decrease of thrombolytic activity of the drug, but the prolongation of embolization time. It is related to the tendency of hemorrhage in the ischemic area.
  • the use of pinocelin can treat bleeding tendency and may prolong the effective treatment time window of thrombolytic drugs.
  • Figure 3 Effect of pinoserine (10 mg/kg) on mortality within 48 h after tPA thrombolytic therapy in rats with intravascular thromboembolic acute stroke model.
  • Example 1 Pinostatin injection was prepared as follows. (1) crushing the raw material of pinoserine, passing through 100 mesh sieve, and standby; (2) weighing the prescribed amount of hydroxypropyl- ⁇ -cyclodextrin, adding 700 ml of water for injection and stirring; (3) adding 0.5% ( g/ml) activated carbon for injection, kept slightly boiled for 30 minutes, filtered and decarbonized; (4) weighed the prescribed amount of pinocelin and added to the above aqueous solution of hydroxypropyl- ⁇ -cyclodextrin at room temperature; ) slowly add 10% aqueous sodium hydroxide solution under stirring, adjust and keep the pH value of the solution between 8.4 and 8.5, stir for about 4 hours, until all the pinoserine is dissolved; (6) add water for injection to 1000 ml, Stir well; (7) Add 0.05% (g/ml) activated carbon for injection, stir at room temperature for 30 minutes, and filter; (8) sterilize and filter with 0.45 ⁇ m and 0.22 ⁇ m micropor
  • Example 2 Pinoline inhibited exudation of Evans blue dye in brain tissue during tPA thrombolysis in a rat model of intravascular thromboembolism.
  • mice Sprague Dawley (SD) rats were purchased from Vitallihua (Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.).
  • tPA was purchased from Boehringer-Ingelheim, Germany.
  • Pinoserine injection (10mg) was provided by Wu Song's group of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • 1 mL of physiological saline for injection was added, and the dose was 10 mg/kg.
  • the injection was stored in the refrigerator at -20 ° C in the dark.
  • SD rats weighing 250-300 g were anesthetized by intraperitoneal injection of chloral hydrate (350 mg/kg). Shave the hair near the front and back, cut the top of the skin and expose the front palate. 2mm after the anterior iliac crest and 5mm on the right side were used as the cerebral blood flow measurement points to locate and fix the laser Doppler blood flow probe base. The supine position was fixed on the mouse plate, and the blood flow reference value was recorded within 5 minutes after the PU reading was stabilized.
  • the neck skin of the rat was incised, the common carotid artery and the external carotid artery were separated, and the external carotid artery was clamped using an arterial clip.
  • the common carotid artery was placed in the groove of the vascular electrical stimulation clip of the YLS-14B small animal thromb apparatus, and the current intensity was 1.00 mA, and the stimulation time was 225 s for electric shock. After the shock was completed, the distal common carotid artery was clamped with an arterial clip. Use a soft head to crush the thrombus from the distal end to the proximal end.
  • the rats were placed in a 37 ° C thermostat system for 6 h, and then the drug was injected into the external jugular vein for 2 min each time.
  • the combination group was injected with pinocelin 5 min before the bolus of tPA.
  • RESULTS Rats were injected with 4% Evans blue 100 ⁇ l before tPA. After 1 h, the rats were perfused with normal saline containing heparin (0.16 mg/ml). The brain tissue homogenate was taken and the absorbance at 620 nm was measured. . The results are shown in Figure 1. In the tPA group, whether in the ischemic side or the non-ischemic side, the absorbance of the rat brain homogenate at 620 nm was significantly higher than that of the model group.
  • the absorbance of the bilateral brain homogenate at 620 nm was significantly lower than that of the tPA group, regardless of whether or not the tPA bolus was injected, suggesting that pinoclinin can significantly reduce Evans blue. Leakage in brain tissue.
  • Example 3 Pinoserine reduces exudation of hemoglobin in brain tissue during tPA thrombolysis in a rat model of intravascular thrombosis.
  • Example 4 The combination of pinoserine and tPA reduced the mortality within 48 hours after thrombolysis in a rat model of acute intracerebral thrombosis.
  • TSP TSP (1 mg/kg) was used for thrombolysis after 6 hours of embolization. As shown in Fig. 3, 10 rats in the model group died within 7 hours. When intravenous injection of pinocelin (10 mg/kg) before thrombolysis, the number of dead rats within 48 hours decreased to 3, which was significantly lower than other groups including the model group.
  • the present invention investigates the anti-cerebral hemorrhage effect of pinocelin by using an intravascular thromboembolic acute stroke model.
  • the results show that pinofelin can significantly inhibit the bleeding in the embolized brain region and the vascular communication caused by tPA. Increased permeability can reduce the exudation of blood in brain tissue and reduce the mortality caused by delayed thrombolytic therapy. Therefore, pinoculin has a significant anti-cerebral hemorrhage effect.
  • the anti-spontaneous cerebral hemorrhage drugs of various dosage forms are prepared by using pinoserine as an active substance, alone or in combination with other pharmacologically active compounds and/or extracts, according to conventional preparation methods in the pharmaceutical field. Or combined with other thrombolytic drugs such as streptokinase, urokinase to reduce bleeding during thrombolysis, can provide a more efficient and safe solution for thrombolytic therapy of thrombotic cerebral embolism.

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Abstract

匹诺塞林在制备治疗脑出血药物中的应用，脑出血包括脑栓塞发病后和因溶栓药物等因素引起的转化性出血。实验研究发现，匹诺塞林能够减轻大鼠脑栓塞发病后梗死脑区的血液渗出，能够有效减轻使用溶栓药物时的出血性转化，显著降低因脑出血造成的大鼠死亡现象。匹诺塞林可用于制备治疗脑出血和出血性转化和溶栓剂副作用引起的出血的药物，缓解缺血区的继发性出血，改善患者预后。

Description

匹诺塞林在制备抗脑出血药物中的应用 技术领域
本发明涉及匹诺塞林化合物在药物制备中的新应用，主要涉及匹诺塞林在制备治疗出血性脑卒中和溶栓药物引起的脑出血副作用中的应用，特别涉及匹诺塞林在制备脑栓塞发病后的出血性转化和因溶栓药物引起的脑血管意外药物中的应用。
背景技术
脑栓塞是指脑血管因各种因素如血液中的各种栓子(如心脏内的附壁血栓、动脉粥样硬化的斑块等)随血流进入脑动脉或由于血管具备栓塞而阻塞血管，引起该动脉供血区脑组织缺血性坏死，进而出现局灶性的神经缺损。
临床治疗脑栓塞的关键措施之一是解除血管栓塞，恢复缺血区血液供应。因此，溶栓治疗成为临床治疗急性脑卒中的关键环节。目前正式批准临床应用的药物非常有限，美国FDA于1996年批准使用重组组织型纤维蛋白酶原激活剂(tissue plasminogen activator,t-PA)进行溶栓治疗急性脑梗死，到目前为止，t-PA溶栓治疗仍是国际公认的唯一的药物治疗方式。
溶栓治疗是急性脑缺血治疗的重大突破，有效降低了发病致死率，挽救了急性脑缺血病人的生命。但是，使用tPA治疗，临床很容易表现出强烈的副作用，即出血性转化(hemorrhagic transformation，HT)。临床研究发现，急性脑梗死后由于栓子迁移引起的自发性HT的发生率为24％～71％，应用tPA或链激酶溶栓后，这一机率会提高2-3倍。HT的发生会直接危及患者的生命，截至目前临床上尚无有效降低HT发生几率或缓解出血程度的药物。因此，通过寻找减小再灌注对血管的损伤以达到抑制脑出血的药物，是缓解脑血管意外，改善卒中患者预后，治疗缺血性卒中和出血性卒中的药物开发方向。
匹诺塞林是源于蜂胶的黄酮类天然产物，是基于多靶点网络作用和神经血管单元整合功能靶点作用理论，通过高通量筛选技术在数万 个化合物中筛选出来的活性化合物。中国医学科学院药物研究所国家药物筛选中心采用高通量筛选技术，在数万个化合物中将匹诺塞林筛选出来，其化学结构如下：
Figure PCTCN2016106556-appb-000001
匹诺塞林目前以治疗缺血性脑卒中作为适应症进行二期临床研究。临床前研究结果表明，匹诺塞林通过促进环腺苷酸反应元件结合蛋白的磷酸化、AGER受体和血管内皮细胞等主要靶点，在永久性脑缺血、暂时性脑缺血、缺血再灌注、慢性脑缺血、急性全脑脑缺血、全脑弥散性脑缺血等多种动物脑缺血模型中均显示出很好的抗脑缺血作用。同时可以提升缺血脑区的血流灌注量并改善行为学症状和学习记忆能力，对急性脑缺血损伤后神经血管单元及其各种组分发挥综合脑保护作用。但至今未见匹诺塞林在制备抗脑出血药物中的应用报道。
发明内容
本发明解决的技术问题在于提供匹诺塞林在制备抗脑出血药物，特别是用于制备脑栓塞发病后的出血性转化和因溶栓药物等因素引起的脑微血管出血中的应用，从而为脑栓塞的溶栓治疗提供一种降低HT发生风险，提高患者生存几率并改善预后的解决办法。
为此，本发明提供了如下技术方案：
本发明提供了匹诺塞林在制备抗脑出血药物中的应用。
进一步，所述匹诺塞林与药学上可接受的载体按照常规制剂方法制成各种剂型的抗脑出血药物；
进一步，所述匹诺塞林与药学上可接受的载体按照常规制剂方法制成注射剂型的抗脑出血药物，与溶栓药物联合使用。
本发明因此还涉及以本发明化合物作为活性成份的药物组合物。 该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95％重量。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、 肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-250mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
本发明的有益效果在于：采用大鼠血管内成栓急性脑卒中模型，对匹诺塞林抗脑出血，特别是防止脑栓塞发病后的出血性转化和因溶栓药物等因素引起的脑微血管出血作用进行了考察，结果显示，通过与tPA联合使用，匹诺塞林能够显著降低在大鼠血管内成栓急性脑卒中模型的tPA溶栓过程中出现的血管损伤，减少伊文氏蓝及血红蛋白在缺血脑组织中的渗出量。降低大鼠接受溶栓治疗后48h内的死亡率， 具有显著的血管保护作用，可以在溶栓治疗中与溶栓药物共同使用以降低HT发生风险或缓解出血程度。因而适用于制备与tPA及同类溶栓药物联合使用的复方制剂。
此外，目前溶栓药物临床应用的主要制约因素是有效时间窗较窄，一般3-4.5个小时，究其时间窗较窄的原因，并不是药物的溶栓活性降低，而是与其栓塞时间延长缺血区出血倾向有关，使用匹诺塞林可以治疗出血倾向，有可能延长溶栓药物的有效治疗时间窗。
附图说明
图1.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后脑组织伊文氏蓝含量的影响。
Figure PCTCN2016106556-appb-000002
n＝5。
图2.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后脑组织血红蛋白含量的影响。
Figure PCTCN2016106556-appb-000003
n＝5。
图3.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后48h内死亡率的影响。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明作进一步的详细描述，其中：
定义：Pinocembrin为匹诺塞林
实施例1.匹诺塞林注射剂按照以下方法制备。(1)将匹诺塞林原料粉碎，过100目筛，备用；(2)称取处方量的羟丙基-β-环糊精，加700ml注射用水搅拌溶解；(3)加入0.5％(g/ml)注射用活性炭，保持微沸30分钟，过滤脱炭；(4)称取处方量的匹诺塞林，于室温下加入上述羟丙基-β-环糊精水溶液中；(5)在搅拌状态下缓慢滴加10％氢氧化钠水溶液，调节并保持溶液pH值在8.4～8.5之间，搅拌大约4小时，直至匹诺塞林全部溶解；(6)加注射用水至1000ml，搅匀；(7)加入0.05％(g/ml)注射用活性炭，室温下搅拌30分钟，过滤；(8)分别用0.45μm和0.22μm微孔滤膜除菌过滤，用HPLC测定滤液匹诺塞林含量后，分装入按标准程序洗涤、干燥后的7ml西林瓶中。(9)按照真空冷冻干燥程序进行干燥，冻干周期约30小时。(10)加塞，压盖，轧铝塑盖；抽样检验，合格后，贴签，即得成品。使用时以生理盐水 溶解使用。
实施例2.匹诺塞林降低大鼠血管内成栓急性脑卒中模型的tPA溶栓过程中的伊文氏蓝染料在脑组织中的渗出。
实验材料：Sprague Dawley(SD)大鼠购自维通利华(北京维通利华实验动物技术有限公司)。tPA购自勃林格殷格翰(Boehringer-Ingelheim，Germany)。匹诺塞林注射剂(10mg)由中国医学科学院药物研究所吴松课题组提供。注射时加入注射用生理盐水(石家庄制药四厂)1mL,按剂量10mg/kg使用。注射剂避光冻存于-20℃冰箱。
使用体重范围250-300g的SD大鼠，通过腹腔注射水合氯醛(350mg/kg)将其麻醉。剃去前囟附近毛发，剪开头顶部皮肤并暴露出前囟。选取前囟后2mm，右侧5mm作为脑血流测定点，定位并固定激光多普勒血流仪探头座。仰卧位固定在鼠板上，稳定PU读数后记录5min内血流基准值。
切开大鼠颈部皮肤，分离颈总动脉与颈外动脉，使用动脉夹夹闭颈外动脉。将颈总动脉放入YLS-14B小动物血栓生成仪的血管电刺激夹的沟槽内，选择电流强度1.00mA，刺激时间225s进行电击。电击结束后，用动脉夹夹闭远心端颈总动脉。用软头镊由远心端至近心端夹碎血栓。放开动脉夹，见到血栓碎片冲走后1-5s，再次夹闭颈总动脉近心端15min后，取下所有动脉夹并消毒缝合，此时血流值下降至基准值的30％以下时，视为形成目的栓塞模型。缝合后将大鼠置于37℃恒温系统中。
随后根据实验设计，将大鼠置于37℃恒温系统中6h后，于颈外静脉推注药，每次推注时间2min。联合用药组在推注tPA前5min推注匹诺塞林。
实验分组：空白组(除电击操作，其余与模型组相同)，n＝5；模型组(造模后6h推注生理盐水)，n＝5；tPA组(造模6h后按1mg/kg推注tPA)，n＝5；匹诺塞林组(造模6h后按10mg/kg推注匹诺塞林)，n＝5；联合用药组(造模6h后按10mg/kg推注匹诺塞林，1mg/kg推注 tPA，n＝5。
结果：推注tPA前对大鼠注射4％伊文氏蓝100μl，1h后使用含有肝素(0.16mg/ml)的生理盐水对大鼠心脏灌流，取脑组织匀浆后测定其在620nm处的吸光度。结果见图1，tPA组中不论是缺血侧还是非缺血侧，其大鼠脑组织匀浆在620nm处的吸光度均显著高于模型组。而在匹诺塞林组和联合用药组中，不论是否进行tPA推注，其双侧脑组织匀浆在620nm处的吸光度均显著低于tPA组，提示匹诺塞林能够显著降低伊文氏蓝在脑组织中的渗漏。
表1.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后脑组织伊文氏蓝渗出量的影响(
Figure PCTCN2016106556-appb-000004
n＝5)。
Figure PCTCN2016106556-appb-000005
实施例3.匹诺塞林降低大鼠血管内成栓急性脑卒中模型的tPA溶栓过程中的血红蛋白在脑组织中的渗出。
动物造模及给药方法同实施例2。取灌流后的脑组织匀浆加入血红蛋白稳定剂，在575nm处检测吸光度，代入标准曲线计算脑组织内的血红蛋白含量。结果见图2，注射tPA后大鼠脑组织匀浆中的血液含量均出现升高趋势。注射匹诺塞林后，不论是否进行溶栓治疗，其双侧脑组织匀浆内血红蛋白含量均显著降低。提示匹诺塞林能够显著降低由tPA引起的出血现象。
表2.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后脑组织血红蛋白渗出量的影响(
Figure PCTCN2016106556-appb-000006
n＝5)。。
Figure PCTCN2016106556-appb-000007
实施例4.匹诺塞林与tPA联用降低大鼠血管内成栓急性脑卒中模型溶栓后48h内的死亡率。
每组10只大鼠，造模及给药方法同实施例2。栓塞6h后使用tPA(1mg/kg)进行溶栓治疗，如图3所示，模型组10只大鼠在48h内死亡7只。而当溶栓前静脉注射匹诺塞林(10mg/kg)后，48h内的死亡大鼠数量降为3只，显著低于包括模型组在内的其它组别。
表3.匹诺塞林(10mg/kg)对大鼠血管内成栓急性脑卒中模型延迟6h进行tPA溶栓治疗后48h内的死亡率影响(
Figure PCTCN2016106556-appb-000008
n＝10)。
Figure PCTCN2016106556-appb-000009
综上所述，本发明采用血管内成栓急性脑卒中模型对匹诺塞林抗脑出血作用进行了考察，结果显示：匹诺塞林能明显抑制栓塞脑区的出血与tPA引起的血管通透性增加，可以减少血液在脑组织中的渗出，降低由延迟溶栓治疗带来死亡率升高。因此，匹诺塞林具有显著的抗脑出血作用。以匹诺塞林为活性物质，单独使用或/与其他具有药理学活性的化合物和/或提取物组成复方使用，按照药学领域的常规制剂方法制成各种剂型的抗自发性脑出血药物，或者与其它溶栓药物如链激酶，尿激酶等制成复方制剂用于减小溶栓过程中的出血现象，可以为血栓性脑栓塞的溶栓治疗提供一种更加高效与安全的解决办法。
最后说明的是，以上实施例仅用于说明本发明的技术方案而非限制，尽管通过参照本发明的优选实施例已经对本发明进行了描述，但本领域普通技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离所附权利要求书所限定的本发明的精神和范围。

Claims (15)

  1. 如式I所示匹诺塞林在制备抗脑出血药物中的应用,
    Figure PCTCN2016106556-appb-100001
  2. 根据权利要求1的应用，其特征在于，所述的脑出血是包括但不限于脑栓塞发病后的出血性转化引起的脑血管出血。
  3. 根据权力要求1的应用，其特征在于，所述的脑出血包括因脑缺血后自发出血性转化或者脑血栓发病后使用溶栓药物引起的脑血管出血。
  4. 根据权利要求2的应用，其特征在于，所述的脑栓塞发病后的出血性转化是指在发病期间，由于栓子移动等原因造成的缺血区血管重新恢复血流灌注所导致的梗死区内的血管继发性出血。
  5. 根据权利要求3的应用，其特征在于，所述的因溶栓药物引起的脑血管出血，是指使用组织型纤溶酶原激活剂(tissue plasminogen activator，tPA)、重组人组织型纤溶酶原激活剂、尿激酶、链激酶治疗脑栓塞时发生的颅内出血，所述的颅内出血包括脑出血、颅内血肿、蛛网膜下腔出血、出血性卒中、缺血性卒中的出血性转化。
  6. 根据权利要求5的应用，其特征在于：所述的颅内血肿是因静脉溶栓治疗中产生的脑血管意外，出血聚集在颅腔的一定部位而且达到相当的体积后，造成颅内压增高，脑组织受压而引起相应的临床症状。
  7. 根据权利要求5的应用，其特征在于：所述的蛛网膜下腔出血是因静脉溶栓治疗中产生的脑血管意外，其中包括原发与继发性蛛网膜下 腔出血两种情况。
  8. 根据权利要求5的应用，其特征在于，所述的溶栓药物只有在一定时间窗内治疗有效，匹诺塞林可以有效延长溶栓药物的治疗窗，表现出更好的治疗效果。
  9. 根据权利要求7的应用，其特征在于，所述的原发性蛛网膜下腔出血是指脑底部或脑及脊髓表面血管因静脉溶栓治疗而产生的脑血管意外。
  10. 根据权利要求7所述的应用，其特征在于，所述的原发性蛛网膜下腔出血是指在静脉溶栓治疗中，脑实质内，脑室，硬膜外或硬膜下出现的脑血管意外，血液穿破脑组织流入蛛网膜下腔的情况。
  11. 根据权利要求5至10任一项的应用，其特征在于，所述因溶栓药物引起的脑血管出血是指因溶栓药物副作用引起的微血管渗透性升高，进而导致渗血以及血管破裂的情况。
  12. 一种药物组合物在制备抗脑出血药物中的应用，其特征在于，所述的药物组合物含有治疗有效量的式I所示的匹诺塞林以及药学上可接受的载体,
    Figure PCTCN2016106556-appb-100002
  13. 根据权利要求12的应用，其特征在于，所述的脑出血包括脑栓塞发病后的出血性转化引起的脑出血、因溶栓药物引起的脑血管出血。
  14. 根据权利要求12-13任一项的应用，其特征在于，所述的药物组合的剂型包括口服制剂，注射给药剂型，皮肤粘膜途径给药剂型。
  15. 根据权利要求14的应用，其特征在于，所述的口服制剂包括片剂、缓释剂、胶囊剂、控释剂、滴丸剂、液体制剂，所述的注射给药剂型包括肌肉注射、静脉注射、静脉滴注。
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