Atrial natriuretic peptide depressor therapeutic agent and prophylactic agent and method for producing same

Abstract

Heart diseases such as mitral valve myxomatous transformation are more effectively suppressed without impairing health of a small animal by using a naturally derived substance. The present invention comprises, as main components: 5%-9% by weight of a pine bark dry extract which originates from bark of pines grown while being exposed to strong ultraviolet rays on a southwestern coast of France and which contains proanthocyanidin; and 5%-9% by weight of a fermented sesame dry extract which is obtained from sesame as a main raw material and which contains sesamin, which is an antioxidant lignan. The present invention comprises 79%-87% by weight of an excipient such as starch or lactose, the excipient being obtained from starch, lactose, or the like as a raw material, making powder homogeneous, being compressed into a tablet, and preventing, for example, quality deterioration due to moisture adsorption.

Description

Atrial natriuretic peptide lowering drugs and preventive drugs and their manufacturing methods

[0001] The present invention relates to atrial natriuretic peptide (ANP)-lowering therapeutic and prophylactic agents for small animals, particularly dogs, suffering from mitral valve regurgitation, and a method for producing the same.

[0002] Recently, small pet animals such as dogs and cats have become obese due to the increased nutritional value of pet food and overfeeding. When small animals become obese, they are at higher risk of developing heart disease, just like humans. One type of heart disease is mitral valve insufficiency.

[0003] <Overview of Mitral Valve Regurgitation> The heart is an important organ that functions as a pump to circulate blood throughout the body and lungs. Blood collected from the entire body in the vena cava passes from the right atrium to the right ventricle, picks up fresh oxygen in the lungs, and then passes from the left atrium to the left ventricle and is sent out again to the entire body via the aorta. When small animals are healthy, blood is always transported along this route.

[0004] The mitral valve in the heart separates the left atrium from the left ventricle, and if there is an abnormality in this valve, the valve will not close properly, allowing blood to flow backward from the left ventricle to the left atrium. "Mitral valve myxomatous degeneration" is the most common heart disease in dogs, and as it progresses, the mitral valve becomes thickened, short, and misshapen, causing blood to flow backward. This heart disease is also known as "mitral valve insufficiency" or simply "mitral valve regurgitation."

[0005] As the amount of blood reflux increases, the blood stagnating within the heart pushes the heart into a larger space, causing cardiac enlargement. To a certain extent, cardiac function improves in a compensatory manner, allowing the increased blood volume to be adequately pumped throughout the body. However, as the condition progresses to severe cardiac enlargement, the heart is unable to compensate and fails. This means that the blood stagnating in the left atrium leaks into the lungs, impairing breathing and causing "pulmonary edema." Once pulmonary edema develops, respiratory failure progresses rapidly, and delayed treatment can lead to death.

[0006] Symptoms of mitral valve regurgitation There are almost no early symptoms of mitral valve regurgitation, and in most cases, symptoms include slight fatigue and reduced play time. As the condition gradually progresses, the child may tire easily when exercising or excited, and the tongue may turn purple (a phenomenon known as cyanosis). Other symptoms include increased sleeping time. Increased coughing is also a bad sign. As the condition progresses further, the child may become less willing to move, tire easily, and even slight stimulation may cause persistent coughing, leading to cyanosis and fainting.

[0007] When mitral regurgitation becomes severe and pulmonary edema develops, symptoms include restlessness due to difficulty breathing, being unable to lie down and breathing with one's shoulders while sitting, heavy breathing and persistent cyanosis, stretching the neck and gasping for breath, etc. Eventually, symptoms include coughing up a pink liquid mixed with blood, lying down listlessly and unresponsive due to hypoxia of the brain, and death from respiratory failure.

[0008] <Diagnosis of Mitral Valve Regurgitation> When regurgitation occurs in the mitral valve, a heart murmur can be heard. However, because it is not possible to diagnose heart disease or assess its severity through auscultation alone, tests are often performed to objectively examine the shape, size, and function of the heart. These tests include X-rays, ultrasound, blood pressure measurements, and electrocardiograms. Furthermore, it is important to perform blood and urine tests to determine whether heart disease is related to problems in other organs.

[0009] <Stages of Mitral Valve Regurgitation> Mitral valve regurgitation is generally divided into the following five stages. This is the classification by the American College of Veterinary Internal Medicine (ACVIM). (1) Stage A: In Stage A, there are currently no abnormalities in the heart. Dog breeds at high risk for future heart failure include Cavalier King Charles Spaniels and Chihuahuas. (2) Stage B1: In Stage B1, heart murmurs, valve degeneration, and mitral valve regurgitation begin to appear, but cardiac enlargement is not observed. (3) Stage B2: In Stage B2, heart murmurs, valve degeneration, mitral valve regurgitation, and cardiac enlargement are present. (4) Stage C: In Stage C, symptoms such as coughing and shortness of breath are present, and the dog has previously been treated for pulmonary edema. (5) Stage D: In Stage D, despite all medical treatments, the dog shows a poor response to treatment.

[0010] This stage classification is very well-known and is used as a reference by many veterinarians who provide cardiology care. While it is simple and easy to understand, the same stage can include patients with different levels of severity, and the rate of progression can vary greatly from patient to patient, so it is essential to regularly check up on the condition.

[0011] Treatment for Mitral Regurgitation: Recommended treatments for mitral regurgitation vary depending on the severity of the condition. However, as mentioned above, individual patients' conditions vary even within the same stage, making actual treatment more complicated. (1) Stage A: Drug therapy and dietary therapy are not recommended. (2) Stage B1: Drug therapy and dietary therapy are not recommended. Cardiac ultrasound and X-ray examinations are recommended every 6-12 months. (3) Stage B2: The use of a cardiac inotropic drug called pimobendan is strongly recommended. Dietary therapy is recommended. Depending on the condition, the use of antihypertensives, beta-blockers, aldactone (a weak diuretic), etc. may be considered. (4) Stage C: In the acute phase, i.e., pulmonary edema, hospitalization and intensive care with potent diuretics (furosemide), pimobendan, sedatives, antihypertensives, and oxygen therapy are strongly recommended. If respiratory distress does not improve and progresses, respiratory support with a ventilator under anesthesia may be considered to save the patient's life. In the chronic stage, i.e., after the pulmonary edema subsides, continued administration of diuretics, pimobendan, and antihypertensive drugs, as well as frequent reevaluation of renal and cardiac values, is strongly recommended. Keeping records of health status, such as diet and weight, at home is also recommended. (5) Stage D: Even with high doses of diuretics, pimobendan, and antihypertensive drugs, the condition remains unstable and requires treatment tailored to the situation. Cardiac surgery by a specialized cardiac surgery team may be a solution.

[0012] Techniques have been proposed for assessing the risk of developing disease in dogs suspected of having mitral regurgitation. For example, Patent Document 1, entitled "Method for assessing the risk of developing disease in dogs," proposes a method for assessing the risk of developing disease in dogs, which includes the steps of measuring the body fat percentage of a dog and classifying the dog into cases where the body fat percentage is 35% or more and cases where the body fat percentage is less than 35%, and the steps of classifying the age of the dog measured into cases where the dog is 5 years old or older and cases where the dog is under 5 years old, and which determines that a dog that is 5 years old or older and has a body fat percentage of 35% or more has a high risk of developing mitral regurgitation and / or trichotomous regurgitation.

[0013] JP 2011-97868 A

[0014] However, this patent document only aims to prevent the onset of diseases in dogs by simply measuring the body fat percentage and maintaining the body fat percentage below a specific value through dietary management. It only contributes greatly to the health management of dogs, but does not improve the health of diseased small animals.

[0015] With conventional treatment methods, it is difficult to detect early stages such as Stage A and Stage B1 because cardiac abnormalities are not readily apparent. In addition, because drug therapy and dietary therapy are not recommended in the early stages of mitral regurgitation treatment, there is a problem that by the time symptoms change significantly, it is often too late.

[0016] In light of these circumstances, the inventors of the present invention conducted extensive research. They discovered that bark extract possesses powerful antioxidant and anti-inflammatory properties. The proanthocyanidins contained in pine bark extract inhibit the oxidation of bad (LDL) cholesterol, preventing lifestyle-related diseases. They also promote blood flow. Therefore, the inventors of the present invention considered that heart diseases such as mitral valve myxomatous degeneration often progress relatively slowly, with no noticeable symptoms, and by the time they are noticed, the condition is terminal, or the patient may suddenly die. They believed that naturally derived substances could be taken regularly like supplements without risking health harm and preventing the rapid worsening of symptoms.

[0017] Furthermore, we have focused on the effectiveness of sesame as a functional food ingredient. Sesame has long been consumed as a highly nutritious food, and sesamin in particular has attracted attention as an antioxidant food ingredient derived from sesame. Furthermore, we have focused on the fact that fermented sesame significantly enhances the antioxidant and immunostimulating effects that sesame naturally possesses, and we believe that it may also contribute to improving blood pressure.

[0018] When dogs suffer from mitral valve insufficiency, the amount of blood pumped from the heart decreases. To prevent a drop in blood pressure, the body constricts peripheral blood vessels to maintain systemic blood pressure through homeostasis. This maintains the amount of blood returning to the heart. However, at the same time, this leads to insufficient peripheral circulation and volume overload on the heart. Cardiac volume overload stretches the right and left atrial muscles. When excessive left atrial volume overload causes excessive left atrial pressure, "pulmonary edema" occurs. When the atrial muscles are stretched in this way, atrial natriuretic peptide (ANP) is secreted excessively. The inventors of the present invention noted that the aforementioned pine bark extract and sesame fermentation product have the effect of relaxing peripheral blood vessels. This peripheral vascular relaxation reduces the amount of blood returning to the heart and alleviates volume overload on the atria. This action reduces ANP secretion. It is believed that the pine bark extract and sesame fermented product will ultimately reduce the left atrial volume overload, thereby suppressing the occurrence of pulmonary edema, etc.

[0019] The inventors of the present invention have noticed that pine bark extract and sesame fermentation product are effective in improving mitral valve insufficiency in dogs, but the blending ratio was unknown. They believed that there was an optimal blending ratio that could reduce left atrial volume overload without increasing the burden on the heart of each dog.

[0020] The present invention has been devised to solve these problems. That is, an object of the present invention is to provide a therapeutic and preventive agent for atrial natriuretic peptide lowering that can more effectively suppress heart diseases such as mitral valve myxomatous degeneration without harming the health of small animals by using naturally occurring substances, and a method for producing the same.

[0021] The atrial natriuretic peptide lowering therapeutic and preventive agents of the present invention are given to animals suffering from mitral valve regurgitation, and are characterized by being obtained by sequentially carrying out the following steps: extracting pine bark grown on the coast of southwestern France exposed to strong ultraviolet rays with an extract solution of 30% by weight or more at 10 to 50°C to produce a pine bark extract; concentrating the pine bark extract to a moisture content of 5 to 20%; adding 30% by weight or more of amino acids to sesame seeds, inoculating the sesame seeds with one or more bacteria selected from lactic acid bacteria, and fermenting the sesame seeds at 10 to 50°C to produce a fermented sesame dry extract; and blending the pine bark dry extract and the fermented sesame dry extract into the concentrated pine bark dry extract so that the weight ratio of the pine bark dry extract to the fermented sesame dry extract is 1:0.5 to 2.0. The atrial natriuretic peptide lowering treatment and prophylactic agent further comprises 0.5 to 0.9% by weight of glutathione yeast, which is composed of glutamic acid, cysteine, and glycine.

[0022] The fermented sesame dry extract contains organic selenium at a weight ratio of 75 ppm or more. Potassium, magnesium, zinc, manganese, or copper can be added as an essential mineral supplement to the atrial natriuretic peptide lowering agent therapeutic and preventive medicine. Antioxidant lignans including sesamin and sesamolin can be added to the atrial natriuretic peptide lowering agent therapeutic and preventive medicine.

[0023] Atrial natriuretic peptide lowering therapeutic and preventive drugs are preferably prepared by coating a tablet formed by pressure to a certain hardness with a polysaccharide such as starch, glycogen, or cellulose, and then coating the outer surface of that with a water-soluble monosaccharide or disaccharide such as starch or dextrin.

[0024] The atrial natriuretic peptide lowering therapeutic and prophylactic drugs can be filled into a double-layered capsule in which the inner coating (12) is made of starch and the outer coating (11) is made of gelatin that is more soluble in water than the inner coating (12).

[0025] The method for producing a therapeutic and preventive agent for atrial natriuretic peptide lowering agents of the present invention comprises extracting pine bark grown on the coast exposed to strong ultraviolet rays with an extract solution of 30% by weight or more at 10 to 50°C to produce a pine bark extract, concentrating the pine bark extract to a moisture content of 5 to 20%, adding 30% by weight or more of amino acids to sesame seeds, inoculating the seeds with one or more bacteria selected from lactic acid bacteria, and fermenting the resulting mixture at 10 to 50°C to produce a fermented sesame dry extract, and blending the pine bark dry extract and the fermented sesame dry extract into the concentrated pine bark dry extract in a weight mixing ratio of 1:0.5 to 2.0.

[0026] The atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention contain naturally derived substances, pine bark dried extract and fermented sesame dried extract, primarily made from sesame seeds, in optimal blend ratios without diminishing the functions of the pine bark dried extract, fermented sesame dried extract, and glutathione yeast, thereby reducing left atrial volume overload without increasing cardiac burden in dogs. This does not harm the health of small animals and prevents rapid deterioration of symptoms. The glutathione yeast possesses the antioxidant properties of glutathione, contributing to the improvement of blood pressure. The proanthocyanidins contained in the pine bark dried extract inhibit the oxidation of bad (LDL) cholesterol, preventing lifestyle-related diseases. The antioxidant and immunostimulatory properties inherent in sesame contribute to the improvement of blood pressure.

[0027] By molding the atrial natriuretic peptide lowering therapeutic and prophylactic drugs into sugar-coated tablets or double-layered capsules, it is possible to prevent the drugs from adhering to the palate or the inner wall of the throat or esophagus, and to administer the drugs to small animals without having to worry about odors or bitter tastes.

[0028] 1. A table showing the blending ratios of an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent of the present invention. 2. An enlarged cross-sectional view showing an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent in the form of a sugar-coated tablet formed with a double sugar coating. 3. An enlarged cross-sectional view showing an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent filled in a double capsule. 4. A flow diagram showing a method for producing an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent of the present invention in Example 2. 5. A flow diagram showing in detail the production process of a pine bark dry extract. 6. A flow diagram showing in detail the production process of a fermented sesame dry extract. 7. A graph showing changes in ANP values ​​before and after administration of an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent of the present invention to animals (dogs) suffering from mitral regurgitation (MR). 8. A graph showing changes in symptoms at each stage. 9. A graph showing the distribution of severity. 10. A graph showing the improvement in clinical symptoms after administration of an atrial natriuretic peptide lowering therapeutic agent and a prophylactic agent to 9 dogs in Group A. Graph showing improvement in clinical symptoms by administration of an atrial natriuretic peptide lowering agent therapeutic drug and a preventive drug of the present invention to 9 cases in Group A. Graph showing improvement in clinical symptoms by administration of an atrial natriuretic peptide lowering agent therapeutic drug and a preventive drug of the present invention to 12 cases in Group B. Image showing comparison of chest X-ray images of dogs. Image showing comparison of X-ray images taken from different angles of the dog's chest. Image showing comparison of ultrasound examination (echo examination) of the right parasternal four-chamber view. Image showing comparison of ultrasound examination (echo examination) of the right parasternal short axis four-chamber view. Image showing comparison of color blood flow jet area, and comparison of ultrasound examination (echo examination) of left ventricular inflow blood velocity waveform. Examination of cardiac movement in a dog with symptoms of bradycardia-tachycardia syndrome. Explanatory diagram showing improvement in clinical symptoms when an atrial natriuretic peptide lowering agent therapeutic drug and a preventive drug of the present invention are administered to a dog with symptoms of bradycardia-tachycardia syndrome. 1. An image showing a comparison of X-ray images when a dog with sick sinus syndrome symptoms is administered an atrial natriuretic peptide lowering agent therapeutic drug and a preventive drug of the present invention. 2. An image showing a comparison of X-ray images when a dog with sick sinus syndrome symptoms is administered an atrial natriuretic peptide lowering agent therapeutic drug and a preventive drug of the present invention.

[0029] The raw materials for the therapeutic and prophylactic atrial natriuretic peptide lowering drugs of the present invention are mainly composed of two ingredients: pine bark extract and fermented sesame extract. The pine bark extract contains a flavonoid called proanthocyanidin. The fermented sesame extract contains sesamin, an antioxidant lignan.

[0030] <Dried Pine Bark Extract> Figure 1 is a table showing the types, raw materials, and blending ratios of the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention. The atrial natriuretic peptide lowering therapeutic and preventive drugs of Example 1 of the present invention are anti-inflammatory drugs, therapeutic drugs, and preventive drugs whose main ingredients are a pine bark dried extract containing proanthocyanidins and a fermented sesame dried extract containing sesamin, an antioxidant lignan derived primarily from sesame. The mixing ratio of the pine bark dried extract to the fermented sesame dried extract is 1:0.5 to 2.0 by weight of the fermented sesame dried extract. This proanthocyanidin is a polyphenol having a structure in which catechin molecules are linked together. It functions as an antioxidant.

[0031] The "dried pine bark extract," one of the main ingredients of the atrial natriuretic peptide lowering therapeutic and preventive medicines of the present invention, is a natural plant extract taken from the bark of maritime pine trees growing on the coast of southwestern France. This French maritime pine bark extract is an ingredient extracted from the bark of pine trees growing on the coast of southwestern France, which are exposed to strong ultraviolet rays. This coastal area of ​​France has sunny weather for more than 320 days a year and is exposed to very strong ultraviolet rays, so the pine trees growing in this area have developed a large accumulation of antioxidants to protect themselves.

[0032] Proanthocyanidins contained in the pine bark dry extract, the main ingredient of this invention, possess excellent antioxidant properties that strengthen the body's antioxidant capacity. They increase nitric oxide and improve blood flow, reinforcing the circulatory system. They bind to collagen and elastin, repairing and strengthening vascular walls. They inhibit NF-kB (nuclear factor-kappa B), providing potent anti-inflammatory effects. NF-kB is a regulator of the acute phase of inflammatory responses and is required for effective immune defense and the elimination of transformed cells. They stabilize blood glucose levels by suppressing postprandial increases in blood glucose levels through α-glucosidase inhibition. α-glucosidase assists in the hydrolysis of sugar bonds by reacting with water.

[0033] The proanthocyanidins contained in pine bark dry extract have the effect of improving blood flow in reducing the risk of heart disease. First, they have the effect of suppressing platelet aggregation. In humans, they are effective against platelet aggregation caused by smoking and against economy class syndrome. They also have the function of dilating blood vessels. They have the function of reducing the production of the vasoconstrictor endothelin-1 and promoting the production of the vasodilator prostacyclin.

[0034] Proanthocyanidins contained in dried pine bark extract have the effect of reducing the risk of heart disease. Vascular regulating factors derived from vascular endothelial cells include the following: Endothelin is a powerful vasoconstrictor peptide derived from vascular endothelial cells, and its production increases during heart failure. Prostacyclin (PG1) ２ Nitric oxide (NO) is a representative vasorelaxant factor derived from vascular endothelial cells.

[0035] <Fermented Sesame Dry Extract> "Fermented Sesame Dry Extract" contains sesamin, an antioxidant lignan unique to sesame. Sesame has long been consumed as a highly nutritious food. In recent years, its functionality has been studied, and sesame lignan, a type of phenylpropanoid, has been used in many supplements as a functional food ingredient. Sesamin, in particular, has attracted attention as an antioxidant food ingredient derived from sesame. Antioxidation and immunity are important elements of modern functional foods, and these can improve the so-called pre-disease state, which is the root cause of all diseases. In this invention, the functionality of conventional sesame fermentation products is enhanced, and in addition to the blood pressure suppressing effect that sesame naturally has, lactic acid fermentation is used to efficiently produce gamma-aminobutyric acid, thereby enhancing the blood pressure suppressing effect.

[0036] Fermented sesame dry extract is a plant-derived physiologically active ingredient containing high concentrations of the essential trace mineral organic selenium, as well as other essential minerals such as potassium, magnesium, zinc, manganese, and copper, as well as antioxidant lignans (sesamin and sesamolin) unique to sesame.

[0037] Glutathione yeast is composed of glutamic acid, cysteine, and glycine. Glutathione yeast has the antioxidant effect of glutathione and can contribute to improving blood pressure. Glutathione yeast is preferably included in an amount of 0.5 to 0.9% by weight.

[0038] The pine bark dry extract, fermented sesame dry extract, and glutathione yeast are molded using excipients made from starch, lactose, and other raw materials. This ensures uniformity of the powder and prevents tablets from hardening and quality deterioration due to moisture absorption. The formulations are tablets, capsules, and powders. As this is a therapeutic and preventative medicine for small animals, tablet form is preferred. Powders are difficult to administer to small animals, but they can be mixed into feed.

[0039] <Bundling Ratio> The optimal blending ratio of the atrial natriuretic peptide lowering agent therapeutic drug and prophylactic drug of the present invention is as shown in the table in Figure 1. The blending ratio is 5-9 wt% of pine bark dry extract, 5-9 wt% of fermented sesame dry extract, and 79-87 wt% of excipients. For small dogs weighing around 10 kg, if the amount of atrial natriuretic peptide lowering agent therapeutic drug and prophylactic drug to be administered is 140 mg, then the appropriate blending ratios are 7-13 mg of fermented sesame dry extract, 7-13 mg of fermented sesame dry extract, 0.7-1.3 mg of glutathione yeast, and 110-122 mg of excipients.

[0040] <Adjuvants> Potassium, magnesium, zinc, manganese, or copper can be blended as an essential mineral supplement in the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention. In addition, antioxidant lignans including sesamin and sesamolin can be blended as an adjuvant in the therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention.

[0041] <Sugar-coated tablets with double sugar coatings> Figure 2 is an enlarged cross-sectional view of a double-coated atrial natriuretic peptide-lowering drug and a prophylactic drug. When administering the atrial natriuretic peptide-lowering drug and a prophylactic drug of the present invention to small animals, the sugar-coated tablets may adhere to the palate of the small animal or to the inner wall of the throat or esophagus. If the sugar in the sugar-coated tablet dissolves before reaching the stomach, exposing the drug inside to the mouth or throat, the odor and taste of the drug can become bothersome, causing the animal to dislike administration of the drug. Therefore, the sugar in the sugar-coated tablet is double-coated with a sugar whose outer coating is more water-soluble than the inner coating, making it less likely to adhere to the inner wall of the throat or esophagus.

[0042] For example, the inner sugar coating 2 that coats the tablet 1 is made of polysaccharides such as starch, glycogen, and cellulose. This is to protect the drug from dissolving until it reaches the stomach. It dissolves in saliva and gastric juices in about five minutes, exposing the drug 1 inside. The outer sugar coating 3 is made of monosaccharides such as glucose and fructose, or disaccharides such as sucrose and lactose, which are more soluble in water than the inner sugar coating 2. This takes advantage of its ability to dissolve easily in the digestive enzymes of saliva. By molding the outer sugar coating 3 of this tablet from a material that dissolves easily, the tablet 1 can be prevented from adhering to the palate or the inner walls of the throat and esophagus.

[0043] <Double-Layer Capsule> Figure 3 is an enlarged cross-sectional view of a double-layered capsule filled with atrial natriuretic peptide-lowering therapeutic and prophylactic drugs. This double-layered capsule also prevents the capsule from adhering to the palate or the lining of the throat or esophagus of small animals. If the capsule's gelatin and sugar dissolve before reaching the stomach, exposing the drug inside to the mouth or throat, the odor and taste of the drug can be bothersome, leading to a reluctance to administer the drug. Therefore, we filled the drug 13 into a double-layered capsule, with an outer coating 11 made of gelatin, which is more water-soluble than the inner coating 12 (starch).

[0044] For example, the inner capsule coating 12 is formed by thoroughly drying vegetable fiber or starch to form a hard coating that protects the drug 13 filled therein. It dissolves in saliva or gastric juice in about five minutes after adhering to the capsule, exposing the drug 13 inside. The outer capsule coating 11 is made of a material that dissolves more easily in water than the inner coating 12. For example, gelatin dissolves more easily in the digestive enzymes of saliva and the stomach than vegetable fiber or starch. Forming the outer capsule out of a material that dissolves easily can prevent the capsule from adhering to the palate or the inner walls of the throat or esophagus.

[0045] <Method for Producing Atrial Natriuretic Peptide-Lowering Therapeutic and Preventive Drugs> Figure 4 is a flow chart showing the method for producing the atrial natriuretic peptide-lowering therapeutic and preventive drug of the present invention in Example 2. Figure 5 is a flow chart showing in detail the manufacturing process for the pine bark dry extract. Figure 6 is a flow chart showing in detail the manufacturing process for the fermented sesame dry extract. In the method for producing the atrial natriuretic peptide-lowering therapeutic and preventive drug of the present invention, pine bark grown on the coast exposed to strong ultraviolet rays is collected, shredded, and pulverized. The pulverized material is extracted with a butylene glycol extract. For example, extraction is performed with a butylene glycol extract of 30% by weight or more at 10 to 50°C. Note that the solvent is not limited to butylene glycol; solvents (oils) such as ethanol can also be used. The pine bark extract is filtered and concentrated under reduced pressure. The pine bark extract is concentrated, for example, to a moisture content of 10 to 30%. The pine bark extract is then spray-dried and pulverized to produce a pine bark dry extract.

[0046] Fermented sesame dry extract is produced by adding amino acids to sesame seeds, inoculating one or more bacteria selected from lactic acid bacteria, and fermenting them to produce a fermented sesame dry extract. To efficiently ferment sesame, it is necessary to sterilize any unwanted bacteria on the surface of the sesame seeds. Sterilization methods include heat sterilization and pH treatment sterilization, and defatting may be performed as needed. Sesame seeds can be fermented in granular form, but for better fermentation, they are finely ground. Sesame fermentation is carried out in the presence of water. Fermentation methods include tank culture, in which a large amount of water is added for fermentation, solid culture, in which a small amount of water is added for fermentation, and a method in between, in which the sesame seeds are fermented in a paste form. Tank culture, which allows for relatively rapid mass processing, is more preferred.

[0047] Examples of the lactic acid bacteria to be inoculated include strains of the genus Lactobacillus, Bifidobacterium, Lactococcus, Pediococcus, and Leuconostoc, and among these, strains that do not produce toxins can be used. Lactobacillus casei is particularly preferred because it efficiently ferments the substrate in sesame and efficiently converts sesaminol to sesamol, and Lactobacillus reuteri is even more preferred because it efficiently produces γ-aminobutyric acid. The amount of lactic acid bacteria to be inoculated is 0.5 to 10% by weight of a liquid-cultured bacterial solution relative to the liquid or solid containing sesame, and it is particularly preferred to inoculate 1.0% by weight under sterile conditions.

[0048] The fermented sesame dry extract thus produced is made by fermenting sesame flakes to reduce their molecular weight, removing unnecessary fiber components, and then further concentrating selenium and other essential minerals through a separation and purification process.This is a pure plant-derived physiologically active material (phytochemicals) powder containing a high concentration of organic selenium (selenium), an essential trace mineral derived from sesame.

[0049] The fermented sesame dry extract is a light brown powder containing 75 ppm or more of selenium (average 100 ppm). The oil content is 20% or less, the moisture content is 8% or less, and the arsenic content is 0. ２ O ３ as Pb) is less than 1 ppm, heavy metals (as Pb) is less than 10 ppm, and the general viable bacteria count is 3 x 10 ３ Less than 100 / g, E. coli is negative.

[0050] The concentrated pine bark dry extract is mixed with fermented sesame dry extract in a weight ratio of 1:0.5 to 2.0 to complete the preparation of a therapeutic and prophylactic atrial natriuretic peptide lowering agent, which is then formulated into tablets, capsules, or other forms to produce the therapeutic and prophylactic atrial natriuretic peptide lowering agent products.

[0051] <Administration of atrial natriuretic peptide lowering therapeutic and prophylactic drugs> The recommended amount of the atrial natriuretic peptide lowering therapeutic and prophylactic drugs of the present invention to be administered to small animals such as dogs is preferably about 560 mg for dogs weighing 10 kg or less.

[0052] <Case Description> The effects of the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention on animals (dogs) suffering from mitral regurgitation (MR) are described below. The atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention were administered to 26 dogs (dogs) with mitral regurgitation (MR) for one month. Table 1 shows the changes in ANP (atrial natriuretic peptide) values. ANP values ​​are hormones secreted primarily from the atria and are values ​​that indicate an important role in regulating body fluid volume and blood pressure. Many cases showed a decrease in values ​​after administration. Three cases (three dogs) were administered the drug alone, and 23 cases (23 dogs) were administered the drug in combination with other drugs.

[0053]

[0054] <Changes in ANP Values ​​in 26 Dogs> Figure 7 is a graph showing changes in ANP values ​​before and after administration of the atrial natriuretic peptide-lowering therapeutic and preventive drugs of the present invention to animals (dogs) suffering from mitral regurgitation (MR). Figure 7 also shows changes in ANP values. The left side of each bar represents the value before administration, and the right side represents the value one month after administration. This shows that the ANP values ​​after administration decreased in 10 of the 26 dogs. In addition, the value increased in 6 dogs, and there was no change in 10 dogs.

[0055] Table 2 shows the changes in QOL (quality of life) scores. This QOL score quantifies the impact of the disease and treatment on the patient's (dog's) subjective sense of well-being (mental health, vitality, pain, etc.) and daily activities. As shown in Table 2, most scores improved after administration.

[0056]

[0057] Figure 8 is a graph showing the change in symptoms at each stage. Figure 9 is a graph showing the distribution of severity. Figure 8 explains "symptoms," "heart murmur," "cardiac enlargement," "need for treatment," and "need for administration of ACEI," "furosemide," and "pimobendan" at stages A to D. Figure 9 is a graph showing the distribution of severity for 20 cases from stage B1 to stage D.

[0058] Figure 10 is a graph showing the improvement in clinical symptoms after administration of an atrial natriuretic peptide-lowering therapeutic drug and a preventive drug to nine dogs in Group A. Dogs diagnosed with mitral valve regurgitation were observed for one month. They were divided into two groups based on the veterinarian's examination. Nine dogs in Group A underwent ANP measurement. Twelve dogs in Group B were primarily clinically monitored. During this observation, each dog's owner monitored their breathing rate while the dog was sleeping. Similarly, coughing and behavior during walks were observed. The dosage of the atrial natriuretic peptide-lowering therapeutic drug and preventive drug of the present invention remained unchanged throughout the one-month administration period. No other supplements were used concomitantly.

[0059] The improvement in clinical symptoms resulting from the administration of the atrial natriuretic peptide lowering therapeutic and preventive drugs of the present invention will be described below. For the nine dogs in Group A, the improvement after administration is shown as "markedly effective," meaning "relieved," "no change," or "worsened." Table 3 shows the improvement in clinical symptoms after the administration of the atrial natriuretic peptide lowering therapeutic and preventive drugs to the nine dogs in Group A. The rates of "remarkable effectiveness" and "relieved effectiveness" were 77.8%.

[0060]

[0061] 11 is a graph showing the improvement in clinical symptoms following administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention for nine cases in Group A. Each pair of bars represents the ANP value for each dog, with the dark gray bar on the left representing the ANP value prior to administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention, and the light gray bar on the right representing the ANP value one month after administration. Many of the values ​​decreased after administration.

[0062] Figure 12 is a graph showing the improvement in clinical symptoms resulting from the administration of the atrial natriuretic peptide lowering therapeutic and prophylactic drugs of the present invention to 12 dogs in Group B. The following shows the changes in the 12 dogs in Group B, indicating whether they were "improved," "no change," or "discontinued due to worsening" after administration. Table 4 is a table showing the improvement in clinical symptoms resulting from the administration of the atrial natriuretic peptide lowering therapeutic and prophylactic drugs. The improvement rate was 66.7%.

[0063]

[0064] Next, we will explain the changes in resting respiratory rate for both Group A and Group B. Table 5 shows the improvement in clinical symptoms for 11 cases after administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. Many of the values ​​decreased after administration compared to before administration, indicating an improvement in resting respiratory rate.

[0065]

[0066] <Comparison of X-ray images of cases> Figures 13 and 14 are images showing a comparison of X-ray images for each case. Figure 13 is an X-ray image of the dog's chest, and the image on the left is an image taken before administration of the atrial natriuretic peptide-lowering agent therapeutic and preventive drugs of the present invention. The image on the right is an image taken 25 days after administration. This image shows that administration of the atrial natriuretic peptide-lowering agent therapeutic and preventive drugs of the present invention has resulted in a clearer outline of the heart and improved lung opacity.

[0067] Figure 14 shows X-ray images of the dog's chest taken from a different angle. The image on the left is before administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. The image on the right is 25 days after administration. This image shows that administration of the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention has resulted in a clearer outline of the heart and improved lung opacity.

[0068] <Comparison of Ultrasound Examination (Echo) Images of Cases> Figures 15 and 16 compare the color blood flow jet area and are images showing a comparison of ultrasound examination (echo) images of the right parasternal four-chamber view. Figure 15 shows ultrasound examination (echo) images of the right parasternal long axis of a dog. The image on the left is an image before administration of the atrial natriuretic peptide-lowering drug therapeutic and preventive drugs of the present invention. The image on the right is an image 25 days after administration. From these images, it can be seen that administration of the atrial natriuretic peptide-lowering drug therapeutic and preventive drugs of the present invention significantly reduced the area of ​​the reflux color blood flow jet in the left atrium, predicting a reduction in the amount of reflux blood. The ARJ / LAA was reduced from 50% to 30%.

[0069] Figure 16 shows images of a right parasternal short axis ultrasound examination (echocardiography) of a dog. The image on the left is before administration of the atrial natriuretic peptide lowering agent therapeutic and prophylactic agents of the present invention. The image on the right is 25 days after administration. The left ventricular end-diastolic internal diameter (LVIDd) changed from 4.36 cm to 3.56 cm. The left ventricular end-systolic internal diameter (LVIDs) changed from 1.57 cm to 1.51 cm.

[0070] Figure 17 is a comparison of color blood flow jet areas and images showing a comparison of ultrasound (echo) examination of left ventricular inflow blood velocity waveforms. Figure 17 shows ultrasound (echo) examination images of left ventricular inflow blood velocity waveforms in a dog. The image on the left is before administration of the atrial natriuretic peptide lowering agent therapeutic and prophylactic drugs of the present invention. The image on the right is 25 days after administration. E-wave velocity (early diastolic wave) changed from 1.24 m / s to 0.89 m / s. E / A changed from 1.56 to 1.17. A-wave velocity is the atrial systolic wave.

[0071] <Sick Sinus Syndrome> This describes the case of a 7.1 kg, 8-year-old, neutered female miniature schnauzer. She had a history of diabetes and Cushing's syndrome. She also had mitral valve insufficiency (III / VI). Clinical symptoms included syncope at rest due to sinus bradycardia (ISACHC classification Ib, ACVIM classification B2). She was also taking Vetmedin, cilostarol, and a traditional Chinese medicine (water leech and plant extract).

[0072] Sick sinus syndrome is a condition that causes bradycardia due to abnormalities in the cells of the sinoatrial node, which issues commands for cardiac contraction. Sinus bradycardia (the patient is aware of a slow heartbeat, causing symptoms such as dizziness, dizziness, and a feeling of floating), sinus arrest (frequent dizziness and dizziness, and prolonged sinus arrest can lead to fainting (Adams-Stokes attack)), sinoatrial block (a condition in which the cells of the atrioventricular node, which transmits commands for cardiac contraction, are impaired, preventing the appropriate transmission of commands from the atria to the ventricles), and supraventricular tachycardia (a condition in which the pulse suddenly becomes (paroxysmal) fast and continues (tachycardia), and when the fast pulse originates in the atria or nearby areas (supraventricular), it is called paroxysmal supraventricular tachycardia). Sick sinus syndrome is a combination of these conditions, not a single disease. Sick sinus syndrome is characterized by (A) severe sinus bradycardia, (B) severe sinus arrest, and (C) bradycardia-tachycardia syndrome.

[0073] Figure 19 shows cardiac activity in a dog with symptoms of bradycardia-tachycardia syndrome. Figure 19 is an explanatory diagram illustrating the improvement in clinical symptoms when a dog with symptoms of bradycardia-tachycardia syndrome was administered the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention. Dogs with bradycardia-tachycardia syndrome alternate between severe bradycardia and severe tachycardia. Bradycardia is often accompanied by syncope. In Figure 18, the oval-marked area indicates a severe bradycardia episode lasting 30 seconds or longer. When this dog was administered the atrial natriuretic peptide-lowering therapeutic and prophylactic drugs of the present invention, the heart rate increased from 40 to 48 beats / min, the respiratory rate decreased from 43 to 35 breaths / min, and the blood pressure increased from 120 / 82 to 125 / 90 mmHg. Furthermore, syncope disappeared approximately two weeks after the start of administration.

[0074] 20 and 21 are images showing a comparison of X-ray images of dogs with sick sinus syndrome symptoms when administered an atrial natriuretic peptide-lowering agent therapeutic drug and a preventive drug of the present invention. The images on the left are images taken before administration of the atrial natriuretic peptide-lowering agent therapeutic drug and a preventive drug of the present invention, and the images on the right are images taken one month after administration.

[0075] The atrial natriuretic peptide lowering therapeutic and prophylactic drugs of the present invention can promote NO synthesis, promote prostacyclin production, and inhibit endothelin production, thereby contributing to the improvement of pulmonary edema and the elimination of bradycardic syncope.

[0076] Furthermore, the present invention is not limited to the above-described embodiments of the invention, and can of course be modified in various ways within the scope of the gist of the present invention, as long as it uses naturally derived substances that can be taken regularly like a supplement without harming the health of small animals and can more effectively suppress heart diseases such as mitral valve myxomatous degeneration.

[0077] The therapeutic and prophylactic atrial natriuretic peptide lowering agents of the present invention can be used as dietary supplements that are effective when given to small animals, particularly dogs, suffering from mitral valve regurgitation.

[0078] 1 Tablet (drug) 2 Inner sugar coating 3 Outer sugar coating 11 Outer coating 12 Inner coating 13 Drug

Claims

1. An atrial natriuretic peptide lowering therapeutic and preventive agent to be given to animals suffering from mitral valve regurgitation, characterized by being obtained by sequentially carrying out the following steps: extracting pine bark grown on the coast of southwest France exposed to strong ultraviolet rays with an extract solution of 30% by weight or more at 10-50°C to produce a pine bark extract; concentrating the pine bark extract to a moisture content of 5-20%; adding 30% by weight or more of amino acids to sesame seeds, inoculating the extract with one or more bacteria selected from lactic acid bacteria, and fermenting the extract at 10-50°C to produce a fermented sesame dry extract; and blending the pine bark dry extract and the fermented sesame dry extract into the concentrated pine bark dry extract so that the weight ratio of the pine bark dry extract to the fermented sesame dry extract is 1:0.5-2.

0.

2. The atrial natriuretic peptide lowering therapeutic and prophylactic drug according to claim 1, further comprising 0.5 to 0.9% by weight of glutathione yeast, which is composed of glutamic acid, cysteine, and glycine.

3. The atrial natriuretic peptide lowering therapeutic and preventive drug according to claim 1, wherein the fermented sesame dry extract contains organic selenium at a weight ratio of 75 ppm or more.

4. The atrial natriuretic peptide lowering therapeutic and prophylactic drug described in claim 1 is characterized in that it contains potassium, magnesium, zinc, manganese or copper as an essential mineral supplement.

5. The atrial natriuretic peptide lowering therapeutic and prophylactic drug according to claim 1 is characterized in that it contains antioxidant lignans including sesamin and sesamolin.

6. The atrial natriuretic peptide lowering therapeutic and prophylactic drug according to claim 1, characterized in that the drug is a tablet formed by compressing it to a certain hardness, which is then coated with starch, glycogen, or cellulose polysaccharides, and then coated on the outside with starch, dextrin, or other water-soluble monosaccharides and disaccharides.

7. The atrial natriuretic peptide lowering drug and prophylactic drug as described in claim 1, characterized in that the drug is filled into a double-layered capsule in which the inner coating (12) is made of starch and the outer coating (11) is made of gelatin that is more water-soluble than the inner coating (12).

8. A method for producing a pine bark extract at 10-50°C using an extract solution of 30% by weight or more, the pine bark extract being grown on the coast and exposed to strong ultraviolet rays being extracted with an extract solution of 30% by weight or more, the pine bark extract being concentrated to a moisture content of 5-20%, the sesame seeds being added with 30% by weight or more of amino acids, the sesame seeds being inoculated with one or more bacteria selected from lactic acid bacteria, and the resulting mixture being fermented at 10-50°C to produce a fermented sesame dry extract, and the concentrated pine bark dry extract being blended with the fermented sesame dry extract in a weight mixing ratio of 1:0.5-2.0.

Images