CN107007812A - A kind of method for extending captopril hypotensive efficacy time - Google Patents

Abstract

The invention discloses a kind of method for extending captopril hypotensive efficacy time, belong to blood-pressure drug field.Used after captopril and soybean blood pressure lowering peptide are mixed according to a certain percentage.In the method, the purpose for extending hypotensive efficacy time while ensureing captopril blood pressure lowering effect is realized, the short shortcoming of captopril effect fierceness, duration of efficacy is overcome.It is gentle with working, the advantage for keeping hypotensive efficacy time longer.

Description

A method for prolonging the drug effect time of captopril for lowering blood pressure

technical field

The invention belongs to the field of antihypertensive drugs, and in particular relates to a method for prolonging the drug effect time of captopril for lowering blood pressure.

Background technique

Hypertension is a high-risk chronic disease mainly manifested by elevated arterial blood pressure. It has a high incidence rate in all ages and ranks first among the causes of death. According to the survey data of the World Health Organization (WHO), about one-third of adults in the world suffer from hypertension, which accounts for about 12.8% of the deaths in the world. Among them, angiotensin I-converting enzyme (ACE, EC 3.4.15.1) plays a key role in the blood pressure regulation system. Human blood pressure is mainly regulated by two antagonistic systems, the renin-angiotensin system and the kinin-kallikrein system. Renin converts angiotensinogen to angiotensin I, and angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II. Angiotensin Ⅱ can strengthen myocardial contraction, and at the same time, it can also strengthen the contraction of vascular smooth muscle, thereby raising blood pressure. ACE can also regulate the kinin system, which can convert kinins with vasodilation function into inactive slow-release peptides. Under the regulation of ACE, the two systems synergistically raise blood pressure.

The earliest antihypertensive peptides were extracted from snake venom. With the deepening of research, more and more plant-based raw materials have become good sources of antihypertensive peptides. For example, enzymolysis of wheat germ to prepare antihypertensive peptides (lowering blood pressure and antioxidant effects of enzymatic hydrolyzates of wheat germ protein components, Jia Junqiang, 2010), or the use of biotechnology to synthesize specific sequences of antihypertensive peptides (gene design of tuna antihypertensive peptides, Clone expression and activity identification, Li Yunliang, 2015). Although the ACE inhibitors of hypotensive peptides have a longer duration of action, their antihypertensive effect is slow and mild.

At present, captopril (proline derivative), as an efficient and rapid synthetic non-peptide ACE inhibitor, is widely used in clinical and scientific research. However, its half-life is only 1.9 h, and it needs to be taken three times a day to maintain its efficacy. When the total intake is 37.5-75 mg, the curative effect is only maintained for 6-8 hours; a single oral dose of 50 mg, the peak blood concentration can reach more than 600 ng/ml, and its therapeutic concentration is 50 ng/ml, which is relatively Large peak-to-trough fluctuations in blood concentration are likely to cause adverse reactions such as dizziness, headache, and gastrointestinal disturbances (research on captopril sustained-release capsules, Huang Ying, 2004). Due to the strong and short duration of captopril alone, many researchers have turned their attention to the study of captopril sustained release, such as captopril sustained release tablets produced by Shanghai Kaibao Pharmaceutical Co., Ltd., the half-life for 3 h.

In addition to the effect of lowering blood pressure, the active peptides prepared from soybeans also have the effects of anti-oxidation, anti-fatigue, improving immunity, and lowering blood lipids (Research progress on physiological functions of soybean peptides, Li Wen, 2012). Compared with captopril, soybean antihypertensive peptide reduces systolic blood pressure less than captopril, but has mild effect and effective antihypertensive duration for a long time. , 2009).

Captopril and soybean antihypertensive peptides have their own advantages and disadvantages in terms of blood pressure lowering effects, but there is no report on the use of antihypertensive peptides and captopril to prolong the antihypertensive effect of captopril.

Contents of the invention

The purpose of the present invention is to overcome the short duration of captopril's drug effect and provide a method for prolonging the effective duration of blood pressure reduction on the basis of ensuring the rapid onset and effect of captopril.

A method for prolonging the drug effect time of captopril for lowering blood pressure is carried out according to the following steps:

The captopril and the soybean hypotensive peptide are mixed according to a certain ratio before use.

The mixing method includes: directly mixing the captopril in solid form and the soybean hypotensive peptide, or mixing the captopril in liquid form and the soybean hypotensive peptide, and then drying it by spray drying or other methods.

The mixing ratio of captopril and soybean hypotensive peptide is: 3:7~8:2 (mass ratio).

The soybean hypotensive peptide described therein is carried out according to the following steps: the soybean protein solution with a substrate mass concentration of 5% is hydrolyzed with 0.1% (v/v) alkaline protease at 50°C and pH 8.5 for 3 h , centrifuged to obtain the supernatant, concentrated and dried.

Wherein the soybean hypotensive peptide can be simply replaced by hypotensive peptides prepared from other raw materials or similar processes to achieve similar effects.

Advantages of the present invention:

(1) Captopril and soybean antihypertensive peptide have their own characteristics when they work. In the early stage, captopril acts quickly and plays the main antihypertensive effect. In the middle and later stages, soybean antihypertensive peptide is digested and absorbed by the stomach and plays a role in reducing blood pressure. Prolongs the action of the hypotensive effect.

(2) The combination of captopril and soybean antihypertensive peptide has a synergistic effect. Compared with single captopril, the antihypertensive effect time of captopril-soybean antihypertensive peptide mixture can be extended by up to 1.29 h . Compared with single soybean peptide, the antihypertensive effect time of captopril-soybean hypotensive peptide mixture can be prolonged by up to 0.91 h.

detailed description

The terms used in the present invention, unless otherwise specified, generally have the meanings commonly understood by those skilled in the art. The present invention will be described in further detail below in conjunction with specific examples and with reference to data. It should be understood that these embodiments are only further illustrations of the present invention, and should not be construed as limiting the protection scope of the present invention. Engineers in this field can make some non-essential improvements and adjustments to the present invention according to the contents of the above inventions.

In the following examples, various procedures and methods not described in detail are conventional methods well known in the art. The sources and trade names of the reagents used, as well as those whose components must be listed, are indicated when they appear for the first time, and the same reagents used thereafter are the same as those indicated for the first time unless otherwise specified.

Captopril used in this comparison and examples was purchased from Sigma.

The soybean hypotensive peptide used in this comparison and embodiment is prepared by the following method:

(1) Prepare a soybean protein solution with a substrate concentration of 5%, stir in a 50°C water bath for 10 min, and enzymatically hydrolyze after the temperature rises to a certain point.

(2) Add alkaline protease at 0.1% (v/v) and maintain the pH at 8.5 with NaOH solution, and enzymatically hydrolyze for 3 h.

(3) After the enzymatic hydrolysis, the enzyme was inactivated in a boiling water bath, and the supernatant obtained by centrifugation (4000 r/m, 10 min) was concentrated and spray-dried to obtain soybean hypotensive peptide powder, which was stored in a dry environment for later use.

The antihypertensive drug effect detection method used in the present embodiment is as follows:

In this example, the purchased rats were essential hypertensive rats (SHR). The temperature of the feeding environment was kept at 22±2°C and the humidity was kept at 50±5%.

(1) One-time gavage test: prepare reagents and gavage rats in each group according to a certain dose, measure the systolic blood pressure of rats regularly after gavage, and take the average value of three consecutive measurements.

(2) The rat systolic blood pressure measurement instrument is the ALC-NIBP non-invasive blood pressure measurement and analysis system, which was purchased from Shanghai Alcott Biotechnology Co., Ltd. The rat systolic blood pressure measurement process was carried out according to the instrument operation instructions.

Control 1

One-time gavage test: Captopril solution was prepared at 15 mg/mL with normal saline as a solvent, and rats were gavaged with a dose of 30 mg/kg bw, and the systolic blood pressure of the rats was measured every 1 h after gavage. Three consecutive measurements were taken to obtain the average value. The effective blood pressure lowering time was 6.78±0.34 h.

Control 2

One-time gavage test: Soybean antihypertensive peptide solution was prepared at 15 mg/mL with normal saline as a solvent, and rats were gavaged with a dose of 30 mg/kg bw, and the systolic blood pressure of the rats was measured every 1 h after gavage. Three consecutive measurements were taken to obtain the average value. The effective blood pressure lowering time was 7.16±0.31 h.

Example 1

One-time gavage test: mix captopril and soybean hypotensive peptide at a mass ratio of 8:2 (mass ratio), and use normal saline as a solvent to prepare a captopril-soybean hypotensive peptide mixed solution at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 7.46±0.38 h. Compared with control 1, the drug effect time of the captopril group was prolonged by 0.68 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.30 h.

Example 2

One-time gavage test: mix captopril and soybean hypotensive peptide at a mass ratio of 7:3 (mass ratio), and use normal saline as a solvent to prepare a captopril-soybean hypotensive peptide mixed solution at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 7.88±0.28 h. Compared with the control group 1, the drug effect time of the captopril group was prolonged by 1.10 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.72 h.

Example 3

One-time gavage test: mix captopril and soybean antihypertensive peptide at a mass ratio of 6:4 (mass ratio), and use normal saline as a solvent to prepare a captopril-soybean antihypertensive peptide mixed solution at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 7.93±0.36 h. Compared with control 1, the drug effect time of the captopril group was prolonged by 1.15 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.77 h.

Example 4

One-time gavage test: mix captopril and soybean hypotensive peptide at a mass ratio of 5:5 (mass ratio), and use normal saline as a solvent to prepare a mixed solution of captopril-soybean hypotensive peptide at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 7.99±0.37 h. Compared with control 1, the drug effect time of the captopril group was prolonged by 1.21 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.83 h.

Example 5

One-time gavage test: mix captopril and soybean hypotensive peptide at a mass ratio of 4:6 (mass ratio), and use normal saline as a solvent to prepare a mixed solution of captopril-soybean hypotensive peptide at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 8.07±0.29 h. Compared with control 1, the drug effect time of the captopril group was prolonged by 1.29 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.91 h.

Example 6

One-time gavage test: mix captopril and soybean hypotensive peptide at a mass ratio of 3:7 (mass ratio), and use normal saline as a solvent to prepare a mixed solution of captopril-soybean hypotensive peptide at 15 mg/mL. Rats were orally gavaged with a dose of 30 mg/kg·bw, and the systolic blood pressure of the rats was measured every 1 h after gavage, and the average value was taken for three consecutive measurements. The effective blood pressure lowering time was 7.76±0.41 h. Compared with control 1, the drug effect time of the captopril group was prolonged by 0.98 h, and compared with the control group 2, the drug effect time of the soybean hypotensive peptide group was prolonged by 0.60 h.

Claims (4)

1. Mix captopril and soybean hypotensive peptide in a certain proportion before use; The mixing ratio of captopril and soybean hypotensive peptide is: 3:7~8:2 (mass ratio). 2. A method for prolonging the antihypertensive drug effect time of captopril according to claim 1, wherein the mixing method comprises: directly mixing captopril in solid form with soybean hypotensive peptide. 3. a kind of method prolonging captopril antihypertensive drug effect time according to claim 1, it is characterized in that wherein mixing method comprises: also can after captopril and soybean antihypertensive peptide in liquid form are mixed, with It can be obtained by drying by means of spray drying or the like. 4. a kind of method prolonging captopril antihypertensive drug effect time according to claim 1, is characterized in that wherein said soybean antihypertensive peptide, carries out according to the following steps: substrate mass concentration is 5% The soybean protein solution was hydrolyzed with 0.1% (v/v) alkaline protease at 50°C and pH 8.5 for 3 h, centrifuged to obtain the supernatant, concentrated and dried.