WO2008124974A1

WO2008124974A1 - Use of human urinary kallidinogenase for manufacturing a medicament for the treatment and/or prevention of hypertension complicated by cerebral infarction

Info

Publication number: WO2008124974A1
Application number: PCT/CN2007/002096
Authority: WO
Inventors: Heliang Fu; Yongmin Hou; Rongrong Wu; Xiaoyan Wang; Yao Lei; Juan Xu
Original assignee: Techpool Bio-Pharma Co., Ltd.
Priority date: 2007-04-16
Filing date: 2007-07-09
Publication date: 2008-10-23
Also published as: CN101024073A

Abstract

A use of human urinary kallidinogenase for manufacturing a medicament for the treatment and/or prevention of hypertension complicated by cerebral infarction is provided. A pharmaceutical composition comprising human urinary kallidinogenase and pharmaceutically acceptable adjuvants is also provided. Human urinary kallidinogenase is efficacious against hypertension complicated by cerebral infarction. The present medicament is a pharmaceutical composition containing an appropriate proportion of human urinary kallidinogenase and pharmaceutically acceptable adjuvants, wherein the dosage form includes freeze-dried powder or injection solution.

Description

人尿激肽原酶在制备治疗和 /或预防高血压 Human urokininogenase in the preparation of treatment and / or prevention of hypertension

合并脑梗塞药物中的应用技术领域 Application in combination with cerebral infarction

本发明涉及药物化学领域。具体而言，本发明涉及人尿激肽原酶的新医药用途，即人尿激肽原酶在制备治疗和 /或预防高血压合并脑梗塞药物中的应用。背景技术 The invention relates to the field of medicinal chemistry. In particular, the present invention relates to a novel pharmaceutical use of human urokininogenase, i.e., the use of human urokininogenase for the preparation of a medicament for the treatment and/or prevention of hypertension combined with cerebral infarction. Background technique

人尿激肽原酶是从健康男性人尿中提取精制的糖蛋白，分子量约 54000道尔顿，它是由 238个氨基酸组成的一条单链， N-末端和 C-末端氨基酸残基分别为异亮氨酸和丝氨酸，分子中含有 5对 S-S键，等电点约为 4.0。人尿激肽原酶具有激活人血浆激肽原转化为激肽、改善血液循环、增加红细胞的变形性和抑制血小板聚集等作用。 Human urinary kininogenase is a purified glycoprotein extracted from the urine of healthy males. It has a molecular weight of about 54,000 Daltons. It is a single chain consisting of 238 amino acids. The N-terminal and C-terminal amino acid residues are Isoleucine and serine contain 5 pairs of SS bonds in the molecule with an isoelectric point of about 4.0. Human urokininogenase activates the conversion of human plasma plasminogen to kinins, improves blood circulation, increases the deformability of red blood cells, and inhibits platelet aggregation.

脑卒中俗称脑中风，是目前危害人类生命的最主要三大杀手（中风、心脏病、癌症）之一。脑卒中大致可以分为两大类，即缺血性脑卒中和出血性脑卒中。缺血性脑卒中导致脑血栓形成和脑栓塞，故缺血性脑卒中又称为脑梗塞。在我国，脑梗塞占整个卒中发病率的 70%〜80%，随着人口老龄化和各种危险因素的增加，脑梗塞所占比例会越来越大。我国每年新发脑梗塞患者 100万人左右，该病对人类健康形成严重威胁的疾病，是临床死亡的重要原因。 Stroke, commonly known as stroke, is one of the three major killers (stroke, heart disease, cancer) that currently endanger human life. Stroke can be roughly divided into two categories, namely ischemic stroke and hemorrhagic stroke. Hypoxic stroke leads to cerebral thrombosis and cerebral embolism, so ischemic stroke is also called cerebral infarction. In China, cerebral infarction accounts for 70%~80% of the total incidence of stroke. As the population ages and various risk factors increase, the proportion of cerebral infarction will increase. There are about 1 million new cases of cerebral infarction in China each year. The disease poses a serious threat to human health and is an important cause of clinical death.

高血压病是临床常见的心血管疾病之一，大量资料表明我国高血压患病率在逐年增加，估计我国目前有高血压病患者 1亿多。高血压是脑卒中最重要的危险因素，脑卒中的发生与高血压的程度以及持续的时间密切相关，血压越高，长时间没有有效控制，导致脑动脉硬化、管腔变窄或闭塞，故高血压是引起脑梗塞（缺血性脑卒中）的重要原因。临床研究证明，单纯收缩期高血压患者血压超过 160mmHg时，脑梗塞的发病率显著增高。高血压患者，其脑梗塞的发病率比血压正常者高两倍。 Hypertension is one of the most common cardiovascular diseases in the clinic. A large amount of data indicates that the prevalence of hypertension in China is increasing year by year. It is estimated that there are more than 100 million patients with hypertension in China. Hypertension is the most important risk factor for stroke. The occurrence of stroke is closely related to the degree of hypertension and duration. The higher the blood pressure, the longer the effective control, the cerebral arteriosclerosis, the narrowing or occlusion of the lumen, so Hypertension is an important cause of cerebral infarction (ischemic stroke). Clinical studies have shown that the incidence of cerebral infarction is significantly higher in patients with isolated systolic hypertension who have a blood pressure of more than 160 mmHg. In hypertensive patients, the incidence of cerebral infarction is twice as high as that of normal blood pressure.

本发明人经过临床研究试验发现，人尿激肽原酶对高血压合并脑梗塞有明显的治疗和 /或预防作用。发明内容 The inventors have found through clinical research that human urokininogenase has significant therapeutic and/or preventive effects on hypertension and cerebral infarction. Summary of the invention

本发明的一个目的是提供人尿激肽原酶用于制备治疗和 /或预防高血压合并脑梗塞的药物的用途。本发明的另一目的是提供一种用于治疗和 /或预防髙血压合并脑梗塞的含有人尿激肽原酶的药物组合物。 It is an object of the present invention to provide the use of human urokininogenase for the preparation of a medicament for the treatment and/or prevention of hypertension combined with cerebral infarction. Another object of the present invention is to provide a pharmaceutical composition comprising human urokininogenase for use in the treatment and/or prevention of sputum blood pressure combined with cerebral infarction.

本发明的人尿激肽原酶对高血压合并脑梗塞有明显的治疗和 /或预防作用。本发明的人尿激肽原酶一般以药物组合物的形式使用，这种组合物含有治疗有效量的作为活性成分的人尿激肽原酶和可药用辅料，活性成分与药用辅料重量比例为 1:1〜1:15000，其中优选比例为 1:1〜1:2500。这种药物组合物通常以静脉注射途径给药，主要剂型包括冻干粉针剂和注射液剂。 The human urokininogenase of the present invention has a significant therapeutic and/or preventive effect on hypertension combined with cerebral infarction. The human urokininogenase of the present invention is generally used in the form of a pharmaceutical composition comprising a therapeutically effective amount of human urokininogenase as an active ingredient and a pharmaceutically acceptable adjuvant, the active ingredient and the weight of the pharmaceutically acceptable excipient The ratio is 1:1~1:15000, and the preferred ratio is 1:1~1:2500. Such pharmaceutical compositions are usually administered by intravenous route, and the main dosage forms include lyophilized powder injections and injection solutions.

经静脉注射给药的人尿激肽原酶组合物，一般是固体的灭菌组合物形式，即冻干粉针剂。这些组合物可以含有药用辅料，特别是甘露醇、右旋糖苷、水解明胶、柠檬酸钠、甘氨酸或聚乙二醇等中的一种或其任意混合物，在使用时可以溶解于灭菌注射用水或各种其它注射用灭菌介质中。 The human urokininogenase composition administered intravenously is typically in the form of a solid sterile composition, i.e., a lyophilized powder injection. These compositions may contain a pharmaceutical excipient, particularly one of mannitol, dextran, hydrolyzed gelatin, sodium citrate, glycine or polyethylene glycol, or any mixture thereof, which may be dissolved in a sterile injection when used. Use water or various other injectable sterilization media.

经静脉注射给药的人尿激肽原酶组合物也可以是水溶液形式，即注射液剂。这些组合物可以含有药用辅料，特别是甘露醇、氯化钠、葡萄糖或聚乙二醇等中的一种或其任意混合物。 The human urokininogenase composition administered intravenously may also be in the form of an aqueous solution, that is, an injection preparation. These compositions may contain a pharmaceutical excipient, especially one of mannitol, sodium chloride, glucose or polyethylene glycol, or any mixture thereof.

应用人尿激肽原酶组合物治疗高血压合并脑梗塞的剂量根据病情的严重程度、治疗时间而定，一般静脉注射给药量是每天给药 1 -3次，每次 0.005— 2.5 PNA 单位。优选，药物的给药量是每天 1次，每次 0.1— 0.2PNA单位。 The dosage of human urokininogenase composition for the treatment of hypertension complicated with cerebral infarction depends on the severity of the disease and the treatment time. Generally, the intravenous administration dose is 1-3 times per day, 0.005-2.5 PNA units per time. . Preferably, the amount of the drug administered is once a day, 0.1 - 0.2 PNA units each time.

PNA的定义为：在 37Ό、 ρΗ8.0条件下， 1分钟水解底物 Val-Leu-Arg-PNA 释放 lumol游离 PNA，即为 1PNA单位。对本发明所进行的临床试验研究表明，人尿激肽原酶对高血压合并脑梗塞患者的疗效要优于非高血压脑梗塞合并症患者，人尿激肽原酶不仅能有效缓解患者高血压表现，还可以减少氧自由基的生成，有利于患者整体病情的恢复。具体实施方式下面用具体实施例对本发明作进一步说明。 PNA is defined as: 1 minute hydrolysis of the substrate Val-Leu-Arg-PNA releases lumol free PNA at 37 Ό, ρ Η 8.0, which is 1 PNA unit. Clinical trial studies conducted on the present invention have shown that human urokininogenase is superior to non-hypertensive cerebral infarction patients in patients with hypertension complicated with cerebral infarction, and human urokininogenase can effectively alleviate hypertension in patients. Performance can also reduce the generation of oxygen free radicals, which is conducive to the recovery of the patient's overall condition. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be further described by way of specific examples.

实施例 1 人尿激肽原酶对高血压合并脑梗死患者的治疗作用 Example 1 Therapeutic effect of human urinary kininogenase on patients with hypertension complicated with cerebral infarction

实验对象和分组：临床随机选取发病 48小时以内的脑梗死患者 646例，分为治疗组和对照组。对照组给予维脑路通常规治疗，每次滴注 200mg，一日一次。治疗组在常规治疗基础上滴注人尿激肽原酶，每次 0.15PNA单位，一日一次。其中非高血压脑梗死患者 232例（对照组 59例，治疗组 173例〉，高血压合并脑梗死患者 414例（对照组 122例，治疗组 292例） Subjects and grouping: 646 patients with cerebral infarction within 48 hours after onset were randomly selected and divided into treatment group and control group. The control group was given regular treatment with Weiluolong, 200 mg per infusion, once a day. The treatment group was instilled with human urokininogenase on a routine basis, 0.15 PNA units per day, once a day. Among them, 232 patients with non-hypertensive cerebral infarction (59 in the control group, 173 in the treatment group), hypertension and cerebral infarction 414 patients (122 in the control group and 292 in the treatment group)

分析项目和指标：患者用药前及用药后的神经功能变化，采用欧洲脑卒中评分（European Stroke Scale, ESS)和日常生活能力评价 (Activity of Daily Life ,ADL) 的标准。疗程为 21天。 Analytical items and indicators: Changes in neurological function before and after administration, using the European Stroke Scale (ESS) and Activity of Daily Life (ADL) criteria. The course of treatment is 21 days.

1、主要疗效指标 ESS评分以增分率来判断疗效，计算方法如下： 1. Main efficacy indicators The ESS score is judged by the rate of increase. The calculation method is as follows:

增分率 . 治疗后积分-治疗前积分 Increase rate. Points after treatment - points before treatment

堦分军— ₁₀0 -治疗前积分 ^{X l00/o} 堦分军 — ₁₀ 0 - Pre-treatment points ^{X l00/o}

o t o t

o o

把增分率分为四级来判断疗效（以基本痊愈和显著进步作为有效），分级如下： The rate of increase is divided into four levels to judge the effect (effective as basic recovery and significant improvement), and the classification is as follows:

A. 基本痊愈：增分率 86— 100% A. Basic recovery: Increase rate 86- 100%

B. 显著进步：增分率 46— 85% B. Significant progress: Increase rate 46-65%

C. 进步：增分率 16—45% C. Progress: Increase rate of 16-45%

D. 无效: 增分率 <16% D. Invalid: Increase rate <16%

2、次要疗效以 ADL评分评价 2. Secondary efficacy is evaluated by ADL score

曰常生活能力缺陷分为如下五档： The deficiencies in normal life ability are divided into the following five files:

A. 极严重功能缺陷： 0— 20分 A. Extremely serious functional defects: 0-20 points

B. 严重功能缺陷： 25— 45分 B. Serious functional defects: 25-45 points

C. 中度功能缺陷： 50— 70分 C. Moderate functional defects: 50-70 points

D. 轻度功能缺陷： 75— 95分 D. Mild functional defects: 75-95 points

E. 无功能缺陷： 100分 E. No functional defects: 100 points

结果：对两组脑梗塞患者的疗效评价结果（ESS和 ADL)见下表。 RESULTS: The results of the evaluation of efficacy (ESS and ADL) in the two groups of patients with cerebral infarction are shown in the table below.

表 1 两类患者 21天各类 ESS增分率比例（％ ) Table 1 Proportion of ESS increase rate in 21 days for two types of patients (%)

卡方检验组别基本痊愈显著改善进步无效 Chi-square test group, basic recovery, significant improvement, progress, invalid

(P) (P)

对照组 Control group

8.47 49.15 30.51 11.86 8.47 49.15 30.51 11.86

非高血压脑 (n=59) Non-hypertensive brain (n=59)

0.0052 梗死组治疗组 0.0052 Infarction group Treatment group

12.14 12.14

(n=173) 髙血压合并对照组 (n=173) 髙 blood pressure combined with control group

9.84 39.34 28.69 22.13 0.0008 脑梗死组 (n=122) 治疗组 9.84 39.34 28.69 22.13 0.0008 Cerebral infarction group (n=122) therapy group

14.04 55.48 15.75 14.73 14.04 55.48 15.75 14.73

(n=292) 表 2 两类患者 21天 ADL疗效评价各级比例（％ ) (n=292) Table 2 Two types of patients 21 days ADL efficacy evaluation ratio (%)

卡方检验组别 0-20 25-45 50-70 75—90 ^95 Chi-square test group 0-20 25-45 50-70 75-90 ^95

(P) 对照组 (P) Control group

8.47 6.78 32.20 22.03 30.51 8.47 6.78 32.20 22.03 30.51

非高血压脑 (n=59) Non-hypertensive brain (n=59)

0.0100 梗死组治疗组 0.0100 infarction group treatment group

4.62 7.51 15.03 17.92 54.91 4.62 7.51 15.03 17.92 54.91

(n=173) (n=173)

对照组 Control group

7.38 21.31 25.41 13.93 31.97 7.38 21.31 25.41 13.93 31.97

高血压合并 (n=122) Hypertension combined (n=122)

0.0079 脑梗死组治疗组 0.0079 Cerebral infarction group Treatment group

4.11 12.33 21.23 17.47 44.86 4.11 12.33 21.23 17.47 44.86

(n=292) 用 Cochran-Mantel-Haenszel统计量分析显示：高血压合并脑梗塞组较非高血压脑梗塞组差异更为显著（PO.0001 , 表 1和表 2)。以上结果说明：对于有髙血压史的患者，治疗组和对照组疗后差异更显著，说明人尿激肽原酶对髙血压合并脑梗塞患者的疗效优于非高血压脑梗塞合并症患者。实施例 2 人尿激肽原酶对高血压合并脑梗塞的治疗 (n=292) Cochran-Mantel-Haenszel statistic analysis showed that the difference between the hypertensive cerebral infarction group and the non-high blood pressure cerebral infarction group was more significant (PO.0001, Table 1 and Table 2). The above results indicate: For patients with a history of sputum blood pressure, the difference between treatment group and control group is more significant, indicating that human urokininogen is superior to non-hypertensive cerebral infarction patients in patients with sputum blood pressure and cerebral infarction. Example 2 Human urokininogenase for the treatment of hypertension complicated with cerebral infarction

实验对象和分组：所有入选病人符合 1995年全国第四届脑血管病会议确定的脑梗死的诊断标准，且入院后首次血压符合 1999年 WHO I ISH高血压治疗指南制定的高血压标准。将 160例病人随机分为对照组与治疗组，两组各 80例，两组年龄、病程、症状、体征等方面无统计学意义（P>0. 05), 具有可比性。对照组常规给予静脉滴注奥扎格雷钠注射液 80mg，一日两次。治疗组在常规治疗基础上滴注人尿激肽原酶，每次 0.15PNA单位，一日一次。两组均连续给药 14天。 Subjects and groupings: All enrolled patients met the diagnostic criteria for cerebral infarction as determined by the Fourth National Conference on Cerebrovascular Diseases in 1995, and the first blood pressure after admission was in accordance with the 1999 WHO I ISH Hypertension Treatment Guidelines. 160 patients were randomly divided into the control group and the treatment group, 80 patients in each group. There were no significant differences in age, duration, symptoms and signs between the two groups (P>0.05), which were comparable. The control group was given an intravenous infusion of 80 mg of ozagrel sodium injection twice a day. The treatment group was instilled with human urokininogenase on a routine basis, 0.15 PNA units per day, once a day. Both groups were administered continuously for 14 days.

检测方法：血压测量方法釆用标准汞柱式血压计，病人取仰卧位，择右上肢肱动脉测量血压，每日晨起 06: 00-07： 00时测量，连续测量 2次，取两次平均值进行统计。以病人入院第一次记录的血压为首次血压，连续记录 10天。氧化应激检测分别于治疗前后取病人外周血，分离血清待检。相关试剂盒购自南京建成生物制品有限公司，严格按照说明进行操作。 Detection method: The blood pressure measurement method uses a standard mercury sphygmomanometer, the patient takes the supine position, and the right upper extremity brachial artery measures the blood pressure. It is measured every morning from 06: 00-07: 00, continuous measurement 2 times, twice The average is used for statistics. The blood pressure recorded for the first time in the patient's admission was the first blood pressure, and was recorded continuously for 10 days. Oxidative stress test The peripheral blood of patients was taken before and after treatment, and serum was separated for examination. Related kits were purchased from Nanjing Jiansheng Products Co., Ltd., in strict accordance with the instructions.

检测指标：观察两组治疗前后收缩压与舒张压的变化，并检测超氧化物歧化酶（SOD) 水平、丙二醛（MDA) 水平和谷胱甘肽过氧化物酶（GSH— PX)活力的变化情况。 Detection index: The changes of systolic and diastolic blood pressure before and after treatment were observed, and the levels of superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-PX) were measured. The change.

结果：两组治疗前后血压变化和氧化应激指标检测的结果如下表 3和表 4。 Results: The results of blood pressure changes and oxidative stress indicators before and after treatment in the two groups are shown in Tables 3 and 4.

两组患者治疗前后血压变化比较（单位： mmHg) Comparison of blood pressure changes before and after treatment in both groups (unit: mmHg)

入院时入院 24h后入院 10d后组别 At the time of admission, after admission for 24 hours, after admission, 10 days later, group

收缩压舒张压收缩压舒张压收縮压舒张压对照组 138.6±8.4 84.5±6.2 172.6±11.8 115.8±9.3 149.4±10.7 98.3±10.2 治疗组 138.8±7.9 88.1±9.5 151.2±10.4 90.6±10.5 121.6±8.5 81.8±8.4 表 4 两组患者治疗前后氧化应激指标检领 |J结果组别 SOD (U/ml) MDA (nmol/ml) GSH-Px (U/L) 治疗前 78.52±10.38 5.16±0.44 72.47±13.41 对照组 Systolic blood pressure, diastolic blood pressure, systolic pressure, diastolic blood pressure, systolic pressure, diastolic blood pressure, control group, 138.6±8.4 84.5±6.2, 172.6±11.8, 115.8±9.3, 149.4±10.7, 98.3±10.2, treatment group, 138.8±7.9, 88.1±9.5, 151.2±10.4, 90.6±10.5, 121.6±8.5, 81.8 ±8.4 Table 4 oxidative stress indicators before and after treatment in the two groups of patients | J results group SOD (U / ml) MDA (nmol / ml) GSH-Px (U / L) before treatment 78.52 ± 10.38 5.16 ± 0.44 72.47 ± 13.41 Control group

治疗后 88.83±9.93 4.62±0.35 75.78±9.47 治疗前 77.26±10.17 5.84±0.37 71.39±8.85 治疗组 After treatment 88.83±9.93 4.62±0.35 75.78±9.47 Before treatment 77.26±10.17 5.84±0.37 71.39±8.85 Treatment group

治疗后 112.58±11.04 3.36±0.50 92.44±9.56 从表 3可以看出，入院后 24小时后对照组和治疗组收缩压与舒张压均有所升高， 10天后均明显回落，且人尿激肽原酶治疗组血压回落尤其明显；人尿激肽原酶治疗组 10天后血压与入院时血压比较有统计学意义（P<0.05)，对照组 10天后血压略高于入院时血压（P>0.05)。说明人尿激肽原酶可有效缓解高血压合并脑梗塞患者血压升高的临床症状。 After treatment, 112.58±11.04 3.36±0.50 92.44±9.56 It can be seen from Table 3 that the systolic and diastolic blood pressures of the control group and the treatment group increased after 24 hours after admission, and all of them decreased significantly after 10 days, and human urokinin The blood pressure of the original enzyme treatment group was especially significant. The blood pressure of the human urokininogenase group was significantly lower than that of the hospitalized group (P<0.05). The blood pressure of the control group was slightly higher than that of the hospital after 10 days (P>0.05). ). It is indicated that human urokininogenase can effectively relieve the clinical symptoms of elevated blood pressure in patients with hypertension and cerebral infarction.

从表 4可以看出，与治疗前相比，对照组和治疗组用药后的超氧化物歧化酶 (SOD)水平上升，丙二醛（MDA)水平下降，谷胱甘肽过氧化物酶（GSH— PX) 活力上升，人尿激肽原酶治疗组的变化较对照组明显（P<0.05)。说明人尿激肽原酶可以有效对抗脑梗塞治疗后发生的氧化应激对机体的损伤作用。 As can be seen from Table 4, the levels of superoxide dismutase (SOD) increased, malondialdehyde (MDA) levels, and glutathione peroxidase (D) decreased in the control and treatment groups compared with before treatment. The activity of GSH-PX) increased, and the change of human urokininogenase treatment group was significantly higher than that of the control group (P<0.05). It is indicated that human urokininogenase can effectively counteract the damage of oxidative stress occurring after cerebral infarction treatment.

本研究发现，人尿激肽原酶不仅能有效缓解高血压合并脑梗塞患者血压升高的症状，还可以减少氧自由基的生成，有利于患者整体病情的恢复，有助于卒中后高血压状态的自发缓解。 This study found that human urokininogenase can not only effectively relieve the symptoms of high blood pressure in patients with hypertension and cerebral infarction, but also reduce the production of oxygen free radicals, which is conducive to the recovery of the overall condition of patients, and contribute to post-stroke hypertension. Spontaneous relief of the state.

Claims

权利要求 Rights request

1.人尿激肽原酶用于制备治疗和 /或预防高血压合并脑梗塞药物的用途。 1. Use of human urokininogenase for the preparation of a medicament for the treatment and/or prevention of hypertension combined with cerebral infarction.

2.根据权利要求 1所述的用途，其中所述的药物含有作为活性成分的人尿激肽原酶和可用药辅料，人尿激肽原酶与药用辅料重量比例为 1 : 1〜1： 15000ο The use according to claim 1, wherein the drug contains human urokininogen and an excipient as an active ingredient, and the weight ratio of human urokininogen to pharmaceutical excipient is 1: 1 to 1 : 15000ο

3.根据权利要求 2所述的用途，其中人尿激肽原酶与药用辅料重量比例为 1 : 1〜1： The use according to claim 2, wherein the weight ratio of human urokininogenase to pharmaceutical excipient is 1: 1 to 1:

2500 ο 2500 ο

4.根据权利要求 3所述的用途，其中所述药物是冻干粉针剂。 4. Use according to claim 3, wherein the medicament is a lyophilized powder injection.

5.根据权利要求 4所述的用途，其中所述的药用辅料选自甘露醇、右旋糖苷、水解明胶、柠檬酸钠、甘氨酸或聚乙二醇中的一种或其任意混合物。 The use according to claim 4, wherein the pharmaceutical adjuvant is selected from one of mannitol, dextran, hydrolyzed gelatin, sodium citrate, glycine or polyethylene glycol or any mixture thereof.

6.根据权利要求 3所述的用途，其中所述药物是注射液剂。 6. Use according to claim 3, wherein the medicament is an injection.

7.根据权利要求 6所述的用途，其中所述的药用辅料选自甘露醇、氯化钠、葡萄糖或聚乙二醇中的一种或其任意混合物。 The use according to claim 6, wherein the pharmaceutical adjuvant is selected from one of mannitol, sodium chloride, glucose or polyethylene glycol or any mixture thereof.

8.根据权利要求 5或 7所述的用途，其中所述药物的给药量是每天给药 1一 3次，每次 0.005— 2.5 ΡΝΑ单位，优选，药物的给药量是每天 1次，每次 0.1— 0.2ΡΝΑ单位。 The use according to claim 5 or 7, wherein the amount of the drug to be administered is one to three times a day, 0.005 to 2.5 units per time, and preferably, the amount of the drug administered is once a day. 0.1 - 0.2 unit each time.

9. 一种用于治疗和 /或预防高血压合并脑梗塞的药物组合物，其含有治疗有效量的作为活性成分的人尿激肽原酶和可药用辅料。 A pharmaceutical composition for treating and/or preventing hypertension combined with cerebral infarction, comprising a therapeutically effective amount of human urokininogenase and a pharmaceutically acceptable excipient as an active ingredient.