WO2022270112A1 - Corosolic acid capable of improving insulin resistance/sensitivity and enhancing metabolic function and analogue thereof - Google Patents

Corosolic acid capable of improving insulin resistance/sensitivity and enhancing metabolic function and analogue thereof Download PDF

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WO2022270112A1
WO2022270112A1 PCT/JP2022/015828 JP2022015828W WO2022270112A1 WO 2022270112 A1 WO2022270112 A1 WO 2022270112A1 JP 2022015828 W JP2022015828 W JP 2022015828W WO 2022270112 A1 WO2022270112 A1 WO 2022270112A1
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corosolic acid
insulin
insulin resistance
dementia
corosolic
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Japanese (ja)
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太 松山
デラクルーズ エリノア デュモン
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太 松山
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Priority claimed from JP2021105866A external-priority patent/JP2023004270A/en
Priority claimed from JP2021127314A external-priority patent/JP2023022438A/en
Priority claimed from JP2022025144A external-priority patent/JP2023121672A/en
Application filed by 太 松山 filed Critical 太 松山
Publication of WO2022270112A1 publication Critical patent/WO2022270112A1/en

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Definitions

  • compositions for prevention and alleviation of dementia which have not yet been reported;2.
  • corosolic acid which is effective for reducing the risk of lifestyle-related diseases that increases with age and preventing and alleviating the onset and alleviation of adult diseases, identification of the crystal structure that determines its structure, methods for producing crystals, and corosolic acid reagents. It relates to a method for mass production, plant extracts containing its analogues and corosolic acid. There are many fields of application.
  • the present invention relates to inventions for prevention and alleviation of geriatric diseases and lifestyle-related diseases in the elderly based on clinical trials. More than 200 species of plants containing corosolic acid have been reported. Corosolic acid is a naturally occurring compound. Corosolic acid reagents (>95% pure) are widely available.
  • the inventor prepared "a method that can claim exclusive rights for a certain period of time similar to synthetic drugs" for corosolic acid as a compound, in addition to the world's first clinical trial results for dementia. did. Specifically, first, 1. The world's first MMSE test and two dementia clinical trials combined with OGTT test analysis, then 2. 2. Discovery of reproducible methods for corosolic acid crystals; 4.
  • a method using plant culture for more efficient production of corosolic acid which is different from conventional methods capable of mass-producing corosolic acid;
  • This corosolic acid-producing callus can be scaled up indefinitely by callus culture "like a mushroom factory", while helping to identify the species that produce the highest content. The inventor strictly keeps all of the above four physical samples.
  • Corosolic acid is a kind of triterpenoid, and in diabetes model animal and cell tests, it has the effect of inducing the glucose transporter GLUT4, which works when sugar is taken up into tissues, to the cell membrane. It has also been reported to promote the uptake of sugar by promoting the phosphorylation of insulin receptors.
  • Corosolic acid is a pentacyclic triterpene. Its structure is similar to that of ursolic acid, oleanolic acid, trimentic acid, and maslinic acid. It differs from ursolic acid only in that it has a hydroxy bond.
  • the path to the industrialization of corosolic acid other than the crystal-making manual is the discovery of "industrialization” (a specific method for mass production at a low cost). More than 100 species of plants containing corosolic acid and its analogues have been reported. In Japan, there are persimmon, mulberry, loquat, shiso, quince, and kumazasa, and all of them are distributed as medicinal herbs for alleviating diabetes.
  • a representative medicinal herb, Lagerstroemia speciosa is a plant belonging to the Lythraceae family and is called Lagerstroemia speciosa in Japanese. The inventor observed the movement of corosolic acid in the banaba plant 24 hours a day, 365 days a year.
  • Corosolic acid plays a special role in plants. Corosolic acid in leaves increases when fire is brought close, cuts are made with a knife, and when insects (army ants, shellworms) eat the leaves.
  • corosolic acid content of the same leaf was measured for 24 hours, but the content varied greatly between day and night, and even in the same night before dawn and midnight. Corosolic acid migrates to the surface of shiny leaves to protect them, but when photosynthesis is active, it is not contained in large amounts. Banaba is a perennial deciduous broadleaf tree. In the case of Southeast Asia, the autumn foliage season begins around October, the leaves fall from December to January, the new green leaves begin to appear around March of the following year, and bloom from April to June. Trying to connect the lost life.
  • the inventor succeeded in developing "callus” in which corosolic acid is maximized by taking advantage of research on the movement and function of corosolic acid in the living body of a plant.
  • the content of corosolic acid is about 0.001 to 0.01% based on the weight of the extract.
  • it is within 0.1 to 1% in order to elute fat-soluble corosolic acid.
  • the "corosolic acid-specific production callus” created by the inventor is: 1. Autumn foliage season, 2. 2. deep reddish yellow; 4. worm-eaten; 4.
  • the subject of the present invention is (1) alleviation and improvement of insulin resistance, (2) improvement of insulin response, and (3) insulin resistance by ingestion of corosolic acid, its analogous compounds, and extracts containing them. Alleviation and delay of onset of adult diseases and lifestyle-related diseases that are said to be caused by resistance, (4) Prevention of infectious diseases and reduction of the risk of aggravation, (5) Aging such as cancer, a malignant neoplasm that is representative of adult diseases The content is to reduce and alleviate the risk of adult diseases, which is increasing along with Recently, mutated strains such as the new coronavirus and the Omicron strain have spread all over the world.
  • coronavirus The leading cause of death from coronavirus is thrombosis.
  • the human body senses that a foreign object has entered the capillaries, it concentrates antibodies. Some infectious diseases dissolve blood vessels, and platelets gather to repair blood vessels, resulting in clogging (thrombosis) of blood vessels. Multiple organ failure due to cytokine explosion is a typical example. For people with underlying medical conditions, even minor metabolic disorders can be fatal. This is the main reason why so many elderly people with diabetes have died from the Corona and Omicron strains. In other words, the new coronavirus and mutant strains caused them to suffer and die from their own "things born from human biological reactions.”
  • Cancers and malignant neoplasms are also “created by human biological reactions” that we have. Human beings are said to develop cancer as many as 2,000 times a day. Cancer does not occur because innate immunity such as "killer T cells” eats and eliminates cancer cells. In other words, whether it's a nuisance that came from outside or a nuisance that was born from the inside, things that you made yourself are putting your life at risk. Whether or not it will explode depends on ⁇ how well natural immunity and acquired immunity work''. Innate immunity and adaptive immunity functioning normally is the same as innate immune cells and adaptive immune cells functioning normally. This is because both killer T cells and corona antibodies are made in each cell. This is the reason why the elderly are at high risk of cancer and corona infection.
  • Insulin resistance is the primary reason for the decline in function of innate and adaptive immune cells with aging (elderly). For many years, nutritious diets, easily digestible foods, and unprecedented longevity have been met by the unique hormone insulin, which is the only hormone for nutrient uptake, due to the adaptability of humans. However, insulin deteriorates with age, and the sensitivity of insulin receptors in cells, which are said to be 60 trillion, is reduced. As a result, hyperglycemia becomes the norm and insulin resistance affects cells throughout the body. This is the mechanism that increases the risk of adult diseases.
  • the gist of the present invention ingestion of corosolic acid, its analogues, and extracts containing them alleviates and improves insulin resistance by the above mechanism. As a result, the intake of corosolic acid is accelerated by aging and insulin resistance. It is also effective against infections.
  • the present invention has novelty, inventive step, and contribution to industry in the above points.
  • Insulin Receptor/Insulin Receptor Insulin receptor is a protein that exists on insulin receptor/cell membrane, specifically binds to insulin, and exerts insulin action on cells. Affects sugar uptake. Insulin receptors are present in the lowest vertebrates, eels and humans. The present invention has inventiveness that is completely different from those known drugs.
  • Insulin resistance refers to excessive fasting insulin levels. If so, was there a blood sample taken before and one month after ingestion of corosolic acid or containing it at the clinical level for about one month for comparison? It hasn't been mentioned yet. (Basics of Invention) All existing insulin resistance drugs act on cell receptors including adipocytes. The significance of corosolic acid in alleviating and improving insulin resistance is that it can be expected to be effective not only for diabetes and dementia, but also for all adult diseases and lifestyle-related diseases caused by insulin resistance. It was all an idea from blood sugar control.
  • the corosolic acid of the present invention acts on insulin itself, not adipocytes or skeletal muscle cells on the receptor side as in conventional products.
  • insulin itself, not adipocytes or skeletal muscle cells on the receptor side as in conventional products.
  • Basal study Suzuka University of Science and Technology MT Professor, Kyoto University School of Medicine SY Professor
  • 1. It enhances the effect of insulin itself and restores its function.
  • In the mechanism of glucose uptake it acts on the spike side, that is, it has a brush-up (saw-toothed) effect on the insulin itself.
  • 2019, 2020 clinical trial High Precision, Republic of the Philippines 2.
  • As a result of long-term ingestion for one year additional insulin was secreted due to a rapid insulin response 30 minutes after a meal, and glucose was taken in immediately to lower the blood sugar level.
  • the main subject of the present invention is "improvement of insulin resistance by corosolic acid". Improving insulin resistance also improved insulin sensitivity and thus insulin response. Alleviation of insulin resistance relieves the burden on the pancreas and, above all, reduces total insulin secretion. In other words, even if the amount of insulin is the same, if "effective", a small amount will suppress the increase in blood sugar level, so the total secretion amount can be saved. This has been confirmed by a total of three clinical trials, one of which was long-term administration for one year.
  • HOMA index is used. This is the value obtained by multiplying the fasting insulin value by the blood sugar value and dividing it by 405, and this value is a measure of insulin resistance. It is a standard calculation method around the world. A score of 3 or higher suggests insulin resistance, and a score of 5 or higher indicates insulin resistance.
  • Insulin resistance is like a rusty tap that won't close properly. It is always in a state of "dropping and dripping". A typical value is the “fasting insulin level”. Originally, the most important role of insulin is to act as a doorman holding the key to open the door of the cell by conveying information so that the glucose and nutrients in the blood are taken into the cell. On the other hand, you don't need as much insulin when you're fasting because there's less glucose in your blood. Since nutrients are taken in at once after a meal, rapid insulin secretion is desired to stabilize the blood sugar level. In other words, insulin resistance is a state in which insulin is secreted more than necessary, and a state in which insulin levels in the blood are high, especially during fasting, is called insulin resistance.
  • Insulin response increased insulin divided by increased blood glucose. The higher the number, the better the insulin response. If it is less than 0.5, it is judged as hyposecretion of insulin.
  • the HOMA index is used to determine insulin resistance. The fasting insulin level multiplied by the blood sugar level and divided by 405 gives a measure of insulin resistance. A score of 3 or higher suggests insulin resistance, and a score of 5 or higher indicates insulin resistance.
  • corosolic acid was clearly the active compound in the banaba extract's action of suppressing elevation of blood sugar level.
  • a human clinical trial of the CRO program was carried out, and it was documented that administration of as little as 1 milligram of corosolic acid significantly lowered blood sugar levels.
  • This OGTT test was performed using a corosolic acid reagent (95% or more purity standard).
  • 1 mg of corosolic acid was administered to 16 males and 15 females with borderline diabetes mellitus, and suppression of elevation of blood sugar level was examined. As a result, it was formally confirmed that corosolic acid has a significant effect of suppressing elevation of blood sugar level.
  • Corosolic acid surprisingly exerted an inhibitory effect on blood glucose elevation in people with insulin resistance.
  • the two points are that if the prescribed amount was increased to only 3 milligrams in insulin-resistant clinical trial subjects, a very significant effect of suppressing the increase in blood sugar level was observed. In other words, corosolic acid has an extremely effective ameliorating effect on people with insulin resistance. This was also a great proof of the present invention.
  • Part 4 Evidence that corosolic acid improves insulin resistance (two human clinical trials) Two clinical trials were conducted with banaba extract. In May 1999, the first experiment confirmed that a banaba hot water extract manufactured in-house was used to suppress the increase in blood sugar level in a subject suspected of having type 2 borderline diabetes. As a result, all subjects with good or excessive insulin secretion (resistant) showed suppression of blood glucose level elevation, and almost no subjects with poor insulin response or insulin secretion showed suppression of blood glucose level elevation. In other words, the inhibitory effect on blood sugar level elevation depends on the presence or absence of insulin secretion.
  • the significance of the present invention lies in the fact that the insulin secretory response 30 minutes after a meal in long-term administration subjects improved to the same level as in Europeans and Americans.
  • the graph of insulin secretion 30 minutes after a meal appeared as a pointed shape like a sharp peak. This is a tendency not seen in Japanese or East Asians who come from an agricultural race.
  • the response of insulin is improved and the blood sugar level at the early stage of eating is lowered, the total secretion of insulin is naturally suppressed and reduced.
  • Ingestion of corosolic acid improved insulin response, resulting in a rapid drop in blood glucose level, which made additional insulin secretion by the pancreas unnecessary and saved insulin secretion.
  • the present invention uses corosolic acid, its analogues, and extracts containing them to protect the ⁇ healthy life expectancy of humans,'' which is a finite life, from ⁇ various diseases caused by insulin resistance'' caused by aging. This is the idea of the invention. There is no description yet of anything that attempts to alleviate or improve insulin resistance from the insulin side.
  • the gist of the present invention is the action of corosolic acid, (1) improving the efficacy of insulin itself, (2) improving the insulin sensitivity of cell receptors, (3) suppressing elevation of blood sugar levels, (4) controlling gluconeogenesis in the liver, and (5) (6) reduce the total amount of insulin secretion, (7) reduce the burden of insulin secretion in the pancreas, and (8) make the insulin itself "saw-toothed”. (9) enhance the function of antibodies, immunity, and T cells, and (10) improve insulin resistance to prolong healthy life expectancy.
  • cancer malignant neoplasm
  • human immune system antibodies, killer T cells, etc.
  • One's own immunity and antibody power are important to prevent the onset and to suppress the progression. It is important to find out what is the key to weakening or improving the immunity and antibody power. That is aging and the degree of insulin resistance.
  • a Japanese Nobel laureate announced that there are individual differences in the amount and strength of antibodies that suppress cancer. In other words, it is thought that the fact that the strength of antibodies weakens and the risk of cancer increases with age is due to aging and insulin resistance.
  • MSI-High microsatellite instability
  • Blood flow in peripheral blood vessels and capillaries is particularly important in heart disease (circulatory disease), diabetes, and hypertension. What hinders this is thrombosis and hyperglycemia, and blood flow control is important.
  • the function of insulin is the most important for smooth metabolic circulation in peripheral blood vessels and capillaries, and reducing insulin resistance is an extremely effective method for preventing and improving cardiovascular disease, diabetes, and hypertension. is.
  • Dementia and depression are caused by amyloid beta, which is produced by the combination of insulin and protein that remain in the cerebral blood vessels without being degraded, and toxins generated by aggregation of tau protein, which are said to be 100 billion nerve cells in the cerebral cortex. It is said to destroy it, which causes cerebral atrophy. Most of the brains of patients with dementia have atrophied and become smaller due to destruction of nerve cells. In recent years, the theory that dementia is caused by aging plus diabetes, especially [insulin resistance] has become mainstream. Previously, the [amyloid ⁇ cascade hypothesis] (the idea that garbage/amyloid ⁇ accumulates in the brain and releases toxins to destroy cranial nerves) was influential.
  • Tablets used clinically had a corosolic acid content of 1 milligram per tablet. I took 3 tablets of this a day. The period is one month. The first time was in August 2019 and the second time was in March 2020. In the first trial, 20 young people and adults with smartphone addiction, 22 elderly people, and 10 elderly people in their 70s in the second trial. As a result, the two clinical trials showed almost similar results. In terms of numbers, orientation (memory and cognitive ability) function as indicated by the MMSE score improved by about 40%, and blood insulin resistance improved by about 40%. Ninety percent of the trial subjects recovered their appetite, motivation, smiles and composure and came out of depression. It also reassured the family.
  • the basis of the clinical trials carried out in the present invention were [MMSE test] and [OGTT blood sampling test].
  • the clinical test was conducted three times (1) before corosolic acid intake, (2) two weeks after corosolic acid intake, and (3) one month after corosolic acid intake.
  • In the OGTT blood collection test (1) fasting, (2) 30 minutes after ingestion of 75 g of sugar water, and (3) after 2 hours, blood was collected a total of three times and analyzed.
  • Blood analysis items are blood sugar level, insulin level, and gamma GTP.
  • the blood was collected 3 times, 3 times a day, a total of 9 times, and analyzed.
  • Blood was collected by Hy-Precision, a global diagnostic company, in Cabanatuan City, Nueva Ecija, Philippines.
  • Insulin resistance refers to a state in which insulin is secreted more than a certain amount even when fasting, and insulin continues to be secreted even when the blood sugar level drops after a meal. It is thought that this is caused by decreased sensitivity of insulin receptors, decreased function of insulin itself, and blunted pancreatic blood sugar level response. It would be an image of a water faucet that does not close tightly and is always dripping. Insulin resistance causes the production of amyloid beta, a substance that causes dementia, and the production of tau protein. Excess undegraded insulin remaining in the capillaries in the brain binds to protein, resulting in tau, which is also called brain garbage.
  • Protein builds up, entwined string-like masses called senile plaques build up, release toxins, destroy cranial nerves, and eventually cause cerebral atrophy and dementia.
  • senile plaques build up, release toxins, destroy cranial nerves, and eventually cause cerebral atrophy and dementia.
  • insulin resistance is a major factor in the onset of dementia. If so, in order to prevent dementia, it is most important to improve insulin resistance, and there is no description other than the present invention that proves this in clinical trials.
  • Erectile dysfunction can be divided into three main categories: There are those who can get an erection at times depending on their psychological state and those who cannot get an erection, those who cannot get an erection due to some disease, and those who have both of the above two characteristics. Specifically, there are nerve damage such as spinal cord injury and cerebrovascular disease, blood vessel damage due to diabetes and trauma, phimosis and urethral malformation (abnormality of the penis), etc., but physical disorders are particularly mentioned. are cerebral vascular disorders. This is because the blood flow in the brain is inhibited by insulin resistance, and there are reports of cases in which the administration of corosolic acid improved the condition. A common physiological challenge in all of these diseases is the development of insulin resistance. Other than corosolic acid, there is no description or report on anything that improves insulin resistance from insulin itself.
  • Corosolic acid itself is an ultra-fine active compound present 1.36 million times as many as 1 trillion per milligram. Corosolic acid acts on insulin protein spikes to sharpen insulin like a saw blade to improve sensitivity and sharpness to conserve insulin while alleviating and improving insulin resistance.
  • the present invention is the first in the world to solve the problem of insulin resistance from insulin itself. All conventional insulin sensitizers act on the receptor side, that is, on the cell side, including adipocytes and muscle cells.
  • Corosolic acid, its analogues, and extracts containing them according to the present invention can be inexpensively mass-produced in abundant amounts that can be used by anyone. As of 2021, the burden on patients and consumers will be 1/5,000 to 1/10,000 lower than that of new dementia drugs under development. That alone would be an epoch-making invention.
  • the industrialization of corosolic acid has already been established, including plant callus containing several hundred times the amount of corosolic acid in the Department of Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University, and the tropical plant laboratory of Tottori University, a large-scale extraction factory in China, and simple yield refining in a huge column in South Korea. ing.
  • corosolic acid which is a type of terpene contained in plants, its class, and its analogous compounds to increase the antibody itself and enhance its function, suppress cancer cells (malignant neoplasms), and reduce the function of the circulatory system. It controls blood clots, blood sugar levels, prevents heart disease, amyloid beta-tau protein in the brain, and helps prevent and alleviate the onset of dementia in the elderly and young people with suspected dementia or mild cognitive impairment. .
  • Corosolic acid and its relatives include trimentic acid, oleanolic acid, ursolic acid, maslinic acid, and many related compounds. (Described at the end of the book) It is assumed that there is a high possibility that these analogous compounds of terpenes have effects similar to those of corosolic acid.
  • corosolic acid and its analogues are contained in many plants such as banaba, loquat, persimmon, mulberry, guava, etc., and have been widely popular among the common people as folk remedies since ancient times, and there is no fear of side effects.
  • the present invention restores insulin function and response to normal in elderly or mature people who secrete insulin or who are suspected of having excessive insulin secretion and are suspected of having insulin resistance, thereby progressing various adult diseases, lifestyle-related diseases, dementia, etc.
  • the present invention relates to a composition that enables the reduction, alleviation or prevention of Also, for young people and adults who suffer from mental difficulties such as depression and ED, it helps to relieve and alleviate anxiety and contribute to health recovery.
  • [plant-derived corosolic acid] restores the original function of insulin once again against [dulling of insulin response and insulin resistance due to aging], which is considered to be the main cause of dementia, and as a result dementia and Alzheimer's disease.
  • the present invention makes it possible to cheaply mass-produce corosolic acid, inexpensively, widely and safely to prevent and alleviate dementia.
  • the triterpene to which corosolic acid belongs is a kind of terpene composed of six isoprenes and having a molecular formula of C30H48. More than 100 analogous compounds have been reported (at the end of the book), and are fat-soluble compounds widely contained in plants.
  • Extraction methods include water extraction, hot water extraction, ethanol hot water extraction, autoclave extraction, and the like. It is economically preferable to subject the dried raw material after several hot water extractions to ethanol hot water. 3.
  • the composition containing corosolic acid used in clinical trials is the composition used in past experiments, which is a corosolic acid reagent (99.5% or more purity), ethanol with a corosolic acid content of 1% to 18%.
  • the composition used in the two dementia clinical trials is a 1-mg tablet containing corosolic acid.
  • the extract manufacturing plant is in Zhejiang, China, and the tablet manufacturing is in Chiba Prefecture, Japan.
  • Ethanol hot water extract and excipients (described later) are used as raw materials, and the content of corosolic acid is 1 milligram per tablet.
  • the prescribed amount per day is 3 tablets.
  • the amount of corosolic acid was 3 milligrams. No side effects or changes in physical condition were confirmed at the time of prescription or in post-test interviews. For this reason, when prescribing or ingesting corosolic acid and the like for the purpose of alleviating and preventing dementia, the amount of corosolic acid is assumed to be 0.15 mg to 60 mg per day, especially [3 mg to 10 mg per day]. degree] is preferred. 6.
  • a preferred dosage of corosolic acid and the like is [1 milligram to 20 milligrams per day].
  • Powder udon, bread, confectionery, etc. using white extract
  • the timing of ingestion is preferably before a meal. However, it can be done between or after meals. In short, it is important to be able to continue on a daily basis without any pain or annoyance.
  • the ultimate goal is to restore the smiles of people suspected of dementia, as well as their willingness and appetite. This will lead to the happiness of the family and will make a great contribution to solving social problems.
  • the biggest [problem] in dementia is the absence of new dementia drugs, preventive drugs, and biomarkers for diagnosis.
  • the present invention solves (delays/prevents) the progress of dementia/Alzheimer's disease, which is rapidly increasing, based on medical scientific evidence. 9. Due to genetic factors and lifestyle habits, especially in Japanese and East Asians [Insulin deficiency is present.
  • corosolic acid, its analogues, and extracts containing them improve insulin function in elderly or mature people who have developed insulin resistance due to excessive fasting insulin secretion due to aging. It restores the response to normal, suppresses the progression of dementia, makes it possible to alleviate or prevent dementia, and maintains or restores the health and smile of the person and his/her family.
  • development of solvents and devices that can be mixed by nasal suction to prevent dysphagia and accidental ingestion safely and cheaply mass-produced dementia and Alzheimer's disease, which are increasing rapidly in the elderly, middle-aged people and their families. It protects against the onset of disease.
  • corosolic acid can be applied as a daily food and can be easily ingested, it can be used as a new dream drug or a daily food that is effective for a wide range of diseases common to the elderly, such as many adult diseases, lifestyle-related diseases, and dementia. It is possible to protect people's health. Above all, corosolic acid, its analogues, and extracts containing them can be produced at low cost, and unlike synthetic drugs, they are safe without side effects. As a specific product to solve the problem, addition to daily foods such as tea, candy, honey, yogurt, etc. is also a desirable means.
  • corosolic acids are plant-derived compounds that have been traditionally eaten for a long time, are safe, and have no reports of side effects. There is no fear of accidents or side effects even if it is addictive or ingested in large amounts.
  • the diseases that account for the number of deaths in modern people are diseases called adult diseases, such as cancer, heart disease, diabetes, hypertension, and pneumonia, or diseases that increase in risk with age, or lifestyle-related diseases, which have never been seen before in human history. It is a disease caused by high blood concentration and thrombus caused by nutritious diet and lack of exercise. The next most important is dementia. It is an urgent problem and the subject of the present invention to propose these concrete solutions together with evidence.
  • corosolic acid has already been successfully developed for "nanization,”"transparency,” and "solubility.” There are liquids that dissolve even in water, so the range of uses is limitless.
  • the effects realized by the invention are as follows. 1. Creation of new industries. Corosolic acid mass production facility. Callus factories, processing equipment, extraction equipment, simple yield purification columns, etc. 2. An increase in the number of working elderly people. We solve the problems of individuals, families, and society by delaying and preventing the progression of adult diseases, dementia, and Alzheimer's disease. 3. Solving the problem of social insurance premiums. Maintaining the health of the elderly and resolving the problem of the shortage of caregivers. 4. Proposal of a simple and affordable dementia prevention method in daily life. Just take 3 small tablets. 5. Creation of new markets. Measures against lifestyle-related diseases, creation of dementia prevention and cure products, and creation of new industries and employment. 6.
  • MMSE Test Scores of Elderly Patients in the First Investigator Group - Part 1 MMSE Test Scores of Elderly Patients in the First Investigator Group - Part 2 Results of the OGTT blood sampling test for the elderly in the first investigator group Part 1 Results of the OGTT blood sampling test of the elderly in the first investigator group Part 2 Participating elderly's name, date of birth, and progress of MMSE MMSE scores before, 2 weeks and 1 month after intake of corosolic acid in the elderly Same MMSE score line graph as above for adults with smartphone addiction OGTT trial data details by investigator As a result of corosolic acid intake, the international standard value HOMA-IR for insulin resistance was improved, and insulin sensitivity was improved, insulin was secreted quickly, and as a result, the total amount of insulin secretion was reduced, and the burden on insulin-degrading enzymes was reduced.
  • the first mode of carrying out the present invention is to make the existence of corosolic acid widely known to the public. Then developers and partners will appear and commercialization will be accelerated. It is important to let people wait for the newsiness that deserves it because it is to aim for SNS and media exposure to inform. Calculating the relationship between corosolic acid and insulin by computer simulation would also be a cost-effective method.
  • the inventor has already crystallized corosolic acid and determined its 3D structure. In addition, the 3D structure of insulin is widely open to the public, and computer simulation (digital simulation) is also possible.
  • the second mode for carrying out the present invention is to utilize corosolic acid and the like in every scene of daily life of people suspected of adult diseases, lifestyle-related diseases, dementia, and dementia (MCI), to improve insulin resistance. It is to develop products such as medicine, food, beverage, environment (spray), IoT, etc. based on the solution of sexuality.
  • insulin which is the main target of the present invention.
  • the human body there is no hormone other than insulin that takes in sugar into cells, and insulin secretion is extremely important. Therefore, it is the most important and unique hormone for sustaining human life.
  • One of the objectives of the present invention recognition and concept of dementia and Alzheimer's disease, which are rapidly increasing among the elderly as adult diseases, is as follows. For example, consider insulin resistance as an example. 1) Dementia and Alzheimer's disease are characterized by [brain atrophy], but this is a [result that has happened] that can only be confirmed by imaging. 2) Brain atrophy is a neurodegenerative disease (destruction of the central nervous system). 3) The majority of the brain consists of about 1 trillion glial cells and about 100 billion nerve cells, and normal metabolism is important. 4) Nourishment for the brain 5) Brain cells require more energy than other cells (equivalent to liver cells). 6) From the above, glucose metabolism is essential for healthy brain function.
  • the blood-brain barrier exists in the brain, making it difficult for drugs to reach. 8)
  • the key to brain metabolism is [insulin] 9) If the action of insulin is weakened, it is likely to cause diabetes, even in the brain, which is dementia This is the reason why Alzheimer's disease is called the third type of diabetes. 10) If the insulin function in the brain is normalized or approaches normal, dementia and Alzheimer's disease may be mitigated and prevented.
  • Insulin resistance refers to a state of reduced insulin function or may be a reduced insulin sensitivity of nutrient uptake cells.
  • Insulin does not work, blood sugar levels do not go down, and insulin is over-secreted. Insulin response also becomes dull, and high-viscosity blood in the brain cannot flow smoothly through the fine capillaries of the brain, and nutrients cannot be delivered to brain cells. Residual insulin in cerebral blood vessels with weakened action binds to protein (amyloid ⁇ precursor protein) to produce the causative substance of amyloid ⁇ peptide. Amyloid ⁇ ⁇ phosphorylation of tau protein ⁇ producing dementia and Alzheimer's disease [results], which is said to produce senile plaques. This is the general pharmacological mechanism of dementia onset.
  • alleviation and improvement of insulin resistance by corosolic acid are typical geriatric diseases, cancer, diabetes, hypertension, diabetes, ED and other typical diseases of the elderly...
  • Alleviation and prevention of dementia and Alzheimer's disease means that (2) it is important to bring blood glucose metabolism in the brain closer to normal, (3) return insulin function to normal, and (4) simply insulin secretion level.
  • Timing in other words, insulin must work normally when it is needed, and quickly lower the blood insulin level after completing its role (insulin normalization of the total secretion amount and timing of ), it is important to discover a composition that enables it, and at the same time, it must be numerically and physicochemically proven to alleviate and prevent dementia and Alzheimer's disease.
  • the ingestible composition is inexpensive, mass-producible, and can be ingested in a manner closely related to daily life. Tens of thousands of yen, hundreds of thousands of yen, or millions of yen per prescription is unrealistic and cannot be prescribed to the general public.
  • the fee for one prescription is several thousand yen, preferably several hundred yen or less.
  • the present invention is the realization of the above order with evidence.
  • the [data proving the gist of the invention] is attached below.
  • the thesis is that (1) corosolic acid intake alleviates and prevents dementia and MCI mild cognitive impairment, (2) it is due to the improvement of brain metabolism, and (3) its physicochemical proof is verified by clinical trials. (4) improvement of insulin response and resistance is important for improving brain metabolism, (5) mitigation and prevention of dementia and MCI mild cognitive impairment have been achieved, (6) the demonstration has been widely conducted around the world. (7) Therefore, corosolic acid supplementation proved to alleviate and prevent dementia/MCI mild cognitive impairment, as demonstrated by the MMSE test accepted in .
  • memory impairment, depressed mood, loss of appetite, loss of motivation, and forgetfulness are observed by ingesting a certain amount of corosolic acid or an analogous compound to people suspected of having dementia, which is an adult disease or lifestyle-related disease, as an example. It aims to relieve the patient and his/her family from anxiety and pain and give them a sense of security and relaxation.
  • the broad mechanism of action is that of a method and composition that alleviates insulin resistance and enables alleviation and prevention of [capillary damage and neurofibrillary tangles and destruction in the brain], which are major causes of dementia. It is a discovery.
  • the composition of the present invention includes extracts containing corosolic acids extracted from various plants, extracts and reagents similarly obtained by plant culture, analogous compounds and semi-synthesized analogous compounds, sugar chains, etc. It refers to a compound modified with , a compound in which the carboxylic acid moiety is cleaved, and the like. All of the above are speculated to involve or partially involve corosolic acid.
  • a reagent level of corosolic acid with a purity of 99.5% or more or a composition containing it is effective against sluggish insulin response and insulin resistance caused by aging and lifestyle habits, which are considered to be the main causes of dementia.
  • Informed consent (participation and disclosure agreement) was obtained from all participants and guardians.
  • An interview was conducted after corosolic acid intake for one month, and no side effects were reported.
  • the cognitive functions (memory, verbal ability, judgment ability, calculation ability, performance ability, etc.) of elderly people aged 80 and over improved significantly by plus 9.8 points.
  • the score of elderly people in their 70s improved to plus 5.8 points.
  • Genome-edited plants rice farmers, vegetable and fruit farmers, agricultural cooperatives, supermarkets, restaurants8. Development of new drugs, preventive health foods for geriatric diseases, beverages, transparent extracts and devices for spraying 9. Crystals for reagent manufacture10. Computer simulation of adult diseases and lifestyle-related diseases using 3D structures obtained from crystals

Abstract

[Abstract] Corosolic acid improves insulin resistance and recovers an insulin function that is deteriorated with age. As a result, the insulin sensitivity in an aged person is improved and the metabolism in all cells gets active. [Problem] The problem to be solved by the present invention is to alleviate and ameliorate an adult disease, a lifestyle-related disease, dementia and the like associated with insulin resistance and achieve a long healthy life-span by corosolic acid and an analogue thereof. There is a finding about a composition which recovers a function inherent to insulin again against the slowing down of an insulin reaction or insulin resistance that is believed as a main cause of an adult disease, a lifestyle-related disease, dementia or the like and is consequently useful for the delay of progression or prevention of an adult disease, a lifestyle-related disease, dementia/Alzheimer's disease or the like, and an idea about a specific method is proposed.

Description

インスリン抵抗性・感受性を改善し代謝機能を向上させるコロソリン酸とその類Corosolic acid and its analogues that improve insulin resistance/sensitivity and improve metabolic function
本発明の新規性、進歩性とは、エビデンスに基づいた・・・１．未だ報告がない認知症の予防と緩和の組成物、２．同じく世界初の当該化合物の結晶とマニュアル化と大量生産の新たな効率的方法の発見である。
具体的には、加齢とともに高まる生活習慣病リスク低減、成人病の発症予防・緩和にために有効なコロソリン酸並びに、その構造を決定した結晶構造の特定と結晶の製造方法、コロソリン酸試薬の大量生産の方法、その類縁化合物とコロソリン酸を含む植物エキスに関するものである。
応用分野は多岐にわたる。産業的には、健康食品、新薬、添加物、透明な溶液し霧状に噴霧したり、クルマのエアコン口に付けたりして昼間はもちろん就寝中でも使用可能な画期的な健康素材、活性化合物、組成物の発明である。 The novelty and inventive step of the present invention are based on evidence...1. Compositions for prevention and alleviation of dementia, which have not yet been reported;2. It is also the world's first discovery of a new efficient method for crystallization of the compound, manualization, and mass production.
Specifically, corosolic acid, which is effective for reducing the risk of lifestyle-related diseases that increases with age and preventing and alleviating the onset and alleviation of adult diseases, identification of the crystal structure that determines its structure, methods for producing crystals, and corosolic acid reagents. It relates to a method for mass production, plant extracts containing its analogues and corosolic acid.
There are many fields of application. Industrially, health foods, new medicines, additives, epoch-making health materials and active compounds that can be used not only during the day but also during sleep by spraying transparent solutions into a mist or attaching them to car air conditioners. , is the invention of the composition.
多くの先進国において、高齢化社会が留まることはない。
日本においては人口の３人に１人が６５歳以上の高齢者で　ある。日本に留まらずお隣の韓国、そして人口世界一の中国でも高齢化社会は待ったなしでやってくる。
人生１００年時代と言われる現代では働ける高齢者、病院にかからない元気な高齢者が未来社会の命運を握っていると言っても過言ではないだろう。本発明は、治験に基づいた高齢者の成人病と生活習慣病の予防と緩和の発明に関するものである。
コロソリン酸を含む植物は２００種以上が報告されている。コロソリン酸は天然由来の化合物である。コロソリン酸試薬（９５％以上純度）は広く流通している。またコロソリン酸をうたった健康製品も多く出回っている。しかし含有量には確たる根拠がないのが現状である。その理由として結晶と結晶作りのマニュアルがなかったことがあげられる。
結晶とは化合物の構造を特定するものであり、カタチ（構造）が特定できて初めて特徴や作用が推定できるのである。しかしコロソリン酸の結晶作りには未だ記載がない上、製造に関する記載がなかったため高速クロマトグラフィーの解析で「当りをつけた」に過ぎなかった。コロソリン酸に関する深い研究はなされてこなかったのである。
殆どの製薬会社は、天然由来の活性化合物に興味を示さない。理由として、物質特許が取得できなければ一定期間利益を独占できないからである。
そこで発明者は産業化へのモチベーションアップとして世界初の認知症臨床試験結果以外に、化合物としてのコロソリン酸に対し、「合成薬と同程度の一定期間の排他的権利を主張できる方法」を準備した。
具体的には、まず１．世界初のMMSE試験とOGTT検査解析と組み合わせた認知症の二度にわたる臨床試験、次に、２．コロソリン酸結晶に再現性のある手法の発見、そして３．コロソリン酸を大量生産可能な従来手法と異なるさらに効率的コロソリン酸製造の植物培養を用いた手法、さらに、４．並びにバナバやグワバや柿や桑や枇杷などコロソリン酸を多く含むとされている緑葉に比較して５０倍～５００倍以上含有するというカルスのゲノム情報の４発明である。
このコロソリン酸産生カルスは、「キノコの製造工場のように」カルス培養によって規模を限りなく増やせると同時に、最高含有量を生み出す種を特定することに役立つものである。発明者は、上記４点の現物サンプルのすべてを厳重に保管している。 In many developed countries, aging societies will not stop.
In Japan, one out of three people is aged 65 or over. Not only in Japan, but also in neighboring Korea, and in China, which has the world's largest population, aging societies are coming soon.
It is no exaggeration to say that in this age of 100-year lifespans, elderly people who are able to work and who are in good health and who do not need to go to hospitals hold the fate of future society. The present invention relates to inventions for prevention and alleviation of geriatric diseases and lifestyle-related diseases in the elderly based on clinical trials.
More than 200 species of plants containing corosolic acid have been reported. Corosolic acid is a naturally occurring compound. Corosolic acid reagents (>95% pure) are widely available. There are also many health products on the market claiming corosolic acid. However, the current situation is that there is no definite basis for the content. The reason for this is that there was no manual for crystals and crystal making.
A crystal specifies the structure of a compound, and only after the shape (structure) can be specified can the characteristics and effects of the compound be inferred. However, since there was no description of the crystal formation of corosolic acid and no description of its production, the analysis by high-speed chromatography merely "got a hit". In-depth research on corosolic acid has not been done.
Most pharmaceutical companies are not interested in naturally occurring active compounds. The reason is that if a substance patent cannot be obtained, profits cannot be monopolized for a certain period of time.
Therefore, in order to increase motivation for industrialization, the inventor prepared "a method that can claim exclusive rights for a certain period of time similar to synthetic drugs" for corosolic acid as a compound, in addition to the world's first clinical trial results for dementia. did.
Specifically, first, 1. The world's first MMSE test and two dementia clinical trials combined with OGTT test analysis, then 2. 2. Discovery of reproducible methods for corosolic acid crystals; 4. A method using plant culture for more efficient production of corosolic acid, which is different from conventional methods capable of mass-producing corosolic acid; In addition, it is the fourth invention of the genome information of callus that contains 50 to 500 times more corosolic acid than green leaves such as banaba, guava, persimmon, mulberry, and loquat, which are said to contain a large amount of corosolic acid.
This corosolic acid-producing callus can be scaled up indefinitely by callus culture "like a mushroom factory", while helping to identify the species that produce the highest content. The inventor strictly keeps all of the above four physical samples.
本発明のコロソリン酸の結晶が作れた意味は大きい。なぜなら現在そして未来の創薬はまず「コンピューターシミュレーション」から始まりからである。コンピューターシミュレーションを実行するためには正確な３D構造が必要である。３D構造は結晶がなければならない。ある意味、結晶化は「神のみぞ知る」世界であり、一定の条件は想定し行いものの、多くの試行錯誤を繰り返し偶然に得られる場合が多い。あの大きな玄武岩の柱状節理は実験室の規模だけでできるものだけではないだろう。
コンピューターシミュレーションは巨額な費用を掛けずに、長い時間を費やさずに活性化合物の最初から最終のフェーズまでの効果、その程度、副作用、その部位などがかなり正確に予測できるのである。現在ではヒト臨床試験よりも信頼性が高いとまでされている。
例えばインスリンタンパクの結晶ができて３D構造が確定できれば、コロソリン酸の３D構造とどこがどのように接合するかを計算し効果や副作用を推定できる。またコロソリン酸の結晶により３ｄ構造が確定されたことにより、癌、心臓病、高血圧症、糖尿病、認知症・鬱、脳梗塞、EDなどの加齢によってリスクが高まる成人病・生活習慣病に関する効果、副作用を一剤、又は合剤によってもコンピューターシミュレーションが可能になる。 It is significant that the corosolic acid crystals of the present invention were produced. This is because current and future drug discovery begins with “computer simulation”. Accurate 3D structures are required to perform computer simulations. The 3D structure must be crystalline. In a sense, crystallization is a world that "only God knows", and although certain conditions are assumed, it is often obtained by chance after repeated trial and error. The columnar joints of that large basalt rock are not only possible on the scale of the laboratory.
Computer simulations can fairly accurately predict the effect, extent, side effects, and location of an active compound from the first to the last phases without spending a lot of money and time. It is now considered more reliable than human clinical trials.
For example, if a crystal of insulin protein is formed and the 3D structure is determined, it is possible to estimate the effects and side effects by calculating where and how they are bonded to the 3D structure of corosolic acid. In addition, since the 3d structure of corosolic acid crystals has been confirmed, it is effective for adult diseases and lifestyle-related diseases that increase with age such as cancer, heart disease, hypertension, diabetes, dementia/depression, cerebral infarction, and ED. , side effects can be simulated using a single drug or a combination drug.
本発明はコロソリン酸の産業化へも二つの道筋をつけた。コロソリン酸はトリテルペノイドの一種であり、糖尿病モデルの動物及び細胞試験において、糖が組織に取り込まれる際に働くグルコース輸送体GLUT4 を細胞膜へ誘導する作用がある。また、インスリン受容体のリン酸化を促進することで、糖の取り込みを促進する作用も報告されている。コロソリン酸とは、五環であるトリテルペン類の一種。構造はウルソール酸や、オレアノール酸、トリメンティック酸、マスリン酸などと似ている。ウルソール酸とはヒドロキシ結合を持っているという点だけが異なっている。化学式はＣ３０Ｈ４８Ｏ４で分子量は４７２．７１０の脂溶性の化合物である。
しかしこれは高速クロマトグラフィーのピーク付近の化合物を単利精製を続けたものである結晶とは別ものである。結晶とは分子間の距離を最短にすることによって得られたものであるため他の原子・分子が入り込んだり「隙間」が無いのが特徴である。これは極めて重要であり特にコンピューターシミュレーションには不可欠である。 The present invention also paves the way for the industrialization of corosolic acid. Corosolic acid is a kind of triterpenoid, and in diabetes model animal and cell tests, it has the effect of inducing the glucose transporter GLUT4, which works when sugar is taken up into tissues, to the cell membrane. It has also been reported to promote the uptake of sugar by promoting the phosphorylation of insulin receptors. Corosolic acid is a pentacyclic triterpene. Its structure is similar to that of ursolic acid, oleanolic acid, trimentic acid, and maslinic acid. It differs from ursolic acid only in that it has a hydroxy bond. It is a fat-soluble compound with a chemical formula of C30H48O4 and a molecular weight of 472.710.
However, this is different from crystals, which are simple purifications of compounds near the peak of high performance chromatography. A crystal is obtained by minimizing the distance between molecules, so it is characterized by the fact that there is no "gap" or other atoms or molecules enter. This is extremely important and especially essential for computer simulations.
結晶作りマニュアル以外のコロソリン酸の産業化への道筋は「工業化」（安価で大量生産の具体的方法）の発見である。
コロソリン酸とその類縁化合物を含む植物は１００種以上が報告されている。日本では柿、桑、枇杷、紫蘇、花梨、熊笹などがありそのすべてが糖尿病緩和の薬草として流通している。代表的な薬草バナバ（Ｌａｇｅｒｓｔｒｏｅｍｉａ　ｓｐｅｃｉｏｓａ）は、ミソハギ科の植物であり、和名をオオバナサルスベリという。発明者は植物バナバにおけるコロソリン酸の動きを２４時間、３６５日観察した。
同時に発明者は国立岡山大学薬学部に３年間にわたり延べ６人の研究生を送り込みコロソリン酸の大量生産の研究をつづけた。
また岡山大学薬学部植物園にはバナバを植樹しコロソリン酸のカルスによる大量生産のためにいつでも直ぐに採葉、観察、実験ができる環境を整えて研究した。
コロソリン酸は植物内では特別な役割を果たしている。火を近づけたり、ナイフで切り目を入れたり、昆虫（軍隊蟻・貝殻虫）が食べると葉中のコロソリン酸は増加する。
２４時間同じ葉のコロソリン酸を測定したが昼夜によっても、同じ夜間でも夜明け前と深夜では含有量は大きく変化するのである。
コロソリン酸は艶のある葉の表面上に移動し葉を守ろうする反面、光合成が活発なときは葉の中には多く含まれない。バナバは多年生落葉の広葉樹である。東南アジアの場合、紅葉時期は１０月ごろに始まり落葉は１２月～１月、新緑葉は翌年３月ごろに出始め４月～６月に開花し、雨季である７月～９月に種を落とし命を繋ごうとする。 The path to the industrialization of corosolic acid other than the crystal-making manual is the discovery of "industrialization" (a specific method for mass production at a low cost).
More than 100 species of plants containing corosolic acid and its analogues have been reported. In Japan, there are persimmon, mulberry, loquat, shiso, quince, and kumazasa, and all of them are distributed as medicinal herbs for alleviating diabetes. A representative medicinal herb, Lagerstroemia speciosa, is a plant belonging to the Lythraceae family and is called Lagerstroemia speciosa in Japanese. The inventor observed the movement of corosolic acid in the banaba plant 24 hours a day, 365 days a year.
At the same time, the inventor sent a total of six research students to the Faculty of Pharmaceutical Sciences, Okayama University for three years to continue research on mass production of corosolic acid.
In addition, we planted banaba trees in the Botanical Garden of the Faculty of Pharmaceutical Sciences, Okayama University, and prepared an environment for mass production of corosolic acid by callus, in which leaves could be harvested, observed, and experimented at any time.
Corosolic acid plays a special role in plants. Corosolic acid in leaves increases when fire is brought close, cuts are made with a knife, and when insects (army ants, shellworms) eat the leaves.
The corosolic acid content of the same leaf was measured for 24 hours, but the content varied greatly between day and night, and even in the same night before dawn and midnight.
Corosolic acid migrates to the surface of shiny leaves to protect them, but when photosynthesis is active, it is not contained in large amounts. Banaba is a perennial deciduous broadleaf tree. In the case of Southeast Asia, the autumn foliage season begins around October, the leaves fall from December to January, the new green leaves begin to appear around March of the following year, and bloom from April to June. Trying to connect the lost life.
発明者はコロソリン酸の植物生体内での動きと働きの研究を生かしてコロソリン酸が最大になる「カルス」の開発に成功した。緑葉の熱水抽出エキスの場合、コロソリン酸含有量はエキス重量に対し０．００１～０．０１％程度である。また脂溶性であるコロソリン酸を溶出させようとエタノール熱水抽出エキスの場合でも０．１～１％以内である。
発明者の作った、「コロソリン酸特化産生カルス」は、１．紅葉時期、２．深い紅黄色、３．虫食い、４．明け方に採葉、５．極めて薄い表面上の細胞を採取し培地に移植しコンタミネーションに注意しながら、条件を変えた多くの種のカルスを育てコロソリン酸含有量を比較し含有量が最大のものである。当該カルスのエタノール熱水抽出エキスのコロソリン酸含有量は５～２５％にも及び、試薬レベルまでの単利精製コストは数十分の１以下になる。このこのカルスは保存され各種のゲノム遺伝子が保管されている。 The inventor succeeded in developing "callus" in which corosolic acid is maximized by taking advantage of research on the movement and function of corosolic acid in the living body of a plant. In the case of the hot water extract of green leaves, the content of corosolic acid is about 0.001 to 0.01% based on the weight of the extract. Also, even in the case of an ethanol hot water extraction extract, it is within 0.1 to 1% in order to elute fat-soluble corosolic acid.
The "corosolic acid-specific production callus" created by the inventor is: 1. Autumn foliage season, 2. 2. deep reddish yellow; 4. worm-eaten; 4. Picking leaves at dawn; Cells on the extremely thin surface were harvested and transferred to the medium, and while careful attention was paid to contamination, many species of callus were grown under different conditions. The content of corosolic acid in the ethanol hot water extract of the callus is as high as 5 to 25%, and the simple refining cost to the reagent level is less than several tenths. This callus is conserved and various genomic genes are stored.
本発明の主題は、コロソリン酸ならびにその類縁化合物そしてそれらを含む抽出物等の摂取よる、（１）インスリン抵抗性の緩和と改善と、（２）インスリン応答の向上、さらには、（３）インスリン抵抗性の起因するとされる成人病、生活習慣病の緩和と発症遅延、（４）感染症の予防と重症化リスクの軽減、（５）成人病の代表たる悪性新生物「癌」など加齢と共にリスクの高まる成人病リスクを低減し緩和するという内容である。
今般、新型コロナウイルス、オミクロン株などの変異株が世界中で大流行した。フィリピンの治験者の高齢者の皆さんには、臨床試験の後も引き続き１日３粒（コロソリン酸換算１日３ミリグラム）の摂取をお願いした。摂取の開始は２０１９年８月開始の第一グループ２０名と、２０２０年３月開始の第二グループ１０名である。いずれも７０歳以上の高齢者男女である。
驚くべきことにこの３０名は２０２０年の４月ごろから流行したコロナアルファ株、デルタ株、オミクロン株でも一人の死亡者もいなかったのである。同じ町内、地区では覆うの高齢者が新型コロナウイルスで亡くなられた。しかしコロソリン酸含有のエキスタブレットを飲み続けた高齢者には一人の犠牲者も出なかったのである。
ウイルスも癌も人間の身体にとっては、「敵であり不法侵入者であり邪魔者」である。これを除外し排泄しているのが、自然免疫と獲得免疫でありそのキラーＴ細胞や、抗体を産生しているのが「自然免疫と獲得免疫細胞」なのである。 The subject of the present invention is (1) alleviation and improvement of insulin resistance, (2) improvement of insulin response, and (3) insulin resistance by ingestion of corosolic acid, its analogous compounds, and extracts containing them. Alleviation and delay of onset of adult diseases and lifestyle-related diseases that are said to be caused by resistance, (4) Prevention of infectious diseases and reduction of the risk of aggravation, (5) Aging such as cancer, a malignant neoplasm that is representative of adult diseases The content is to reduce and alleviate the risk of adult diseases, which is increasing along with
Recently, mutated strains such as the new coronavirus and the Omicron strain have spread all over the world. We asked the elderly participants in the Philippine trial to continue to take 3 capsules per day (3 mg per day in terms of corosolic acid) after the clinical trial. The start of intake is 20 people in the first group starting in August 2019 and 10 people in the second group starting in March 2020. Both are elderly men and women aged 70 or over.
Surprisingly, none of these 30 people died from the Corona Alpha, Delta, and Omicron strains that have been prevalent since April 2020. In the same town and district, more elderly people died of the new coronavirus. However, none of the elderly who continued to take corosolic acid-containing extract tablets died.
Both viruses and cancer are "enemies, intruders, and nuisances" for the human body. It is natural immunity and acquired immunity that exclude and excrete this, and it is "natural immunity and acquired immune cells" that produce killer T cells and antibodies.
高齢者にオミクロン株死亡者が多かったり、加齢によって発癌リスクが高まるのは上記の細胞にもインスリン抵抗性があり、十分な機能発揮がなされないためである。中高年の人々がコロソリン酸を１日３ミリ摂取すれば、感染症のみならず、癌、心臓病、高血圧症、糖尿病、認知症・鬱、脳梗塞、EDのリスクを低下させることは治験者の現在の健康ぶりから判断すれば間違いないだろう。 The reason why there are many deaths of Omicron strains among elderly people and that the risk of carcinogenesis increases with age is that these cells also have insulin resistance and do not perform their functions sufficiently. If middle-aged and elderly people take 3 milligrams of corosolic acid a day, the risk of not only infectious diseases but also cancer, heart disease, hypertension, diabetes, dementia/depression, cerebral infarction, and ED is reduced. Judging from his current health, there is no doubt.
コロナウイルスの死亡原因の最たるものは「血栓症」である。毛細血管に異物が入ってきたと人体が感知して抗体を集中させる。感染症によっては血管を溶解するものもなり血小板が補修に集まり血管の詰り（血栓）を生じる。サイトカイン爆発による多臓器不全はその代表である。基礎疾患を持っている人にとっては僅かな代謝不全は死に至る危険がある。糖尿病を持つ高齢者の多くがコロナとオミクロン株で亡くなられたのもこれが主因である。つまり新型コロナウイルスや変異株がきっかけになり自身の有する「人間の生体反応によって生まれたもの」によって苦しんだり、死んだりすることになったのである。 The leading cause of death from coronavirus is thrombosis. When the human body senses that a foreign object has entered the capillaries, it concentrates antibodies. Some infectious diseases dissolve blood vessels, and platelets gather to repair blood vessels, resulting in clogging (thrombosis) of blood vessels. Multiple organ failure due to cytokine explosion is a typical example. For people with underlying medical conditions, even minor metabolic disorders can be fatal. This is the main reason why so many elderly people with diabetes have died from the Corona and Omicron strains. In other words, the new coronavirus and mutant strains caused them to suffer and die from their own "things born from human biological reactions."
癌や悪性新生物も自身の有する「人間の生体反応によって生まれたもの」である。ヒトは毎日２０００回もの癌が発生しているとされている。癌にならないのは「キラーT細胞」などの自然免疫が癌細胞を食べて消滅させているからである。つまり外部から入ってきた邪魔者も、内部から生まれた邪魔者もどちらも自身で作ったモノが命を危険にさらしているのであり、それが正常に働くか？暴発するかは「自然免疫と獲得免疫が上手く働くか如何に」かかっているのである。
自然免疫と獲得免疫が正常に働くとは、それぞれの自然免疫細胞と獲得免疫細胞は正常に働くと同じである。キラーT細胞もコロナ抗体もそのぞれの細胞で作られているのからである。高齢者が癌リスクやコロナ感染で重症化リスクが高いのはここに原因がある。 Cancers and malignant neoplasms are also “created by human biological reactions” that we have. Human beings are said to develop cancer as many as 2,000 times a day. Cancer does not occur because innate immunity such as "killer T cells" eats and eliminates cancer cells. In other words, whether it's a nuisance that came from outside or a nuisance that was born from the inside, things that you made yourself are putting your life at risk. Whether or not it will explode depends on ``how well natural immunity and acquired immunity work''.
Innate immunity and adaptive immunity functioning normally is the same as innate immune cells and adaptive immune cells functioning normally. This is because both killer T cells and corona antibodies are made in each cell. This is the reason why the elderly are at high risk of cancer and corona infection.
加齢（高齢者）によって自然免疫細胞と獲得免疫細胞の機能が低下する一番の理由はインスリン抵抗性である。長年にわたる冨栄養食、消化の良い食べ物、歴史上例をみない長寿はヒトの持つ適応能力により栄養取り込みの唯一無二のホルモン「インスリン」で対応してきた。しかしインスリンは加齢により劣化し、６０兆個とも言われる細胞のインスリン受容体もその感度を鈍らせている。その結果、高血糖状態が常態化しインスリン抵抗性が体の隅々の細胞に及んでる。これが成人病リスクの高まるメカニズムである。 Insulin resistance is the primary reason for the decline in function of innate and adaptive immune cells with aging (elderly). For many years, nutritious diets, easily digestible foods, and unprecedented longevity have been met by the unique hormone insulin, which is the only hormone for nutrient uptake, due to the adaptability of humans. However, insulin deteriorates with age, and the sensitivity of insulin receptors in cells, which are said to be 60 trillion, is reduced. As a result, hyperglycemia becomes the norm and insulin resistance affects cells throughout the body. This is the mechanism that increases the risk of adult diseases.
以下は、京都大学医学部、広島大学医学部、慈恵会医科大で論文化された内容である。
１．       コロソリン酸はインスリン感受性を向上させる。
２．       素早く出して素早く手仕舞いする。血糖値も正常に保たれる。
３．       結果、インスリンの総分泌量は節約される。
４．       余分なインスリンがなくなればインスリン抵抗性は緩和される。
５．       インスリン抵抗性が緩和されれば成人病や生活習慣病のリスクは低下する。
６．       それに留まらず、自然免疫と獲得免疫の機能回復も見込めるのである。 The following is the contents of papers published at Kyoto University School of Medicine, Hiroshima University School of Medicine, and Jikei University School of Medicine.
1. Corosolic acid improves insulin sensitivity.
2. Take it out quickly and close it quickly. It also keeps blood sugar levels normal.
3. As a result, total insulin secretion is spared.
4. When excess insulin is removed, insulin resistance is alleviated.
5. Alleviation of insulin resistance reduces the risk of adult diseases and lifestyle-related diseases.
6. In addition to that, functional recovery of innate immunity and acquired immunity can also be expected.
以下に成人病、生活習慣病に関する記述はあるものの、発明者が二回のフィリピン臨床試験で医科学的に証明したものは糖尿病、認知症、インスリン、血糖値、安全性、インフォームドコンセント、摂取後のインタビューなどである。
一方、発明者が共同研究した先行文献としては、発明者のすでに成立させた特許がある。その要約は、（１）コロソリン酸が血糖値を下げること、（２）インスリン感受性を高めることは周知の事実でありその部分には発明性はない、（３）同時にコロソリン酸を含むバナバ・グワバ・柿・桑・琵琶などの植物抽出物にも血糖値上昇抑制があることは広く知られた事実のため、その部分にも発明性は存在しない。本発明は、それを十分に理解した上で新たな発見とアイデアに基づくものである。 Although there are descriptions about adult diseases and lifestyle-related diseases below, what the inventor has scientifically proven in two clinical trials in the Philippines is diabetes, dementia, insulin, blood sugar level, safety, informed consent, intake Later interviews, etc.
On the other hand, there is a patent already established by the inventor as a prior art document jointly researched by the inventor. Its summary is that (1) corosolic acid lowers blood sugar levels, (2) it is a well-known fact that it enhances insulin sensitivity and that part is not inventive, and (3) banaba guava containing corosolic acid at the same time.・Since it is a well-known fact that plant extracts such as persimmon, mulberry, biwa, etc., also have the ability to suppress increases in blood sugar levels, there is no inventiveness in that part either. The present invention is based on new discoveries and ideas after fully understanding them.
本発明の主旨、コロソリン酸ならびにその類縁化合物そしてそれらを含む抽出物の摂取が上記のメカニズムによって、インスリン抵抗性の緩和と改善させる。
その結果コロソリン酸の摂取は、加齢とインスリン抵抗性によって加速される、認知症、癌、心臓病、高血圧症、糖尿病、認知症・鬱、脳梗塞、EDなどの成人病、生活習慣病のみならず感染症にも効果を発揮するのである。本発明は、上記の点で新規性、進歩性、産業への貢献を有する点である。 The gist of the present invention, ingestion of corosolic acid, its analogues, and extracts containing them alleviates and improves insulin resistance by the above mechanism.
As a result, the intake of corosolic acid is accelerated by aging and insulin resistance. It is also effective against infections. The present invention has novelty, inventive step, and contribution to industry in the above points.
本発明の新規性について述べる。その１としてインスリン抵抗性をインスリン本体サイド（インスリンのブラッシュアップ／機能回復／ノコギリの目立て）から発想したものや数字をあげて証明したものは未だ記載がない。
本発明のコロソリン酸のインスリン抵抗性の緩和と改善のアイデアと医科学検証に裏付けられたインビボ・インビトロ実験数字は、世界初の査証である。従来のインスリン抵抗性の薬剤などは全てインスリンレセプター（細胞サイド）からのものである。
このように従来品、既発の糖尿病薬には、インスリン分泌を促すものや、インスリン抵抗性を改善するものなど完成の域に達したものも多数存在する。そのすべてがインスリン受容体に働きかけるものである。インスリン本体の改善を比較数字を挙げて言及した先行論文や先行技術も未だ記載も報告もない。インスリン受容体／インスリン受容体インスリン受容体とは、インスリンレセプター／細胞膜上に存在してインスリンと特異的に結合し，細胞のインスリン作用をする蛋白質である。糖の取り込みに作用する。
インスリン受容体は，最も下等な脊椎動物であるホソヌタウナギからヒトにいたるまでに存在する。本発明にはそれらの公知の薬剤とも全く違う発明性が存在する。 The novelty of the present invention will be described. As one of them, there is no description yet of what was conceived of insulin resistance from the side of insulin itself (insulin brush-up/function recovery/saw sharpening) or what was proved by giving numbers.
The idea of relieving and improving insulin resistance of corosolic acid of the present invention and the in vivo and in vitro experimental figures supported by medical scientific verification are the first visas in the world. All conventional insulin-resistant drugs and the like are from the insulin receptor (cell side).
As described above, there are many conventional products and existing antidiabetic drugs that have reached perfection, such as those that promote insulin secretion and those that improve insulin resistance. All of them act on the insulin receptor. There has been no description or report of prior papers or prior arts referring to the improvement of insulin itself by citing comparative figures. Insulin Receptor/Insulin Receptor Insulin receptor is a protein that exists on insulin receptor/cell membrane, specifically binds to insulin, and exerts insulin action on cells. Affects sugar uptake.
Insulin receptors are present in the lowest vertebrates, eels and humans. The present invention has inventiveness that is completely different from those known drugs.
１．新規性・進歩性の証明
すでに公知の先行論文や推量とは以下のとおりである。（下段にも記載あり）
１）コロソリン酸が血糖値を下げたという多くの論文や特許
２）インスリンが唯一の血糖値上昇抑制ホルモンであるゆえ、血糖値は下がるのはインスリンが関係しているの当然ではないかとの推量
３）KKA-yマウスによるインスリン感受性向上の論文
４）コロソリン酸を含むタブレットなどによる血糖値コントロール論文などコロソリン酸とインスリン抵抗性との関連を推測させるものは数十を超える。 1. Proof of Novelty and Inventive Step Prior papers and conjectures already known to the public are as follows. (Also listed below)
1) Many papers and patents claiming that corosolic acid lowers blood sugar levels 2) Since insulin is the only hormone that suppresses the increase in blood sugar levels, it is speculated that the lowering of blood sugar levels is related to insulin. 3) Articles on insulin sensitivity improvement by KKA-y mice 4) Blood sugar level control by tablets containing corosolic acid More than dozens of papers suggest the relationship between corosolic acid and insulin resistance.
一方、本発明の要点である下記の１～７項目の検証未だ記載がない。
インスリン抵抗性とは空腹時のインスリン値が必要以上に出過ぎていることを指す。ならばコロソリン酸またはそれを含むのを臨床レベルの約１か月摂取して摂取前と摂取１か月後を採血し比較したものがあっただろうか？それは未だ記載がない。（発明の基本）
既存のインスリン抵抗性薬はすべて脂肪細胞を始めとする細胞受容体に働きかけるものである。コロソリン酸のインスリン抵抗性の緩和と改善する意義は、糖尿病や認知症のみならずインスリン抵抗性に起因する成人病、生活習慣病すべてに効果が期待できる点にある。すべて血糖値コントロールからの発想であった。
具体的には、本発明のコロソリン酸は、働きかけ対象が従来品のように受容体側の脂肪細胞や骨格筋細胞ではなく、インスリン本体である。（２００６年非臨床試験、鈴鹿科学医療大学ＭＴ教授、京都大学医学部ＳＹ教授）
１．          インスリンそのものの効きを高め機能を回復する。グルコースの取り込みのメカニズムではスパイク側に作用する、つまりインスリン本体のブラッシュアップ（鋸の目立て）効果である。（２０１９年、２０２０年臨床試験フィリピン共和国ハイプレシション）
２．          一年間の長期摂取の結果、食後３０分で素早いインスリン応答によるインスリン追加分泌が行われ、直ちにグルコースを取り込ませ血糖値をさげた。（２００６年Ｓ社長期投与臨床試験、東京ＪＫ医科大学ＩＹ教授）
３．          さらに同じ臨床試験では、素早い血糖値上昇抑制により追加インスリンが節約されインスリン総分泌量が抑制された。（２００６年S社長期投与臨床試験、東京ＪＫ医科大学ＩＹ教授）
４．          バナバ抽出物で行った臨床試験であっても、それ以前に多様な抽出物からコロソリン酸と他の含有物から最も糖移動活性の強力なものを単利精製し、約４０名のボランティア治験者で二重盲検試験を実施し、バナバ抽出物たるタブレットの活性化合物はタンニン等ではなくコロソリン酸であると同定した。（２００６年京都大学医学部ＦＭ教授、実行場所京都市伏見区ＹＨ総合病院）その際、用量を３ミリグラムを摂取した人インスリン抵抗性があり高血糖の人には効果が際立っていた。処方量とインスリン抵抗性効果が示唆された。
５．          さらにコロソリン酸の臨床試験に参加者の、採血分析した（１）コロソリン酸摂取前、（２）コロソリン酸摂取２週間後、（３）コロソリン酸摂取１か月後のそれぞれ３時点の「絶食８時間後の空腹時インスリン値」（最も重要なインスリン抵抗性を示す値）を比較し差異を明示することこそ何より明確なコロソリン酸がインスリン抵抗性を緩和と改善する証拠になると考える。
６．          また、インスリン抵抗性の緩和と改善によって「インスリン応答の向上があった」とするならば、（１）コロソリン酸摂取前、（２）コロソリン酸摂取２週間後、（３）コロソリン酸摂取１か月後のそれぞれの、砂糖水７５グラム相当摂取の３０分後のそれぞれ３時点のインスリン値を比較すればコロソリン酸摂取がインスリン応答が良くなったとの主張根拠になるだろう。 On the other hand, verification of the following items 1 to 7, which are essential points of the present invention, has not yet been described.
Insulin resistance refers to excessive fasting insulin levels. If so, was there a blood sample taken before and one month after ingestion of corosolic acid or containing it at the clinical level for about one month for comparison? It hasn't been mentioned yet. (Basics of Invention)
All existing insulin resistance drugs act on cell receptors including adipocytes. The significance of corosolic acid in alleviating and improving insulin resistance is that it can be expected to be effective not only for diabetes and dementia, but also for all adult diseases and lifestyle-related diseases caused by insulin resistance. It was all an idea from blood sugar control.
Specifically, the corosolic acid of the present invention acts on insulin itself, not adipocytes or skeletal muscle cells on the receptor side as in conventional products. (2006 non-clinical study, Suzuka University of Science and Technology MT Professor, Kyoto University School of Medicine SY Professor)
1. It enhances the effect of insulin itself and restores its function. In the mechanism of glucose uptake, it acts on the spike side, that is, it has a brush-up (saw-toothed) effect on the insulin itself. (2019, 2020 clinical trial High Precision, Republic of the Philippines)
2. As a result of long-term ingestion for one year, additional insulin was secreted due to a rapid insulin response 30 minutes after a meal, and glucose was taken in immediately to lower the blood sugar level. (2006 S company long-term administration clinical trial, Tokyo JK Medical University IY Professor)
3. Furthermore, in the same clinical trial, rapid suppression of blood glucose spikes spared additional insulin and reduced total insulin secretion. (2006 S company long-term administration clinical trial, Professor IY, Tokyo JK Medical University)
4. Even in the clinical trial conducted with banaba extract, we had previously purified the one with the strongest sugar transfer activity from various extracts, corosolic acid and other ingredients, and had about 40 volunteer clinical trial participants. A double-blind study was conducted to identify the active compound of the banaba extract tablets as corosolic acid rather than tannins and the like. (2006 FM Professor, Faculty of Medicine, Kyoto University, YH General Hospital, Fushimi Ward, Kyoto City) At that time, the effect was remarkable in those who took 3 mg of insulin resistance and hyperglycemia. Prescription dose and insulin resistance effects were suggested.
5. In addition, participants in the clinical trial of corosolic acid were analyzed by blood collection at three time points (1) before corosolic acid intake, (2) two weeks after corosolic acid intake, and (3) one month after corosolic acid intake. We believe that comparing "fasting insulin levels after hours" (the most important value indicating insulin resistance) and clarifying the difference is the most clear evidence that corosolic acid alleviates and improves insulin resistance.
6. In addition, if "insulin response was improved" due to alleviation and improvement of insulin resistance, (1) before corosolic acid intake, (2) after 2 weeks of corosolic acid intake, (3) after corosolic acid intake Comparing insulin levels at three time points, 30 minutes after ingesting the equivalent of 75 grams of sugar water each month, would support the claim that corosolic acid supplementation improved insulin response.
ここで、フィリピンで行った２回の臨床試験の一部を、「インスリン抵抗性の緩和」の面から検証する。
１）以下は左が摂取前のインスリン値、右側が摂取１か月後のインスリン値である。
２）重要な点は下線を引いた「インスリン抵抗性が疑われる空腹時インスリン値が高い群」の変化率である。下線のない群はほぼインスリン抵抗性がない治験者である。
３）インスリン抵抗性の疑われる治験者の平均数値は摂取前は７．５９、１か月の摂取後は５．８９となり、一人を除けほぼ正常値に回復、抵抗性改善率は２３％である。
４）以下は詳細である。
５．０１―＞４．１４、７．２７―＞４．８０，２．０４―＞１．９３
７．０１―＞５．１６、６．４３―＞３．５１，４．５０―＞５．１７
２．０５―＞２．８２、５．２５―＞５．３２、４．１０―＞５．１３
１６．２―＞１３．２、５．９９―＞５．１２　以上
単純平均：コロソリン酸摂取前平均５．９７―＞摂取１か月後５．１１　（改善１４．４％）
以下は個別の７５グラム砂糖水摂取３０分後の追加インスリン値のコロソリン酸摂取前と１か月後の比較である。単純平均２０．８―＞２６．９となり１２９％インスリン応答の向上が見られた。左はコロソリン酸摂取前、右はコロソリン酸摂取３０日後の
２９．５―＞３１．６，５６．１－＞１１５．５，１３．９―＞１７．６、
７.７１－＞１０．５、１５．１－＞１３．４，４．３３－＞６．４２，
２７．５－＞１７．８，２２．５－＞１２．４、７．２３－＞１５．９，
２４．１－＞２７．５　以上 Here, we will examine a part of the two clinical trials conducted in the Philippines from the aspect of "alleviation of insulin resistance".
1) Below, the left is the insulin level before ingestion, and the right is the insulin level one month after ingestion.
2) The important point is the underlined rate of change in the "high fasting insulin level group suspected of insulin resistance". The non-underlined group is the trial subjects with almost no insulin resistance.
3) The average value of subjects with suspected insulin resistance was 7.59 before taking insulin, and 5.89 after one month of taking insulin. be.
4) The following are details.
5.01->4.14, 7.27->4.80, 2.04->1.93
7.01->5.16, 6.43->3.51, 4.50->5.17
2.05->2.82, 5.25->5.32, 4.10->5.13
16.2 -> 13.2, 5.99 -> 5.12 or more simple average: average before taking corosolic acid 5.97 -> 5.11 after 1 month (improvement 14.4%)
Below are individual comparisons of additional insulin levels 30 minutes after ingestion of 75 grams of sugar water before and one month after corosolic acid ingestion. A simple average of 20.8->26.9 was obtained, indicating a 129% improvement in insulin response. Left: 29.5->31.6, 56.1->115.5, 13.9->17.6, before corosolic acid intake, right: 30 days after corosolic acid intake,
7.71->10.5, 15.1->13.4, 4.33->6.42,
27.5->17.8, 22.5->12.4, 7.23->15.9,
24.1->27.5 or more
さらに６か月後の２０２０年３月再度臨床試験が行われた。これは正確さと偏りのなさを求めるため治験者の地域と対象治験者をすべて入れ替えて行ったものである。治験者は全員が７０歳代であった。臨床試験はコロソリン酸１ミリグラム含有のタブレット一日３粒を摂取し、摂取前、２週間後、１か月後の計３回正式な検査機関にて採血試験を行った。採血試験はＯＧＴＴ試験と同様に、８時間の絶食、７５グラム砂糖水摂取３０分後、２時間後の一日３回の採血試験を行った。分析項目は、１．血糖値、２．インスリン値、３．ガンマーＧＴＰであった。結果は２０１９年８月の上記臨床試験以上に、「インスリン抵抗性の緩和と改善は顕著」であった。下記参照。 Another clinical trial was conducted in March 2020, six months later. This was done by permuting all investigator regions and target investigators to ensure accuracy and impartiality. All trial subjects were in their 70s. In the clinical test, 3 tablets containing 1 mg of corosolic acid were ingested a day, and a blood sampling test was performed at an official laboratory three times before, 2 weeks after, and 1 month after ingestion. Similar to the OGTT test, the blood sampling test was performed 3 times a day after 8 hours of fasting and 30 minutes and 2 hours after ingestion of 75 g of sugar water. Analysis items are 1. blood sugar level;2. insulin levels;3. It was gamma GTP. The results were "remarkable alleviation and improvement of insulin resistance" than the above clinical trial in August 2019. See below.
本発明の主題は「コロソリン酸によるインスリン抵抗性の改善」に集約される。インスリン抵抗性の改善はインスリン感受性、それに伴うインスリン応答も向上させた。インスリン抵抗性の緩和は膵臓の負担をやわらげ、何よりインスリン総分泌量を低下させる。
つまり同量のインスリン量であっても「効き目がよければ」少量で血糖値上昇抑制するので総分泌量はセーブできる。このことは、合計３回の臨床試験（そのうち一回は一年間の長期投与）により、確認されている。 The main subject of the present invention is "improvement of insulin resistance by corosolic acid". Improving insulin resistance also improved insulin sensitivity and thus insulin response. Alleviation of insulin resistance relieves the burden on the pancreas and, above all, reduces total insulin secretion.
In other words, even if the amount of insulin is the same, if "effective", a small amount will suppress the increase in blood sugar level, so the total secretion amount can be saved. This has been confirmed by a total of three clinical trials, one of which was long-term administration for one year.
さらに重要なことは、血糖値コントロールがうまくいっている上にインスリン総分泌量が軽減されていることは「インスリン分解酵素の節約」にもつながっている。脳内を始めとする毛細血管内の残留インスリンはタンパクと結合しアミロイドベータやタウタンパクの産生に繋がったり、血栓になったり、末梢血管の硬化を促進したり、免疫や抗体の働きを抑える物質を作る原因となる。インスリン抵抗性の解決は万病防止につながる可能性が高いのである。 More importantly, good blood sugar control and reduced total insulin secretion also lead to "saving of insulin-degrading enzymes." Residual insulin in capillaries, including the brain, binds to proteins, leading to the production of amyloid beta and tau protein, resulting in thrombus formation, promoting hardening of peripheral blood vessels, and suppressing the action of immunity and antibodies. cause to make. There is a high possibility that resolving insulin resistance will lead to the prevention of all kinds of diseases.
以下はインスリン抵抗性に関する一般的な計算方法（公式）と一般的な判断基準である。参考までに示すこととする。
コロソリン酸がインスリン抵抗性を緩和したという絶対的な証拠は、コロソリン酸の摂取前と、一か月摂取後の「空腹時のインスリン値の比較」が最もフェアな方法である。世界中で用いられているインスリン抵抗性の測定方法が以下の方法である。
インスリン抵抗性の判定：HOMA指数が用いられる。
これは空腹時のインスリン値に血糖値を掛けてそれを４０５で割った数値であり、この数値がインスリン抵抗性の目安となる。世界中でスタンダードになっている計算方法である。3以上でインスリン抵抗性の疑い，5以上でインスリン抵抗性と診断できる． Below are general calculation methods (formulas) and general criteria for insulin resistance. It is shown for reference.
The fairest way to obtain definitive proof that corosolic acid alleviated insulin resistance is to compare fasting insulin levels before taking corosolic acid and after one month of taking corosolic acid. The following method is used to measure insulin resistance all over the world.
Determination of insulin resistance: HOMA index is used.
This is the value obtained by multiplying the fasting insulin value by the blood sugar value and dividing it by 405, and this value is a measure of insulin resistance. It is a standard calculation method around the world. A score of 3 or higher suggests insulin resistance, and a score of 5 or higher indicates insulin resistance.
インスリン抵抗性とは、あたかも水道の蛇口がさび付いてキチンと閉まらない状態に似ている。常に「ポタポタとしずくが零れ落ちている」状態となる。その典型数値が「空腹時のインスリン値」である。
本来インスリンの働きの最も重要な役目は血中のグルコースや栄養分を細胞内に取り込ませるように情報を伝えて、細胞の扉を開かせるカギを持ったドアマンのようなものである。半面、空腹時には血中のグルコースは少ないため多くのインスリンは必要とされない。食事の後には一気に栄養が取りこまれるため血糖値の安定のため素早いインスリン分泌が望まれる。
つまりインスリン抵抗性とは必要とされる以上の分泌が行われれている状態で、特に空腹時において血中のインスリン値が高い状態をインスリン抵抗性という。 Insulin resistance is like a rusty tap that won't close properly. It is always in a state of "dropping and dripping". A typical value is the “fasting insulin level”.
Originally, the most important role of insulin is to act as a doorman holding the key to open the door of the cell by conveying information so that the glucose and nutrients in the blood are taken into the cell. On the other hand, you don't need as much insulin when you're fasting because there's less glucose in your blood. Since nutrients are taken in at once after a meal, rapid insulin secretion is desired to stabilize the blood sugar level.
In other words, insulin resistance is a state in which insulin is secreted more than necessary, and a state in which insulin levels in the blood are high, especially during fasting, is called insulin resistance.
また多くの成人病、生活習慣病はそのほとんどが「加齢とインスリン抵抗性」に関係しているとされ始めた。成人病、生活習慣病とされる、癌、心臓病、糖尿病、高血圧症、認知症、鬱（うつ）、ED（勃起障害）」に対し、主たる原因の一つである「加齢とインスリン抵抗性」を、コロソリン酸とその類並びにそれらの抽出物の摂取により疾患の症状を緩和させ改善することにより怖い厄介な病気の発症と進行を遅延させ治癒を実現させようというものである。
本発明はコロソリン酸とその類の摂取によってインスリン抵抗性の緩和と改善に限ったものであり、個々の疾患に対する効果の検証は後の研究を待たねばならない。それらは本発明の発展形であり、本発明の請求項は「コロソリン酸とその類縁化合物及びそれらを含む抽出物によるインスリン抵抗性の緩和と改善」関連のみである。         In addition, many adult diseases and lifestyle-related diseases have begun to be associated with "aging and insulin resistance". Cancer, heart disease, diabetes, hypertension, dementia, depression, and ED (erectile dysfunction), which are regarded as adult diseases and lifestyle-related diseases, are mainly caused by aging and insulin resistance. By ingesting corosolic acid, its analogues, and their extracts, the symptoms of diseases are relieved and improved, thereby delaying the onset and progress of scary and troublesome diseases and realizing cure.
The present invention is limited to alleviation and improvement of insulin resistance by ingestion of corosolic acid and the like, and verification of effects on individual diseases must await later research. They are developments of the present invention, and the claims of the present invention are only related to "alleviation and amelioration of insulin resistance by corosolic acid and its analogous compounds and extracts containing them".
コロソリン酸がインスリンに直接関与し、インスリン抵抗性を緩和することは１９９９年の「バナバ抽出物タブレット」を使った臨床試験を始めとして合計６回のヒト臨床試験、２回の非臨床試験、２回のインビトロ試験合計１０回のインビボ・インビトロ実験において示唆、証明されてきた。
最終的に２０１９年、２０２０年自社のフィリピンでのヒト臨床試験結果が発明を惹起した。それに加えて近年の世界の大手製薬会社の認知症治験によるアミロイドベータカスケード仮説の総崩れと認知症からの撤退、医科学学会の重要疾患のインスリン抵抗性原因説、癌の抗体に差異があるとのノーベル賞学者などの発表などにより、発明者はコロソリン酸の摂取が成人病・生活習慣病に広く役立つと確信し本発明に至ったものである。 The fact that corosolic acid is directly involved in insulin and alleviates insulin resistance has been shown in a total of 6 human clinical trials, 2 non-clinical trials, 2, including a 1999 clinical trial using "banaba extract tablets". In Vitro Tests A total of 10 in vivo and in vitro experiments have been suggested and proven.
Ultimately, in 2019 and 2020, the company's own human clinical trial results in the Philippines triggered the invention. In addition, recent clinical trials for dementia by the world's major pharmaceutical companies have completely collapsed the amyloid beta cascade hypothesis and withdrawal from dementia. Based on presentations by Nobel laureates and others, the inventor is convinced that corosolic acid intake is widely useful for adult diseases and lifestyle-related diseases, and has arrived at the present invention.
３．裏付け証拠の再チェック
以下はその発明を裏付けるに十分な過去から昨年までのインビボインビトロ実験である。
その１：コロソリン酸がインスリン抵抗性を改善する根拠（ヒト臨床試験）
２０２０年３月、フィリピン国タラベラ、治験者MCIの７０歳代のみ１０名。エタノール熱水エキス、一日３錠、１ヶ月服用、MMSEとOGTT採血試験、摂取前、２週間後、１か月後の計３回、OGTTは絶食時、７５グラム砂糖水摂取３０分後、２時間後の計３回採血し血糖値、インスリン値を測定した。
結論は、コロソリン酸が活性化合物であることが確認されたバナバエタノール熱水抽出エキスタブレットは、７０歳代のＭＣＩ軽度認知障害の高齢者の記憶機能を回復しインスリン反応を向上させインスリン抵抗性を改善した。 3. Review of Supporting Evidence The following are in vivo in vitro experiments from the past to the last year sufficient to support the invention.
Part 1: Evidence that corosolic acid improves insulin resistance (human clinical trial)
March 2020, Talavera, Philippines. Ethanol hot water extract, 3 tablets per day, taken for 1 month, MMSE and OGTT blood sampling test, before, 2 weeks after, 1 month after, 3 times in total, OGTT is fasting, 30 minutes after 75g sugar water intake, After 2 hours, blood was collected 3 times in total to measure blood sugar level and insulin level.
In conclusion, banaba ethanol hot water extract tablets, in which corosolic acid was confirmed to be the active compound, restored memory function, improved insulin response, and reduced insulin resistance in elderly people in their 70s with MCI mild cognitive impairment. Improved.
その２：コロソリン酸がインスリン抵抗性を改善する根拠（ヒト臨床試験）
２０１９年８月、フィリピン国タラベラ、サンパスクアルにて治験者６０歳以下スマホ中毒者２０名、７０歳８０歳代２１名合計４１名。エタノール熱水エキス、一日３錠、１ヶ月服用、MMSEと（高齢者グループ２１名のみ）OGTT採血試験、摂取前、２週間後、１か月後の計３回、OGTTは絶食時、７５グラム砂糖水摂取３０分後、２時間後の計３回採血し血糖値、インスリン値を測定した。結論は、コロソリン酸がエキスタブレットの活性化合物であることが確認されたバナバエタノール熱水抽出エキスタブレットは、スマホ中毒の若年、成人並びに７０歳、８０歳代のＭＣＩ軽度認知障害の高齢者の記憶機能を回復しインスリン反応を向上させインスリン抵抗性を改善した。　
コロソリン酸服用から一か月後の、二回のOGTTの採血試験においてインスリン応答、インスリン抵抗性ともにイエローカードの治験者たちには共に改善しほぼ正常になった。
１）インスリン応答：インスリンの増加分を血糖値の増加分で割ったもの。数値が高かればインスリン反応が良いとされる。0.5以下なら，インスリン低分泌と判定される．
２）インスリン抵抗性の判定にはHOMA指数が用いられる。空腹時のインスリン値に血糖値を掛けてそれを４０５で割った数値がインスリン抵抗性の目安となる。3以上でインスリン抵抗性の疑い，5以上でインスリン抵抗性と診断できる． Part 2: Evidence that corosolic acid improves insulin resistance (human clinical trial)
August 2019, in San Pascual, Talavera, Philippines. Ethanol hot water extract, 3 tablets per day, taken for 1 month, MMSE and (21 elderly group only) OGTT blood collection test, before, 2 weeks after, 1 month after intake, 3 times in total, OGTT at fasting, 75 After 30 minutes and 2 hours after ingestion of the gram-sugar water, blood was collected three times in total to measure the blood sugar level and insulin level. In conclusion, it was confirmed that corosolic acid is the active compound of the extract tablet. It restored function, improved insulin response and improved insulin resistance.
One month after taking corosolic acid, both insulin response and insulin resistance improved and became almost normal in the yellow card subjects in two OGTT blood sampling tests.
1) Insulin response: increased insulin divided by increased blood glucose. The higher the number, the better the insulin response. If it is less than 0.5, it is judged as hyposecretion of insulin.
2) The HOMA index is used to determine insulin resistance. The fasting insulin level multiplied by the blood sugar level and divided by 405 gives a measure of insulin resistance. A score of 3 or higher suggests insulin resistance, and a score of 5 or higher indicates insulin resistance.
その３：コロソリン酸がインスリン抵抗性を改善する根拠（ヒト臨床試験）
２００６年１月、本臨床試験に先がけてバナバ抽出物の活性化合物特定の必要性が京都大学Y.S教授から指摘され、指示に従い「プレテスト」を行った。バナバ抽出物の活性化合物を同定する臨床試験が京都市伏見区の民間総合病院にて実行された。
（１）コロソリン酸試薬レベルの標品（９５％以上純度）と、（２）すべてのバナバ抽出物の６５～７０％を占めるタンニン類の中でも最も糖移動活性の高いことが確認されたエラジタンニン系のラガーストロエミンの２種を単利精製し、血糖値上昇抑制の比較試験が４０名のボランティアを集め上記民間総合病院にて二重盲検方式で行われた。
結果は歴然であった。バナバ抽出物の血糖値上昇抑制作用の活性化合物は明らかにコロソリン酸であることが確認された。その結果CRO計画のヒト臨床試験が実行され、コロソリン酸僅か１ミリグラムの投与で血糖値を有意に低下させたことが論文化し証明された。
当OGTT試験はコロソリン酸試薬（９５％以上純度標品）を用いて行った。二重盲検試験にてコロソリン酸１ミリグラムを男性１６名、女性１５名の境界型糖尿病投与して血糖値の上昇抑制を調べた。その結果、コロソリン酸による有意な血糖値上昇抑制効果が正式に確認された。
本発明につながるプレテストに大きな発見があった。まず１．コロソリン酸はインスリン抵抗性のある人には驚くほど血糖値上昇抑制作用を発揮したことである。次に２．同じくインスリン抵抗性の治験者に処方量を僅か３ミリグラムに上げれば極めて有意な血糖値上昇抑制効果が見られたという２点である。つまりコロソリン酸はインスリン抵抗性を持つ人には極めて有効な改善作用が見られのである。これも本発明の大きな証拠となった。 Part 3: Evidence that corosolic acid improves insulin resistance (human clinical trial)
In January 2006, prior to this clinical trial, Professor YS of Kyoto University pointed out the need to identify the active compounds of the banaba extract, and a "pre-test" was conducted according to his instructions. A clinical trial to identify the active compounds of banaba extract was carried out at a private general hospital in Fushimi-ku, Kyoto.
(1) Corosolic acid reagent level standard (95% or higher purity), and (2) ellagitannins that have been confirmed to have the highest sugar transfer activity among tannins that account for 65-70% of all banaba extracts. 40 volunteers were collected at the above-mentioned private general hospital, and a comparison test of suppression of blood sugar elevation was conducted by a double-blind method.
The results were striking. It was confirmed that corosolic acid was clearly the active compound in the banaba extract's action of suppressing elevation of blood sugar level. As a result, a human clinical trial of the CRO program was carried out, and it was documented that administration of as little as 1 milligram of corosolic acid significantly lowered blood sugar levels.
This OGTT test was performed using a corosolic acid reagent (95% or more purity standard). In a double-blind test, 1 mg of corosolic acid was administered to 16 males and 15 females with borderline diabetes mellitus, and suppression of elevation of blood sugar level was examined. As a result, it was formally confirmed that corosolic acid has a significant effect of suppressing elevation of blood sugar level.
A major discovery was made in the pretest that led to the present invention. First, 1. Corosolic acid surprisingly exerted an inhibitory effect on blood glucose elevation in people with insulin resistance. Next, 2. The two points are that if the prescribed amount was increased to only 3 milligrams in insulin-resistant clinical trial subjects, a very significant effect of suppressing the increase in blood sugar level was observed. In other words, corosolic acid has an extremely effective ameliorating effect on people with insulin resistance. This was also a great proof of the present invention.
その４：コロソリン酸がインスリン抵抗性を改善する根拠（２回のヒト臨床試験）
バナバ抽出物を用いて行われた臨床試験は２度行われた。１９９９年５月、最初の実験は、自社で製造したバナバ熱水抽出エキスを用いて２型の境界型糖尿病が疑われる治験者で血糖値上昇抑制作用を確認した。その結果、血糖値上昇抑制があった治験者はすべてインスリン分泌が良好または出過ぎ（抵抗性）の治験者で、インスリン応答や分泌不良の治験者にはほとんど血糖値上昇抑制が見られなかった。つまり血糖値上昇抑制作用はインスリン分泌のあるなしにかかっていたのである。
２０００年８月、二度目の臨床試験は飲料大手のS社が製造したバナバエタノール熱水抽出エキス（コロソリン酸含有量１％以上、1錠あたり１ミリグラム）を用いて２０～７０歳代の血糖値が気になる人に二重盲検試験を実行した。この二回とも東京のCROを使い東京JK医科大学のIK教授の指導のもとに行われた。
結論として重要なことは、下がった血糖値の平均値ではなく、「どんな治験者にどのように効いた」かであった。有意に血糖値上昇抑制があったのはインスリン分泌が一定以上あった治験者グループで、血糖値が下がらなかったのはインスリン分泌不全の治験者グループであった。この結果は一回目の結果と同じであった。このことから、コロソリン酸はインスリン本体に強く働きかけていることが示唆された。 Part 4: Evidence that corosolic acid improves insulin resistance (two human clinical trials)
Two clinical trials were conducted with banaba extract. In May 1999, the first experiment confirmed that a banaba hot water extract manufactured in-house was used to suppress the increase in blood sugar level in a subject suspected of having type 2 borderline diabetes. As a result, all subjects with good or excessive insulin secretion (resistant) showed suppression of blood glucose level elevation, and almost no subjects with poor insulin response or insulin secretion showed suppression of blood glucose level elevation. In other words, the inhibitory effect on blood sugar level elevation depends on the presence or absence of insulin secretion.
In August 2000, the second clinical trial was conducted using a banaba ethanol hot water extract (corosolic acid content of 1% or more, 1 mg per tablet) manufactured by company S, a major beverage company. A double-blind study was performed on those concerned about the value. Both sessions were conducted using a CRO in Tokyo under the guidance of Professor IK of Tokyo JK Medical College.
What was important in the conclusion was not the average blood glucose level that was lowered, but "what kind of trial participants and how they worked." The group of subjects with insulin secretion above a certain level showed significant suppression of blood glucose level elevation, and the group of subjects with insufficient insulin secretion did not reduce blood glucose levels. This result was the same as the first result. This suggests that corosolic acid acts strongly on insulin itself.
その５：コロソリン酸がインスリン抵抗性を改善する根拠（ヒト臨床試験）
２００２年１１月、弊社と共同開発の関係にあった日本の飲料大手S社は、治験者１８名（男性１４名、女性４名）二重盲検試験、クロスオーバー試験にてコロソリン酸を含むバナバエタノール熱水抽出エキス錠剤を用い単回摂取試験と長期摂取試験を行い、血糖値上昇抑制効果とインスリン分泌変化などを治験した。
バナバエタノール熱水抽出エキスは有意に食後血糖値を下げることが確認され、長期投与においての副作用は一切報告されなかった。このことよりバナバ抽出物の血糖値上昇抑制に対する有効性と安全性が確認された。
本発明としての意義は、長期投与治験者の食後３０分のインスリン分泌反応が欧米人と同じように良くなった点にあった。食後３０分のインスリン分泌のグラフは鋭い山頂にように尖ったカタチとなって表れたのである。これは農耕民族由来の日本人や東アジア人には見られない傾向である。
一方インスリンの反応が向上し摂食初期の血糖値が下がれば当然インスリンの総分泌量は抑えられ低減する。コロソリン酸摂取によりインスリンレスポンスが向上しその結果素早く血糖値が下がり、膵臓による追加インスリン分泌が不必要になりインスリン分泌量がセーブされたものと考えらる。 Part 5: Evidence that corosolic acid improves insulin resistance (human clinical trial)
In November 2002, a major Japanese beverage company S, which had a joint development relationship with our company, conducted a double-blind study with 18 clinical trial participants (14 males and 4 females), including corosolic acid, in a crossover study. A single ingestion test and a long-term ingestion test were conducted using banaba ethanol hot water extract tablets, and clinical trials were conducted on the effect of suppressing elevation of blood sugar level and changes in insulin secretion.
It was confirmed that the banaba ethanol hot water extract significantly lowered the postprandial blood glucose level, and no side effects were reported during long-term administration. From this, the efficacy and safety of the banaba extract in suppressing elevation of blood sugar level were confirmed.
The significance of the present invention lies in the fact that the insulin secretory response 30 minutes after a meal in long-term administration subjects improved to the same level as in Europeans and Americans. The graph of insulin secretion 30 minutes after a meal appeared as a pointed shape like a sharp peak. This is a tendency not seen in Japanese or East Asians who come from an agricultural race.
On the other hand, if the response of insulin is improved and the blood sugar level at the early stage of eating is lowered, the total secretion of insulin is naturally suppressed and reduced. Ingestion of corosolic acid improved insulin response, resulting in a rapid drop in blood glucose level, which made additional insulin secretion by the pancreas unnecessary and saved insulin secretion.
その６：コロソリン酸がインスリン抵抗性を改善する根拠（非臨床試験）
２００６年１１月、三重県鈴鹿市の鈴鹿科学医療大学のMT教授のコロソリン酸の非臨床試験がある。KKA-y（２型糖尿病・インスリン抵抗発症マウス）に対する、コロソリン酸試薬（９９％以上純度標品）の摂取はインスリン感受性を向上させ、同時に血糖値を有意に下げることも確認された。結論は、KKA-yマウスで、コロソリン酸試薬はインスリン感受性を高め有意に血糖値を下げたことである。インスリン反応のグラフは驚くべき有意差をもって示された。 Part 6: Evidence that corosolic acid improves insulin resistance (non-clinical study)
In November 2006, there is a non-clinical study of corosolic acid by Prof. MT of Suzuka University of Science and Medicine, Suzuka City, Mie Prefecture. It was also confirmed that ingestion of a corosolic acid reagent (99% or more pure sample) improved insulin sensitivity in KKA-y (type 2 diabetic/insulin resistant mice) and at the same time significantly decreased blood sugar levels. The conclusion is that the corosolic acid reagent increased insulin sensitivity and significantly lowered blood glucose levels in KKA-y mice. The insulin response graph showed surprisingly significant differences.
その７：コロソリン酸がインスリン抵抗性を改善する根拠（非臨床試験）
２００４年３月、コロソリン酸が GLUT4 トランスローケーションを促進し血糖値の低下作用を示すことがわかった。コロソリン酸の血糖値上昇抑制は広く知られていたが糖取り込みのメカニズムが解明されたのは初めてである。
結論は、KKA-yマウスで、コロソリン酸の血糖値上昇抑制作用が確認されそれがＧＬＵＴ４メカニズムという糖取り込み作用であることが確認された。 Part 7: Evidence that corosolic acid improves insulin resistance (non-clinical study)
In March 2004, it was found that corosolic acid promotes GLUT4 translocation and exhibits a blood glucose lowering effect. It was widely known that corosolic acid suppresses the increase in blood sugar level, but this is the first time that the mechanism of sugar uptake has been elucidated.
In conclusion, it was confirmed that corosolic acid suppresses blood sugar elevation in KKA-y mice, and that it is a sugar uptake action called GLUT4 mechanism.
その８：コロソリン酸がインスリン抵抗性を改善する根拠（インビトロ実験）
エネルギーのもとであるグルコースは肝臓によって貯蔵され再生される。その作用は血中のグルコースとインスリン濃度によってコントロールされている。血中のコロソリン酸濃度に依存して肝臓における糖新生が変化することが確認された。結論は、コロソリン酸がインスリン感度を高めることにより、摂取したコロソリン酸濃度により肝臓における糖新生が依存していることが確認された。 Part 8: Evidence that corosolic acid improves insulin resistance (in vitro experiment)
Glucose, the source of energy, is stored and regenerated by the liver. Its action is controlled by blood glucose and insulin levels. It was confirmed that gluconeogenesis in the liver changes depending on the blood corosolic acid concentration. The conclusion is that corosolic acid enhances insulin sensitivity, thus confirming the dependence of hepatic gluconeogenesis on the concentration of corosolic acid ingested.
その９：コロソリン酸がインスリン抵抗性を改善する根拠（インビトロ実験）
１９９３年５月、広島大学医学部薬学科のYK教授と研究員MCらは、多くのフィリピンの薬草の中から現地で植物インスリンとして広く知られているバナバ（オオバナサルスベリ）に糖移動活性があることを発見し、活性化合物がコロソリン酸であることを突き止めた。またコロソリン酸の糖移動は細胞膜１２回貫通型の糖取り込み型であることを確認した。結論は、バナバはアジア各国で古来より代替インスリンと称され糖尿病対策薬草として用いられてきた。バナバ抽出物はインスリンの代わりをするかインスリン分泌を減らして血糖値を下げるとされている。伝承的にバナバのコロソリン酸がインスリン様の働きをすることが人知の証明にもなる。 Part 9: Evidence that corosolic acid improves insulin resistance (in vitro experiment)
In May 1993, Professor YK and researcher MC of the Department of Pharmacy, Hiroshima University School of Medicine discovered that among many Philippine medicinal herbs, banaba (Lagerstroemia speciosa), which is widely known locally as plant insulin, has a sugar transfer activity. discovered and determined that the active compound is corosolic acid. In addition, it was confirmed that the corosolic acid sugar transfer is a 12-pass transmembrane type sugar uptake type. In conclusion, banaba has been called an alternative insulin and has been used as a medicinal herb against diabetes since ancient times in Asian countries. Banaba extract is said to lower blood sugar levels by replacing insulin or reducing insulin secretion. It is also proof of human wisdom that corosolic acid in banaba traditionally acts like insulin.
高齢になっても元気で楽しく生き続けることは多くの人々の願いである。本発明は、コロソリン酸とその類縁化合物及びそれらを含む抽出物を用いて限りある命である、「人間の健康寿命」を加齢などからくる「インスリン抵抗性に起因する種々の疾患」から守ろという発明のアイデアである。インスリン抵抗性をインスリンサイドから緩和と改善しようとするものは未だ記載がない。
本発明の主旨はコロソリン酸の働きによって，
（１）インスリンそのものの効きを良くし、（２）細胞受容体のインスリン感受性を向上させ、（３）血糖値の上昇を抑制しながら、（４）肝臓における糖新生をコントロールさせ、（５）脳内ほかの分解されない残留インスリンを減らし、（６）インスリン分泌の総量を低減し、（７）膵臓のインスリン分泌の負担を軽減し、（８）インスリンそのものを「鋸の目立て」のようにブラッシュアップして、（９）抗体、免疫、T細胞の働きを高め、（１０）インスリン抵抗性を改善によって健康寿命を長くしようというものである。 It is a wish of many people to continue to live in good health and enjoyment even in old age. The present invention uses corosolic acid, its analogues, and extracts containing them to protect the ``healthy life expectancy of humans,'' which is a finite life, from ``various diseases caused by insulin resistance'' caused by aging. This is the idea of the invention. There is no description yet of anything that attempts to alleviate or improve insulin resistance from the insulin side.
The gist of the present invention is the action of corosolic acid,
(1) improving the efficacy of insulin itself, (2) improving the insulin sensitivity of cell receptors, (3) suppressing elevation of blood sugar levels, (4) controlling gluconeogenesis in the liver, and (5) (6) reduce the total amount of insulin secretion, (7) reduce the burden of insulin secretion in the pancreas, and (8) make the insulin itself "saw-toothed". (9) enhance the function of antibodies, immunity, and T cells, and (10) improve insulin resistance to prolong healthy life expectancy.
近年の成人病研究によれば、加齢とともに増加する生活習慣病のリスクの低減は、インスリン抵抗性の解決次第と言われるようになってきた。一方現在まで糖尿病関連としてのインスリン抵抗性改善には種々の薬剤が開発されてきた。
脂肪細胞に働きかけて脂肪細胞から分泌されるインスリン抵抗性を引き起こす物質を減少させるチアゾリジン薬（グリタゾン）や、同系列の新しいくすりピオグリタゾン薬はインスリンに対する体の感受性を高める作用し、結果的にインスリンの働きがよくなり、血糖値が下がるとされている。おもに２型糖尿病（インスリン非依存型糖尿病）に用い、肝臓、筋肉、脂肪組織などのインスリン感受性を高める作用がるとされ、肝臓での糖の産生がおさえられたり、血液中の糖分は筋肉などに取り込まれる（膵外作用）。 According to recent studies on adult diseases, it has come to be said that the reduction of the risk of lifestyle-related diseases, which increases with aging, depends on the resolution of insulin resistance. On the other hand, until now, various drugs have been developed to improve insulin resistance associated with diabetes.
Thiazolidinediones (glitazones), which work on adipocytes to reduce insulin resistance-causing substances secreted by adipocytes, and new pioglitazone drugs in the same series act to increase the body's sensitivity to insulin, resulting in insulin resistance. It works well and is said to lower blood sugar levels. It is mainly used for type 2 diabetes (non-insulin dependent diabetes), and is said to have the effect of increasing the insulin sensitivity of the liver, muscle, and adipose tissue. taken up (extrapancreatic action).
しかし本発明のコロソリン酸のように、（１）インスリンそのものの効きを良くしたり、（２）インスリン効きをシャープにブラッシュアップさせる化合物は未だ報告がない。従来薬はすべて細胞側に働きかけたものであり、インスリンサイドからインスリン抵抗性を解決可能なものは世界初である。同一の記載がない以上画期的な世界初の発明であろう。 However, like the corosolic acid of the present invention, there has been no report of a compound that (1) improves the efficacy of insulin itself or (2) sharply improves the efficacy of insulin. All conventional drugs work on the cell side, and this is the first drug in the world that can resolve insulin resistance from the insulin side. As long as there is no identical description, it must be an epoch-making world first invention.
対象疾患について述べれば、癌（悪性新生物）はいかなるヒトにも一日２０００回以上も発生しているとされている。にもかかわらず癌が発症しないのはヒト本来の免疫力（抗体・キラーT細胞など）が癌細胞を壊滅させ増殖させないからである。発症させないのも、また進行を抑えるのも自身の免疫力、抗体力が重要である。
その免疫力や抗体の力を弱めたり、向上させる「カギが何か？」が重要である。それが加齢でありインスリン抵抗性の程度などである。２０２１年６月、日本のノーベル賞受賞者が癌を抑える抗体の量や強さには個人差があることを発表した。つまり高齢者になるほど抗体の力が弱まり癌リスクが高まるのは、加齢とインスリン抵抗性であることを示唆したものと考える。その発言が本発明の大きなヒントとなった。
加齢とインスリン抵抗性により高頻度マイクロサテライト不安定性（MSI-High）状態に起因する癌への抗体不全（リンパ球、キラーT細胞、B細胞などの産生不全や抗体力の低下）が発生し癌細胞の増殖を食い止められない状態をコロソリン酸投与や摂取で食い止めることが可能と考えたからである。
糖尿病、認知症、鬱以外の各種の疾患に対する実験は今後において必要なことは言うまでもない。例えば癌、高血圧症、循環器系疾患、EDなど本特許で効果や技術が広く知れ渡れば、確立した安価で大量生産方法で大きな社会貢献となることは疑いようがない。 As for target diseases, cancer (malignant neoplasm) is said to occur more than 2000 times a day in every human being. Despite this, cancer does not develop because the human immune system (antibodies, killer T cells, etc.) destroys cancer cells and prevents them from growing. One's own immunity and antibody power are important to prevent the onset and to suppress the progression.
It is important to find out what is the key to weakening or improving the immunity and antibody power. That is aging and the degree of insulin resistance. In June 2021, a Japanese Nobel laureate announced that there are individual differences in the amount and strength of antibodies that suppress cancer. In other words, it is thought that the fact that the strength of antibodies weakens and the risk of cancer increases with age is due to aging and insulin resistance. That remark was a big hint for the present invention.
Due to aging and insulin resistance, there is a deficiency of antibodies against cancer (failed production of lymphocytes, killer T cells, B cells, etc., and a decrease in antibody strength) due to high-frequency microsatellite instability (MSI-High). This is because we thought that it would be possible to stop the growth of cancer cells by administering or ingesting corosolic acid.
Needless to say, experiments on various diseases other than diabetes, dementia, and depression are necessary in the future. For example, cancer, hypertension, circulatory system disease, ED, etc., if the effects and technology of this patent become widely known, there is no doubt that the established low-cost mass production method will make a great contribution to society.
心臓病（循環器疾患）、糖尿病、高血圧症においては末梢血管、毛細血管の血液の流れが特に重要である。これを妨げるものは血栓と高血糖であり、血流のコントロールが重要である。つまり末梢血管、毛細血管において円滑な代謝循環が行われるためにはインスリンの働きが最も重要であり特にインスリン抵抗性を低減することが循環器、糖尿病、高血圧症の予防と改善にとってきわめて有効な方法である。 Blood flow in peripheral blood vessels and capillaries is particularly important in heart disease (circulatory disease), diabetes, and hypertension. What hinders this is thrombosis and hyperglycemia, and blood flow control is important. In other words, the function of insulin is the most important for smooth metabolic circulation in peripheral blood vessels and capillaries, and reducing insulin resistance is an extremely effective method for preventing and improving cardiovascular disease, diabetes, and hypertension. is.
認知症や鬱（うつ）は分解されず脳血管に残留したインスリンとタンパクの結合によって産生されたアミロイドベータ、さらにタウ・タンパクの凝集から発生する毒素が１０００億個ともいわれる大脳皮質の神経細胞を破壊するとされ、これが大脳委縮の原因となる。認知症を発症した患者の脳はほとんど神経細胞の破壊により委縮し小さくなっている。近年、認知症の原因は、加齢プラス糖尿病、特に［インスリン抵抗性］が大きく影響しているという学説が主流になってきた。以前は［アミロイドβカスケード仮説］(脳のゴミ／アミロイドベータが蓄積し毒素を出して脳神経を破壊するという考え)が有力であった。ところがアミロイドベータに基づく新薬開発は悉く失敗し、仮説そのものが間違っていたとの考えが近年になり一般的になった。しかしこの考えは、認知症とアミロイドベータの関係を否定するものではなく新薬開発のプロセスに疑問が起こったというだけである。
台頭してきた仮説が［認知症は加齢プラス第三の糖尿病学説］である。糖尿病や境界型糖尿病、または糖尿病予備軍とされる高齢者の殆どには、インスリン抵抗性が存在する。
糖尿病と認知症の関係はすでに多くの学者が指摘しており、一般的学説となっている。そこで発明者は、科学的検証に基づきコロソリン酸を含むバナバ（ラガーストロエーミア・スペシオーサ・和名オオバナ百日紅）のエタノール熱水抽出エキスの錠剤を用い、二度の認知症臨床試験を行った。臨床に使った錠剤はコロソリン酸含有量１錠中１ミリグラムであった。これを１日３粒服用してもらった。期間は一か月間である。
一回目は２０１９年８月、二回目は２０２０年３月に実行した。治験者は一回目が、スマホ中毒若年と成人２０名、高齢者２２名、二回目は７０歳台の高齢者のみ１０名である。その結果、二度の臨床試験はほぼ同様の結果を表した。数字で述べれば、MMSEスコアで示される見当識（記憶や認識能力）機能は約４０％回復向上し、血中のインスリン抵抗性は約４０％改善した。治験者の９０％は、食欲、意欲、笑顔と落ち着きを取り戻しうつ状態を脱した。さらに家族を安心させたのである。 Dementia and depression are caused by amyloid beta, which is produced by the combination of insulin and protein that remain in the cerebral blood vessels without being degraded, and toxins generated by aggregation of tau protein, which are said to be 100 billion nerve cells in the cerebral cortex. It is said to destroy it, which causes cerebral atrophy. Most of the brains of patients with dementia have atrophied and become smaller due to destruction of nerve cells. In recent years, the theory that dementia is caused by aging plus diabetes, especially [insulin resistance] has become mainstream. Previously, the [amyloid β cascade hypothesis] (the idea that garbage/amyloid β accumulates in the brain and releases toxins to destroy cranial nerves) was influential. However, in recent years, it has become common to think that the development of new drugs based on amyloid beta has failed, and that the hypothesis itself was wrong. However, this idea does not deny the relationship between dementia and amyloid beta, but merely raises questions about the process of new drug development.
The emerging hypothesis is [Dementia is aging plus the third diabetes theory]. Most elderly people with diabetes, borderline diabetes, or pre-diabetes have insulin resistance.
Many scholars have already pointed out the relationship between diabetes and dementia, and it has become a popular theory. Therefore, based on scientific verification, the inventor conducted two dementia clinical trials using tablets of ethanol hot water extract of banaba (Lagerstroemia speciosa, Japanese name: Oobana periwinkle) containing corosolic acid. Tablets used clinically had a corosolic acid content of 1 milligram per tablet. I took 3 tablets of this a day. The period is one month.
The first time was in August 2019 and the second time was in March 2020. In the first trial, 20 young people and adults with smartphone addiction, 22 elderly people, and 10 elderly people in their 70s in the second trial. As a result, the two clinical trials showed almost similar results. In terms of numbers, orientation (memory and cognitive ability) function as indicated by the MMSE score improved by about 40%, and blood insulin resistance improved by about 40%. Ninety percent of the trial subjects recovered their appetite, motivation, smiles and composure and came out of depression. It also reassured the family.
本発明で実行された臨床試験の基本は［MMSEテスト］と［OGTT採血試験］であった。臨床試験は、（１）コロソリン酸摂取前、（２）コロソリン酸摂取２週間後、（３）コロソリン酸摂取１ヶ月後の３回にわたって実行した。OGTT採血試験は、（１）絶食時、（２）７５グラム砂糖水摂取３０分後、（３）２時間後の合計３回採血し、分析を行った。
血液の分析項目は、血糖値、インスリン値、ガンマーGTPの３項目である。これを３度、一日三回の合計９回採血してもらい分析した。採血は世界的ダイアグノスティック会社のハイプレシション社で、場所はフィリピン国ヌエバエシハ州カバナツアン市である。
結果は、一回目も二回目もほぼ同様であった。コロソリン酸含有錠剤の［中長期的な摂取］は、［MMSEテスト］（見当識／記憶や認識能力を具体的な数値で示すことができる）のスコアを約４０％向上させ、物理的事実を示すOGTT（耐糖能試験）では、インスリン反応が敏感になり応答が良くなった。さらに特筆すべきはインスリン抵抗性が約４０％改善したことである。 The basis of the clinical trials carried out in the present invention were [MMSE test] and [OGTT blood sampling test]. The clinical test was conducted three times (1) before corosolic acid intake, (2) two weeks after corosolic acid intake, and (3) one month after corosolic acid intake. In the OGTT blood collection test, (1) fasting, (2) 30 minutes after ingestion of 75 g of sugar water, and (3) after 2 hours, blood was collected a total of three times and analyzed.
Blood analysis items are blood sugar level, insulin level, and gamma GTP. The blood was collected 3 times, 3 times a day, a total of 9 times, and analyzed. Blood was collected by Hy-Precision, a global diagnostic company, in Cabanatuan City, Nueva Ecija, Philippines.
The results were almost the same for the first time and the second time. [Medium- to long-term intake] of corosolic acid-containing tablets improves the score of [MMSE test] (which can express orientation/memory and cognitive ability in concrete numerical values) by about 40%, and improves physical facts. In the OGTT (glucose tolerance test) shown, the insulin response became sensitive and responsive. More notably, insulin resistance was improved by approximately 40%.
インスリン抵抗性とは、空腹時でも一定以上にインスリンが出過ぎ、また食後血糖値が下がってもインスリンが出続けている状態をさす。これはインスリン受容体の感度低下や、インスリンそのものの機能低下、膵臓の血糖値反応の鈍化などが考えられている。水道の蛇口がキチッと閉まらず常にポタポタを出ているようなイメージだろう。
インスリン抵抗性が、認知症を引き起こす原因物質アミロイドベータ更にタウ・タンパク質を産生する原因として、脳内の毛細血管に余分に残留した未分解インスリンがタンパクと結合し、脳のゴミとも言われるタウ・タンパク質が蓄積し、老人斑と呼ばれる絡み合ったひも状の塊が蓄積し、毒素を出し、脳神経を破壊し、最終的には大脳を委縮させ認知症を発症させるというものである。
このほかにもインスリン抵抗性が認知症の原因と考えられる要因は数多くあるが、認知症発症にインスリン抵抗性が大きな要因であることは疑いがない。とするならば、認知症を予防するためには、インスリン抵抗性を改善することが何より重要で、このことを臨床試験で証明したものは本発明以外、未だ記載がない。 Insulin resistance refers to a state in which insulin is secreted more than a certain amount even when fasting, and insulin continues to be secreted even when the blood sugar level drops after a meal. It is thought that this is caused by decreased sensitivity of insulin receptors, decreased function of insulin itself, and blunted pancreatic blood sugar level response. It would be an image of a water faucet that does not close tightly and is always dripping.
Insulin resistance causes the production of amyloid beta, a substance that causes dementia, and the production of tau protein. Excess undegraded insulin remaining in the capillaries in the brain binds to protein, resulting in tau, which is also called brain garbage. Protein builds up, entwined string-like masses called senile plaques build up, release toxins, destroy cranial nerves, and eventually cause cerebral atrophy and dementia.
There are many other factors that are thought to cause dementia due to insulin resistance, but there is no doubt that insulin resistance is a major factor in the onset of dementia. If so, in order to prevent dementia, it is most important to improve insulin resistance, and there is no description other than the present invention that proves this in clinical trials.
従来のインスリン抵抗性のクスリは細胞の受容体に働きかけるもので、本発明のインスリン機能の正常化とは全く異なるものである。また従来の多くの糖尿病薬が、認知症の発症予防や治癒に効果があったという正式な治験結果の報告は未だ記載がない。ここにも本発明の新規性・進歩性が科学的根拠に基づき実証されている。 Conventional insulin-resistant drugs act on cell receptors and are completely different from the normalization of insulin function of the present invention. In addition, there is still no report of formal clinical trial results that many conventional antidiabetic drugs are effective in preventing the onset of dementia and curing it. The novelty and inventive step of the present invention are also demonstrated here on the basis of scientific grounds.
勃起障害（ＥＤ）は大きく分けて、下記3つに分けられる。心理状態によって勃起できるときと勃起できないときがあるもの、何らかの病気が原因となって勃起できなくなるもの、そして上記2つの特徴を合わせ持つものである。
具体的には、脊髄損傷や脳血管障害などの神経の損傷、糖尿病や外傷などによる血管の損傷、包茎や尿道の奇形（陰茎の異常）などが挙げられるが、特に身体的障害としてあげられるものが脳の血管障害である。これは脳内における血流がインスリン抵抗性によって阻害されいているためでありコロソリン酸の服用で改善した例も報告されている。これらの疾患のすべてに共通する生理的課題がインスリン抵抗性の進行である。このインスリン抵抗性をインスリン本体から改善するものはコロソリン酸以外に未だ記載がなく報告もない。 Erectile dysfunction (ED) can be divided into three main categories: There are those who can get an erection at times depending on their psychological state and those who cannot get an erection, those who cannot get an erection due to some disease, and those who have both of the above two characteristics.
Specifically, there are nerve damage such as spinal cord injury and cerebrovascular disease, blood vessel damage due to diabetes and trauma, phimosis and urethral malformation (abnormality of the penis), etc., but physical disorders are particularly mentioned. are cerebral vascular disorders. This is because the blood flow in the brain is inhibited by insulin resistance, and there are reports of cases in which the administration of corosolic acid improved the condition. A common physiological challenge in all of these diseases is the development of insulin resistance. Other than corosolic acid, there is no description or report on anything that improves insulin resistance from insulin itself.
コロソリン酸そのものは、１ミリグラム中に１兆個の１３６万倍も存在する超微細な活性化合物である。コロソリン酸はインスリンタンパクのスパイクに働きかけ、あたかも鋸（ノコギリ）の目立てのようにインスリンを研ぎ澄まし感度と切れ味を良くしてインスリンを節約しながらインスリン抵抗性を緩和、改善するものである。本発明は、世界初のインスリン本体からのインスリン抵抗性という問題を解決証明したものである。従来のインスリン抵抗性改善薬はすべて受容体サイド、つまり脂肪細胞や筋肉細胞をはじめとしてすべて細胞側の受容体レセプターに働きかけたものである。 Corosolic acid itself is an ultra-fine active compound present 1.36 million times as many as 1 trillion per milligram. Corosolic acid acts on insulin protein spikes to sharpen insulin like a saw blade to improve sensitivity and sharpness to conserve insulin while alleviating and improving insulin resistance. The present invention is the first in the world to solve the problem of insulin resistance from insulin itself. All conventional insulin sensitizers act on the receptor side, that is, on the cell side, including adipocytes and muscle cells.
本発明のコロソリン酸とその類縁化合物及びそれらを含む抽出物は安価で誰にでも使用可能な豊富な量を大量に生産できる。２０２１年現在において、開発中の認知症新薬に比べ患者や消費者の負担は５０００分の１から１万分の１の低価格である。それだけでも画期的発明であろう。すでにコロソリン酸の工業化は、岡山大学薬学部生薬教室や鳥取大学熱帯植物研究室におけるコロソリン酸を数百倍含有する植物カルス、中国の大規模抽出工場、韓国の巨大カラムにおける単利精製など技術が確立している。
開発目的は植物に含まれるテルペン類の一種であるコロソリン酸とその類とその類縁化合物を用いて、抗体そのものを増やしその機能高めて癌細胞（悪性新生物）を抑え込み、循環器の機能低下させる血栓、血糖値をコントロールし、心臓病を予防し、脳内のアミロイドベータ・タウタンパク、認知症や軽度認知障害が疑われる高齢者と若年層の、認知症発症の予防と緩和に役立てるものである。 Corosolic acid, its analogues, and extracts containing them according to the present invention can be inexpensively mass-produced in abundant amounts that can be used by anyone. As of 2021, the burden on patients and consumers will be 1/5,000 to 1/10,000 lower than that of new dementia drugs under development. That alone would be an epoch-making invention. The industrialization of corosolic acid has already been established, including plant callus containing several hundred times the amount of corosolic acid in the Department of Pharmacy, Faculty of Pharmaceutical Sciences, Okayama University, and the tropical plant laboratory of Tottori University, a large-scale extraction factory in China, and simple yield refining in a huge column in South Korea. ing.
The purpose of development is to use corosolic acid, which is a type of terpene contained in plants, its class, and its analogous compounds to increase the antibody itself and enhance its function, suppress cancer cells (malignant neoplasms), and reduce the function of the circulatory system. It controls blood clots, blood sugar levels, prevents heart disease, amyloid beta-tau protein in the brain, and helps prevent and alleviate the onset of dementia in the elderly and young people with suspected dementia or mild cognitive impairment. .
コロソリン酸とその類にはトリメンティック酸、オレアノール酸、ウルソール酸、マスリン酸を始め、多くの類縁化合物がある。（巻末に記載）これらのテルペン類の類縁化合物はコロソリン酸と同様の効果効能を持つものがある可能性が高いと想定される。またコロソリン酸とその類はバナバを始め、枇杷、柿、桑、グワバなど多くの植物に含まれるものであり古来の民間療法で広く庶民に親しまれてきたもので副作用等の不安がない。
  Corosolic acid and its relatives include trimentic acid, oleanolic acid, ursolic acid, maslinic acid, and many related compounds. (Described at the end of the book) It is assumed that there is a high possibility that these analogous compounds of terpenes have effects similar to those of corosolic acid. In addition, corosolic acid and its analogues are contained in many plants such as banaba, loquat, persimmon, mulberry, guava, etc., and have been widely popular among the common people as folk remedies since ancient times, and there is no fear of side effects.
特開2003-219853、JP 2003-219853, 特開2002-205949、JP 2002-205949, 特開2001-039880、JP 2001-039880, 特開2019-011305、JP 2019-011305, 特開2018-139530、JP 2018-139530, 特開2018-137712　などJP 2018-137712, etc.
本発明はインスリン分泌があり、若しくは分泌が過剰気味でインスリン抵抗性を疑われる高齢者または熟年者の、インスリン機能と応答を正常に戻して、各種成人病や生活習慣病、認知症などの進行を抑え、緩和または予防を可能にする組成物に関するものである。また鬱［うつ］やEDなど精神的なつらさに悩む若年や成人などにも、不安の解消や緩和となり健康回復に寄与するものである。
例えば［植物由来のコロソリン酸］が、認知症の主たる原因とされる［加齢によるインスリン反応の鈍化やインスリン抵抗性］に対し、もう一度インスリンの本来機能を回復させ、その結果として認知症・アルツハイマー病進行遅延・予防に役立ち、記憶機能や意欲を回復させるという今までになかった組成物の発見である。
同時にその発見を生かした摂取の方法や家庭内での機器類、コロソリン酸とその類縁化合物及びそれらを含む抽出物の安価で大量生産の方法、バイオマーカーとしての簡易な認知症診断方法、遺伝子組み換え植物の開発によりコロソリン酸とその類が日常的に摂取できる認知症予防などへの工夫に関するものでもある。認知症の緩和と改善に関する有意性はコロソリン酸のインスリン抵抗性効果の一例である。 The present invention restores insulin function and response to normal in elderly or mature people who secrete insulin or who are suspected of having excessive insulin secretion and are suspected of having insulin resistance, thereby progressing various adult diseases, lifestyle-related diseases, dementia, etc. The present invention relates to a composition that enables the reduction, alleviation or prevention of Also, for young people and adults who suffer from mental difficulties such as depression and ED, it helps to relieve and alleviate anxiety and contribute to health recovery.
For example, [plant-derived corosolic acid] restores the original function of insulin once again against [dulling of insulin response and insulin resistance due to aging], which is considered to be the main cause of dementia, and as a result dementia and Alzheimer's disease. This is the discovery of an unprecedented composition that is useful for delaying and preventing disease progression, and restores memory function and motivation.
At the same time, the method of ingestion and household equipment that make use of the discovery, the method of inexpensive and mass production of corosolic acid and its analogues and extracts containing them, the simple diagnostic method of dementia as a biomarker, and genetic recombination. It is also related to dementia prevention, etc. that can be ingested on a daily basis by corosolic acid and the like through the development of plants. The significance with respect to alleviation and improvement of dementia is an example of corosolic acid's insulin resistance effect.
本発明は、コロソリン酸を安価に大量生産し安価で広く安全に認知症を予防し緩和させることが可能にする。
１．コロソリン酸の属するトリテルペンは、6つのイソプレンから構成され、C30H48の分子式を持つテルペンの一種である。類縁化合物は１００種以上の報告があり（巻末）広く植物にふくまれる脂溶性の化合物である。
２．抽出方法には水抽出、熱水抽出、エタノール熱水抽出、高圧釜抽出などから得ることができる。好ましいのは数次の熱水抽出後の乾燥原料をエタノール熱水するのが経済的にも好ましい。
３．臨床試験で用いられたコロソリン酸を含む組成物とは、過去の実験で用いられた組成物は、コロソリン酸試薬（９９．５％以上の純度）、コロソリン酸含有量１％～１８％のエタノール熱水エキス、コロソリン酸含有量１％以下の熱水抽出エキス並びにそれらに賦型剤剤やオイル類を用いた錠剤、カプセル、白色エキス、透明水溶液などである。
４． 得られた事実と今後の臨床試験の想定範囲は、二度の認知症臨床試験で用いられた組成物（詳細は後述）はコロソリン酸含有量１錠１ミリグラムの錠剤である。バナバ（ラガーストロエーミア・スペシオーサ・和名オオバナ百日紅）のエタノール熱水エキスをもとに作られた。同様の植物は、グワバ、枇杷、桑、柿、花梨（巻末参照）など１２０種類以上が報告されている。実験がバナバ由来であること、米国FDAの認証や多くの販売製品と実績、韓国ではトクホ取得などに理由により安全の面からも抽出原料植物としてより好ましいと考えられる。
５． 処方されたコロソリン酸を含む組成物のあらましと効果が期待される想定の範囲
原料となった［バナバ］はフィリピンのサンバレス州で採集された。抽出物製造工場は中国浙江省であり、錠剤製造は国内千葉県である。エタノール熱水エキスと賦型剤（後述に記載）を原料としたものでコロソリン酸含有量は１錠あたり１ミリグラムである。１日あたりの処方量は３粒である。コロソリン酸量は３ミリグラムであった。
処方時並びに試験後のインタビューで副作用、体調の変異は確認されていない。このことから、コロソリン酸とその類の認知症の緩和と予防を目的に処方または摂取する場合、一日あたりコロソリン酸量０．１５ミリグラムから６０ミリグラムが想定され特に［一日３ミリグラム～１０ミリグラム程度］が好ましい。
６．薬理上の安全性については、カナダにおいてエタノール熱水エキスのコロソリン酸ソフトジェル錠剤で一日１０ミリグラムの安全性確認臨床試験結果があり論文化されている。そのことから一日最大コロソリン酸処方量２００ミリグラムまでは安全と考えられる。また２０倍量の安全性はマウス実験、ビーグル犬などの解剖実験でも確認済みである。
これで得られる抑認知症効果、認知症の緩和と予防効果は、見当識（記憶や認識能力）機能の回復と、インスリン応答の素早さ、インスリン抵抗性の改善などが見込める。
７．組成物の投与の量と方法各種は、好ましいコロソリン酸とその類の投与量は、［一日１ミリグラムから２０ミリグラム］である。これは、固形物（錠剤、グミ、カプセル、ソフトジェル、飴、キャンディーなど）、液体（ジュレ、ドリンク、乳酸菌飲料、炭酸飲料、透明エキス）、気体（透明エキスを使った噴霧）。粉体（白色エキスを使用した、うどん、パン、菓子類など）が考えられるが、認知症、軽度認知障害者には、高齢者も多く、［嚥下障害］などを配慮する必要がある。好ましいのは、小さい錠剤または蜂蜜状のジェルまたは６０～１００mlの乳酸菌飲料である。
８．摂取のタイミングは、食前が好ましい。しかし食間でも食後でも可能である。要は決して苦痛や、煩わしさがなく日常的に毎日続けられることが大切である。最終的な目的は認知症が疑われる人々の笑顔の回復であり意欲、食欲でもある。このことは家族の幸福にもつながり、社会の問題解決にも大きな貢献を果たすものとなる。認知症最大の［課題］は認知症新薬または予防薬、診断のバイオマーカーがないことに尽きる。本発明は激増する認知症・アルツハイマー病の進行に対し、医科学的証拠を以って解決（遅延・予防）するものである。
９．特に日本人や東アジア人に多いとされる遺伝的要因と生活習慣に起因する［インスリン分泌不全がある。しかし本発明の目的は、コロソリン酸とその類縁化合物及びそれらを含む抽出物は、加齢になどにより空腹時のインスリン分泌が過剰になりでインスリン抵抗性発症した高齢者または熟年者のインスリン機能と応答を、正常に戻し認知症の進行を抑え、緩和または予防を可能にし、本人とその家族の健康と笑顔を維持または回復させるものである。同時に発明を応用し嚥下障害や誤飲を防げるように鼻腔吸引で摂取できるように混合する溶剤や機器の開発、安全で安価に大量し高齢者、熟年層とその家族を激増する認知症・アルツハイマー病発症から守るものである。
  INDUSTRIAL APPLICABILITY The present invention makes it possible to cheaply mass-produce corosolic acid, inexpensively, widely and safely to prevent and alleviate dementia.
1. The triterpene to which corosolic acid belongs is a kind of terpene composed of six isoprenes and having a molecular formula of C30H48. More than 100 analogous compounds have been reported (at the end of the book), and are fat-soluble compounds widely contained in plants.
2. Extraction methods include water extraction, hot water extraction, ethanol hot water extraction, autoclave extraction, and the like. It is economically preferable to subject the dried raw material after several hot water extractions to ethanol hot water.
3. The composition containing corosolic acid used in clinical trials is the composition used in past experiments, which is a corosolic acid reagent (99.5% or more purity), ethanol with a corosolic acid content of 1% to 18%. Hot water extracts, hot water extracts with a corosolic acid content of 1% or less, and tablets, capsules, white extracts, clear aqueous solutions, etc. using these with excipients and oils.
4. Based on the facts obtained and the expected range of future clinical trials, the composition used in the two dementia clinical trials (details will be described later) is a 1-mg tablet containing corosolic acid. It was made based on ethanol hot water extract of banaba (Lagerstroemia speciosa, Japanese name: Oobana myrrh). More than 120 kinds of similar plants such as guava, loquat, mulberry, persimmon, and quince (see end of book) have been reported. It is considered to be a more preferable raw material for extraction from a safety point of view because of the fact that it was derived from banaba in the experiment, the US FDA certification, many sales products and achievements, and the acquisition of FOSHU in South Korea.
5. Outline of the composition containing corosolic acid prescribed and expected range of effects [Banaba], which was used as a raw material, was collected in Zambales Province in the Philippines. The extract manufacturing plant is in Zhejiang, China, and the tablet manufacturing is in Chiba Prefecture, Japan. Ethanol hot water extract and excipients (described later) are used as raw materials, and the content of corosolic acid is 1 milligram per tablet. The prescribed amount per day is 3 tablets. The amount of corosolic acid was 3 milligrams.
No side effects or changes in physical condition were confirmed at the time of prescription or in post-test interviews. For this reason, when prescribing or ingesting corosolic acid and the like for the purpose of alleviating and preventing dementia, the amount of corosolic acid is assumed to be 0.15 mg to 60 mg per day, especially [3 mg to 10 mg per day]. degree] is preferred.
6. With regard to pharmacological safety, the safety confirmation clinical trial results of 10 mg per day of ethanol hot water extract corosolic acid softgel tablets have been published in Canada. Therefore, a maximum dose of 200 milligrams of corosolic acid per day is considered safe. In addition, the safety of 20 times the dose has already been confirmed in mouse experiments and dissection experiments with beagle dogs.
The antidementia effect, mitigation and prevention effect of dementia obtained from this are expected to include recovery of orientation (memory and cognitive ability) function, rapid insulin response, and improvement of insulin resistance.
7. Amounts and Methods of Administration of the Compositions A preferred dosage of corosolic acid and the like is [1 milligram to 20 milligrams per day]. This includes solids (tablets, gummies, capsules, softgels, candies, candies, etc.), liquids (jelly, drinks, lactic acid beverages, carbonated beverages, transparent extracts), and gases (spray using transparent extracts). Powder (udon, bread, confectionery, etc. using white extract) can be considered, but there are many elderly people with dementia and mild cognitive impairment, and it is necessary to consider [dysphagia]. Preferred are small tablets or honey-like gels or 60-100 ml lactobacillus beverages.
8. The timing of ingestion is preferably before a meal. However, it can be done between or after meals. In short, it is important to be able to continue on a daily basis without any pain or annoyance. The ultimate goal is to restore the smiles of people suspected of dementia, as well as their willingness and appetite. This will lead to the happiness of the family and will make a great contribution to solving social problems. The biggest [problem] in dementia is the absence of new dementia drugs, preventive drugs, and biomarkers for diagnosis. The present invention solves (delays/prevents) the progress of dementia/Alzheimer's disease, which is rapidly increasing, based on medical scientific evidence.
9. Due to genetic factors and lifestyle habits, especially in Japanese and East Asians [Insulin deficiency is present. However, it is an object of the present invention that corosolic acid, its analogues, and extracts containing them improve insulin function in elderly or mature people who have developed insulin resistance due to excessive fasting insulin secretion due to aging. It restores the response to normal, suppresses the progression of dementia, makes it possible to alleviate or prevent dementia, and maintains or restores the health and smile of the person and his/her family. At the same time, by applying the invention, development of solvents and devices that can be mixed by nasal suction to prevent dysphagia and accidental ingestion, safely and cheaply mass-produced dementia and Alzheimer's disease, which are increasing rapidly in the elderly, middle-aged people and their families. It protects against the onset of disease.
日常食品としての流通、病院での処方、ドラッグストアーでのOTC販売、ＳＮＳ通販などが好ましい手段である。コロソリン酸を日常食品として応用し手軽に摂取できるようになれば、多くの成人病、生活習慣病、認知症などなど広範な高齢者に多い疾患の全てに有効な夢の新薬あるいは日常食品として高齢者の健康を守ることが可能である。なによりコロソリン酸とその類縁化合物及びそれらを含む抽出物は安価で製造可能であり合成薬と違い副作用の心配がなく安全である。課題を解決する具体的製品として、日常食品例えばお茶、飴、はちみつ、ヨーグルトなどへの添加も望ましい手段である。
またコロソリン酸類は長きにわたり伝承的食経験ある安全で副作用の報告がない植物由来の化合物である。常習性や大量に摂取しても事故や副作用の心配がない。
現代人の死亡数を占める疾患とは癌、心臓病、糖尿病、高血圧、肺炎など成人病と呼ばれる加齢とともにリスクの高まる疾患か、または生活習慣病と呼ばれる人類史上かってなかった「消化の良い冨栄養な食事」「運動不足」に起因する高濃度血液と血栓に起因する疾患である。次に重要なのが認知症である。これらの具体的解決方法をエビデンスと共に提案することが喫緊の課題であり本発明の主題である。
課題を解決するための第三の手段として、コロソリン酸は「ナノ化」「透明化」「水溶化」技術の開発に成功済みであり、水のように「無色透明」「無味無臭」の何にでも溶ける液体もあり利用範囲は無限である。
  Distribution as a daily food, prescription at hospitals, OTC sales at drugstores, SNS mail order, etc. are preferable means. If corosolic acid can be applied as a daily food and can be easily ingested, it can be used as a new dream drug or a daily food that is effective for a wide range of diseases common to the elderly, such as many adult diseases, lifestyle-related diseases, and dementia. It is possible to protect people's health. Above all, corosolic acid, its analogues, and extracts containing them can be produced at low cost, and unlike synthetic drugs, they are safe without side effects. As a specific product to solve the problem, addition to daily foods such as tea, candy, honey, yogurt, etc. is also a desirable means.
In addition, corosolic acids are plant-derived compounds that have been traditionally eaten for a long time, are safe, and have no reports of side effects. There is no fear of accidents or side effects even if it is addictive or ingested in large amounts.
The diseases that account for the number of deaths in modern people are diseases called adult diseases, such as cancer, heart disease, diabetes, hypertension, and pneumonia, or diseases that increase in risk with age, or lifestyle-related diseases, which have never been seen before in human history. It is a disease caused by high blood concentration and thrombus caused by nutritious diet and lack of exercise. The next most important is dementia. It is an urgent problem and the subject of the present invention to propose these concrete solutions together with evidence.
As a third means to solve the problem, corosolic acid has already been successfully developed for "nanization,""transparency," and "solubility." There are liquids that dissolve even in water, so the range of uses is limitless.
発明が実現する効果は次の通りである。
１．新しい産業の創出。コロソリン酸大量生産設備。カルス工場、加工設備、抽出設備、単利精製カラムなど。２．働く高齢者の増加。成人病、認知症・アルツハイマー病進行遅延・予防により本人と家族と社会の問題を解決する。３．社会保険料負担の問題解決。高齢者の健康維持、介護人材の不足解消問題の解決。４．日常生活における簡単で手ごろな認知症予防方法の提案。小粒３錠を飲むだけ。５．新しいマーケットの創出。生活習慣病対策、認知症予防・治癒製品の創出と新しい産業と雇用の創出。
６．日本発の認知症予防・治癒製品・機器・ノウハウの輸出など産業の振興。７．成人病、認知症・アルツハイマー病進行や薬効の定期診断と早期発見への寄与。８．簡易な人間ドック、認知症診断やスマホ利用項目への追加やVR技術とのコラボ。９．採血による一般的健康診断での成人病や認知症早期発見バイオマーカー技術の向上。１０．採血時に応答式の成人病や認知症項目にバイオマーカーとしてインスリン応答数値とインスリン抵抗性数値を加え早期発見の参考とする。１１．ＩＯＴやＡＩ技術の認知症市場参入を促進し、新しい認知症ハイテク新産業を創出する。
  The effects realized by the invention are as follows.
1. Creation of new industries. Corosolic acid mass production facility. Callus factories, processing equipment, extraction equipment, simple yield purification columns, etc. 2. An increase in the number of working elderly people. We solve the problems of individuals, families, and society by delaying and preventing the progression of adult diseases, dementia, and Alzheimer's disease. 3. Solving the problem of social insurance premiums. Maintaining the health of the elderly and resolving the problem of the shortage of caregivers. 4. Proposal of a simple and affordable dementia prevention method in daily life. Just take 3 small tablets. 5. Creation of new markets. Measures against lifestyle-related diseases, creation of dementia prevention and cure products, and creation of new industries and employment.
6. Promotion of industries such as the export of dementia prevention and cure products, equipment, and know-how from Japan. 7. Contribution to regular diagnosis and early detection of adult diseases, progression of dementia and Alzheimer's disease, and efficacy of drugs. 8. Simple medical checkup, dementia diagnosis, addition to smartphone usage items, and collaboration with VR technology. 9. Improving biomarker technology for early detection of adult diseases and dementia in general health checkups by blood sampling. 10. At the time of blood sampling, insulin response values and insulin resistance values are added as biomarkers to response-type geriatric diseases and dementia items, and used as a reference for early detection. 11. Promote the entry of IOT and AI technologies into the dementia market and create new dementia high-tech industries.
一回目治験者グループ高齢者のMMSEテストスコアーその１MMSE Test Scores of Elderly Patients in the First Investigator Group - Part 1 一回目治験者グループ高齢者のMMSEテストスコアーその２MMSE Test Scores of Elderly Patients in the First Investigator Group - Part 2 一回目治験者グループ高齢者のOGTT採血試験結果その１Results of the OGTT blood sampling test for the elderly in the first investigator group Part 1 一回目治験者グループ高齢者のOGTT採血試験結果その２Results of the OGTT blood sampling test of the elderly in the first investigator group Part 2 参加高齢者の名前と誕生日とMMSE途中経過Participating elderly's name, date of birth, and progress of MMSE 高齢者のコロソリン酸摂取前と摂取２週間後と一か月後のMMSEスコアーMMSE scores before, 2 weeks and 1 month after intake of corosolic acid in the elderly スマホ中毒の成人の上記と同じMMSEスコアー折れ線グラフSame MMSE score line graph as above for adults with smartphone addiction 治験者別のOGTT治験データの詳細OGTT trial data details by investigator コロソリン酸摂取の結果、インスリン抵抗性の国際基準値HOMA-IRが改善した結果、並びにインスリン感受性の向上、インスリンの素早い分泌、その結果としてインスリン分泌の総量を低減し、インスリン分解酵素の負担軽減とアミロイドベータやタウ・タンパクの原因物質を産生を低減したことが示されたAs a result of corosolic acid intake, the international standard value HOMA-IR for insulin resistance was improved, and insulin sensitivity was improved, insulin was secreted quickly, and as a result, the total amount of insulin secretion was reduced, and the burden on insulin-degrading enzymes was reduced. It was shown to reduce the production of causative substances of amyloid beta and tau protein 治験に参加の高齢者のMMSE写真とコロソリン酸２５％の透明な水溶液MMSE photographs of the elderly participants in the clinical trial and a clear aqueous solution of corosolic acid 25% 成人、高齢者の参加者写真と透明化したコロソリン酸水溶液Photographs of adult and elderly participants and clear corosolic acid solution 上段左：M電工で試作した既発の糖尿病治療器上段右：寝ている間にダイエットできるナイトダイエットマシン中段左：コロソリン酸を含んだ食パン、プラセボと食後血糖値を比較した中段右：コロソリン酸入り食パンの血糖値チェック採血試験下段左：コロソリン酸９９％の試薬下段中：同じくコロソリン酸９９％以上純度の試薬下段右：発明者が作った針状結晶Upper left: An existing diabetes treatment device prototyped by M Denko Upper right: Night diet machine that allows you to lose weight while you sleep Middle left: Bread containing corosolic acid, comparing postprandial blood glucose levels with placebo Middle right: Corosolic acid Blood sugar level check blood sampling test Lower left: Corosolic acid 99% reagent Lower middle: Corosolic acid 99% or higher purity reagent Lower right: Needle crystals made by the inventor 上段：国立岡山大学医学部で発見した紅黄葉虫食い葉の表面から得られたカルス下段：コロソリン酸が大量生産可能なカルス実験のデータの一部Top: Callus obtained from the surface of worm-eaten leaves found at the National Okayama University School of Medicine. 上段：東京農業大学との共同研究で２４時間のコロソリン酸の含有率解析下段：京都大学医学部において脂溶性のコロソリン酸を水で摂取した場合の血中のコロソリン酸摂取と排泄時間をLC/MS/MSで測定Top: Corosolic acid content analysis for 24 hours in joint research with Tokyo University of Agriculture. Measured with /MS 上段：家庭用の透明コロソリン酸溶液の噴霧健康機器のモデル画像中段：大脳の萎縮が見られる認知症患者のCT画像下段：アミロイドベータとタウタンパク（コロソリン酸の３D構造をアミロイドベータタンパクもしくはタウタンパク結晶があればコンピューターシミュレーションが可能）Upper row: Model image of home-use nebulized corosolic acid solution spray health equipment Middle row: CT image of a dementia patient with cerebral atrophy Lower row: Amyloid beta and tau protein computer simulation possible) 図１４の採血をLC／MS／MSで測定し血中から見つかったコロソリン酸のピーク（四重極質量計による血液内のコロソリン酸測定データThe blood sample in Fig. 14 was measured by LC/MS/MS and the peak of corosolic acid found in the blood (measurement data of corosolic acid in blood using a quadrupole mass spectrometer) 二回目治験者データその１Second trial patient data 1 二回目治験者データその２Second trial participant data 2 二回目治験者データその３Second trial participant data 3 コロソリン酸の化学式Chemical formula of corosolic acid コロソリン酸の３D画像3D image of corosolic acid コロソリン酸の３D構造式3D structural formula of corosolic acid 岡山大学で開発したコロソリン酸を５００倍以上含有したカルスの写真Photo of callus containing 500 times more corosolic acid developed at Okayama University
本発明を実施するための形態の第一とは、何よりコロソリン酸の存在を広く世間に知らしめなければならいだろう。そうすれば開発者や提携先が現れ製品化が加速する。知らせるとはSNSやメディア露出を図ることでありそれに値するニュース性を待たせることが重要である。コンピューターシミュレーションでコロソリン酸とインスリンの関連性を計算するのもコストパーフォーマンスの良い方法であろう。当該発明者によりコロソリン酸はすでに結晶化され３D構造も判明している。またインスリンの３D構造も広く公開されておりコンピューターシミュレーション（デジタル模擬実験）も可能である。
本発明を実施するための形態の二番目とは、成人病、生活習慣病、認知症、認知症（MCI）が疑われる人々の日常生活のあらゆるシーンでコロソリン酸とその類を生かし、インスリン抵抗性の解決を基本とした、クスリ、食品、飲料、環境（噴霧）、IoTなどの製品を開発することである。 The first mode of carrying out the present invention is to make the existence of corosolic acid widely known to the public. Then developers and partners will appear and commercialization will be accelerated. It is important to let people wait for the newsiness that deserves it because it is to aim for SNS and media exposure to inform. Calculating the relationship between corosolic acid and insulin by computer simulation would also be a cost-effective method. The inventor has already crystallized corosolic acid and determined its 3D structure. In addition, the 3D structure of insulin is widely open to the public, and computer simulation (digital simulation) is also possible.
The second mode for carrying out the present invention is to utilize corosolic acid and the like in every scene of daily life of people suspected of adult diseases, lifestyle-related diseases, dementia, and dementia (MCI), to improve insulin resistance. It is to develop products such as medicine, food, beverage, environment (spray), IoT, etc. based on the solution of sexuality.
本発明を実施するための形態として、日本人の食後の追加インスリンについての問題解決がある。アジア人と西欧人のインスリンの食後の追加分泌のパターンは異なる。歴史的に農耕民族と狩猟民族という食べ物の違いに起因していると考えられる。本発明のコロソリン酸とその類は［穀物］を主食にしている民族の高齢者に使われるのがより好ましい。
日本人・アジア人は農耕民族（旧石器時代から）故にＤＮＡはゆっくりとインスリン分泌を始める。一方血糖値が下がってもインスリンを出し続ける。このインスリン反応遅延がインスリン抵抗性の原因の一つになっている。食事前にコロソリン酸を摂取したり、日常食品として摂取すれば上記の課題を解決し、本発明を実施する具体的な形態となる。 As a mode for carrying out the present invention, there is a solution to the problem of postprandial additional insulin for Japanese people. The pattern of postprandial boosting of insulin in Asians and Westerners is different. It is thought that this is due to the difference in food between agricultural and hunter-gatherers historically. The corosolic acid and the like of the present invention are more preferably used in the elderly of grain-based ethnic groups.
Japanese and Asians are an agricultural race (from the Paleolithic era), so their DNA slowly begins to secrete insulin. Insulin continues to be released even when blood sugar levels are low. This delayed insulin response is one of the causes of insulin resistance. If corosolic acid is ingested before meals or as a daily food, the above problems will be solved and the present invention will be implemented in a specific form.
本発明の主たるターゲットであるインスリンに関する説明の一つである。人体には糖を細胞に取り込むホルモンはインスリン以外にほかには一つもなくインスリン分泌は極めて重要である。故に人体の生命維持のためには最も重要な唯一無二のホルモンなのである。 This is one of the explanations about insulin, which is the main target of the present invention. In the human body, there is no hormone other than insulin that takes in sugar into cells, and insulin secretion is extremely important. Therefore, it is the most important and unique hormone for sustaining human life.
本発明の解決目的の一つ、成人病として高齢者に急増している認知症・アルツハイマー病への認識・概念は以下の通りである。例えばこれを一例としてインスリン抵抗性を考察してみよう。
１）認知症・アルツハイマー病は［脳萎縮］が特徴的である、しかしこれは画像でしか確認できない［起こってしまった結果］である、２）脳萎縮は脳神経変性疾患（中枢神経の破壊）が原因とされる、３）脳の大半は約1兆個の glial cell（グリアルセル・脳細胞）と約１千億の神経細胞で構成され正常な代謝が重要である、４）脳への栄養はグルコース（糖）だけでありタンパクや脂肪は取り込まれず脳内でもインスリンの働きが重要である、５）脳細胞は他の細胞に比較し多くのエネルギーを必要とする（肝細胞に匹敵する）、６）以上により糖代謝が健全な脳機能に不可欠である、７）脳には血液脳関門といわれるバリアーが存在し薬剤が届きにくいとされてきたが分子量の大きいホルモンであるインスリンが関門を通過することが確認された、８）脳代謝のキーマンは［インスリン］であろう、９）インスリンの働きが弱まれば糖尿病原因を引き起こしやすく脳内であっても例外ではない、そこが認知症・アルツハイマー病が第三の糖尿病と呼ばれるようになった所以である。１０）脳内のインスリン機能が正常化、もしくは正常に近づけば認知症・アルツハイマー病も緩和と予防の可能性がある。 One of the objectives of the present invention, recognition and concept of dementia and Alzheimer's disease, which are rapidly increasing among the elderly as adult diseases, is as follows. For example, consider insulin resistance as an example.
1) Dementia and Alzheimer's disease are characterized by [brain atrophy], but this is a [result that has happened] that can only be confirmed by imaging. 2) Brain atrophy is a neurodegenerative disease (destruction of the central nervous system). 3) The majority of the brain consists of about 1 trillion glial cells and about 100 billion nerve cells, and normal metabolism is important. 4) Nourishment for the brain 5) Brain cells require more energy than other cells (equivalent to liver cells). 6) From the above, glucose metabolism is essential for healthy brain function. 7) The blood-brain barrier exists in the brain, making it difficult for drugs to reach. 8) The key to brain metabolism is [insulin] 9) If the action of insulin is weakened, it is likely to cause diabetes, even in the brain, which is dementia This is the reason why Alzheimer's disease is called the third type of diabetes. 10) If the insulin function in the brain is normalized or approaches normal, dementia and Alzheimer's disease may be mitigated and prevented.
２例目として、糖尿病といえば高血糖、高粘度血液が毛細血管の破壊とそれによる毒性が問題とされる。近年、長寿（加齢）と生活習慣による高齢者の糖尿病が急増している。その主因とされるのが［インスリン抵抗性］である。インスリン抵抗性とは、インスリン機能が低下した状態を意味するかあるいは栄養を取り込む細胞のインスリン感受性の低下が考えられる。 As a second example, when it comes to diabetes, hyperglycemia and high-viscosity blood destroy capillaries and cause toxicity. In recent years, the number of elderly people with diabetes due to longevity (aging) and lifestyle habits is rapidly increasing. The main cause is [insulin resistance]. Insulin resistance refers to a state of reduced insulin function or may be a reduced insulin sensitivity of nutrient uptake cells.
インスリンが効かないから血糖値が下がらず、さらにインスリンが分泌過多になる。インスリン反応も鈍感になり脳内の高粘度血液は、微細な脳の毛細血管をスムーズに流れることができなくなり脳細胞への栄養も届けられない。また働きの弱った脳内血管中の残留インスリンはタンパクと結合し（アミロイドβ前駆体タンパク質）アミロイドβペプチドの原因物質を産生する。アミロイドβ→タウ・タンパクのリン酸化→老人斑産生とされる認知症・アルツハイマー病の［結果］を産み出すこととなる。これが一般的な認知症発症の薬学的メカニズムである。 Insulin does not work, blood sugar levels do not go down, and insulin is over-secreted. Insulin response also becomes dull, and high-viscosity blood in the brain cannot flow smoothly through the fine capillaries of the brain, and nutrients cannot be delivered to brain cells. Residual insulin in cerebral blood vessels with weakened action binds to protein (amyloid β precursor protein) to produce the causative substance of amyloid β peptide. Amyloid β → phosphorylation of tau protein → producing dementia and Alzheimer's disease [results], which is said to produce senile plaques. This is the general pharmacological mechanism of dementia onset.
発明の論旨をまとめると、コロソリン酸によるインスリン抵抗性の緩和と改善は代表的成人病、癌、糖尿病、高血圧症、糖尿病、EDその他高齢者の代表的疾患である・・・
（１）認知症・アルツハイマー病を緩和予防するということは、（２）脳内の血糖代謝を正常に近づけることが大切、（３）インスリン機能を正常に戻す、（４）単純にインスリン分泌値を上げ、血糖値を下げるだけでは不十分である、（５）タイミング、つまりインスリンが必要なときには正常に働き、役目が終了したらすばやく血中のインスリン値を低下させるものでなくてはならない（インスリンの総分泌量とタイミングの正常化）、それを可能にする組成物の発見が重要であり同時に認知症・アルツハイマー病の緩和と予防を数字的、理化学的に証明するものでなくてはならない。 To summarize the gist of the invention, alleviation and improvement of insulin resistance by corosolic acid are typical geriatric diseases, cancer, diabetes, hypertension, diabetes, ED and other typical diseases of the elderly...
(1) Alleviation and prevention of dementia and Alzheimer's disease means that (2) it is important to bring blood glucose metabolism in the brain closer to normal, (3) return insulin function to normal, and (4) simply insulin secretion level. (5) Timing, in other words, insulin must work normally when it is needed, and quickly lower the blood insulin level after completing its role (insulin normalization of the total secretion amount and timing of ), it is important to discover a composition that enables it, and at the same time, it must be numerically and physicochemically proven to alleviate and prevent dementia and Alzheimer's disease.
同時にそれが高齢者・成人の認知症・アルツハイマー病やMCI軽度認知障害が疑われる人々にとって認知機能（記憶力、言語能力、判断力、計算力、遂行力など）に一定の自覚レベル効果が伴わなくてはならない。　副作用やストレスがあっては逆効果となりそれも確認したものでなくてはならない。健康増進こそ最終目標であるからである。さらに摂取組成物が、安価で大量生産が可能で、生活に密着カタチで摂取できるものであることが望ましい。一回の処方が何万円、何十万円、何百万円というのでは非現実的で大衆には処方できない。将来数億人にもなろうかという鬱［うつ］や認知症、軽度認知障害者のためには月収の数十分の１以下でなくてはならないであろう。具体的には１回の処方料金は数千円、できれば数百円以下が好ましい。 At the same time, it does not have a certain level of effect on cognitive functions (memory, verbal ability, judgment, arithmetic, performance, etc.) for elderly people, adults with dementia, Alzheimer's disease, and people with MCI mild cognitive impairment. must not. If there are side effects or stress, it will have the opposite effect, and it must be confirmed. This is because health promotion is the ultimate goal. Furthermore, it is desirable that the ingestible composition is inexpensive, mass-producible, and can be ingested in a manner closely related to daily life. Tens of thousands of yen, hundreds of thousands of yen, or millions of yen per prescription is unrealistic and cannot be prescribed to the general public. For people with depression, dementia, and mild cognitive impairment, who are expected to number in the hundreds of millions of people in the future, it will have to be less than a few tenths of their monthly income. Specifically, the fee for one prescription is several thousand yen, preferably several hundred yen or less.
以下は１例とした、認知症・アルツハイマー病の発症までの［プロセス］と本発明による緩和と予防の順序を示したものである。コロソリン酸のインスリン抵抗性問題解決の意義を示すものであろう。［認知症・アルツハイマー病］←［脳神経細胞の破滅］←［脳内糖代謝の不良］←［脳の毛細血管破壊と毒性］←［脳の高血糖と高粘度血液と脳内血管残留インスリン］←［インスリン抵抗性］、コロソリン酸摂取 ＝［インスリン抵抗性改善］→［脳内代謝改善］→［残留インスリン低減］→［結果としてアミロイドβ→タウ・タンパクのリン酸化→老人斑産生の減少］→［神経変性疾患（中枢神経）の緩和と予防］→［認知症・アルツハイマー病の緩和と発症予防］に繋がる。 The following is an example showing the [process] up to the onset of dementia/Alzheimer's disease and the order of mitigation and prevention according to the present invention. This would indicate the significance of corosolic acid in solving the problem of insulin resistance. [Dementia/Alzheimer's disease] ← [Destruction of brain nerve cells] ← [Defective glucose metabolism in the brain] ← [Destruction of brain capillaries and toxicity] ← [Hyperglycemia in the brain, highly viscous blood, and residual insulin in blood vessels in the brain] ← [Insulin resistance], Corosolic acid intake = [Improvement of insulin resistance] → [Improvement of brain metabolism] → [Reduction of residual insulin] → [As a result, amyloid β → Phosphorylation of tau protein → Decrease in senile plaque production] → [Alleviation and prevention of neurodegenerative diseases (central nervous system)] → [Alleviation and prevention of dementia and Alzheimer's disease].
上記の順序を、エビデンスを持って実現させたものが本発明である。下記にその［発明の論旨を証明するデータ］を添付する。論旨とは、（１）コロソリン酸摂取は認知症・MCI軽度認知障害を緩和と予防する、（２）それは脳の代謝の改善によるものである、（３）その理化学的証明は臨床試験により実証された、（４）脳代謝改善はインスリン応答と抵抗性の改善が重要である、（５）それにより認知症・MCI軽度認知障害を緩和と予防が実現した、（６）その実証は広く世界で認められているMMSEテストで証明された、（７）故にコロソリン酸摂取は、認知症・MCI軽度認知障害を緩和と予防することを証明した。 The present invention is the realization of the above order with evidence. The [data proving the gist of the invention] is attached below. The thesis is that (1) corosolic acid intake alleviates and prevents dementia and MCI mild cognitive impairment, (2) it is due to the improvement of brain metabolism, and (3) its physicochemical proof is verified by clinical trials. (4) improvement of insulin response and resistance is important for improving brain metabolism, (5) mitigation and prevention of dementia and MCI mild cognitive impairment have been achieved, (6) the demonstration has been widely conducted around the world. (7) Therefore, corosolic acid supplementation proved to alleviate and prevent dementia/MCI mild cognitive impairment, as demonstrated by the MMSE test accepted in .
本発明の有効と考えられる対象たる人々を大まかに定義（イメージ）すると、
１．          インスリン分泌はあるがインスリン応答と抵抗性を疑われる高齢者または成人とは、
２．          空腹時の血中のインスリン値が１～12マイクロ/ＭＬの範囲内にあり（インスリンは分泌されている）、インスリン抵抗性を示すHOMA-IR数値が正常とされる≦1.6~2.6ポイント以上（インスリン抵抗性が疑われる）、
３．          あるいはインスリン応答や分泌不全の目安とされるＩＮＳＬＩＮ－ＯＧＥＮＩＣが０．４以下（インスリン応答に問題あり）のいずれかで、同時にＭＭＳＥテストのスコアが２６ポイント以下（認知症・ＭＣＩ軽度認知障害が疑われる）で、
４．          ６５歳以上の高齢者ならびに２０歳以上６５歳以下の成人］ということになる。つまりインスリン抵抗性を持った人々である。 Roughly defining (image) the people who are considered to be effective in the present invention,
1. Elderly or adults with insulin secretion but suspected insulin response and resistance are:
2. Fasting blood insulin level within the range of 1 to 12 micro/ML (insulin is secreted), and HOMA-IR value indicating insulin resistance is normal ≤ 1.6 to 2.6 points or more ( suspected insulin resistance),
3. Or, INSLIN-OGENIC, which is a measure of insulin response and secretion failure, is 0.4 or less (problems with insulin response), and at the same time, the MMSE test score is 26 points or less (dementia/MCI mild cognitive impairment is suspected). in the
4. Elderly persons aged 65 and over and adults aged 20 to 65]. People with insulin resistance.
本発明は一例として挙げた成人病、生活習慣病たる認知症が疑われる人々に対し、コロソリン酸またはその類縁化合物を一定量摂取して、記憶障害、鬱気分、食欲減退、意欲喪失、もの忘れなどを改善し、本人はもとよりご家族を不安や苦痛から解放して、安心感とリラックス感を与えようとするものである。おおまかな作用機序は、インスリン抵抗性を緩和し、認知症の大きな原因とされる［脳内の毛細血管損傷や神経原繊維変化と破壊］の緩和と予防を可能にする方法と組成物の発見である。 In the present invention, memory impairment, depressed mood, loss of appetite, loss of motivation, and forgetfulness are observed by ingesting a certain amount of corosolic acid or an analogous compound to people suspected of having dementia, which is an adult disease or lifestyle-related disease, as an example. It aims to relieve the patient and his/her family from anxiety and pain and give them a sense of security and relaxation. The broad mechanism of action is that of a method and composition that alleviates insulin resistance and enables alleviation and prevention of [capillary damage and neurofibrillary tangles and destruction in the brain], which are major causes of dementia. It is a discovery.
本発明の当該組成物とは、種々の植物から抽出したコロソリン酸類を含むエキス類、同じく植物培養によって得られたエキス類と試薬、同じく類縁化合物並び類縁化合物を半合成した化合物、同じく糖鎖などで修飾した化合物、同じくカルボン酸部分を切断した化合物など指す。上記のすべてはコロソリン酸が関与したか、部分関与したと推測されるものである。またコロソリン酸の純度99.5％以上の試薬レベルまたはそれを含む組成物が、認知症の主因とされる［加齢と生活習慣］に起因するインスリン応答の鈍化やインスリン抵抗性に対し、インスリンの本来機能を回復させ、時には人体のシグナルネットワークの中で脳内あるいは生体内でインスリンと共にリガンドまたはアゴニストとして機能し、効果的に認知症・アルツハイマー病進行遅延・予防に役立つものである。脳内における作用機序については今後の研究を待たねばならないだろう。
さらに当該発明を応用した摂取の方法、揮発器類、大量生産方法、認知症診断の簡易な方法とバイオマーカー、遺伝子組み換えやゲノム編集植物、更に飼料や肉類などの開発は、新しい認知症予防の製品類や産業ならびに市場の創造と発展をもたらすものである。 The composition of the present invention includes extracts containing corosolic acids extracted from various plants, extracts and reagents similarly obtained by plant culture, analogous compounds and semi-synthesized analogous compounds, sugar chains, etc. It refers to a compound modified with , a compound in which the carboxylic acid moiety is cleaved, and the like. All of the above are speculated to involve or partially involve corosolic acid. In addition, a reagent level of corosolic acid with a purity of 99.5% or more or a composition containing it is effective against sluggish insulin response and insulin resistance caused by aging and lifestyle habits, which are considered to be the main causes of dementia. It restores function, sometimes functions as a ligand or agonist in the human body's signal network together with insulin in the brain or in vivo, and is effectively useful for delaying or preventing progression of dementia and Alzheimer's disease. The mechanism of action in the brain will have to wait for future research.
Furthermore, the development of ingestion methods, volatiles, mass production methods, simple methods and biomarkers for diagnosing dementia, genetically modified and genome-edited plants, as well as feed and meat, etc. that apply the invention will be new ways to prevent dementia. It brings about the creation and development of products, industries and markets.
５．コロソリン酸長期摂取の効果
（１）　コロソリン酸の一ヶ月摂取後では、８０歳以上の高齢者の認知機能（記憶力、言語能力、判断力、計算力、遂行力など）がプラス９．８点と大幅に改善された。（２）　コロソリン酸の１ヶ月摂取後では、７０歳台の高齢者のスコアもプラス５．８点と改善された。（３）コロソリン酸摂取の中長期（２週間～１ヶ月）の摂取は治験者の大半の認知機能を回復させた。笑顔、食欲、落ち着き、意欲の回復が顕著に戻った。（４）選ばれた治験者は７０～８０歳台の健康な高齢者だった。（５） 開始前は全員にＭＣＩ軽度認知障害が認められた。（６） 最終的にテストに参加した高齢者は２２名だった。（７） 特に８０歳以上の高齢者の認知機能は大きく改善した。（８）８名それ以外からハイプレシションでの２名の合計１０名が臨床試験に参加した。（９）参加者と後見人の全員からインフォームドコンセント（参加・公開承諾書）得た。（１０） 参加者は軽い鬱（うつ）があったが１月後には緩和され笑顔と食欲が戻った。（１１）１ヶ月のコロソリン酸摂取後インタビューを実行したが副作用の報告はなかった。（１２）コロソリン酸の１ヶ月摂取後では、８０歳以上の高齢者の認知機能（記憶力、言語能力、判断力、計算力、遂行力など）がプラス９．８点と大幅に改善された。（１３）コロソリン酸の一ヶ月摂取後では、７０歳台の高齢者のスコアもプラス５．８点と改善された。（１４）コロソリン酸摂取の長期（２週間～１ヶ月）の摂取は治験者の大半の認知機能を回復させた。（１５）選ばれた治験者は７０～８０歳台の身体的には健康な高齢者だった。（１６）開始前は全員にＭＣＩ軽度認知障害が認められた。（１７）最終的にテストに参加した高齢者は２２名だった。（１８）特に８０歳以上の高齢者の認知機能は大きく改善した。（１９）そのなかから８名、それ以外からハイプレシションでの２名の合計１０名が臨床試験に参加した。（２０）参加者と後見人の全員から「インフォームドコンセント」（参加・公開承諾書）をえた。（２１）参加者には軽い鬱（うつ）があったが一ヵ月後には緩和され笑顔と食欲が戻った。（２２）１ヶ月のコロソリン酸摂取後インタビューを実行したが副作用の報告はなかった。（２３）スマホへの過度依存があり、脳疲労が疑われる３０歳から５０歳を中心とした成人にも２週間のコロソリン酸摂取を実施し、摂取前、摂取後にＭＭＳＥテストを実行した。
  5. Effect of long-term intake of corosolic acid (1) After taking corosolic acid for one month, the cognitive functions (memory, verbal ability, judgment, arithmetic, performance, etc.) of the elderly aged 80 and over increased by 9.8 points. Greatly improved. (2) After taking corosolic acid for one month, the score of the elderly in their 70s also improved to plus 5.8 points. (3) Medium- and long-term intake of corosolic acid (2 weeks to 1 month) restored cognitive function in most of the subjects. Smiles, appetite, composure, and motivation returned markedly. (4) The selected trial subjects were healthy elderly people in their 70s and 80s. (5) All participants had MCI mild cognitive impairment before the start of the study. (6) There were 22 elderly people who finally participated in the test. (7) The cognitive function of the elderly aged 80 years and over has greatly improved. (8) A total of 10 people, including 8 people and 2 people from high precision, participated in the clinical trial. (9) Informed consent (participation and disclosure agreement) was obtained from all participants and guardians. (10) The participant had mild depression, but after one month it was relieved and smile and appetite returned. (11) An interview was conducted after corosolic acid intake for one month, and no side effects were reported. (12) After taking corosolic acid for one month, the cognitive functions (memory, verbal ability, judgment ability, calculation ability, performance ability, etc.) of elderly people aged 80 and over improved significantly by plus 9.8 points. (13) After taking corosolic acid for one month, the score of elderly people in their 70s improved to plus 5.8 points. (14) Long-term (2 weeks to 1 month) intake of corosolic acid restored cognitive function in most of the trial subjects. (15) The selected trial subjects were physically healthy elderly people in their 70s to 80s. (16) All had MCI mild cognitive impairment before initiation. (17) There were 22 elderly people who finally participated in the test. (18) In particular, the cognitive function of the elderly over 80 years old improved greatly. (19) A total of 10 people, 8 of them and 2 of the other high-precision patients, participated in the clinical trial. (20) Obtained "informed consent" (participation and disclosure agreement) from all participants and guardians. (21) The participant had mild depression, which was alleviated after one month, and smiles and appetite returned. (22) An interview was conducted after one month of corosolic acid intake, and no side effects were reported. (23) Adults aged 30 to 50 who are overly dependent on smartphones and suspected of having brain fatigue were also given corosolic acid for two weeks, and MMSE tests were performed before and after the intake.
新しい産業の創造として本発明が産業上の利用可能性として以下の業界・業種・製品が考えられる。
１．コロソリン酸の大量生産：キクラゲ、エリンギなど植物・キノコ培養業界
２．バイオマーカー：検査機器メーカー、試薬会社、日本赤十字、病院
３．認知症対策：製薬会社、健康食品会社、製茶会社、通販会社、介護施設
４．車載の揮発カセット：使い捨て芳香器、ジェットプリンター機器業界
５．据え置き噴霧器：家電メーカー、医療機器メーカー、通信会社、携帯電話会社
６．コロソリン酸含有農作物：種苗会社、大学農学部、農業共同組合、JAICA
７．ゲノム編集植物：米農家、野菜・果物農家、農協、スーパー、食堂
８．新薬開発、成人病予防健康食品、飲料、噴霧用透明エキスと機器
９．試薬製造のための結晶
１０．結晶から得られた３D構造による成人病・生活習慣病とのコンピューターシミュレーション
  As the creation of new industries, the following industries, business types, and products are conceivable as industrial applicability of the present invention.
1. Mass production of corosolic acid: plant and mushroom cultivation industry such as wood ear fungus and king oyster mushroom 2. Biomarkers: test equipment manufacturers, reagent companies, Japanese Red Cross, hospitals3. Measures against dementia: pharmaceutical companies, health food companies, tea companies, mail-order companies, nursing homes 4. Volatile cassettes for vehicles: disposable air fresheners, jet printer equipment industry5. Stationary nebulizers: home appliance manufacturers, medical device manufacturers, telecommunications companies, mobile phone companies6. Crops containing corosolic acid: seed companies, university agricultural departments, agricultural cooperatives, JAICA
7. Genome-edited plants: rice farmers, vegetable and fruit farmers, agricultural cooperatives, supermarkets, restaurants8. Development of new drugs, preventive health foods for geriatric diseases, beverages, transparent extracts and devices for spraying 9. Crystals for reagent manufacture10. Computer simulation of adult diseases and lifestyle-related diseases using 3D structures obtained from crystals

Claims (15)

  1. 　大量生産を目的に開発された枇杷の葉カルス、バナバ紅葉や虫食い葉カルスなどのエタノール抽出で、総重量中コロソリン酸を３～９０％含むエキス並びそのカルス遺伝子、ならびに植物培養カルスで生産し単利精製されたコロソリン酸、一連の生産方法と技術ならびにそれを含む組成物と製品。 Ethanol extraction of loquat leaf callus, banaba autumn leaves, wormy leaf callus, etc., which was developed for the purpose of mass production. Purified corosolic acid, a range of production methods and techniques, and compositions and products containing same.
  2. コロソリン酸とその類縁化合物及びそれらを含む抽出物を、コロソリン酸試薬レベル純度の９５％以上を含有する量への換算で、一日当たり体重５０キログラムあたり０．００１ミリグラムから１グラムを用いて、インスリン抵抗性を緩和と改善をさせる乃至それによって、インスリン感受性を向上させインスリンの総分泌量を低下させる組成物。 Corosolic acid and its analogues and extracts containing them, converted to an amount containing 95% or more of corosolic acid reagent level purity, using 0.001 milligram to 1 gram per 50 kilograms of body weight per day, insulin A composition that alleviates and improves resistance or thereby improves insulin sensitivity and reduces total insulin secretion.
  3. コロソリン酸を含むエキスの場合、熱水抽出エキス、エタノール熱水抽出エキスを問わず、体重５０キログラム当たりコロソリン酸とその類を０．０１ミリグラムから１００グラムを用いてインスリン抵抗性の緩和と改善を目的として使用する組成物。 In the case of extracts containing corosolic acid, 0.01 milligrams to 100 grams of corosolic acid and the like per 50 kilograms of body weight, whether hot water extract or ethanol hot water extract, is used to alleviate and improve insulin resistance. The composition used for the purpose.
  4. コロソリン酸とその類縁化合物及びそれらを含む抽出物を用いてインスリン抵抗性に起因する成人病や生活習慣病などの各種疾患の緩和と治療の方法。 A method for alleviating and treating various diseases such as geriatric diseases and lifestyle-related diseases caused by insulin resistance using corosolic acid, analogous compounds thereof, and extracts containing them.
  5. コロソリン酸とその類縁化合物及びそれらを含む水溶性の透明な組成物を用いて加齢やスマホ依存からくる情報過多並びにインスリン抵抗性に起因するＭＣＩなどの精神的な疾患を緩和と改善するための組成物。 Corosolic acid, its analogues, and water-soluble transparent compositions containing them are used to alleviate and improve mental disorders such as information overload caused by aging and smartphone addiction, and MCI caused by insulin resistance. Composition.
  6. コロソリン酸を用いて成人病、生活習慣病、認知症などの進行程度を推測するために単回もしくは複数回の微量の血液を摂取し、それをHPLC（高速液体クロマトグラフィー）またはLC/MS/MS(四重極質量計)によって分析し、血中のインスリン値とコロソリン酸値の増減を解析することにより認知症の進行程度や、薬剤などの効果を「数字で示すことが可能な」認知症・アルツハイマー病バイオマーカー組成物。 In order to estimate the progress of adult diseases, lifestyle diseases, dementia, etc. using corosolic acid, a small amount of blood is ingested once or multiple times, and it is analyzed by HPLC (high performance liquid chromatography) or LC / MS / The degree of progression of dementia and the effects of drugs, etc., can be expressed numerically by analyzing changes in insulin and corosolic acid levels in the blood using an MS (quadrupole mass spectrometer). disease and Alzheimer's disease biomarker composition.
  7. バナバの紅葉・黄色・茶色のカルス技術もしくは、枇杷、グワバ葉、柿の葉、桑の葉、紫蘇の葉などコロソリン酸とその類を含む植物カルスを用いたコロソリン酸の安価で大量生産可能な、植物培養方法。 Ability to mass-produce corosolic acid at a low cost using the callus technology of banaba autumn leaves, yellow and brown, or plant callus containing corosolic acid and the like such as loquat, guava leaves, persimmon leaves, mulberry leaves, perilla leaves, etc. , plant culture methods.
  8. バナバの紅葉・黄色・茶色のカルス技術もしくは、枇杷、グワバ葉、柿の葉、桑の葉、紫蘇の葉などコロソリン酸とその類を含む植物カルスを用いたコロソリン酸の安価で大量生産可能なカルス遺伝子の情報。 Ability to mass-produce corosolic acid at a low cost using the callus technology of banaba autumn leaves, yellow and brown, or plant callus containing corosolic acid and the like such as loquat, guava leaves, persimmon leaves, mulberry leaves, perilla leaves, etc. Callus gene information.
  9. インスリン抵抗性や各種成人病、生活習慣病、認知症予防のための鼻腔吸引の機器。 Equipment for nasal aspiration to prevent insulin resistance, various adult diseases, lifestyle-related diseases, and dementia.
  10. 認知症予防や脳疲労の回復のために、当該組成物を従来の経口摂取と比べ少量の処方量で、嚥下障害や誤飲を防ぎ素早く効果的に、自然呼吸の一部として鼻腔または気管から安全に身体に取り込む溶液・粉末と器材並びに味や処方量などを工夫した当該組成物(溶液)を経口摂取しやすくした食品。 In order to prevent dementia and recover from brain fatigue, the composition is prescribed in a smaller amount than conventional oral ingestion, prevents dysphagia and accidental ingestion, and is quickly and effectively delivered from the nasal cavity or trachea as part of natural respiration. A food that makes it easier to orally ingest the composition (solution) that has been devised, such as a solution/powder and equipment that can be safely taken into the body, as well as the taste and dosage.
  11. 新型コロナウイルスなどの感染症の予防や緩和のために使用される自然免疫と獲得免疫細胞のインスリン抵抗性を改善し抵抗力をたかめるコロソリン酸ならびにコロソリン酸を含む食品、飲料、組成物、液体類とそれらを用いた道具ならびに機器類。 Corosolic acid and foods, beverages, compositions, and liquids containing corosolic acid that improve insulin resistance and enhance resistance of innate and acquired immune cells used for the prevention and alleviation of infectious diseases such as novel coronavirus and tools and equipment using them.
  12. 　癌、心臓病、高血圧症、糖尿病、認知症・鬱、脳梗塞、EDなどの成人病の予防と緩和ののために自然免疫と獲得免疫細胞のインスリン抵抗性を改善し、本来機能を回復させるコロソリン酸並びにコロソリン酸を含む組成物、食品、飲料、液体とそれを用いた道具ならびに機器類 To prevent and alleviate adult diseases such as cancer, heart disease, hypertension, diabetes, dementia/depression, cerebral infarction, and ED, improve insulin resistance of innate and acquired immune cells and restore their original functions Corosolic acid and compositions containing corosolic acid, foods, beverages, liquids and tools and equipment using them
  13. コロソリン酸とその類縁化合物及びそれらを含む水溶性の透明な組成物を用いて加齢やスマホ依存からくる情報過多並びにインスリン抵抗性に起因するＭＣＩなどの精神的な疾患を緩和と改善するための情報ネットワーク。 Corosolic acid, its analogues, and water-soluble transparent compositions containing them are used to alleviate and improve mental disorders such as information overload caused by aging and smartphone addiction, and MCI caused by insulin resistance. information network.
  14. コロソリン酸の結晶とその基準となる結晶をもとに高速クロマトグラフィーなどで測定し定義されたコロソリン酸試薬 A corosolic acid reagent defined by high-performance chromatography, etc., based on corosolic acid crystals and standard crystals.
  15. コロソリン酸結晶と純度９５％以上の試薬、並びに溶解度試験を数回試行して得られたコロソリン酸の結晶と試薬、ならびにそれを使用した組成物と製品類 Corosolic acid crystals and reagents with a purity of 95% or more, corosolic acid crystals and reagents obtained by several trials of solubility tests, and compositions and products using them
PCT/JP2022/015828 2021-06-25 2022-03-30 Corosolic acid capable of improving insulin resistance/sensitivity and enhancing metabolic function and analogue thereof WO2022270112A1 (en)

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JP2021127314A JP2023022438A (en) 2021-08-03 2021-08-03 Composition for alleviating and improving function recovery and excretion deficiency of insulin by digestion of such as corosolic acid or the like simultaneously and with one or mixed preparation or the like and method of use
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094497A1 (en) * 2006-02-17 2007-08-23 Use-Techno Corporation Ameliorating agent for metabolic syndrome
KR20080005724A (en) * 2006-07-10 2008-01-15 주식회사 삼양제넥스 Method for separation and purification of corosolic acid from corosolic acid-containing materials
JP2013245213A (en) * 2012-05-29 2013-12-09 Jx Nippon Oil & Energy Corp Clathrate of eriobotrya japonica leaf culture extract and cyclodextrin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007094497A1 (en) * 2006-02-17 2007-08-23 Use-Techno Corporation Ameliorating agent for metabolic syndrome
KR20080005724A (en) * 2006-07-10 2008-01-15 주식회사 삼양제넥스 Method for separation and purification of corosolic acid from corosolic acid-containing materials
JP2013245213A (en) * 2012-05-29 2013-12-09 Jx Nippon Oil & Energy Corp Clathrate of eriobotrya japonica leaf culture extract and cyclodextrin

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