KR100577674B1 - A curing and preventing pharmaceutical composition having an effect of anti-hypertension inducing by containing a extract of chinese herb - Google Patents

Abstract

The present invention is an extract of Banja (백 夏), Baekchul (白 朮), Cheonma (天麻), dermis (복), Fuling (茯 笭), Sansa (山査), Happiness and Huangshan (黄蓮) as an active ingredient The present invention relates to a pharmaceutical composition for treating or preventing hypertension, which may be effectively used as an agent for treating or preventing hypertension.

Half body, baekchul, cheonma, dermis, biryeong, sansa, pity, barren, high blood pressure

Description

Anti-hypertension treatment or prevention pharmaceutical composition having an effect of anti-hypertension inducing by containing a extract of chinese herb}

1 is a graph showing the vascular relaxation effect on the vasoconstriction of phenylephrine of the compositions prepared in Example 1 of the present invention.

Figure 2 is a graph showing the vascular relaxation effect of the composition (HMC05) according to the present invention on the vascular contraction of phenylephrine with or without endothelial cells.

Figure 3 is a graph showing the vascular relaxation effect of the composition (HMC05) according to the present invention on the vascular contraction of phenylephrine after indomethacin pretreatment.

Figure 4 is a graph showing the vascular relaxation effect of the composition (HMC05) according to the present invention on the vascular contraction of phenylephrine after atropine pretreatment.

Figure 5 is a graph showing the vascular relaxation effect of the composition (HMC05) according to the present invention on the vasoconstriction of phenylephrine after glabenclamide and TEA pretreatment.

6 is a graph showing the vascular relaxation effect of the composition (HMC05) according to the present invention for the addition of calcium by concentration to the blood vessels induced depolarization with high concentration of KCl.

7 is a graph showing the blood pressure and heart rate lowering effect of hypertensive rats using the composition according to the present invention (HMC05) and amlodipine together with the control group.

Figure 8 is a composition (C) and amlodipine (B) according to the present invention is a photograph showing the effect of relieving liver tissue damage of hypertensive rats with the control (A).

The present invention relates to a pharmaceutical composition for treating or preventing hypertension, which contains a mixed extract of halved, baekchul, cheonma, dermis, bokyeong, hawthorn, hungry and rhubarb as an active ingredient.

Cardiovascular disease is the number one cause of death worldwide, with 45 million people annually, and 44 of the world's 200 prescriptions account for 22% of all cardiovascular treatments (Statistics 2004). The global market size of the cardiovascular treatment market was $ 52.2 billion in 2003, and the estimated global market in 2012 is estimated to be about $ 96.6 billion (Business Communication Co. Inc Market Research Report).

Hypertension is the most frequent disease among chronic circulatory diseases and is relatively symptomatic. However, active management and treatment are required because they can cause fatal complications caused by damage to the target organs such as the brain, heart, kidneys, and eyes. Complications are that blood is sent at high blood pressure, resulting in poor heart function, heart failure, blood vessels bursting at high blood pressure, cerebral hemorrhage, high blood pressure in the blood vessel wall (intima), and wounds, and lipid components build up, causing blood clots to block blood vessels. Atherosclerosis, cerebral infarction, and blockage of the coronary artery to the heart can cause angina and myocardial infarction. In addition, kidney function is not good, causing kidney failure, and also affects the blood vessels in the eye, causing vision damage.

High blood pressure, which belongs to the category of headache, hyeonhun, liver yangyang (향 陽 上 亢) of oriental medicine is causing factors such as stroke, arteriosclerosis, heart failure, kidney disease. Therefore, active management and treatment are required, but the need for the development of herbal medicines or new drugs to improve the existing therapeutic drugs due to the side effects of the drugs are emerging.

Accordingly, the present inventors have attempted to develop an antihypertensive or therapeutic agent using a herbal medicine, and measure the vascular relaxation effect from several mixed extraction compositions prepared by adding or subtracting another herbal medicine to the conventional prescription of Banhabaekchulcheon Matang, and then the most relaxing effect. The onset was completed by selecting an excellent composition and demonstrating the mechanism and antihypertensive efficacy of the selected composition.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for treating or preventing hypertension using as an active ingredient an extract containing half, white, chunkyuk, dermis, bokyeong, hawthorn, euphoria, and yellow lotus.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the treatment or prevention of hypertension, including a mixed extract of Baja, Baekchul, Cheonma, Dermis, Bokryeong, Sansa, Happiness and Rhododendron as an active ingredient.

Hereinafter, the present invention will be described in detail.

At this time, if there is no other definitions in the technical terms and scientific terms used herein, those having ordinary skill in the art to which this invention belongs have the meaning that is commonly understood.

In addition, repeated description of the same technical configuration and operation as in the prior art will be omitted.

The present invention is used for the treatment or prevention of hypertension, which is not known at all, by using extracts including halved, baekchul, cheonma, dermis, fukryeong, hawthorn, bliss, and yellow lotus.

At this time, it is preferable to use a hot water extract as a mixed extract of half, white, cheonma, dermis, bokyeong, sansa, haeju, rhubarb used in the present invention. Specifically, 9 to 17% by weight, 12 to 22% by weight, 6 to 12% by weight, 6 to 12% by weight, 6 to 12% by weight of dermis, 9 to 17% by weight of Fuling, 9 to 17% by weight of hawthorn, and 9 to 17% of weight % And 9 to 17% by weight of rhubarb are mixed and mixed, and the mixture is extracted by hot water extraction and dried. More specifically, it is 9 g, baekrye 12 g, Cheonma 6 g, dermis 6 g, Bokryeong 9 g, 9 g Sansa , 9 g of Happiness and 9 g of Rhubarb were placed in a round flask, 500 ml of distilled water was added thereto, and extracted by heating at 100 ° C. for 3 hours. The extract was filtered through a filter paper, and the filtrate was concentrated under reduced pressure with a rotary evaporator. Preference is given to using 10.65 g of powder obtained by lyophilization.

In the present invention, the eight kinds of medicines are not particularly limited in use capacity, but less than 6% by weight, 9% by weight, 9% by weight, and 12% by weight of Baekchul, Cheonma, Dermis, Fuling, Sansa, Happiness and Rhododendron, respectively. If the combination of the above medicines to improve the hypertension or treatment effect is insignificant, and if it exceeds 12% by weight, 17% by weight and 22% by weight it is not enough to use other medicines without being balanced with the addition amount of other medicines in the whole composition This is because, particularly, the extract prepared by mixing in the blending ratio is because the improvement effect on hypertension appears optimally.

However, it will be apparent to those skilled in the art that the extractable mixture can be mixed in the blending ratio according to the amount of extract to be obtained.

In addition to the above-described extraction method, any method may be used as long as it can extract the active ingredient of the herbal medicine harmless to the human body.

And, the medicinal herbs used in the present invention are already well known in oriental medicine or herbal medicine-related books, looking at its efficacy are as follows.

First of all, half-harm is an agent of moisturizing phlegm, which acts to remove swelling, and when combined with huang, the bloating and loss of appetite of the forearm due to the effect of strong consumption. When used in combination with Bokryeong, it removes the phlegm and acts on the earth. When combined with the dermis, it is impregnated, vomiting, and nausea. It is known to be used for heart and anorexia.

In addition, Baekchul (白 朮) is effective in dry humidity control (健脾 燥濕), Jihan (止汗), and when combined with Bokryeong (茯 笭) is effective for edema due to soil and soil (吐瀉) It is known.

In addition, Cheonma (天麻) is effective in the treatment of headaches, vertigo, and limbs as a symptom of Geopung (祛風), landscaping, and swallowing. It is known to be effective in treating headache and dizziness due to the efficacy of expectoration.

In addition, it is known that Fuling is effective in dry rain, diarrhea and anxin, and dermis in dry skin and dry expectancy.

Sansa is used for the indigestion of hyaluronic acid and live-blooded wild fish, and it is useful for postpartum relieving pain after mixing cheongung. It is known.

In addition, Huang Lian (黄連) has the effect of antibacterial and antipyretic effect of detoxification (청 火 解毒), blue heat humidity control (淸 熱 燥濕), Hee-pung (heeheung) is Geopung damp (祛風濕), Tong Kyung-rak (通經絡), it is known that it is used as a medicine to treat myalgia pain, limbs, headache and dizziness due to the efficacy of the muscle.

However, it is not known that the medicines used in the present invention are directly used as a therapeutic or prophylactic agent for hypertension, and even if it is known individually, it is not known that an appropriate combination extract of the above medicines has an excellent effect on hypertension.

On the other hand, the composition of the present invention extracted as described above, according to the administration method, dosage form and therapeutic purpose, the active ingredient is mixed with a pharmaceutically acceptable carrier and diluted or encapsulated in a carrier in a container form. It is preferable to make it use.

When the carrier is used as a diluent, at least one carrier selected from the group consisting of saline, buffer, dextrose, water, glycerol, Ringer's solution, lactose, sucrose, calcium silicate, methyl cellulose and ethanol is used. Prepared in unit or multiple dose formulations, such as oral or parenteral formulations such as tablets, capsules, powders, granules, suspensions, emulsions, which are used for the treatment and prevention of hypertension. Can be. However, the carrier of the present invention is not limited to the above carrier. In this case, parenteral administration means administration of the drug through rectal, intravenous, peritoneal, muscle, arterial, transdermal, nasal, inhalation, etc. in addition to oral.

In addition, the formulation may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like, and may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

In addition, the pharmaceutical composition containing the extract extracted according to the method of the present invention as an active ingredient may be parenterally or orally administered as desired, and the dosage level for a particular patient is determined by the specific compound to be used, weight, and age gender. May vary depending on health, diet, time of administration, method of administration, inoculation rate, drug mixture and severity of disease. However, preferably based on the daily dose described in the method of the present invention and the herbal medicine of the present invention, it is preferable that the extracted Banhabaekchulchonmatang extract is administered at 1000 mg / kg body weight per day on an oral administration basis.

Hereinafter, the present invention will be described in more detail based on the following examples. However, the following examples are merely to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1 Preparation of a Composition According to the Present Invention

In this example, to compare the effect of the composition according to the present invention, as shown in Table 1, the composition of the composition (composition 1) similar to the composition of Banha Baekchulcheon Matang (Wonbang; Clinical handbook of Internal) Medicine, Maclean, W, 2000) was prepared as a control. In addition, a total of five mixed extract compositions were prepared by adding or subtracting herbal medicines based on the composition of the present invention and the composition of Banhabaekchulcheon Martang (Compositions 2 to 6).

At this time, the method for obtaining a mixed extract of the composition was carried out as follows.

First, each prepared medicine was put in a round flask, and 500 ml of distilled water was added thereto, followed by heating at 100 ° C. for 3 hours to obtain an extract. And the extract was No. 2 filter paper (Watmans), the filtrate was concentrated using a rotary vacuum evaporator (Heidolph vv 2000, Germany) and dried using a centrifugal vacuum dryer (Ilsin, Korea).

As a result, 15.33 g of far, 10.65 g of composition 1, 17.93 g of composition 2, 34.95 g of composition 3, 17.76 g of composition 4, 19.76 g of composition 5, and 13.24 g of composition 6 were obtained.

Example 2 Vasorelaxation Efficacy Search

This example was intended to confirm the relaxation effect of the composition of the present invention on blood vessels constricted with phenylephrine using the reference method of the Organ Bath Study. At this time, the mixed extract composition prepared in Example 1 was used as a control.

First, rats were anesthetized with ether and blood was lost, and the abdominal cavity was opened to extract the thoracic aorta. Then, the extracted tissue was placed in a Krebs-Ringer bicarbonate solution to remove soft tissues and fat around blood vessels at room temperature and cut to about 2 mm to prepare a ring-shaped vascular section.

At this time, the Kreb-Ringer bicarbonate solution used for the normal maintenance of the vascular muscle was 119.8mM sodium chloride (NaCl) and potassium chloride while continuously injecting a gas mixed with 95% oxygen (O ₂ ) and 5% carbon dioxide (CO ₂ ). (KCl) 4.6 mM, CaCl ₂ 2.5 mM, MgCl ₂ 1.2 mM, NaHCO ₃ 25 mM, KH ₂ PO ₄ 1.2 mM, glucose (10 mM) and pH adjusted to 7.4 were used.

Then, a gaseous mixture of 95% O ₂ and 5% CO ₂ was continuously fed and maintained at 37 ± 0.5 ° C. with a Kreb-Ringer bicarbonate solution via a peristaltic pump at 4 ml / min. The vessel sections were suspended in an organ bath (volume 1.5 mL) flowing at a speed of 1, fixed at one end to the bottom of the organ bath, and connected at the other end to the muscle contractor to record isotonic contraction and relaxation. . In this case, the blood vessel sections were printer (phenylephrine) were used to then load the initial tension by using a micro-tensioning device (Grass FT-03) 1g and recover more than one hour test, the test fragment to the phenyl of the 10 ^-4 M When the maximum systolic period was reached, each mixed extracted composition was diluted and administered at each concentration to continuously record a response on a physiological signal recorder (physiograph, Gass 7, USA).

The results are shown in Table 2 and FIG. 1.

As shown in FIG. 1, it can be seen that the composition of Composition 1 exhibited the strongest concentration-dependent vasorelaxant activity. Thereafter, the most active composition 1 was named HMC05.

Example 3 Vasorelaxation Mechanism Search of HMC05 Composition

In this embodiment, whether HMC05 can relax contractile vessels induced by phenylephrine (10 ^-4 M) with or without endothelial cells, blood vessels with and without endothelial cells, indomethacin, and atropine We tried to confirm through pretreatment (atropin). At this time, the experimental method was performed in the same manner as in Example 2.

1. Endothelial Cell Independent Vasorelaxant Effects of HMC05

As a result, as shown in Figure 2 in the relaxation effect on the phenylephrine-induced contractile vessels of HMC05 with or without endothelial cells, in the presence of endothelial cells at 8.07 ± 4.21%, 0.3 mg / ㎖ at 0.1 mg / ㎖ Relaxation effect of 37.26 ± 5.95%, 55.76 ± 6.93% at 0.5mg / ml, 79.69 ± 5.42% at 1.0mg / ml, and -1.36 ± 7.35%, 0.3mg at 0.1mg / ml even when endothelial cells were removed / Ml showed a relaxation effect of 16.67 ± 9.62%, 27.47 ± 9.39% at 0.5mg / ml and 74.49 ± 4.38% at 1.0mg / ml.

2. Vasorelaxant Effect of HMC05 on Indomethacin Pretreatment

In order to confirm the involvement of the cyclooxygenase-1 (COX-1) pathway in vascular relaxation by HMC05, pretreatment with instathacin (10 ^-5 M), a prostacyclin inhibitor, was performed by HMC05. The effect on the vasorelaxation was observed.

As a result, as shown in Figure 3 indomethacin (indomethacin, 10 ^-5 M) did not significantly affect the vascular relaxation (53.82 ± 19.52%) of HMC05 (1.0 mg / ml) on phenylephrine shrink It was found that.

3. Vasorelaxant Effect of HMC05 on Atroline Pretreated Veins

Effect of pretreatment of muscarinic receptor inhibitor atroprine (10 ^-5 M) on vascular relaxation of HMC05 to determine if muscarinic receptors are involved in vascular relaxation by HMC05 Was observed.

As a result, as shown in Fig. 4, atroprine (10 ^-5 M) reduced the vascular relaxation effect of HMC05 (1.0 mg / ml) on phenylephrine contraction from 79.69 ± 5.42% to 68.62 ± 13.16%. Although it was reduced, it did not show any inhibitory effect.

4. Potassium channel (K ⁺ channel) independent vasorelaxant effect of HMC05

In the embodiment according to HMC05 phenyl F. nerin (phenylephrine, 10 ^-4 M) in inducing the contraction vasodilator City, potassium channel (K ⁺ channel) related calcium activated potassium channel to determine the release of a (Ca ^{2 +} - Phenyl F was pretreated with tetraethylammonium chloride hydrate (TEA), an activated K ⁺ (Kca) channel inhibitor, and glibenclamide, an ATP-sensitive K ⁺ (K _ATP ) channel inhibitor. After contraction with nerine, the effect of vascular relaxation on HMC05 was observed.

As a result, as shown in FIG. 5, pretreatment of tetraethylammonium chloride hydrate (TEA) and glabenclamide (10 ^-5 M) did not significantly affect vascular relaxation of HMC05 (1.0 mg / ml). It was found that.

5. Vasorelaxant effect of HMC05 by inhibiting calcium (Ca ^{2 +} ) influx through cell membrane

In this example, to determine whether HMC05 relaxes blood vessels contracted with phenylehprine (10 ^-4 M) through inhibition of calcium (Ca ^{2 +} ) influx, external calcium-free (Ca ^{2 +} -free) Effect of HMC05 on Vascular Contraction Response by Induced Depolarization with High Concentration (60mM) KCl to Induce Vascular Flow and Addition of Calcium (0.3, 0.6, 1.0, 1.5, 2.5, 5.0, 10.0mM) Was observed.

As a result, the pretreatment of HMC05 (1.0mg / ml) as shown in Figure 6 is contraction reaction due to the addition of calcium (Ca ^{2 +} ) of blood vessels induced by depolarization with calcium free (Ca ^{2 +} -free) high concentration KCl It can be seen that the decrease strongly.

Example 4 HMC05 and Amlodipine Administration to Lower Blood Pressure and Heart Rate in Spontaneous Hypertansive Rats (SHR)

In this example, the effects of amlodipine (amlodipine) and HMC05 of the present invention on the blood pressure and heart rate drop were compared and analyzed for hypertension symptoms. At this time, the subjects with hypertensive symptoms were hypertensive-induced rats (SHR, spontaneous hypertensive rats).

First, a 12-week-old rat with hypertension induced was divided into a control group administered with saline, an experimental group A administered with 200 mg / kg of HMC05, and an experimental group B administered with 1 mg / kg of amlodipine. Once oral administration.

After 4 weeks of administration, anesthesia (pentobarbital sodium, Entobar, 50mg / Kg) was injected into the intraperitoneal anesthesia and a polyethylene tube was inserted into the carotid artery to measure blood pressure and heart rate. At this time, blood pressure and heart rate were measured using a pressure transducer, and blood pressure change was measured on a physiograph.

As a result, as shown in FIG. 7, the systolic blood pressure of the control group, the HMC05 treatment group, and the amlodipine treatment group was 191.15 ± 7.26, 108.87 ± 10.77, and 141.11 ± 32.10 mmHg, and the diastolic blood pressure was 179 ± 8.09 and 97.44 ±, respectively. 11.12, 130.97 ± 30.30 mmHg, both HMC05 and amlodipin treated groups had decreased systolic and diastolic blood pressure (FIG. 7A), and heart rate was also 416.82 ± 11.45min ^{−1 in the} control group and 316.42 ± in the HMC05 treated group. 8.65 min ⁻¹ and the amlodipine treated group was 369.50 ± 43.15 min ^{− 1} , and both experimental group A and experimental group B fell (FIG. 7B).

In particular, the HMC05 of the present invention is very effective than the amlodipine, it is determined that the drug efficacy is very excellent when used in hypertensive patients.

[Example 5] HMC05 and Amlodipine Administration to Alleviate Hepatic Tissue Injury of Spontaneous Hypertansive Rats

In this example, we compared and analyzed the effects of the existing hypertension drugs, amlodipine (amlodipine) and HMC05 on liver tissue damage caused by hypertension.

First, 12-week-old hypertensive rats were divided into control group administered saline, experimental group A administered 200 mg / Kg HMC05, and experimental group B administered 1 mg / kg amlodipine, and orally administered once daily for 4 weeks.

Four weeks later, anesthesia (pentobarbital sodium, Entobar, 50 mg / kg) was injected into the abdominal cavity to anesthetize, dissect, and then dissected the cardiac perfusion with vascular rinse and 10% neutral buffered formalin (NBF). Jeongjeong was performed.

The obtained liver tissues were fixed in neutral formalin solution at room temperature for 24 hours, and then fixed in paraffin in a conventional manner, and serial sections were made to have a thickness of 5 μm. The continuous sections thus prepared were hematoxylin-eosin staining method ( Hematoxylin-Eosin) stained to prepare a sample.

The results are shown in Table 3 below.

In the control group shown in FIG. 8A, the appearance of hepatocytes with degeneration or necrosis of the cytoplasm was increased in the periphery of the central vein of the hypertensive rat, and the loss of the hepatic plate was also observed. It became. In addition, hepatitis was observed in sinusoidal capillary in some lobules, but cirrhosis and fibrosis were not observed. However, there is an increase in the appearance of portal triads that are over-infiltrated with lymphocytes, including lymphocytes, the most distinctive characteristic of hypertension rat liver tissue, and the appearance of hepatic artery with increased thickness of the tunica media. Was observed.

As shown in FIG. 8B, the degeneration and necrosis of hepatocytes in the periphery of the central vein of amlodipine-administered hypertensive rats were reduced compared to the control group, but in some lobules, the increase of hepatocellularized hepatocytes and hepatocellular plate loss. This was observed. Inflammatory symptoms were also reduced in the same capillaries. In addition, the appearance of hepatic tricuspids infiltrated with lymphocytes and other inflammatory cells was decreased, and hepatic arteries with reduced mesenteric thickness were observed compared with the control group.

As shown in FIG. 8C, in the periphery of the central vein of HMC05-administered hypertensive rats, hepatic cell depletion, degeneration, and necrosis resulted in a decrease in hepatocellular plate loss and inflammation compared to the control group. In hepatic trigeminal bodies, hepatic artery with decreased lymphocytes and other invasive cells was decreased, and the mesenteric median thickness was decreased compared with the control group. This means alleviation of liver damage in hypertensive rats by HMC05.

Therefore, in summary, as shown in Figure 9, it can be seen that the administration of HMC05 shows the effect of alleviating the liver damage caused by the control and amlodipine (amlodipin) administration.

As described above, Banha Baekchulcheon Maetang extract (HMC05), which includes half of the present invention, Baekchul, Cheonma, Dermis, Fuling, Sansa, Happiness, and yellow lotus, relaxes the constricted blood vessels and at the same time lowers blood pressure and heart rate, high blood pressure. It can be effectively used as a therapeutic or prophylactic agent related to the disease.

Claims (2)

Contrary to, anti-hypertensive, cheonma, dermis, Bokryeong, hawthorn, haeju and anti-hypertensive pharmaceutical composition comprising as an active ingredient an extract. The method of claim 1, The mixed extract is less than 9 to 17% by weight, 12 to 22% by weight, 6 to 12% by weight, 6 to 12% by weight dermis, 6 to 12% by weight dermal, 9 to 17% by weight Fusan, 9 to 17% by weight sand, 9 to 17 A composition, characterized in that the mixture is obtained by mixing at a blending ratio of 9% to 17% by weight and sulfuric acid, and hot water extraction and drying the mixture.

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