Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/69—Polygalaceae (Milkwort family)
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to an Polygala tenuifolia extract for the prevention or treatment of ischemic heart diseases, and more particularly to, an Polygala tenuifolia extract for recovering the heart failing to function properly by ischemic heart diseases, as well as a pharmaceutical composition and health food containing the same.
• Heart diseases can be classified into congenital heart diseases and acquired heart diseases.
• the acquired heart diseases include congestive heart disease (heart failure), ischemic heart diseases (angina, myocardial infraction), valve disease, myocardial disease, endomyocardial disease, arrhythmia, cardiac neurosis, etc.
• ischemic heart diseases which are generally called “coronary heart diseases” are caused by ateriosclerosis where the arteries become thicker and hardened by plaques resulting from the accumulation of fat and cholesterol on the tunica intima of the coronary arteries supplying blood flow to the heart, and the diameter of the coronary arteries becomes narrower so that a sufficient amount of oxygen cannot be supplied.
• the ischemic heart disease is a main attack occupying the most majority of death causes in highly advanced countries, and it is reported that the ischemic heart disease is found in 12,000,000 patients only in USA, two of 5 deaths are caused by the ischemic heart diseases, and in Europe and America, 80% of sudden deaths result from the ischemic heart diseases. In Korea, the ischemic heart disease is becoming the greatest cause of death, and mortality resulting therefrom shows a tendency to increase rapidly due to westernized dietary habits, high smoking rate, increased stress and the like.
• Agents for treating the ischemic heart disease generally include sympathetic blocking agents, nitrate preparations and calcium antagonists.
• the sympathetic blocking agents (also so-called “beta-blocking agents”) reduce myocardial oxygen demand by reducing heart rate and myocardial contractility by an inhibitory action against sympathetic receptors to blood cathe- cholamine, and are most preferably used in acute coronary syndromes and myocardial infarction. This action is known to be particularly effective against an anginal attack occurring in exercise and an anginal attack occurring in sympathetic activation because it prevents increases in blood pressure in exercise and in cardiovascular contractility.
• the combined use of the sympathetic blocking agents with dihydropyridine- based calcium antagonists has the risk of bradycardia and heart block.
• the nitrate preparations are first-line drugs which are most widely used together with the sympathetic blocking agents. Their anti- ischemic mechanisms operate through the effects of reducing preload and afterload, expanding blood vessels and collateral vessels, and reducing coronary vasospasms. Also, there is a report that the nitrate preparations inhibit platelet coagulation. Generally, the nitrate preparations are used by intravenous injection while increasing or reducing the dose depending on conditions. However, they can cause a headache and an increase in pulse, and tolerance when injected continuously.
• the calcium antagonists also so-called “calcium blocking agents” have the effects of coronary vasodilation and blood pressure lowering and can be broadly classified into dihydropyridine (DHP)-based agents and non-dihydropyridine (non-DHP)-based agents.
• DHP dihydropyridine
• non-DHP non-dihydropyridine
• the DHP-based preparations such as nifedipine, cause an increase in myocardial oxygen demand because they have a strong vaso dilation effect but a weak pulse lowering effect or myocardial contractility lowering effect.
• nifedipine caused progression into myocardial infraction and an increase of about 16% in recurrent angina, and thus, the single use of nifedipine has a risk and it must be used in combination with the sympathetic blocking agents.
• the non-DHP-based agents cause reductions in pulse frequency and myocardial contractility, resulting in a reduction in heart oxygen consumption.
• These calcium antagonists are used as second-line drugs in patients with contraindications to the sympathetic blocking agents, patients with acute coronary symptoms, who have normal myocardial function, and patients with angina caused by coronary vasospasms.
• the present invention provides an Polygala tenuifolia extract for the prevention or treatment of ischemic heart disease, which is prepared by extracting Polygala tenuifolia with a solvent.
• the present invention provides a pharmaceutical composition and health food for the prevention or treatment of ischemic heart diseases, which contain said extract as an active ingredient.
• the Polygala tenuifolia extract according to the present invention is a natural herbal material harmless to the human body and has the effect of recovering the heart failing to function properly by ischemic heart diseases.
• the inventive extract will be useful for the prevention or treatment of ischemic heart disease-related diseases.
• FIG. 1 is a graphic diagram showing changes in the recovery of blood pressure with time in working heart beat on a test group treated with the inventive Polygala tenuifolia extract and a control group.
• FIG. 2 shows a graphic diagram showing changes in the recovery of aortic output with time in working heart beat on a test group treated with the inventive Polygala tenuifolia extract and a control group.
• FIG. 3 shows a graphic diagram showing changes in the recovery of coronary perfusion rate with time in working heart beat on a test group treated with the inventive Polygala tenuifolia extract and a control group.
• FIG. 4 shows a graphic diagram showing change in the recovery of cardiac output with time in working heart beat on a test group treated with the inventive Polygala tenuifolia extract and a control group. Best Mode for Carrying Out the Invention
• Polygala tenuifolia is a perennial dicotyledonous plant of Geraniales, Polygalaceae, and its roots are thick and long, have the group of several main stems sprouted from their end, and have little or no fluff. Its leaves cross each other, are striped and 1.5-3 cm in length and have no petiole. Its flowers have purple color from July to August and hang on the raceme at intervals.
• the root of this plant is called "Polygala tenuifolia” and used as expectorants, tonics and aphrodisiacs. It is reported to have sedative, antibiotic, expectorant, blood pressure- lowering, hemolytic, uterus-exciting, and anticancer actions, and thus, the effects and clinical applications of Polygala tenuifolia were already suggested.
• Korean patent laid-open publication No. 1999-74052 discloses a method for extracting Polygala tenuifolia to obtain an active ingredient able to be used for the treatment of various mental disorders such that the active ingredient has a composition showing the most excellent activity, as well as a herbal composition containing the Polygala tenuifolia extract, which can be used as an antipsychotic drug.
• the Polygala tenuifolia extract according to the present invention can be prepared by extraction with water, lower alcohol, hexane, ethyl acetate or a mixture thereof. More preferably, it can be prepared by an organic solvent extraction process of using an organic solvent to separate volatile or non-volatile substances.
• the organic solvent extraction process comprises the steps of performing extraction with lower alcohol, hexane, ethyl acetate or a mixture thereof, filtering the extract, concentrating the filtrate, and freeze-drying the concentrate.
• the lower alcohol is selected from the group consisting of methanol, ethanol and butanol.
• the extraction processes which can be used in the present invention include percolation extraction, ultrasonic extraction, filtration, reflux extraction, vacuum extraction, and other conventional extraction processes.
• the Polygala tenuifolia extract may also be prepared by a hot water extraction process of using high-temperature hot water to separate soluble substances.
• the hot-water extraction is preferably carried out at a temperature of 80-100 °C for 1-3 hours, and comprises the steps of adding water to Polygala tenuifolia, filtering and concentrating the solution, and freeze-drying the concentrate.
• concentration and freeze-drying steps can be carried out by various conventional methods known in the art. Mode for the Invention
• Example 1 Preparation of Polygala tenuifolia extract by hot- water extraction
• the inventive Polygala tenuifolia extract was administered orally to white rats according to a conventional method and tested for toxicities in intraabdominal administration and subcutaneous injection. As a result, it was shown that the 50% lethal dose (LD ) of the inventive extract was at least 20 g/kg, indicating that the inventive extract is a safe substance.
• LD lethal dose
• Sprague-Dawley male rats weighing about 250-300 gm were purchased and accommodated in a cage at a temperature of 24-26 °C and a relative humidity of 50-60% under a 12-hr light/dark cycle controlled with an automatic power unit while the animals were permitted to free access to water and feed. All test procedures were performed according to the ethics of animal experiments. The animals were fasted for two hours before experiments and injected intraabdominally with 5 mg/lOOgm body weight of pentobarbital to induce anesthesia. The anesthetized rats were fixed to a test bed by tying the legs and arms, and the inguinal region was incised to expose the femoral veins.
• the exposed femoral veins were injected with 100 units/100 gm body weight of heparin.
• the rats were subjected to median sternotomy to isolate the heart.
• the isolated heart was immersed in 4 °C physiological saline to induce the arrest of the heart.
• catheters were inserted into the aorta and the left atrium and fixed with No. 3 silk suture.
• the lung tissue was separated, and then, the incision marks were made in the pulmonary aorta to prevent a perfusate from filling in the right atrium.
• the non-working ex vivo perfusion system is countercurrent-perfused from an aortic reservoir placed 100 cm above the heart into the heart under a water pressure of 100-cm H O, and called the "non- working heart" because it maintains the heart function by coronary perfusion resulting from countercurrent perfusion has no isolation of the heart through the left ventricle.
• This non- working heart is used for 15 minutes of the initial experimental period and 15 minutes of the first recovery stage after the induction of myocardial infarction, and induces the recovery of the heart from enzyme deficiency in heart isolation and myocardial infarction.
• the working ex vivo perfusion system refers to a left heart preparation which is perfused from an atrial bubble trap reservoir placed 20 cm above the heart into the left atrium at a water pressure of 20-cm H O, and a perfusate flowed in the left atrium flows through the left ventricle into the atrial bubble trap reservoir at a height corresponding to a water pressure of 100-cm H O in a flow rate of 20-30 ml min (this amount is "aortic output") for each heart beat. In the heart beat, an electrical pacing is not used.
• This working heart is used for 20 minutes before the induction of myocardial infarction and for 60 minutes after the 15-minute use of the Langendorff persusion system after the induction of myocardial infarction and is critical to compare the heart recovery before and after the induction of myocardial infarction.
• aortic perfusate and coronary perfusate are not used in reperfusion.
• the heart prepared in the part (i) was connected to the modified Langendorff perfusion system prepared as described above, and subjected to Langendorff perfusion for 15 minutes to remove a blood component from the heart and to balance the concentrations of a solution in the extracellular matrix and a substrate in the perfusate. At this time, infusion into the left atrium was also performed. Furthermore, the controls of heart rate, the maximum aortic systolic pressure and coronary blood flow rate were determined.
• the Langendorff perfusion continued to perform while perfusing the left atrium, thus converting the heart into the working heart. After 15 minutes of the working heart before the induction of myocardial infarction, the left artial vessels and the aortic vessels were closed.
• FIG. 1 shows measurement results for changes in the recovery of blood pressure as a function of time in working heart beat on the test group and the control group. Numerical results shown in Table 1 below indicate mean blood pressure and standard deviations. In FIG. 1, the symbol "**" indicates probability (P) ⁇ 0.01 as compared to the control group.
• FIG. 2 shows measurement results for changes in the recovery of cardiac output as a function of time in working heart beat on the test group and the control group, and numerical results shown in Table 1 indicate mean output per minute and standard deviation.
• FIG. 1 shows measurement results for changes in the recovery of blood pressure as a function of time in working heart beat on the test group and the control group.
• FIG. 3 shows measurement results for changes in the recovery of coronary perfusion rate with time in working heart beat on the test group and the control group, and numerical results shown in Table 1 indicate mean perfusion rate per minute and standard deviation.
• FIG. 4 shows measurement results for changes in the recovery of cardiac output with time in working heart beat on the test group and the control group, and numerical results shown in Table 1 indicate mean output per minute and standard deviation.
• the symbol "*” indicates probability (P) ⁇ 0.05 as compared to the control group
• the symbol "**” indicates probability (P) ⁇ 0.01 as compared to the control group.
• the present pharmaceutical composition for treating ischemic heart diseases includes the Polygala tenuifolia extract which is safe to the human body, and for the prevention or treatment of ischemic heart diseases as an active ingredient.
• the p har- maceutical composition may be administered orally or parenterally and may be formulated into typical pharmaceutical preparations.
• the Polygala tenuifolia extract of the present invention may be formulated into various formulations for oral and parenteral administration upon clinical ap ⁇ plication.
• diluents or excipients may be used, which are ex ⁇ emplified by fillers, thickeners, binders, humectants, disintegrators, surfactants, etc.
• solid formulations for oral administration include tablets, pills, powders, granules and capsules.
• the solid formulations may include, in addition to the Polygala tenuifolia extract, at least one excipient selected from among starch, calcium carbonate, sucrose, lactose, gelatin, etc.
• the solid formulations may include, in addition to a simple excipient, a lubricant such as magnesium stearate or talc.
• a lubricant such as magnesium stearate or talc.
• Examples of liquid formulations for oral administration include suspensions, internal solutions, emulsions and syrups.
• the liquid formulations may include, in addition to commonly used simple diluents such as water and liquid paraffin, various excipients which are exemplified by humectants, sweeteners, aromatics and preservatives.
• preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories.
• propylene glycol In the formulation into non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
• injectable esters such as ethyl oleate
• suppositories witepsol, macrogol, Tween 61, cacao fat, lanolin fat, glycerol and gelatin may be used.
• the unit dose may, for example, occurs one, two, three or four times, or a half, third or quarter of an individual dose.
• the individual dose preferably contains the amount of an effective drugs which is given in one administration and usually corresponds to a whole daily dose or a half, third or quarter of the daily dose.
• an effective amount of the Polygala tenuifolia extract ranges from 30 to 700 mg/kg, and preferably 100 to 500 mg/kg, and may be administered once to six times daily.
• the dosage for a specific patient may vary according to the patient's weight, age, sex, health state and diet, administration duration, administration routes, excretion rates and severity of the illness.
• the present invention provides a health food for treating ischemic heart diseases, comprising the Polygala tenuifolia extract as an active ingredient.
• the present extract may be added as it exists or in combination with other food or food ingredients, and may be used suitably according to general methods. Mixed amounts of active ingredients may be suitably determined according to the intended use (preventive, health or therapeutic purposes).
• the present extract may be added in an amount of 0.01 to 1 wt%, and preferably 0.1 to 1 wt%, based on the total weight of raw materials used in preparing a food or drink.
• An effective amount of the present extract may be determined based on an effective amount of the pharmaceutical composition.
• the present extract When consumed for a long period of time for health and sanitary purposes or health control, the present extract may be used in an amount lower than the range. Also, it is apparent that the present extract can be used in an amount higher than the range because the active ingredient carries no safety risk.
• the type of the food is not particularly limited.
• foods to which the present extract can be added include meats, sausages, breads, chocolates, candies, snacks, confectionary, pizza, instant noodles, other noodles, gums, dairy products including ice creams, various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes, as well as traditional therapeutic preparations for use as an antianemic, a body function-strengthening agent, a skin whitening agent, and the like.
• it can be used in various herbal medicinal formulations, such as Bul-Mang-San, In-Sam- Yang- Young-Tang, and Gui-Bi-Tang.
• a soft capsules were prepared according to a soft capsule preparation method described in General Rules for Preparation in a guidebook, Korean Pharmacopoeia, using 100.0 mg of the Polygala tenuifolia extract prepared in Example 1, 175.0 mg of soybean oil, 45.0 mg of cera flava, 127.5 mg of hydrogenated palm oil, 21.0 mg of soybean phospholipids, 212.0 mg of gelatin, 50.0 mg of glycerin (gravity: 1.24), 76.0 mg of di-sorbitol, 0.54 mg of methyl-paraoxybenzoate, 0.90 mg of propyl- paraoxybenzoate, 0.56 mg of methylvanillin, and a proper amount of yellow no. 203.
• Chewing gum was prepared according to a general method using 0.24-0.64% of the Polygala tenuifolia extract prepared in Example 1, 20% of gum base, 1% of a fruit aromatic, 2% of water and the balance of sugar.
• Ice cream was prepared according to a general method using 0.24-0.64% of the Polygala tenuifolia extract prepared in Example 1, 10.0% of milk fat, 10.8% of SNF (Solids Not Fat), 12.0% of sugar, 3.0% of starch syrup, 0.5% of an emulsion stabilizer (span), 0.15% of an aromatic (strawberry) and the balance of water.
• a beverage was prepared according to a general method using 0.48-1.28 mg of the Polygala tenuifolia extract prepared in Example 1, 522 mg of honey, 5 mg of thioctic acid amide, 10 mg of nicotinic acid amide, 3 mg of riboflavin hydrochloride sodium, 2 mg of pyridoxine hydrochloride, 30 mg of inositol, 50 mg of orotic acid and 200 ml of water.

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Citations (4)

• 2004
  • 2004-06-09 KR KR1020040042191A patent/KR100672952B1/ko active IP Right Grant
• 2005
  • 2005-06-09 WO PCT/KR2005/001740 patent/WO2005120533A1/en active Application Filing

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