KR20110071507A - Pharmaceutical composition for the prevention of restenosis comprising 4-o-methylhonokiol as active ingredient - Google Patents

Abstract

PURPOSE: An anti-restenosis agent containing 4-O-methylhonokiol is provided to safely prevent and treat coronary arthery diseases. CONSTITUTION: An anti-restenosis agent contains 4-O-methylhonokiol of general formula 1 as an active ingredient and pharmaceutically acceptable carrier. A method for preparing 4-O-methylhonokiol comprises: a step of obtaining crude extract from leaves or stem barks of Magnolia officinalis Rehd. et Wils.; a step of isolating the crude extract with non-polar solvent to obtain a soluble extract; a step of dissolving the non-polar solvent solution extract; and a step of performing column chromatography using C18 column, silicagel column, and Shim-pak prep-ODS colum.

Description

Pharmaceutical Composition for the Prevention of Restenosis Comprising 4-O-methylhonokiol as Active Ingredient}

The present invention relates to a vascular restenosis preventive agent comprising 4-O-methylhonokiol (4-O-methylhonokiol) as an active ingredient. More specifically, the present invention relates to a vascular restenosis preventive agent comprising 4-O-methylhonokiol as an active ingredient and a pharmaceutically acceptable carrier, which can prevent vascular restenosis occurring after a stent procedure. .

Heart diseases such as heart failure, coronary artery disease, hypertensive heart disease, arrhythmia, congenital heart disease, myocardial infarction, and angina pectoris and cardiovascular diseases such as stroke and peripheral vascular disease occur in various age groups. In addition, it can lead to death. In particular, the recent incidence of coronary artery disease is rapidly increasing due to westernized diet, and efforts to effectively treat coronary artery disease continue.

Treatments for coronary artery disease developed to date include drug therapy, gene therapy, percutaneous transluminal coronary angioplasty and stenting (PTCA), and coronary artery bypass graft (CABG). Revascularization therapy) is known.

Recently, percutaneous coronary angioplasty and stent implantation have been widely used, but it has been reported that vascular restenosis occurs in about 40% of patients after 3 to 6 months (see reference). Ryan et al., J. Am. Coll. Cardiol., 22. 2033-2054, 1993). The vascular restenosis promotes the migration and proliferation of vascular smooth muscle cells by producing and secreting various cytokines from vascular endothelial cells, activated platelets or macrophages damaged by balloon ware, thereby promoting extracellular epilepsy. It is known that the production and secretion of the extracellular matrix (ECM) are promoted, which causes thickening of the vascular endothelium and is caused (Godfried et al, Am. Heart J., 129, 203-210, 1995).

On the other hand, vascular smooth muscle cells in a normal state does not proliferate, but the stroma of the endothelial cells through the damage, etc. through the various stages of signal transduction, vascular smooth muscle cell division, migration and proliferation is induced. The mechanisms of vascular smooth muscle cell proliferation include the removal of proliferation inhibitory factor due to normal endothelial cell damage and the activation of proliferative inducers, the transmission of proliferative signals through receptors on the surface of vascular smooth muscle cells, and the proliferation delivered into the nucleus of vascular smooth muscle cells. And a change in the cell cycle caused by the trigger signal. Normal endothelial cells secrete substances that inhibit the proliferation of vascular smooth muscle cells.When endothelial cells are damaged, their secretion is suppressed, and platelet derived growth factor, which is released from activated platelets, is contained in plasma. Proliferation of vascular smooth muscle cells is caused by various cytokines.

Various methods have been considered to prevent vascular restenosis after such a stent procedure. For example, Herdeg et al. Reported that Taxol may inhibit the development of vascular restenosis that occurs after stent implantation (Herdeg et al., Zeischrift fur Kardiologie, 89, 390-397, 2000). ), Korean Patent Registration No. 478671 discloses a pharmaceutical composition for preventing and treating vascular restenosis comprising clotrimazole as an active ingredient, and Korean Patent Registration No. 516026 discloses 3'-dioxyadenosine (3 A composition for preventing and treating vascular restenosis using '-deoxyadenosine) as an active ingredient is disclosed, and Korean Patent Publication No. 2001-110793 discloses an agent for preventing and treating vascular stenosis using a compound having Rho kinase inhibitory activity as an active ingredient. Korean Patent Laid-Open Publication No. 2003-46314 discloses graft vascular disease, restenosis, in-stent restenosis and pulmonary hypertension with antithrombin as an active ingredient. A composition for preventing and treating vascular proliferative diseases such as pressure is disclosed, and Korean Patent Laid-Open Publication No. 2005-23249 discloses revascularization after percutaneous coronary angioplasty using an endovascular stent containing retinoid and a retinoid action modifier. A pharmaceutical composition for preventing and / or treating vascular diseases such as stenosis and / or reclosure is disclosed, and Korean Patent Publication No. 2005-43183 discloses a pharmaceutical for preventing and treating vascular restenosis including curcumin. A composition is disclosed.

However, the above-described vascular restenosis inhibitors exhibit various side effects other than preventing vascular restenosis and exhibit various side effects such as wound regeneration inhibition, vascular injury, hepatotoxicity, kidney damage, and increased blood loss due to platelet aggregation inhibition. Research into the development of a material that can suppress vascular restenosis derived from a variety of natural products that have been proven safe, but the research results have not been reported yet.

Therefore, there is a constant need to develop materials that can safely and effectively inhibit vascular restenosis, particularly natural materials that are harmless to the human body.

Currently used as a medicinal herb for the treatment of dyes or for the treatment of nausea, vomiting, vomiting and diarrhea, the Chinese pepper is also known as Magnolia officinalis Rehd. Et Wils., Magnolia officinalis var. Biloba belonging to Magnoliaceae. Magnolia obovata, a deciduous tree belonging to the Magnolia family, and Korean evergreen tree (Machilus thunbergii, Machilus thunbergii var. Obovata) belonging to the tree family Lauraceae, which are substitutes for the planting or the planting plant, respectively. (Lee Lee et al., Kor. J. Pharmacogn., 17, p199, 1986).

Recently, studies to develop a prophylactic and therapeutic agent for diabetic complications including extracts of groceries have been conducted in Korea, and anti-diabetic agents utilizing the efficacy of magnool (refer to Patent No. 550934) and obovatol ( anti-anxiety inhibitors (see Patent Registration No. 695781) utilizing obovatol) have been developed.

Meanwhile, 4-O-methylhonokiol was first isolated from Hupak in 1978 (El-Feraly, F. S. et al., Lloydia, 41, p493, 1978). 4-O-methylhonokiol, along with magnool, is known to have antimicrobial and pesticidal effects on mosquito larvae and brine shrimp (Nitao JK et al., Phytochemistry, 30, p2193, 1991), also known to have neuroprotective and neurotrophic effects (Tomoyuki E. et al., Bioorganic & Medicinal Chemistry Letters, 14, p2621, 2004).

However, no antiproliferative effect of vascular smooth muscle cells by 4-O-methyl-honokiol isolated from Hak tree has been reported.

Accordingly, the present inventors have diligently researched to develop a material that can safely and effectively inhibit vascular restenosis, and as a result, 4-O-methylhonokiol isolated from the posterior tissues prevented the proliferation of vascular smooth muscle cells. As a result, it was confirmed that the generation of vascular restenosis occurring after the stent procedure can be effectively suppressed, and the present invention has been completed.

After all, it is an object of the present invention to provide an agent for preventing vascular restenosis, which comprises 4-O-methylhonokiol as an active ingredient.

In order to achieve the above object, the vascular restenosis preventive agent of the present invention contains 4-O-methylhonokiol represented by the following general formula (1) as an active ingredient and includes a pharmaceutically acceptable carrier.

[일반식 1]

[Formula 1]

The vascular restenosis preventive agent of the present invention may prevent vascular restenosis occurring after stent surgery without side effects, and thus may be widely used for the prevention and treatment of safer coronary artery disease.

The vascular restenosis preventive agent of the present invention is a 4-O-methyl honokiol isolated from the extract of bakbak as an active ingredient and includes a pharmaceutically acceptable carrier.

4-O-methyl-honokiol used in the present invention is obtained commercially, or the crude extract is obtained from dried leaf or stem bark, and the crude extract is extracted again with a non-polar solvent to obtain a soluble extract. By dissolving the non-polar solvent soluble extract in an organic solvent, it can be obtained by applying sequentially to column chromatography using a C ₁₈ column, silica gel column and Shim-Pak prep-ODS (Shim-Pak prep-ODS) column.

At this time, the hummus is not particularly limited, but Chinese humbac (Magnolia officinalis Rehd. Et Wils., Magnolia officinalis var.biloba), Japanese humbac (Magnolia obovata), Korean humbac (Machilus thunbergii, Machilus thunbergii var. Obovata), etc. It is possible to use, and it is particularly preferable to use Chinese thick foil. In addition, the crude extract is not particularly limited thereto, but the dried leaf or stem bark of dried thick gourd, hot water extraction method using a lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof, reflux cooling extraction method or ultrasonic extraction method The liquid component obtained by applying to is obtained by concentrating under reduced pressure at 20 to 100 ° C, preferably about 50 to 70 ° C, and preferably 200 to 2,000% (v / w) by weight of dried leaf or stem bark. ) Water is added by extraction and hot water extraction at an extraction temperature of 0 to 100 ° C. for about 1 hour to 15 days, or dried to the leaf or stem bark of the dried gourd, 200 to 2,000% (v / w) by weight of 75 to It can be obtained by adding 100% ethanol, and solvent extraction at an extraction temperature of 10 to 30 ℃.

In addition, the non-polar solvent soluble extract is not particularly limited thereto, but is dispersed by adding water to the crude extract obtained by adding a non-polar solvent of 10 to 50% (v / v) to the volume of the added water, and then fractionated It can be obtained by extraction, the non-polar solvent used at this time is not particularly limited, hexane, chloroform, methylene chloride, ethyl acetate, glycerin, propylene glycol, butylene glycol, ether and the like can be used. Preferably, 200 to 2,000% (v / w) of water is added to the crude extract to disperse it, and 10 to 50% (v / v) of hexane is added to the volume of the added water, followed by fractional extraction. The hexane fraction obtained can be used as a nonpolar solvent soluble extract.

The organic solvent used to dissolve the obtained non-polar solvent soluble extract is not particularly limited thereto, but preferably a lower alcohol having 1 to 4 carbon atoms is used.

The non-polar solvent soluble extract dissolved in the organic solvent is an eluate mixed with a lower alcohol having 1 to 4 carbon atoms, preferably methanol: water, at about 10: 1 to 4: 1 (volume ratio) after adsorption on a C ₁₈ column. By eluting, the active fraction can be obtained.

The active fraction obtained from the C ₁₈ column was again adsorbed onto a silica gel column, followed by silica gel column chromatography 2 to 5 times to separate the active fraction, and finally subjected to high performance liquid chromatography to 4-O-methyl. Honokiol is finally obtained.

On the other hand, in order to confirm the effect of 4-O-methyl-honokkiol on vascular restenosis, the treatment of 4-O-methyl-honokinool in rat aortic smooth muscle cells, the concentration of 4-O-methyl-honokinool It was confirmed that the inhibition of aortic smooth muscle cell proliferation and the concentration-dependent inhibition of DNA synthesis in the aortic smooth muscle cell of rats, the proliferation of vascular smooth muscle cell that occurs after stent procedure Inhibition of the vascular restenosis can be effectively prevented.

4-O-methyl-honokiol contained as an active ingredient of the vascular restenosis prevention agent of the present invention is a pharmaceutically acceptable binder (eg polyvinylpyrrolidone, hydroxypropyl cellulose), disintegrant (eg carboxymethyl cellulose) Calcium, sodium starch glycolate), diluents (e.g. corn starch, lactose, soybean oil, crystalline cellulose, mannitol), glidants (e.g. magnesium stearate, talc), sweeteners (e.g. white sugar, fructose, sorbitol, aspartame), stabilizers (E.g. sodium carboxymethylcellulose, alpha or beta cyclodextrin, vitamin C, citric acid, white lead), preservatives (e.g. methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate) and flavorings (e.g. ethylvaninirin, after masking Leva, menthol flavono, herbal flavor) can be prepared into pharmaceutical preparations such as tablets, capsules, solutions, ointments or injections.

Effective amount

The dosage of 4-O-methylhonokiol, which is an active ingredient of the vascular restenosis preventing agent of the present invention, is 0.0001 to 100 mg per kg of body weight per day, depending on the age, sex, symptoms, administration method or purpose of the patient. The dose may be divided three times, and is preferably administered at 0.001 to 10 mg / kg. Dosage levels for patients with specific symptoms may vary by those skilled in the art depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, severity of disease, and the like.

Acute Toxicity Test

Non-rodent beagles, 6-7 weeks old, were administered orally with 4-O-methylhonokiol and examined for mortality within 24 hours. At this time, the females used 6 individuals of 8 to 8 kg and the males used 8 individuals of 7 to 9 kg. As a result, the dead individuals do not occur up to 5 g / kg, the 4-O-methyl-honoquiol of the present invention is safe enough to observe acute toxicity even up to 5 g per kg, it can be safely administered in vivo as a vascular restenosis prevention agent Can be.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention more specifically, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example 1 Separation and Purification of 4-O-Methyl Honokiol Compound

Example 1-1 Preparation of Stem Bark Extract

After extracting 95% ethanol 9L to 3 kg of the stem bark obtained from drying and cutting off the stem bark of Magnolia officinalis Rehd. Et Wils., Extracted three times at room temperature, the filtrate was filtered under reduced pressure (EYELA Co., Ltd.). , N-1000, Japan) was concentrated under reduced pressure to obtain 450 g of dried crude extract (hereinafter referred to as "hc-1").

Subsequently, 200 g of the crude thin extract was suspended in 2 L of distilled water, and dissolved by adding 500 ml of hexane, followed by the fractional extraction process twice, collecting the portions dissolved in the hexane layer, and concentrating the hexane layer under reduced pressure. 70 g of hexane soluble extract (hereinafter referred to as "hc-2") was obtained.

Example 1-2 Separation and Purification of the Final Compound

70 g of the thick hexane soluble extract obtained in Example 1-1 was dissolved in 300 ml of methanol and adsorbed onto a 300 g of C ₁₈ column, and then the fractions were separated using a mixed solvent of methanol: water = 4: 1 (v / v). The eluent was concentrated under reduced pressure to obtain 40 g of a yellowish brown concentrate, which was dissolved in methylene chloride. The fractions were then adsorbed onto 1 kg of silica gel (Merck, 9385) packed in a column (4.5 x 40 cm) using a mixed solvent of hexane: ethyl acetate = 9: 1 (v / v), hexane and acetic acid Fractions were separated by performing a total of two silica gel column chromatography conversion of the ratio of ethyl from 9: 1 (v / v) to 6: 4 (v / v). Then, finally, high performance liquid chromatography under the conditions shown in Table 1 below was used to obtain 2 g of 4-O-methylhonokiol having the following physical properties and used in the examples below.

For structural analysis, spectrometers of ¹ H-NMR (Varian, GEMINI, 400 MHz) and ¹³ C-NMR (Varian, GEMINI, 100 MHz) were used. As a solvent, CDCl ₃ (Chloroform- d , Aldrich), internal standard As a substance, trimethylsilane (TMS) was used as the δ value (ppm). The NMR result was confirmed to be in agreement with known data (see Shoji Y. et al., Chem. Pharm. Bull. 39, p 2024, 1991).

¹ H-NMR (400 MHz, CDC _l3 ): δ ppm 3.45 (2H, d, J = 6.0 Hz, H-7 ′), 3.45 (2H, d, J = 6.0 Hz, H-7), 3.90 (3H, s, OMe), 5.10 (4H, m, H-9 and H-9 '), 6.01 (2H, m, H-8 and H-8'), 6.95 (1H, dd, J = 8, 1.5 Hz, H-3 '), 6.97 (1H, dd, J = 8.0, 1.5 Hz, H-3), 7.05 (2H, m, H-2 and H-6'), 7.23 (1H, dd, J = 8.5, 1.6 Hz, H-6), 7.30 (1H, doublet of doublets, J = 8.5, 1.6 Hz, H-4 ′);

¹³ C-NMR (100 MHz, CDC _l3 ): δ ppm 129.09 (C-1), 130.67 (C-2), 128.67 (C-3), 156.94 (<95> C-4), 115.53 (C-5) , 127.86 (C-6), 34.22 (C-7), 136.48 (C-8), 115.47 (C-9), 127.83 (C-1 '), 150.79 (C-2'), 110.88 (C-3 '), 129.64 (C-4'), 132.09 (C-5 '), 130.46 (C-6'), 39.36 (C-7 '), 137.77 (C-8'), 115.77 (C-9 ') , 55.47 (OMe).

 Column  Shim-Pak prep-ODS column, Shimachusa  Column temperature  30 ℃  Flow rate  18mL / min  Detector  UV 254nm  Injection volume  400 μl  Mobile phase  80% methanol

Reference Example 1 : Purity Analysis

The purity of 4-O-methyl honokiol obtained in Example 1-2 was analyzed using high performance liquid chromatography (HPLC) under the conditions described in Table 2 below, and the results are shown in Table 3 below.

Column Capsule Park C ₁₈ 4.6 X 250mm, Shiseido Column temperature 30 ℃ Flow rate 1.0 mL / min Detector UV 254 nm Injection volume 20 μl Mobile phase 80% methanol

  Experimental substance   Content of 4-O-Methyl Honokiol (%)   hc-1   12.50   hc-2   30.28

As shown in Table 3, the purified hc-2 in Example 1 was found to have a much higher content of 4-O-methyl honokiol than hc-1 of 12.50% to 30.28%.

Example 2 Aortic Smooth Muscle Cell Proliferation Inhibitory Effect of 4-O-Methyl Honokiol

To determine whether 4-O-methylhonokiol inhibits aortic smooth muscle cell growth in rats, 3.0 x 10 ⁴ aortic smooth muscle cells were added to DMEM medium containing 0.5% (v / v) fetal bovine serum in 12-well plates. Incubated for 24 hours. Subsequently, 1, 2 or 4 uM of 4-O-methylhonokiol was treated, incubated for another 24 hours, and platelet-derived growth factor (PDGF-BB, Sigma Chem) at a concentration of 25 ng / ml. Co., USA) and again incubated for 24, 48 or 72 hours. After the incubation was completed, trypsin treatment was applied to each cultured cell to disperse the cultured cells, and the number of cells was measured by a counter.

As shown in Figure 1, it can be seen that as the treatment concentration of 4-O-methyl honokiol increases, the degree of proliferation by platelet-derived growth factor of aortic smooth muscle cells is suppressed. In addition, it was found that the growth inhibitory effect of 4-O-methyl honokiol was continuously maintained over time.

Example 3 Inhibitory Effect of 4-O-Methyl Honokiol on DNA Synthesis of Aortic Smooth Muscle Cells

The purpose of this study was to determine whether the cell proliferation inhibitory effect of 4-O-methylhonokiol identified in Example 2 is related to the synthesis of DNA.

That is, the aortic smooth muscle was treated in the same manner as in Example 2 except for treating platelet-derived growth factors, incubating for 20 hours, and then adding 1 μl of [ ³ H] thymidine to the culture solution and incubating for another 4 hours. Cells were cultured. Subsequently, the cultured cells were washed with PBS, and 500 μl of TCA (trichloroacetic acid) was added thereto and reacted for 30 minutes. Then, TCA was removed, washed with a washing solution (ethanol / ether, 1: 1 (v / v)), and 500 μl of NaOH was added to lyse the cells. Then, 5 ml of a scintillation cocktail was added to the cell lysate, and the radiation dose was measured to compare the relative amounts of the synthesized DNA (see FIG. 2).

Figure 2 is a graph showing the effect of inhibiting DNA synthesis according to the treatment concentration of 4-O-methyl honokiol on the DNA synthesis of platelet-derived growth factor treated aortic smooth muscle cells. As shown in Figure 2, it was found that the amount of DNA synthesis of aortic smooth muscle cells decreased as the throughput of 4-O-methyl-honokinool increased.

Therefore, it was found that the proliferation inhibitory effect of aortic smooth muscle cells by 4-O-methyl-honokinool in Example 2 was caused by 4-O-methyl-honokinool inhibiting DNA synthesis of the cells.

Example 4 Effect of 4-O-Methyl Honokiol on the Development of Vascular Restenosis After Stent

The purpose of this study was to determine whether the effects of 4-O-methylhonokiol identified in Examples 2 and 3 can be applied to the actual stent procedure.

A stent (Humed, Korea) was inserted into four coronary vessels of 10 pigs 3 months old after birth, and a stent was inserted into 4 coronary vessels of 10 pigs 3 months after birth. Stents were inserted into each of the four coronary blood vessels of experimental group 1 and 10-month-old pigs, each administered 4-O-methyl-honokinool at a dose of 100 mg / kg body weight / day. Experimental group 2, in which the taxol used as the restenosis preventive agent was administered at a dose of 1 mg / kg body weight / day, was bred for 4 weeks. Then, the average weight change of each pig was measured, a stent-inserted coronary artery was extracted from the pigs of the control group and the experimental group, and the incidence of vascular restenosis was measured and compared with each other (see Table 4). At this time, the average weight change was calculated as the average value of the weight of the pig after 4 weeks minus the weight of the pig before the stent procedure.

Comparison of the Inhibitory Effects of Vascular Restenosis on the Prevention of Vascular Restenosis  Experimental group  Incidence of Vascular Restenosis  Average weight change (kg) Control
Experiment group 1
Experiment group 2 72%
26%
53% 62
58
32

As shown in Table 4, the control group that was not administered the vascular restenosis preventive agent showed a vascular restenosis rate of about 72% after 4 weeks, but the experimental group 1, which received 4-O-methyl-honokinool, was about 4 weeks later. The vascular restenosis rate was 26%, and Experimental Group 2, which had been used as a conventional vascular restenosis prevention agent, showed a vascular restenosis rate of about 53% after 4 weeks. Therefore, it can be seen that 4-O-methylhonokiol exhibits a superior vascular restenosis prevention effect than conventional vascular restenosis inhibitors.

In addition, since pigs in the growing phase (3 months old) were used, the weight of about 62kg should be increased as in the case of 4 weeks of breeding. Although the body weight was increased to a similar degree, the experimental group 2 administered Taxol, which has been used as a conventional vascular restenosis preventive agent, was found to significantly reduce the increase in body weight, which was predicted to be due to side effects of Taxol.

Therefore, it was found that 4-O-methylhonokiol can safely and effectively prevent vascular restenosis.

Example 5 Formulation of Vascular Restenosis Preventive Agents

4-O-methylhonokiol was mixed with carriers such as conventional excipients, binders, lubricants, disintegrants, diluents and the like to prepare various pharmaceutical formulations.

Example 5-1 Preparation of Tablets

Tablets were prepared by compressing 10 mg of 4-O-methylhonokiol, 20 mg of lactose, 20 mg of starch, and magnesium stearate into 50 mg of tablets according to a conventional tablet preparation method.

Example 5-2 Preparation of Capsule

10 mg of 4-O-methylhonokiol, 20 mg of lactose, 19 mg of starch, 1 mg of talc, and magnesium stearate were appropriately packed into a 50 mg capsule according to a method for preparing a capsule, thereby preparing a capsule.

Example 5-3 Preparation of Liquid

100 mg of 4-O-methylhonocyol, 10 g of isomerized sugar, 500 mg of honey, 20 mg of thycotinamide (pharmaceutical), 30 mg of anhydrous caffeine (pharmaceutical), and 70 mg of sodium benzoate were prepared according to a conventional method of preparing a liquid, and a brown bottle of 100 ml capacity. After filling in, and then tightly pasteurized to prepare a liquid.

Example 5-4 Preparation of Injections

6 mg of 4-O-methylhonokiol and an appropriate amount of sterile purified water were prepared according to a conventional injection method, and filled into 2 ml of ampoules, and then sealed and sterilized to prepare an injection.

Example 5-5 Preparation of Granules

A granule was prepared by extruding 10 mg of 4-O-methylhonocyol and 25 mg of lactose into a conventional extrusion granulator.

1 is a graph showing the treatment concentration of 4-O-methyl honokiol and the effect of inhibiting cell proliferation with time on aberrant proliferation of aortic smooth muscle cells by platelet-derived growth factors.

Figure 2 is a graph showing the effect of inhibiting DNA synthesis according to the treatment concentration of 4-O-methyl honokiol on the DNA synthesis of platelet-derived growth factor treated aortic smooth muscle cells.

Claims (11)

A vascular restenosis preventive agent containing 4-O-methylhonokiol represented by the following general formula (1) as an active ingredient and a pharmaceutically acceptable carrier.

[Formula 1] The method of claim 1, The 4-O-methyl honokiol obtained crude extract from dried leaf or stem shell of Magnolia officinalis Rehd. Et Wils., And the crude extract was extracted again with a nonpolar solvent to obtain a soluble extract. Obtained by dissolving the non-polar solvent soluble extract in a lower alcohol having 1 to 4 carbon atoms, and sequentially applying it to column chromatography using a C ₁₈ column, a silica gel column and a Shim-Pak prep-ODS column. Characterized by Prevent vascular restenosis. 3. The method of claim 2, The crude extract is a reduced pressure of the liquid component obtained by applying the dried leaf or stem bark of dried bakbak, water, low-temperature alcohol having 1 to 4 carbon atoms or a mixed solvent thereof, reflux cooling extraction method or ultrasonic extraction method Characterized in that obtained by concentration Prevent vascular restenosis. The method of claim 2 or 3, The crude extract is obtained by adding 200 to 2,000% (v / w) of water to the dried leaf or stem bark of dried thick gourd and hot water extraction at an extraction temperature of 0 to 100 ° C. for about 1 hour to 15 days, Or 75 to 100% ethanol of 200 to 2,000% (v / w) relative to the weight of the dried leaf or stem of the dried gourd, and is obtained by solvent extraction at an extraction temperature of 10 to 30 ℃ Prevent vascular restenosis. 3. The method of claim 2, The non-polar solvent soluble extract is dispersed by adding water to the crude extract, and 10 to 50% (v / v) of hexane, chloroform, methylene chloride, ethyl acetate, glycerin, propylene glycol, butylene based on the volume of water added thereto. A nonpolar solvent fraction obtained by adding a nonpolar solvent selected from the group consisting of glycol and ether and then fractionally extracting Prevent vascular restenosis. The method according to claim 2 or 5, The non-polar solvent soluble extract is dispersed by adding 200 to 2,000% (v / w) of water to the crude extract by weight, and adding 10 to 50% (v / v) of hexane to the volume of water added thereto, Characterized in that the hexane fraction obtained by fractional extraction Prevent vascular restenosis. A capsule vascular restenosis prevention agent comprising a 4-O-methyl-honokiol represented by the general formula (I) disclosed in claim 1 as an active ingredient. A liquid type vascular restenosis prevention agent comprising 4-O-methylhonokiol represented by the general formula (I) disclosed in claim 1 as an active ingredient. A vascular restenosis prevention agent of an injection type comprising 4-O-methylhonokiol represented by the general formula (I) disclosed in claim 1 as an active ingredient. A granule-type vascular restenosis prevention agent comprising 4-O-methylhonokiol represented by the general formula (I) disclosed in claim 1 as an active ingredient. A tablet-type vascular restenosis preventing agent comprising 4-O-methylhonokiol represented by the general formula (I) disclosed in claim 1 as an active ingredient.

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