WO2006105726A1 - Composition pour le traitement de l’hypertension - Google Patents

Composition pour le traitement de l’hypertension Download PDF

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Publication number
WO2006105726A1
WO2006105726A1 PCT/CN2006/000592 CN2006000592W WO2006105726A1 WO 2006105726 A1 WO2006105726 A1 WO 2006105726A1 CN 2006000592 W CN2006000592 W CN 2006000592W WO 2006105726 A1 WO2006105726 A1 WO 2006105726A1
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calcium
group
blood pressure
containing component
diuretic
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PCT/CN2006/000592
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English (en)
French (fr)
Inventor
Jidao Peng
Lisheng Liu
Jinping Su
Jiaxiu Yang
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Cp Drug Development Co., Ltd.
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Publication of WO2006105726A1 publication Critical patent/WO2006105726A1/zh

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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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a pharmaceutical composition, and more particularly to a pharmaceutical composition for treating hypertension. Background technique
  • Hypertension is one of the most common cardiovascular diseases at present. The clinical manifestations of increased systemic arterial pressure are mostly accompanied by various complications such as stroke, myocardial infarction, heart failure, coronary heart disease and diabetes. Europe and North America are high-risk areas for hypertension. According to the survey, the prevalence of hypertension in adults in China is 18.8%. It is estimated that the number of patients in the country is 160 million, an increase of more than 70 million compared with 1991. The prevalence of hypertension in rural areas has increased rapidly, and the gap between urban and rural areas is not obvious. In general, patients with hypertension have a shorter life span than normal people by 15-20 years. 95% of hypertensive patients have primary high blood pressure, and 15-30% of patients with essential hypertension are associated with abnormal renal renin circulating levels.
  • CN1562369 ⁇ discloses a pharmaceutical composition for treating hypertension, which contains a certain weight ratio of a calcium ion antagonist, a diuretic, and the like.
  • Route 1 shows that the main pathogenic factors affect a small number of target organs leading to cytopathological activities leading to pathological symptoms. However, other organs or cells in the body are unaffected and the cells are normal. The response of "pathological defects” and "normal” tissues to different pathogenic factors is a key focus of therapeutic drug design and development.
  • Pathway 2 represents the current state of treatment of most western medicines, and such drugs act on one or several pathological tissues.
  • biochemical or physiological abnormalities of the body have been clearly explained, and the designed drugs improve clinical symptoms by changing one or several diseased tissues.
  • a large amount of medication is required.
  • These drugs have strong pharmacological activities and also have an effect on other normal tissues, thus causing side effects.
  • Route 3 represents a more desirable state of medication. If the main cause of the disease is known, the disease can be inhibited by designing the drug or directly producing physiological activity, so that the diseased tissue returns to normal, and the disease symptoms are controlled. Drug-induced pathogenic factors have an effect on healthy tissues, and normal healthy tissues are not affected by pathogenic factors. Therefore, the side effects of drugs are less. In theory, this is an ideal way to develop new drugs. However, the following problems exist: First, most diseases, the main pathogenic factors are unknown; secondly, most diseases have more complications; N2006/000592 Third, even if the cause is known, it is almost impossible to suppress all causes by one chemical component.
  • Antihypertensive drugs have developed greatly over the past 50 years. However, hypertension is a disease with an uncertain cause. The cure rate of one or several drugs for a cause or mechanism of action is low. Usually, the cure rate of a drug is about 40-50%, and The prognosis is poor. In recent years, although there are many new antihypertensive drugs with low efficacy and few side effects, the blood pressure control rate can only reach 50-60%. Therefore, a new treatment mode is gradually applied to the clinic, and the compound antihypertensive drug preparation is an internationally recognized treatment direction. Many years of research by the inventors have shown that 50% of patients with sputum blood pressure need to be combined.
  • Another object of the present invention is to provide an use of the composition for the preparation of a medicament for the treatment of hypertension.
  • the present invention provides a pharmaceutical composition for treating hypertension, characterized in that the composition comprises a diuretic, a calcium-containing component, and a pharmaceutically acceptable excipient, wherein the ratio of the diuretic to the calcium-containing component is The weight is from 1:10 to 2000, wherein the calcium-containing component is based on Ca 2+ .
  • the ratio of the diuretic to the calcium-containing component in the group is 1:20-500 by weight, and the calcium-containing component is calculated as Ca 2+ .
  • the ratio of the group / intermediate diuretic to the calcium-containing component is more preferably from 1:30 to 300 by weight, wherein the calcium-containing component is based on Ca 2+ .
  • the diuretic is selected from the group consisting of furosemide (furosemide), uric acid, bumetanide, tolathiamide, hydrochlorothiazide (hydrochlorothiazide), chlorothiazide, indapamide, chlorthalidone, metolazone, A type of quinidine, triamterene, amiloride, spironolactone or acetazolamide.
  • the diuretic is preferably furosemide or hydrochlorothiazide.
  • Calcium-containing component refers to various calcium substances available for human body, which are selected from one or more of shell, keel, inorganic calcium salt and organic calcium salt, wherein the shell includes mother-of-pearl, oyster, stone cassia or its activation.
  • Product calcium oxide, inorganic calcium salts and organic calcium salts include calcium chloride, calcium carbonate, calcium phosphate, calcium citrate, calcium lactate, calcium gluconate or calcium L-threonate.
  • the calcium-containing component is preferably calcium gluconate and/or calcium citrate.
  • the pharmaceutical composition for treating sputum blood pressure of the present invention contains an appropriate amount of excipients which are sucrose, lactose, galactose, maltose, mannitol, sorbitol, starch, corn starch.
  • the pharmaceutical composition of the present invention may further contain an appropriate amount of a pharmaceutically acceptable disintegrating agent, a lubricant, and a coloring agent.
  • a pharmaceutically acceptable disintegrating agent e.g., a lubricant, and a coloring agent.
  • the pharmaceutical composition of the present invention can be formulated into tablets, capsules, and powders for oral administration.
  • the invention also relates to the use of the composition for the manufacture of a medicament for the treatment of hypertension.
  • Diuretic hypotension began in 1948, but due to the toxicity of mercury diuretics and the need for intramuscular injection, it is not possible to promote the application. With the advent of thiazide diuretics in the 1950s, it was one of the main methods to treat hypertension by changing Na + balance in the body. All kinds of diuretics have a hypotensive effect and can enhance the effects of other antihypertensive drugs. According to the results of large-scale clinical trials in the world, it is proved that the antihypertensive effect of diuretics is positive.
  • Several high-pressure treatment principles committees in Europe and the United States recommend non-complexed hypertensive patients, with diuretics as the drug of choice. Diuretics are especially effective in elderly patients and obese sputum blood pressure patients.
  • Diuretics lower blood pressure, can reduce the extracellular fluid volume and cardiac output in the initial stage of administration; after long-term administration, cardiac output gradually returns to the pre-dose level and the antihypertensive effect can still be maintained. At this time, the extracellular fluid capacity still has a certain degree. Reduction; vascular resistance decreased after long-term administration.
  • Diuretic monotherapy for hypertension according to the general recommended dose, the typical case is compared with placebo, the average blood pressure is 160/95mmHg, usually single drug treatment reduces systolic blood pressure 7-15ramHg and diastolic blood pressure 4-10mHg; combined with other Antihypertensive drugs can lower blood pressure by 8-15%, that is, systolic blood pressure drops by 12-24mmHg and diastolic blood pressure drops by 8_12mmHg.
  • diuretics include "cardiotoxicity", hypokalemia, and disorders of glucose and lipid metabolism.
  • thiazide diuretics and furosemide cause hypokalemia
  • hypokalemia caused by hydrochlorothiazide is dose-related. The higher the dose, the higher the incidence of hypokalemia. Therefore, the diuretic dose should be small.
  • Furosemide is widely used in clinical practice. As a first-line antihypertensive drug, furosemide plays an important role in the treatment of hypertension. The diuretic effect of furosemide is rapid and powerful. For patients with hypertensive emergencies and hypertension with azotemia or uremia, furosemide should be selected. Furosemide orally, the dose is 80mg / day, divided into two doses. Thiazide diuretics are the most commonly used class of diuretic antihypertensive drugs. When thiazide is used alone as antihypertensive treatment, the dose should be as small as possible. 12. 5 mg of hydrochlorothiazide has a hypotensive effect.
  • the antihypertensive effect does not necessarily increase, but the adverse reaction is increased, and long-term use of hydrochlorothiazide is used in addition. In addition to electrolyte changes, it also has an adverse effect on lipid metabolism and glucose metabolism.
  • compositions of the present invention provide a solution to the above problems.
  • the present invention uses a spontaneously hypertensive rat to test the antihypertensive effect of a combination of calcium and a diuretic, and observes the clinical patient.
  • the result is as follows -
  • the core of the present invention is the special role of calcium in the treatment of hypertension, which enhances the blood pressure lowering effect of low-dose diuretics, achieving the goals shown in Figure 12.
  • Figure 1 shows an experimental study of calcium-enhanced furosemide lowering blood pressure.
  • Figure 2 shows a statistical table of experimental data for the effect of calcium accelerated urine on human systolic blood pressure (SBP).
  • FIG 3 shows a statistical table of experimental data for the effect of calcium accelerated urine on human diastolic blood pressure (DBP).
  • Figure 4 shows a statistical table of experimental data for the effect of calcium accelerated urine on human body pressure difference (PBP).
  • Figure 5 shows a statistical table of experimental data for the effect of calcium accelerated urine on human heart rate (HRR).
  • Figure 6 shows an experimental study of the hypotensive effect of calcium-enhanced hydrochlorothiazide.
  • Figure 7 is a graph showing the experimental data of the effect of calcium hydrochlorothiazide on human systolic blood pressure (SBP).
  • FIG 8 is a graph showing the experimental data of the effect of calcium hydrochlorothiazide on human diastolic blood pressure (DBP).
  • Figure 9 is a graph showing the experimental data of the effect of calcium hydrochlorothiazide on human body pressure difference (PBP).
  • Figure 10 is a graph showing the experimental data of the effect of calcium hydrochlorothiazide on human heart rate (HRR).
  • FIG 11 shows three ways in which the usual drugs are treated in the prior art.
  • Figure 12 shows the specific role of calcium in the treatment of hypertension, the goal achieved. detailed description
  • the pharmaceutical compositions of the present invention are first formulated into tablets and capsules using the following methods and ratios:
  • Preparation method 1 The fine powder of the active ingredient in the pharmaceutical composition and an appropriate amount of the auxiliary material are uniformly mixed, and are dry-pressed or granulated and tableted according to a conventional method.
  • the tablet may be coated with sugar, film or uncoated, and the tablet weight is 100-100 mg;
  • Preparation method 2 uniformly mix the fine powder of the active ingredient in the pharmaceutical composition and the appropriate amount of the auxiliary material, wet granulation or powder directly according to a conventional method. Fill the capsules. The capsule weighs 100-1000 mg.
  • Example 1 Example 1:
  • Indapamide l.Omg calcium citrate 2000 mg, sucrose 350 mg, starch 49 mg. It is worth mentioning that the amount of calcium is added according to the proportion of Ca 2+ in the calcium-containing component.
  • Wca 2+ indicates the amount of calcium used
  • WHF indicates the amount of calcium component in the formulation
  • M CA 2+/MHF*100% indicates the percentage of calcium in the calcium-containing component.
  • the beneficial effects of the composition of the present invention in the preparation of a medicament for treating hypertension can be further illustrated by animal testing and human observation.
  • Figures 1 to 5 are based on experimental results of the furosemide + calcium group;
  • Figures 6 to 10 are based on the experimental effects of the hydrochlorothiazide + calcium group. Animal test
  • SHR is an animal model with a genetic background that is most suitable for studying human essential hypertension.
  • Eight-week-old male SHR rats purchased from National Experimental Animal Center of Yangming University, Taipei, Taiwan) were kept in a laboratory environment for two weeks, then stroked for two consecutive weeks or more, and placed in a fully awake state.
  • the tail vein blood pressure measuring device [ ⁇ hysiograph (Model: DMP-4B) Narco Bio-systems, Inc. Houston, TX, USA], the tail blood pressure is measured by the tail, and the blood pressure is measured three times a week until the blood pressure value is relatively stable. Can be tested.
  • SHR was randomly divided into 3 groups.
  • a certain amount of the test sample and distilled water were taken according to the body weight of the rat. 5 ⁇ /kg/d ⁇
  • the furosemide group was 35mg/kg/d; the furosemide + calcium group was furosemide 35rag/kg/d + mother-of-pearl ultrafine powder 2000mg/kg/d; the control group was distilled water 7. 5ml/kg/d.
  • the rats were fed with a stomach tube in an awake state, and the blood pressure was measured three times a week. When the blood pressure dropped to a certain level and no longer decreased, the administration was stopped and the blood pressure recovery was further observed, and the blood pressure value was collected and calculated.
  • the hydrochlorothiazide + calcium group was hydrochlorothiazide 4 mg/kg.
  • control group is distilled water 7. 5ml/kg. qd, the rats are fed through the stomach tube in awake state, blood pressure is measured three times a week, when the blood pressure drops to a certain When the level is no longer falling, the administration is stopped and the recovery of blood pressure is further observed, and the blood pressure value is collected and calculated. After two months of observation, the blood pressure of both groups was significantly decreased, and there was no significant difference in the blood pressure drop between calcium and calcium.
  • the control is distilled water 7. 5ml / kg.
  • the control group is distilled water 7.
  • the hydrochlorothiazide + calcium group is hydrochlorothiazide 1. 33mg / kg. qd + mother-of-pearl ultrafine powder 500mg / kg. qd; Qd, continued to observe for one and a half months, the blood pressure of the calcium-added group was significantly lower than that of the uncalcified group, and the difference between the two groups was 5-10 raiHg. The results are shown in Fig. 6. The results showed that: calcium addition can enhance the blood pressure lowering of hydrochlorothiazide at lower doses. effect. Observation of human medication, the effect of furosemide + calcium on human blood pressure
  • Figure 2-5 shows a human observed study of the blood pressure lowering effect of calcium-enhanced furosemide.
  • Patients with primary hypertension with a mild to moderate blood pressure of 140-180/90-109 mraHg were selected from the community clinic. The gender was not limited, and the age was over 35 years old. Secondary hypertension, hypertension combined with heart and kidney failure, serum creatinine 3mg/dl, history of allergies to ACEI, pregnant women and patients who cannot cooperate with doctors are not included, and daily intake of calcium tablets is not included.
  • the test was emptied for two weeks before the start of the test, and continuous administration was observed for four weeks. The designated drug was taken orally once a day.
  • the blood pressure and heart rate were reviewed weekly during the treatment, and the right upper arm was recorded three times.
  • FIG. 1 shows the effects of drugs on systolic blood pressure (SBP), diastolic blood pressure (DBP), differential pressure (PBP, systolic-diastolic blood pressure), and heart rate (HRR).
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • PBP differential pressure
  • HRR heart rate
  • the systolic and diastolic blood pressures of the observation group were significantly lower than those of the control group, especially the systolic blood pressure decreased significantly.
  • the effective rate of the observation group was 96%, and the effective rate was 4%; while the effective rate of the control group was 48%, the effective rate was 44%, and the ineffective rate was 8%.
  • the blood pressure and heart rate of the right upper arm were recorded three times, and the patient's adverse reactions were asked.
  • the patients were randomly divided into two groups.
  • the observation group F1 and the control group F2 each had 25 patients.
  • the dosage of the F1 group is hydrochlorothiazide 6.25 mg / d + calcium gluconate 2000 mg / d (corresponding to calcium 178.6 mg / d), and the F2 group hydrochlorothiazide is 6. 25 mg / d.
  • Figure 7-10 shows the effects of drugs on systolic blood pressure (SBP), diastolic blood pressure (DBP), differential pressure (PBP, systolic-diastolic blood pressure), and heart rate (HRR).
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • PBP systolic-diastolic blood pressure
  • HRR heart rate
  • the composition of the present invention is compared with a separate diuretic and a novel antihypertensive drug as follows: Diuretic new antihypertensive drug The therapeutic effect of the present invention is low.

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Description

一种治疗高血压的药物组合物 技术领域
本发明涉及一种药物组合物，更确切地说，本发明涉及一种治疗高血压的药物组 合物。 背景技术
高血压病是目前最常见的心血管疾病之一， 临床以体循环动脉压增高为主要表 现， 多伴有脑卒中、 心肌梗塞、心衰、 冠心病、糖尿病等多种并发症。 欧洲和北美是 高血压病的高发区。 调査表明， 我国成人高血压患病率为 18.8%， 估计全国患病人数 为 1.6亿， 比 1991年增加 7000多万，农村高血压患病率上升迅速，城乡差距不明显。 总体上讲， 高血压病人较正常人寿命缩短 15-20年。 95%的高血压病人是原发性高血 压， 15-30%的原发性高血压患者与肾脏肾素循环水平异常有关。
目前抗高血压药物有很多类型， 常用的药物有利尿剂、 α受体阻断剂、 β受体阻 断剂、 钙通道抑制剂和肾素 -血管紧张素系统调节剂。 CN1562369 Α 中公开了一种治 疗高血压的药物组合物， 其中含有一定重量比的钙离子拮抗剂、 利尿剂等。
通常药物治病一般按图 11所示的三种途径。
途径 1 显示主要致病因素对少数靶器官产生作用导致细胞病理活动从而出现病 理症状。 然而， 体内其它器官或细胞未受到影响， 细胞活动正常。 "病理缺陷"组织 和 "正常"组织对致病因素不同的响应是治疗药物设计与开发的关键着眼点。
途径 2代表多数西药治病的现状， 此类药物针对一个或几个病理组织发挥作用。 大多数情况下机体的生化或生理异常都已阐述得较清楚，设计的药物通过改变一个或 某几个病变组织以改善临床症状。为了使目标组织或组织症状得到实质性的控制，需 要服用大量的药物。这些药物有很强的药理活性，同时对其它正常组织也会产生影响， 因此产生副作用。
途径 3代表药物治疗的一种较理想的状态。假若主要致病因素知道，可以通过设 计药物抑制致病因素或直接产生生理活性， 因此病变组织恢复正常，从而疾病症状得 以控制。药物抑制致病因素对健康组织产生作用，正常健康组织不受致病因素的影响， 因而， 药物的副作用较少。 在理论上,这是新药开发的一个很理想的途径。 然而， 存 在以下问题：首先，大部分疾病，其主要致病因素不详；其次，多数疾病并发症较多； N2006/000592 第三， 即使病因知道， 一种化学成分能抑制所有病因几乎是不可能的。
抗高血压药物五十年来得到很大的发展。但是，高血压作为一种病因不确定的疾 病，药物针对一种病因或作用机理产生的一种或几种的作用治愈率较低，通常一种药 物的治愈率约为 40-50%， 而且预后较差。 近年来， 虽有很多新的疗效好副作用少的 降压药， 控制血压率也只能达到 50-60%。 因此， 一种新的治疗模式逐渐应用于临床， 复方降压药制剂是国际公认的一种治疗方向。本发明人多年的研究证明： 50%的髙血 压患者需要联合用药。由于复方抗高血压药物组方通常遵循不同作用机制药物进行配 比的原则， 因此表现为增加疗效或者降低副作用的优点， 取得了较好血压控制效果， 从而完成了本发明。 发明内容
本发明的一个目的在于提供一种用于治疗高血压的药物组合物。
本发明的另一个目的在于提供该组合物在制备治疗高血压病药物中的应用。 本发明提供的一种治疗高血压的药物组合物， 其特征在于该组合物包含利尿剂、一 种含钙组分、制药上可接受的辅料， 其中利尿剂与含钙组分的配比以重量计为 1:10-2000， 其中含钙组分以 Ca2+计。
该组^ l中利尿剂与含钙组分的配比以重量计鶴为 1:20-500,其中含钙组分以 Ca2+计。 该组^ /中利尿剂与含钙组分的配比以重量计更优选为 1:30-300, 其中含钙组分以 Ca2+ 计。
所述利尿剂选自速尿 （呋噻米）、 利尿酸、 布美他尼、 托拉噻米、 氢氯噻嗪（双 氢克尿塞)、 氯噻嗪、 吲哚帕胺、 氯噻酮、 美托拉宗、 喹乙宗、 氨苯蝶啶、 阿米洛利、 螺内酯或乙酰唑胺之一种。 该利尿剂优选为速尿或氢氯噻嗪。
含钙组分指可供人体服用的各种钙质，其选自贝壳、龙骨、无机钙盐和有机钙盐 之一种或多种， 其中贝壳包括珍珠母、牡蛎、石决明或其活化产品氧化钙， 无机钙盐 和有机钙盐包括氯化钙、 碳酸钙、 磷酸钙、 柠檬酸钙、 乳酸钙、 葡萄糖酸钙或 L-苏 糖酸钙。 该含钙组分优选为葡萄糖酸钙和 /或柠檬酸钙。
本发明治疗髙血压的药物组合物中含有适量的辅料， 该辅料为蔗糖、乳糖、半乳 糖、 麦芽糖、 甘露醇、 山梨醇、 淀粉、 玉米淀粉。
本发明的药物组合物中还可以加入适量的制药上可接受的崩解剂、润滑剂、着色 剂、 矫味剂。
本发明的药物组合物可以制成口服给药的片剂、 胶囊剂、 粉末剂。
本发明还涉及该组合物在制备治疗高血压病药物中的应用。
利尿剂降压始于 1948年， 但由于汞利尿剂的毒性和必须肌肉注射， 无法推广应 用。 随着 20世纪 50年代噻嗪类利尿剂的问世， 以药物改变体内 Na+平衡成为治疗高 血压的主要方法之一。 各类利尿药单用即有降压作用， 并可增强其它降压药的作用。 根据国际上大规模临床试验的结果，证明利尿剂降压效果是肯定的。欧美几个高血压 处理原则委员会都建议无并发症的高血压病人， 以利尿剂为首选药物。利尿剂尤其对 老年人、 肥胖的髙血压患者效果更加明显。
利尿剂降低血压，用药初期可以减少细胞外液容量及心输出量；长期给药后心输 出量逐渐恢复至给药前水平而降压作用仍能维持，此时细胞外液容量仍有一定程度的 减少； 长期给药后血管阻力有所下降。
利尿剂单药治疗高血压， 按一般推荐剂量， 典型的情况是与安慰剂对照比， 平均 血压为 160/95mmHg，则通常单药治疗降低收缩压 7— 15ramHg及舒张压 4一 lOmmHg;联 合其它抗高血压药物， 可使血压下降 8— 15%， 即收缩压下降 12— 24mmHg及舒张压下 降 8_12mmHg。
利尿剂临床常见的副作用包括 "心脏毒性"、 低钾血症以及糖、脂代谢紊乱等。 在各种利尿剂中，噻嗪类利尿剂和速尿引起低血钾较为明显，氢氯噻嗪引起的低血钾 与剂量相关， 剂量越大， 低血钾的发生率越高。 因此， 利尿剂剂量宜小。
速尿在临床上用得比较广泛，作为一线降压药，速尿在治疗高血压方面发挥了重 要的作用。速尿的利尿作用迅速、强大，对高血压急症以及高血压合并氮质血症或尿 毒症的患者宜选速尿。 速尿口服降压， 剂量为 80mg/日， 分两次服用。 噻嗪类利尿药 是利尿降压药中最常用的一类。 单独使用噻嗪类作为降压治疗时， 剂量应尽量小， 12. 5mg的氢氯噻嗪即有降压作用， 超过 25mg时降压作用并不一定增强， 反而使不良 反应增加，长期大量使用氢氯噻嗪除引发电解质改变外， 尚对脂质代谢、糖代谢产生 不良影响。
由于以上原因， 以及新型降血压药的研制成功和投放市场， 近年来， 作为第一代 降压药的利尿剂在临床上应用受到了一定的限制。
据报道， 大剂量钙的摄入可以产生降压效应。 然而， 这个发现在整个研究过程中 不能成功地重复。此外， 饮食钙产生的此类降压效应在低肾素水平、盐敏感患者中已 相当清楚， 钙拮抗剂对这类患者有较好的疗效。这似乎是一个很荒谬的结论。这个研 究领域的很多专家试图找到一个合理的解释，都没有取得成功。本发明人发现： 钙是 一个肾素水平抑制因子,具有甲状旁腺活性， 从而减少患者体内甲状旁腺高血压因子
(PHF) 的循环水平和 1， 25-二-羟基-维生素 D3的生理活性。
经过长期研究和大量试验， 本发明的组合物为上述问题提供了解决方案。
本发明采用自发性高血压大鼠测试了钙与利尿剂联合用药的降压效应，并对临床 病人进行观察。 结果如下-
1. 钙加强了利尿剂的降压作用；
2. 钙提高了预后效果和有效率。 但相关作用在单独服用利尿剂中没有出现。 本发明的核心是钙在高血压治疗中的特殊作用，能增强低剂量的利尿剂的降低血 压的作用， 实现图 12所示的目标。 附图说明
图 1表示钙增强速尿降血压作用的实验研究。
图 2表示钙加速尿对人体收缩压（SBP) 的影响的试验数据统计表。
图 3表示钙加速尿对人体舒张压（DBP) 的影响的试验数据统计表。
图 4表示钙加速尿对人体压差（PBP) 的影响的试验数据统计表。
图 5表示钙加速尿对人体心率（HRR) 的影响的试验数据统计表。
图 6表示钙增强氢氯噻嗪的降血压作用的实验研究。
图 7表示钙加氢氯噻嗪对人体收缩压 （SBP) 的影响的试验数据统计表。
图 8表示钙加氢氯噻嗪对人体舒张压（DBP) 的影响的试验数据统计表。
图 9表示钙加氢氯噻嗪对人体压差 （PBP) 的影响的试验数据统计表。
图 10表示钙加氢氯噻嗪对人体心率 （HRR) 的影响的试验数据统计表。
图 11表示现有技术中通常药物治病的三种途径。
图 12表示钙在高血压治疗中的特殊作用即实现的目标。 具体实施方式
下面将通过实施例对本发明作进一步说明。
首先采用以下方法和配比将本发明药物组合物分别制成片剂和胶囊： 制备方法 1 : 将该药物组合物中有效成分的细粉以及适量辅料混合均匀， 按常规 方法干法压片或制粒压片。 片剂可包糖衣、 薄膜衣或不包衣， 片重 100-lOOOmg; 制备方法 2: 将该药物组合物中有效成分的细粉以及适量辅料混合均匀， 按常规 方法湿法制粒或用粉末直接填充胶囊。 胶囊重 100-1000mg。 实施例 1 :
速尿 5mg， 葡萄糖酸钙 2000mg， 蔗糖 350mg， 淀粉 45mg。 实施例 2:
氢氯噻嗪 6.25mg， 葡萄糖酸钙 2000 mg， 蔗糖 350mg， 淀粉 43.75mg。 实施例 3:
吲哚帕胺 l.Omg, 柠檬酸钙 2000 mg， 蔗糖 350mg, 淀粉 49mg。 值得一提的是， 钙的用量根据 Ca2+在含钙组分中所占的比例加入。
Figure imgf000007_0001
Wca2+ 表示钙的用量；
WHF 表示配方中含钙组分的用量；
MCA2+/MHF*100% 表示钙在含钙组分中的百分含量。 下面将通过动物试验及人体观察进一步说明本发明组合物在制备治疗高血压病 药物应用中的有益效果。附图 1至 5基于速尿 +钙组的实验结果；附图 6至 10基于氢 氯噻嗪 +钙组的实验效果。 动物试验
SHR是一种具有遗传背景的最适宜研究人类原发性高血压病的动物模型。 取 8周龄雄性 SHR大鼠 （购自国立阳明大学实验动物中心， 台北， 台湾）， 在实 验室环境下饲养两周，然后每天抚摸训练连续两周以上，并在完全清醒的状态下放入 尾静脉血压测量装置 [Γ hysiograph (Model :DMP-4B) Narco Bio-systems, Inc. Houston, TX， USA] , 通过夹尾测定尾部血压， 每周测定三次血压， 直到血压值相对 稳定， 方可进行试验。 速尿的降压试验 试验时， SHR随机分成 3组。 根据大鼠的体重取一定量被测试样品及蒸馏水。速 尿组为 35mg/kg/d; 速尿 +钙组为速尿 35rag/kg/d +珍珠母超微粉 2000mg/kg/d; 对 照组为蒸馏水 7. 5ml/kg/d。 通过一个胃管在清醒状态下给大鼠喂药， 血压每周测量 三次， 当血压降至一定水平不再下降时，停止给药并进一步对血压的恢复情况进行观 测， 收集血压值并计算。 观察两周， 结果表明：低剂量时单独的速尿没有明显的降压 作用 （血压下降 3-6画 )， 加钙可以增强相同剂量的速尿的降血压作用 （血压下降 10 - 15mmHg)， 结果如图 1所示。 结果表明： 钙可以增强低剂量的速尿的降压作用。 氢氯噻嗪的降压试验 试验时， SHR随机分成 3组， 并根据大鼠的体重取被测试样品及蒸馏水， 试验开 始时， 氢氯噻嗪组为 4mg/kg. qd; 氢氯噻嗪 +鈣组为氢氯噻嗪 4mg/kg. qd +珍珠母超 微粉 500mg/kg. qd; 对照组为蒸镏水 7. 5ml/kg. qd， 通过胃管在清醒状态下给大鼠喂 药， 血压每周测量三次， 当血压降至一定水平不再下降时， 停止给药并进一步对血压 的恢复情况进行观测， 收集血压值并计算。观察两个月， 给药两组的血压均有明显的 下降， 加钙与不加钙二者的血压下降值没有明显的差异。调整给药剂量： 氢氯噻嗪组 为 1. 33mg/kg. qd ; 氢氯噻嗪 +钙组为氢氯噻嗪 1. 33mg/kg. qd + 珍珠母超微粉 500mg/kg. qd; 对照组为蒸馏水 7. 5ml/kg. qd， 继续观察一个半月， 加钙组较未加钙 组的血压下降明显， 二者相差 5-10raiHg， 结果如图 6所示， 结果表明： 加钙可以增 强较低剂量下的氢氯噻嗪的降血压作用。 人体用药观察 ， 速尿 +钙对人体血压的影响
图 2-5为钙增强速尿的降血压作用的人体观察研究。选取社区门诊轻、中度血压 在 140-180/90- 109mraHg的原发性高血压患者， 性别不限， 年齢 35岁以上。继发性高 血压、 高血压合并心肾功能衰竭、 血肌酐 3mg/dl、 对 ACEI有过敏史、 孕妇和不能 和医生合作的病人不入选， 日常服用钙片的不入选。试验开始前清空两周， 连续给药 观察四周。指定药物每天一次口服， 治疗期间每周复查血压和心率， 记录三次右上臂 坐位血压和心率， 并询问患者不良反应情况。 病人随机分为两组， 观察组 C1和对照 组 C2各为 25名患者。 C1 组剂量为速尿 5mg/d+葡萄糖酸钙 2000rag/d (相当于钙 178. 6mg/d)， 而 C2组速尿为 5mg/d。 图 2-5分别为药物对患者收缩压（SBP)、 舒张 压 （DBP)、 压差 （PBP， 收缩压 -舒张压） 以及心率（HRR) 的影响的统计数据。 统计 结果表明：速尿在低剂量时， 对照组和观察组比较， 观察组的收缩压和舒张压均较对 照组的收缩压和舒张压降低明显， 尤其是收缩压降低明显。 根据"中国高血压防治指 南"的标准，经治疗后收缩压达到 </= 140 mmHg者为正常（即为显效）； 达到 </= 160 mmHg者为控制（即有效）。 本实验中经服药 2周后： 观察组显效率为 96%， 有效率为 4%； 而对照组显效率为 48%， 有效率为 44%， 无效率为 8%。 氢氯噻嗪 +钙对人体血压的影响 图 7-10: 钙增强氢氯噻嗪的降血压作用的人体观察研究。 选取社区门诊轻、 中 度血压在 140- 180/90-109mmHg的原发性高血压患者， 性别不限， 年龄 35岁以上。继 发性高血压、 高血压合并心肾功能衰竭、 血肌酐 3mg/dl、 对 ACEI有过敏史、 孕妇 和不能和医生合作的病人不入选， 日常服用钙片的不入选。试验开始前清空两周， 连 续给药观察四周。指定药物每天一次口服， 治疗期间每周复査血压和心率， 记录三次 右上臂坐位血压和心率， 并询问患者不良反应情况。 病人随机分为两组， 观察组 F1 和对照组 F2各为 25名患者。 F1组剂量为氢氯噻嗪 6. 25mg/d+葡萄糖酸钙 2000mg/d (相当于钙 178. 6mg/d)，而 F2组氢氯噻嗪为 6. 25mg/d。图 7-10分别为药物对患者收 缩压（SBP) 、 舒张压 （DBP) 、 压差 （PBP， 收缩压 -舒张压） 以及心率 （HRR) 的影 响的统计数据。统计结果表明， 对照组和观察组比较， 观察组的收缩压和舒张压均较 对照组的收缩压和舒张压降低效果明显， 尤其是收缩压降低明显。 根据"中国高血压 防治指南"的标准，经治疗后收缩压达到 </= HOmmHg者为正常（即为显效）； 达到 </= 160 mmHg者为控制（即有效）。 本实验中经服药 2周后： 观察组显效率为 92%， 有效率 为 8%; 而对照组显效率为 72%， 有效率为 24%， 无效率为 4%。 将本发明组合物与单独的利尿剂以及新型的降压药物比较如下表: 利尿剂 新型降压药物 本发明产品 疗效 低 高 髙
有效率（％) 低 低 高
专利 无 保护期内 可申请 副作用 明显 低 低
投资 低 高 低 虽然本发明已经进行了详细说明和描述， 但本领域技术人员应当理解： 在不离开本发明权利要求所述的精神和范围的前提下，可以对本发明的形式 和细节作出各种改变。

Claims

权 利 要 求 书
1. 一种治疗高血压的药物组^ /， 其特征在于该组^！包渊尿剂、一种含钙组分、 制药上可接受的辅料， 其中利尿剂与含钙组分的配比以重量计为 1:10-2000， 其中含钙组分 以 Ca2+计。
2. 权利要求 1所述的药物组合物， 其特征在于利尿剂与含钙组分的配比以重量计为 1:20-500, 其中含钙组分以 Ca2+计。
3. 权利要求 1所述的药物组合物， 其特征在于利尿剂与含钙组分的配比以重量计为 1:30-300, 其中含钙组分以 Ca2+计。
4. 权利要求 1-3任意一项所述的药物组合物， 其特征在于利尿剂选自速尿、 利尿酸、 布美他尼、 托拉噻米、 氢氯噻嗪、 氯噻嗪、 吲哚帕胺、 氯噻酮、 美托拉宗、 喹乙宗、 氨苯蝶啶、 阿米洛利、 螺内酯或乙酰唑胺之一种。
5. 权利要求 4戶舰的药物组 勿， 漏正在于利尿剂为 氯嚇。
6. 权利要求 1-5任意一项難的药物组^ 4勿， 難征在 钙组分选自贝壳、龙骨、无 机钙盐和有机钙 ifc —种或多种， 其中贝壳包 母、 、石决明^^活化产品氧化钙， 无机钙盐和有机钙盐包擴化钙、碳薩、磷讓、機薩、乳廳丐、葡萄糖難1 ϋ鎌 麵。
7. 权利要求 6腿的药物组 辦征在 丐组舰自備體丐雄讓丐。
8.权利要求 1纖的药物组" ^勿，赚征在于辅料为纖、乳糖、半乳糖、麦芽糖、甘 露醇、 山梨醇、淀粉、 淀粉， 还可加 Aig*的制药上可接受的崩解剂、润滑剂、糖剂、 矫味剂。
9.权利要求 1舰的药物组^ I，難征在于该组 勿可制成口腿合药的片剂、藤剂、 粉末剂。
10. 权利要求 1纖的药物组 赃制备治疗髙血压病药物中的細。
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WO2012065953A1 (en) 2010-11-16 2012-05-24 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as nep inhibitors

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