Compositions for improving insulin resistance by intake of corosolic acid, analogs thereof and extract of them, and use methods thereof

Abstract

To provide compositions for bringing insulin function and response of elderly or mature-aged people who are suspected to have insulin resistance to normal, thereby to suppress, alleviate or prevent the progression of various adult diseases, lifestyle diseases or cognitive impairment.SOLUTION: Disclosed is a composition for alleviating and improving insulin resistance, thereby improving insulin sensitivity and reducing total insulin secretion amount, by administering corosolic acid and analogs thereof and an extract containing them at a dosage of 0.001 mg to 1 g / 50 kg / day.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The technical fields of this invention are medicine, chemistry, pharmaceuticals, and biotechnology.

[0002] The applied technical fields of this invention are medicine, biochemistry, pharmacology, agriculture, botany, and business models.

[0003] Potential applications of this invention in commercial applications include agriculture, food, beverages, reagents, genetic engineering, factory farming, genome editing, medical equipment, analytical equipment, electrical appliances, collaborative business models, air fresheners, jet printers, IC chips, and analytical engineering. [Background technology]

[0004] Corosolic acid is a triterpenoid that, in animal and cell studies of diabetic models, has been shown to induce the glucose transporter GLUT4, which is involved in the uptake of sugar into tissues, in the cell membrane. It has also been reported to promote glucose uptake by promoting insulin receptor phosphorylation. Corosolic acid is a pentacyclic triterpene. Its structure is similar to ursolic acid, oleanolic acid, trimentic acid, and maslinic acid. It differs from ursolic acid only in the presence of a hydroxyl bond. It is a lipid-soluble compound with the chemical formula C30H48O4 and a molecular weight of 472.710. Banaba, a representative medicinal herb containing corosolic acid and related compounds, is a plant of the Lythraceae family and is known in Japanese as Oobana Sarusuberi. Its scientific name is Lagerstroemia speciosa, and it is a perennial deciduous broadleaf tree. It is widely distributed from Southeast Asia and southern China to northern Australia. Because the components contained in banaba leaves have the ability to lower blood sugar levels, it has attracted attention as a supplement for diabetes. Other well-known herbs that contain large amounts of corosolic acid and related terpenes include loquat leaves, guava leaves, persimmon leaves, mulberry leaves, quince leaves, shiso leaves, and Japanese bamboo leaves.

[0005] The subject of the present invention is (1) the alleviation and improvement of insulin resistance, (2) the improvement of insulin response, and (3) the alleviation and delay of the onset of adult diseases and lifestyle-related diseases that are believed to be caused by insulin resistance, through the intake of corosolic acid and its related compounds, and extracts containing them. Although the text contains descriptions of adult diseases and lifestyle-related diseases, the only things that the inventor has scientifically proven are diabetes, dementia, insulin, blood sugar levels, safety, informed consent, and post-ingestion interviews, and everything else is merely an idea based on appropriation and inference.

[0006] As stated in the inventor's other patents as prior art documents, (1) it is well known that corosolic acid lowers blood sugar levels, and (2) it increases insulin sensitivity, so there is no inventive element in that respect. (3) At the same time, it is widely known that plant extracts containing corosolic acid, such as banaba, guava, persimmon, mulberry, and biwa, also have the ability to inhibit blood sugar levels, so there is no inventive element in that respect either. Therefore, it will be necessary to clearly prove the essence of the invention, what is novel, what is inventive, and whether it is based on scientific evidence. The gist of the present invention, that the ingestion of corosolic acid and its related compounds, and extracts containing them, can alleviate and improve insulin resistance, thereby improving insulin response, is novel, inventive, and scientifically proven, and this is what distinguishes it from the prior art.

[0007] The novelty of this invention is as follows. First, there have been no reports of insulin resistance that have been conceived from the perspective of insulin itself (improving insulin, restoring its function, or sharpening its teeth) or that have been proven with numerical data. The idea of ​​corosolic acid alleviating and improving insulin resistance in this invention, and the in vivo and in vitro experimental data backed up by medical and scientific verification, are the world's first proof of this. Among the existing and existing diabetes medications, there are many that have reached a state of completion, such as those that stimulate insulin secretion or improve insulin resistance. All of these act on the insulin receptor. There have been no previous papers or reports that mention improvements to insulin itself with comparative figures. Insulin Receptor / Insulin Receptor The insulin receptor is a protein that exists on the insulin receptor / cell membrane, specifically binds to insulin, and acts as an insulin receptor on cells. It acts on glucose uptake. Insulin receptors exist in all vertebrates, from the slimy hagfish, the lowest of all vertebrates, to humans. This invention possesses inventiveness that is completely different from those known drugs. Even if it improves insulin response in the same way, how does it differ? Are there any advantages? Also, even if it improves insulin resistance in the same way, how does it differ from conventional drugs? How does it differ from other compositions? How superior is it? Unless these are clearly shown, it will not be recognized as an invention. Below are the specific answers.

[0008] 1. Proof of novelty and inventive step The already publicly known prior papers and speculations are as follows: 1) There are many papers and patents stating that corosolic acid lowers blood sugar levels. 2) Since insulin is the only hormone that suppresses blood sugar levels, it is natural to assume that insulin is involved in lowering blood sugar levels. 3) A paper on improved insulin sensitivity in KKA-y mice, 4) There are more than a dozen papers suggesting a link between corosolic acid and insulin resistance, including papers on blood sugar control using tablets containing corosolic acid. However, verification of the following seven points, which are the key points of the present invention, has never been carried out. Insulin resistance refers to the production of insulin levels higher than necessary during fasting. So, has there been any research comparing blood samples taken before and after taking corosolic acid or a substance containing it at clinical levels for about a month? This has yet to be reported. (The basis of the invention) All existing insulin resistance medications act on cell receptors, including those in fat cells. The significance of corosolic acid in alleviating and improving insulin resistance is that it is expected to be effective not only for diabetes and dementia, but also for all adult diseases and lifestyle-related diseases caused by insulin resistance. All of these ideas were conceived from the perspective of blood sugar control. Specifically, the corosolic acid of the present invention acts on insulin itself, rather than on the receptor side of fat cells or skeletal muscle cells as with conventional products (non-clinical trials conducted in 2006 by Professor MT of Suzuka University of Science and Medical Science and Professor SY of Kyoto University School of Medicine). 1. It enhances the effectiveness of insulin itself and restores its function. In the mechanism of glucose uptake, it acts on the spike side, which means it has a brushing-up effect on the insulin itself. (Clinical trials conducted in 2019 and 2020 in the Philippines, High Precision) 2. As a result of long-term intake for one year, a rapid insulin response was observed within 30 minutes after eating, resulting in additional insulin secretion, which immediately absorbed glucose and lowered blood sugar levels. (Long-term administration clinical trial conducted by S Company in 2006, Professor IY of Tokyo JK Medical University) 3. Furthermore, in the same clinical trial, rapid suppression of blood sugar rise saved additional insulin and suppressed total insulin secretion. (2006 Long-term Administration Clinical Trial by Company S, Professor IY, Tokyo JK Medical University) 4. Even in clinical trials conducted with banaba extract, corosolic acid and other ingredients with the strongest glucose-transferring activity were purified from various extracts, and a double-blind study was conducted with approximately 40 volunteers. The active compound in the banaba extract tablets was identified as corosolic acid, not tannins. (2006, Kyoto University Faculty of Medicine, Professor FM, conducted at YH General Hospital, Fushimi Ward, Kyoto City.) In those taking a dose of 3 milligrams, the effects were particularly pronounced in people with insulin resistance and hyperglycemia. The effects of the prescribed dosage and insulin resistance were suggested. 5. Furthermore, we believe that the best evidence that corosolic acid alleviates and improves insulin resistance would be to clearly compare and clearly show the differences in "fasting insulin levels after 8 hours of fasting" (the most important value that indicates insulin resistance) from blood samples taken from participants in clinical trials of corosolic acid at three time points: (1) before taking corosolic acid, (2) two weeks after taking corosolic acid, and (3) one month after taking corosolic acid. 6. Furthermore, if we assume that "improvement in insulin response" has been achieved by alleviating and improving insulin resistance, then a comparison of insulin levels at three time points, 30 minutes after ingesting the equivalent of 75 grams of sugar water, (1) before ingestion of corosolic acid, (2) two weeks after ingestion of corosolic acid, and (3) one month after ingestion of corosolic acid, would provide evidence for the claim that ingestion of corosolic acid has improved insulin response.

[0009] 2. Scientific Proof Some clinical trials will be examined from the perspective of insulin resistance. 1) Below, the insulin level before intake is on the left, and the insulin level one month after intake is on the right. 2) The important point is the rate of change in the underlined "group with high fasting insulin levels suspected of insulin resistance." The group without underline is comprised of subjects with almost no insulin resistance. 3) The average value of subjects suspected of insulin resistance was 7.59 before intake, and after one month of intake it was 5.89, and with the exception of one subject, all values ​​returned to normal, with an improvement rate of insulin resistance of 23%. 4) The following are the 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 higher Simple average: 5.97 before taking corosolic acid -> 5.11 after one month of taking it (improvement 14.4%) Below is a comparison of the boosted insulin levels 30 minutes after ingesting 75 grams of sugar water, before and after one month of corosolic acid intake. The simple average was 20.8->26.9, showing a 129% improvement in insulin response. The left is before corosolic acid intake, and the right is after 30 days of corosolic acid intake. 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 or more

[0010] Six months later, in March 2020, another clinical trial was conducted. This time, the regions and subjects were all switched to ensure accuracy and bias. All subjects were in their 70s. The clinical trial involved taking three tablets containing 1 mg of corosolic acid per day, and blood tests were conducted three times a day at an official testing facility: before intake, two weeks later, and one month later. Similar to the OGTT test, blood samples were taken three times a day: 8 hours of fasting, 30 minutes after ingesting 75 grams of sugar water, and two hours later. Analyzed parameters were 1) blood glucose level, 2) insulin level, and 3) gamma-GTP. The results showed even more significant alleviation and improvement of insulin resistance than in the August 2019 clinical trial. See below.

[0011] The main theme of this invention is "improvement of insulin resistance by corosolic acid." Improvement of insulin resistance also improves insulin sensitivity and the associated insulin response. Alleviating insulin resistance eases the burden on the pancreas and, above all, reduces the total amount of insulin secreted. In other words, even if the same amount of insulin is administered, if it is "effective," a small amount will be enough to suppress blood sugar levels, so the total amount secreted can be reduced. This has been confirmed in a total of three clinical trials (one of which involved long-term administration for one year).

[0012] More importantly, successful blood sugar control and reduced total insulin secretion also lead to "saving insulin-degrading enzymes." Residual insulin in capillaries, including those in the brain, binds to proteins, leading to the production of amyloid beta and tau protein, causing blood clots, promoting hardening of peripheral blood vessels, and producing substances that suppress immune and antibody activity. Resolving insulin resistance has a high potential for preventing a variety of diseases.

[0013] Below are the general calculation methods (formulas) and general criteria for insulin resistance, which are provided for reference. The fairest method of absolute proof that corosolic acid alleviates insulin resistance is to compare fasting insulin levels before and after taking corosolic acid for one month. The following method is used to measure insulin resistance around the world. Determining insulin resistance: The HOMA index is used. This is calculated by multiplying fasting insulin levels by blood glucose levels and then dividing the result by 405. This number is used as a measure of insulin resistance. This calculation is standard worldwide. A score of 3 or higher indicates suspicion of insulin resistance, and a score of 5 or higher indicates a diagnosis of insulin resistance.

[0014] Insulin resistance is like a rusty tap that won't shut off properly. It's constantly dripping. A typical example of this is fasting insulin levels. The most important role of insulin is to convey information to allow glucose and nutrients in the blood to enter the cells, acting like a doorman with a key to open the cell door. On the other hand, when you are fasting, there is little glucose in the blood, so not much insulin is needed. After a meal, nutrients are absorbed all at once, so rapid insulin secretion is desired to stabilize blood sugar levels. In other words, insulin resistance is a state in which more insulin is secreted than necessary, and is characterized by high levels of insulin in the blood, especially when fasting.

[0015] Furthermore, it has become increasingly believed that most adult and lifestyle-related diseases are related to aging and insulin resistance. The idea is that ingesting corosolic acid and its derivatives, as well as their extracts, can alleviate and improve the symptoms of "aging and insulin resistance," one of the main causes of adult and lifestyle-related diseases such as cancer, heart disease, diabetes, hypertension, dementia, depression, and erectile dysfunction (ED), thereby delaying the onset and progression of these frightening and troublesome diseases and achieving a cure. The present invention is limited to the alleviation and improvement of insulin resistance by taking corosolic acid and its analogues, and verification of their effectiveness for individual diseases must await further research. These are developments of the present invention, and the claims of the present invention relate only to "the alleviation and improvement of insulin resistance by corosolic acid, its analogues, and extracts containing them."

[0016] The direct involvement of corosolic acid in insulin and the alleviation of insulin resistance has been suggested and proven in a total of 10 in vivo and in vitro experiments, including a clinical trial using "banaba extract tablets" in 1999, a total of 6 human clinical trials, 2 non-clinical trials, and 2 in vitro trials. Ultimately, the results of the company's human clinical trials in the Philippines in 2019 and 2020 led to the invention. In addition, recent developments such as the complete collapse of the amyloid beta cascade hypothesis in dementia clinical trials by major pharmaceutical companies around the world, their withdrawal from dementia treatment, the medical science society's theory that insulin resistance is the cause of major diseases, and announcements by Nobel Prize-winning scientists that there are differences in cancer antibodies led the inventor to believe that taking corosolic acid could be useful for a wide range of adult and lifestyle-related diseases, which led to the invention of this invention.

[0017] 3. Recheck supporting evidence Below are in vivo and in vitro experiments from the past to the present that are sufficient to support the invention. Part 1: Evidence that corosolic acid improves insulin resistance (human clinical trial) The trial took place in Talavera, Philippines, in March 2020. The participants were 10 people in their 70s with mild cognitive impairment (MCI). They took three tablets of the ethanol hot water extract per day for one month. MMSE and OGTT blood tests were conducted three times: before intake, two weeks later, and one month later. Blood glucose and insulin levels were measured during the OGTT, with blood samples taken three times: before intake, two weeks later, and one month later. The conclusion was that banaba ethanol hot water extract tablets, in which corosolic acid was confirmed to be the active compound, restored memory function, improved insulin response, and improved insulin resistance in elderly people in their 70s with mild cognitive impairment (MCI).

[0018] Part 2: Evidence that corosolic acid improves insulin resistance (human clinical trial) In August 2019, a clinical trial was conducted in San Pascual, Talavera, Philippines, with a total of 41 participants, including 20 smartphone addicts under 60 years of age and 21 in their 70s and 80s. Three tablets of the ethanol hot water extract were administered daily for one month. Subjects underwent MMSE and (only the 21 elderly group) OGTT blood tests. Blood was collected three times: before administration, two weeks later, and one month later. Blood glucose and insulin levels were measured in the fasting state, 30 minutes after ingestion of 75 grams of sugar water, and two hours later. The results showed that corosolic acid, the active compound in the extract tablets, improved memory function, insulin response, and insulin resistance in smartphone addicts (young and adult), as well as in elderly people in their 70s and 80s with mild cognitive impairment (MCI). One month after taking corosolic acid, two OGTT blood tests showed that both insulin response and insulin resistance improved and were almost normal in the Yellow Card participants. 1) Insulin response: The increase in insulin divided by the increase in blood glucose. A higher value indicates a good insulin response. A value below 0.5 indicates low insulin secretion. 2) The HOMA index is used to assess insulin resistance. It is calculated by multiplying fasting insulin levels by blood glucose levels and then dividing the result by 405. A score of 3 or higher suggests insulin resistance, while a score of 5 or higher indicates insulin resistance.

[0019] Part 3: Evidence that corosolic acid improves insulin resistance (human clinical trial) In January 2006, Professor YS of Kyoto University pointed out the need to identify the active compounds in banaba extract prior to the actual clinical trial, and a "pre-test" was conducted in accordance with his instructions. A clinical trial to identify the active compounds in banaba extract was carried out at a private general hospital in Fushimi Ward, Kyoto City. Two types of pure and purified products were obtained: (1) a corosolic acid reagent-level preparation (more than 95% pure), and (2) lagerstroemin, an ellagitannin that has been confirmed to have the highest sugar-transfer activity among the tannins that make up 65-70% of all banaba extracts. A comparative study of the inhibition of blood glucose levels was conducted in a double-blind manner at the above-mentioned private general hospital, involving 40 volunteers. The results were clear. It was clearly confirmed that the active compound in banaba extract that suppresses blood sugar levels is corosolic acid. As a result, a CRO-planned human clinical trial was carried out, and it was documented and proven that administration of just 1 milligram of corosolic acid significantly lowered blood sugar levels. The OGTT test was performed using corosolic acid reagent (prepared with a purity of 95% or higher). In a double-blind study, 1 milligram of corosolic acid was administered to 16 men and 15 women with borderline diabetes to examine its effect on suppressing increases in blood glucose levels. The results officially confirmed that corosolic acid has a significant effect on suppressing increases in blood glucose levels. The pre-tests that led to the present invention yielded two major discoveries. First, 1. Corosolic acid demonstrated a remarkable effect in suppressing blood glucose levels in people with insulin resistance. Second, 2. Increasing the prescribed dose to just 3 milligrams in the same insulin-resistant subjects showed a highly significant effect in suppressing blood glucose levels. In other words, corosolic acid has an extremely effective improving effect on people with insulin resistance. This also served as major evidence for the present invention.

[0020] Part 4: Evidence that corosolic acid improves insulin resistance (two human clinical trials) Two clinical trials have been conducted using banaba extract. The first experiment, conducted in May 1999, used a banaba hot water extract manufactured in-house to confirm its effect of suppressing blood sugar levels in subjects suspected of having borderline type 2 diabetes. The results showed that all subjects who showed suppression of blood sugar levels had good or excessive insulin secretion (resistance), while subjects with poor insulin response or secretion showed almost no suppression of blood sugar levels. In other words, the effect of suppressing blood sugar levels depended on whether or not insulin was secreted. In August 2000, a second clinical trial was conducted using a banaba ethanol hot water extract (containing 1% or more corosolic acid, 1 mg per tablet) manufactured by the major beverage company S. The trial was conducted on people in their 20s to 70s who were concerned about their blood sugar levels. Both trials were conducted using a CRO in Tokyo under the guidance of Professor IK of Tokyo JK Medical University. The important conclusion was not the average reduction in blood glucose levels, but "which subjects it worked on and how." The group of subjects who had a certain level of insulin secretion or higher experienced a significant reduction in blood glucose levels, while the group whose blood glucose levels did not decrease were those with insulin secretion deficiency. This result was the same as the first time. This suggests that corosolic acid has a strong effect on insulin itself.

[0021] Part 5: Evidence that corosolic acid improves insulin resistance (human clinical trial) In November 2002, S Company, a major Japanese beverage manufacturer with which we had a joint development relationship, conducted a double-blind and crossover study with 18 subjects (14 men and 4 women) using tablets of banaba ethanol hot water extract containing corosolic acid, in both a single-dose and long-term intake test to examine the blood sugar level suppression effect and changes in insulin secretion. It was confirmed that the ethanol hot water extract of banaba significantly lowered postprandial blood glucose levels, and no side effects were reported with long-term administration. This confirmed the effectiveness and safety of banaba extract in suppressing blood glucose levels. The significance of this invention is that the insulin secretion response 30 minutes after a meal in long-term administration subjects improved to the same level as that of Westerners. The graph of insulin secretion 30 minutes after a meal appeared sharply peaked, like a mountain peak. This tendency is not seen in Japanese or East Asians, who are of agricultural origin. On the other hand, if insulin response improves and blood glucose levels drop at the beginning of a meal, the total amount of insulin secreted will naturally be suppressed and reduced. Corosolic acid intake improves insulin response, resulting in a rapid drop in blood glucose levels, making additional insulin secretion by the pancreas unnecessary and saving insulin secretion.

[0022] Part 6: Evidence that corosolic acid improves insulin resistance (non-clinical trials) In November 2006, Professor MT of Suzuka University of Science and Medical Science in Suzuka City, Mie Prefecture, conducted a non-clinical trial of corosolic acid. It was confirmed that administration of corosolic acid reagent (prepared with a purity of over 99%) to KKA-y mice (mice with type 2 diabetes and insulin resistance) improved insulin sensitivity and significantly lowered blood glucose levels. The conclusion was that corosolic acid reagent increased insulin sensitivity and significantly lowered blood glucose levels in KKA-y mice. The insulin response graphs showed a surprisingly significant difference.

[0023] Part 7: Evidence that corosolic acid improves insulin resistance (non-clinical trials) In March 2004, it was discovered that corosolic acid promotes GLUT4 translocation and lowers blood glucose levels. While the ability of corosolic acid to suppress increases in blood glucose levels was widely known, this was the first time that the mechanism of glucose uptake was elucidated. In conclusion, the blood glucose level rise suppression effect of corosolic acid was confirmed in KKA-y mice, and it was confirmed that this was due to the glucose uptake effect known as the GLUT4 mechanism.

[0024] Part 8: Evidence that corosolic acid improves insulin resistance (in vitro experiment) Glucose, a source of energy, is stored and regenerated by the liver. This function is controlled by blood glucose and insulin concentrations. It was confirmed that gluconeogenesis in the liver depends on the concentration of corosolic acid in the blood. The conclusion was that corosolic acid increases insulin sensitivity, and that gluconeogenesis in the liver depends on the concentration of ingested corosolic acid.

[0025] Part 9: Evidence that corosolic acid improves insulin resistance (in vitro experiment) In May 1993, Professor YK and researcher MC of the Department of Pharmaceutical Sciences, Hiroshima University School of Medicine, discovered that banaba (Lagerstroemia indicum), widely known locally as plant insulin, possessed glucose transport activity among many Philippine medicinal herbs, and identified the active compound as corosolic acid. They also confirmed that corosolic acid transported glucose via a 12-pass transmembrane glucose uptake mechanism. Their findings suggest that banaba has long been used in Asian countries as an alternative insulin and as a medicinal herb for diabetes prevention. Banaba extract is believed to either replace insulin or reduce insulin secretion, thereby lowering blood sugar levels. Traditionally, the insulin-like properties of banaba corosolic acid are evidence of human knowledge.

[0026] Many people wish to continue living a healthy and happy life even as they age. The idea behind this invention is to protect "human healthy lifespan," which is a limited life span, from "various diseases caused by insulin resistance" that come with aging and other factors, using corosolic acid, its related compounds, and extracts containing them. There have been no reports to date of methods that attempt to alleviate or improve insulin resistance from the insulin side. The main purpose of this invention is to: (1) improve the effectiveness of insulin itself, (2) improve the insulin sensitivity of cell receptors, (3) suppress the rise in blood sugar levels, (4) control gluconeogenesis in the liver, (5) reduce residual insulin that is not broken down in the brain and other areas, (6) reduce the total amount of insulin secreted, (7) reduce the burden on insulin secretion on the pancreas, (8) sharpen insulin itself like a saw, (9) enhance the function of antibodies, immunity, and T cells, and (10) improve insulin resistance in order to extend healthy lifespan.

[0027] Recent research into adult diseases has suggested that reducing the risk of lifestyle-related diseases, which increase with age, depends on addressing insulin resistance. Meanwhile, various drugs have been developed to improve insulin resistance related to diabetes. Thiazolidinedione drugs (glitazones), which act on fat cells to reduce substances secreted by fat cells that cause insulin resistance, and the newer drug in the same series, pioglitazone, are believed to increase the body's sensitivity to insulin, resulting in improved insulin function and lower blood sugar levels. They are primarily used for type 2 diabetes (non-insulin-dependent diabetes), and are believed to increase insulin sensitivity in the liver, muscles, and adipose tissue, suppressing sugar production in the liver and allowing sugar in the blood to be absorbed into muscles (extrapancreatic action).

[0028] However, no compound has yet been reported that (1) improves the effectiveness of insulin itself or (2) sharpens the effectiveness of insulin, as the corosolic acid of this invention does. All previous drugs act on the cellular side, and this is the first in the world to resolve insulin resistance from the insulin side. As there are no similar descriptions, this is a groundbreaking invention that is the first of its kind in the world.

[0029] Regarding the target disease, it is said that cancer (malignant neoplasms) occurs more than 2,000 times per day in any human being. Despite this, cancer does not develop because the human body's natural immune system (antibodies, killer T cells, etc.) destroys cancer cells and prevents them from multiplying. One's own immune system and antibody strength are important for preventing the onset of cancer and suppressing its progression. The key to weakening or improving immunity and antibody power is "what is the key?" This key is aging and the degree of insulin resistance. In June 2021, a Japanese Nobel Prize winner announced that there are individual differences in the amount and strength of antibodies that suppress cancer. In other words, this suggests that the reason antibody power weakens and cancer risk increases with age is due to aging and insulin resistance. This statement provided a major clue for this invention. This is because it is thought that the condition in which cancer cell proliferation cannot be stopped by administering or ingesting corosolic acid can be stopped when antibodies to cancer (defective production of lymphocytes, killer T cells, B cells, etc. and reduced antibody strength) occur due to a high frequency of microsatellite instability (MSI-High) state caused by aging and insulin resistance. Needless to say, future experiments on various diseases other than diabetes, dementia, and depression will be necessary. For example, cancer, high blood pressure, cardiovascular disease, erectile dysfunction, etc. If the effectiveness and technology of this patent become widely known, there is no doubt that the established, inexpensive mass production method will make a great contribution to society.

[0030] Blood flow in peripheral blood vessels and capillaries is particularly important in heart disease (circulatory disease), diabetes, and hypertension. Blood clots and hyperglycemia hinder this, so controlling blood flow is crucial. In other words, the function of insulin is crucial for smooth metabolic circulation in peripheral blood vessels and capillaries, and reducing insulin resistance in particular is an extremely effective method for preventing and improving cardiovascular disease, diabetes, and hypertension.

[0031] Dementia and depression are thought to be caused by amyloid beta, produced by the binding of insulin and proteins that remain in the cerebral blood vessels without being broken down. Furthermore, toxins generated by the aggregation of tau proteins destroy the estimated 100 billion neurons in the cerebral cortex, leading to cerebral atrophy. The brains of patients with dementia shrink due to the destruction of most neurons. In recent years, the prevailing theory has been that aging, diabetes, and especially insulin resistance play a major role in the cause of dementia. Previously, the amyloid beta cascade hypothesis (the idea that brain waste / amyloid beta accumulates and releases toxins that destroy brain neurons) was widely accepted. However, drug development based on amyloid beta has failed, and in recent years, the hypothesis itself has been deemed flawed. However, this view does not deny the relationship between dementia and amyloid beta; it merely raises questions about the drug development process. An emerging hypothesis is that dementia is a third cause of aging and diabetes. Most elderly people with diabetes, pre-diabetes, or pre-diabetes have insulin resistance. The relationship between diabetes and dementia has already been pointed out by many scholars and is now a commonly held theory. Based on scientific verification, the inventor conducted two clinical trials on dementia using tablets of an ethanol-hot water extract of banaba (Lagerstroemia speciosa, Japanese name: Oobana Crape Myrtle), which contains corosolic acid. The tablets used in the clinical trials contained 1 milligram of corosolic acid per tablet. Participants were asked to take three tablets daily for one month. The first trial was conducted in August 2019, and the second in March 2020. The first trial involved 20 smartphone-addicted young adults and 22 elderly participants, while the second trial involved only 10 elderly participants in their 70s. The results of the two clinical trials were nearly identical. Numerically, orientation (memory and cognitive ability) as measured by the MMSE score improved by approximately 40%, and blood insulin resistance improved by approximately 40%. 90% of participants regained their appetite, motivation, smiles, and calmness, and were able to overcome their depression. This also provided relief to their families. The clinical trials conducted in this invention were based on the MMSE test and the OGTT blood sampling test. The clinical trials were conducted three times: (1) before ingestion of corosolic acid, (2) two weeks after ingestion of corosolic acid, and (3) one month after ingestion of corosolic acid. The OGTT blood sampling test involved blood samples being collected three times: (1) during fasting, (2) 30 minutes after ingestion of 75 grams of sugar water, and (3) two hours after ingestion, and the samples were analyzed. The blood samples were analyzed for three items: blood glucose, insulin, and gamma-GTP. These were collected three times a day, a total of nine times, and analyzed. The blood samples were collected by Hi-Precision, a global diagnostics company, in Cabanatuan City, Nueva Ecija, Philippines. The results were similar between the first and second doses. Medium- to long-term intake of corosolic acid tablets improved scores on the MMSE test (which can show orientation, memory, and cognitive ability in concrete numerical values) by approximately 40%, and the OGTT (glucose tolerance test), which shows physical evidence, showed a more sensitive and responsive insulin response. Even more notable was the approximately 40% improvement in insulin resistance. Insulin resistance refers to a condition in which too much insulin is produced even when fasting, and insulin continues to be produced even after blood sugar levels drop after eating. This is thought to be due to a decrease in the sensitivity of insulin receptors, a decrease in the function of insulin itself, and a slowdown in the pancreas' blood sugar response. It's like a water faucet that doesn't shut off properly and is constantly dripping. Insulin resistance is the cause of the production of amyloid beta and tau protein, which are substances that cause dementia. Excess unbroken insulin remaining in the capillaries in the brain binds to proteins, causing the accumulation of tau protein, also known as brain garbage, which then accumulates as tangled string-like masses called senile plaques, which release toxins and destroy brain nerves, ultimately causing the cerebral atrophy and the onset of dementia. Although there are many other factors that are thought to cause insulin resistance to dementia, there is no doubt that insulin resistance is a major factor in the onset of dementia. If this is the case, improving insulin resistance is the most important factor in preventing dementia, but no clinical trials have been published to prove this other than this invention. Conventional insulin resistance drugs act on cellular receptors, which is completely different from the insulin function normalization of the present invention. Furthermore, no formal clinical trial results have yet been reported showing that many conventional diabetes medications are effective in preventing or curing dementia. Here again, the novelty and inventive step of the present invention are scientifically proven.

[0032] Erectile dysfunction (ED) can be broadly divided into three types: ED where the man can sometimes get an erection and sometimes can't, ED where the man is psychologically unable to get an erection, ED where the man is unable to get an erection due to some kind of illness, and ED where the two above characteristics are combined. Specifically, these include nerve damage such as spinal cord injury and cerebrovascular disease, vascular damage due to diabetes or trauma, phimosis, and urethral malformations (penile abnormalities), but cerebrovascular disease is particularly prominent as a physical disability. This is caused by the inhibition of blood flow in the brain due to insulin resistance, and there have been reported cases in which this condition has improved with the administration of corosolic acid. A physiological issue common to all of these diseases is the progression of insulin resistance. Other than corosolic acid, there have been no reports or descriptions of anything that can improve this insulin resistance from within insulin itself.

[0033] Corosolic acid itself is an ultra-fine active compound, present at a concentration of 1.36 million trillion particles per milligram. Corosolic acid acts on insulin protein spikes, sharpening insulin like a saw, improving its sensitivity and sharpness, thereby conserving insulin while alleviating and improving insulin resistance. This invention is the world's first to demonstrate a solution to the problem of insulin resistance stemming from the insulin itself. All previous insulin sensitizers act on the receptor side, that is, on the cellular receptors, including those in fat cells and muscle cells.

[0034] The corosolic acid, related compounds, and extracts containing them of this invention can be mass-produced in affordable, abundant quantities suitable for anyone to use. As of 2021, the cost to patients and consumers is 5,000 to 10,000 times lower than new dementia drugs currently under development. This alone makes it a groundbreaking invention. Technology for industrializing corosolic acid has already been established, including the development of plant callus containing hundreds of times more corosolic acid at the Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University and the Tropical Plant Laboratory, Tottori University, a large-scale extraction plant in China, and simple purification using giant columns in Korea. The purpose of the development is to use corosolic acid, a type of terpene found in plants, and its related compounds to increase the number of antibodies themselves, improve their function, suppress cancer cells (malignant neoplasms), control blood sugar levels and blood clots that impair circulatory function, prevent heart disease, and help prevent and alleviate the onset of dementia in elderly and young people suspected of having amyloid beta and tau proteins in the brain, as well as dementia or mild cognitive impairment.

[0035] Corosolic acid and its analogues include many related compounds, including trimentic acid, oleanolic acid, ursolic acid, and maslinic acid (see the end of this book). It is highly likely that some of these terpene analogues have similar effects to corosolic acid. Corosolic acid and its analogues are found in many plants, including banaba, loquat, persimmon, mulberry, and guava, and have been widely used by the general public as folk remedies since ancient times, without the risk of side effects. [Prior art documents] [Patent documents]

[0036] [Patent Document 1] Patent Publication No. 2003-219853, [Patent Document 2] Patent Publication No. 2002-205949, [Patent Document 3] Patent Publication No. 2001-039880, [Patent Document 4] Patent Publication No. 2019-011305, [Patent Document 5] Patent Publication No. 2018-139530, [Patent Document 6] Patent Publication No. 2018-137712, etc. [Non-patent literature]

[0037] [Non-Patent Document 1] Antidiabetic effects of corosolic acid in KK-Ay diabetic mice. [Non-patent document 2] Research Achievements - Academic Journals, [Non-patent document 3] Ellagitannins from Lagerstroemia speciosa as activators of glucose transport in fat cells. [Non-patent document 4] J-GLOBAL Science and Technology Information Site for Patent Researchers and Others Total Abstracts 179 Summary of the Invention [Problem to be solved by the invention]

[0038] The present invention relates to a composition that restores normal insulin function and response in elderly or mature individuals who secrete insulin or who have excessive insulin secretion and are suspected of having insulin resistance, thereby enabling the slowing of the progression of, and the alleviation or prevention of, various adult diseases, lifestyle-related diseases, dementia, etc. It also alleviates and relieves anxiety in young people and adults who suffer from mental distress such as depression and erectile dysfunction, contributing to the recovery of health. For example, plant-derived corosolic acid is a novel compound that has been discovered that restores the original function of insulin, addressing the slowing of insulin response and insulin resistance due to aging, which are believed to be the main causes of dementia. As a result, it is useful for delaying and preventing the progression of dementia and Alzheimer's disease, and also restores memory function and motivation. At the same time, the research also explores various ideas for utilizing these discoveries to develop methods of ingestion, home use devices, inexpensive methods for mass production of corosolic acid and its related compounds and extracts containing them, simple methods for diagnosing dementia as a biomarker, and the development of genetically modified plants that allow daily intake of corosolic acid and its related compounds for dementia prevention. The significance of corosolic acid in alleviating and improving dementia is one example of its insulin resistance-inducing effect.

[0039] 4. Mass-produce corosolic acid cheaply 1. Corosolic acid is a type of triterpene terpene that is composed of six isoprenes and has the molecular formula C30H48. More than 100 related compounds have been reported (see end of book). It is a fat-soluble compound that is widely found in plants. 2. Extraction methods include water extraction, hot water extraction, ethanol hot water extraction, autoclave extraction, etc. It is economically preferable to extract the dried raw material after several hot water extractions with ethanol hot water. 3. Compositions containing corosolic acid used in clinical trials include corosolic acid reagent (purity of 99.5% or more), ethanol hot water extracts containing 1% to 18% corosolic acid, hot water extracts containing 1% or less corosolic acid, and tablets, capsules, white extracts, and clear aqueous solutions made from these extracts with excipients or oils. 4. Regarding the findings and expected scope of future clinical trials, the composition used in the two dementia clinical trials (details below) was a tablet containing 1 milligram of corosolic acid. It was made from a hot water ethanol extract of banaba (Lagerstroemia speciosa, Japanese name: Oobana Crape Myrtle). More than 120 similar plants have been reported, including guava, loquat, mulberry, persimmon, and quince (see end of document). Because the experiments were conducted using banaba, its US FDA certification, numerous commercially available products, and special health food status in Korea make it a preferable plant for extraction from a safety perspective. 5. Overview of the prescribed composition containing corosolic acid and the expected range of effects The raw material, Banaba, was collected in Zambales, Philippines. The extract was manufactured in Zhejiang Province, China, and the tablets were manufactured in Chiba Prefecture, Japan. The ingredients were an ethanol hot water extract and excipients (described below), each containing 1 milligram of corosolic acid. The prescribed daily dosage was three tablets. The total amount of corosolic acid was 3 milligrams. No side effects or changes in physical condition were found at the time of prescription or in interviews after the study. Based on this, when corosolic acid and its related compounds are prescribed or taken for the purpose of alleviating or preventing dementia, the recommended daily dose is 0.15 to 60 milligrams, with 3 to 10 milligrams being particularly preferable. 6. Regarding pharmacological safety, clinical trials conducted in Canada have confirmed the safety of 10 mg of corosolic acid softgel tablets, an ethanol hot water extract, daily, and these results have been published. Therefore, a maximum daily dose of 200 mg of corosolic acid is considered safe. Furthermore, the safety of 20 times the dose has also been confirmed in experiments on mice and autopsy experiments on beagles and other animals. The anti-dementia effects, alleviation and prevention of dementia that can be obtained from this are expected to include the recovery of orientation (memory and cognitive ability), rapid insulin response, and improvement of insulin resistance. 7. Dosage and Method of Administration of the Composition: The preferred dosage of corosolic acid and its analogs is 1 to 20 milligrams per day. This can be administered in solid forms (tablets, gummies, capsules, softgels, candies, lollipops, etc.), liquid forms (jelly, drinks, lactic acid bacteria drinks, carbonated drinks, clear extracts), or gas forms (sprays using clear extracts). Powder forms (white extracts, such as udon noodles, bread, and confectioneries) are also possible, but since many elderly people suffer from dementia or mild cognitive impairment, swallowing disorders must be taken into consideration. Small tablets, honey-like gels, or 60 to 100 ml of lactic acid bacteria drinks are preferred. 8. The preferred timing for intake is before meals. However, it can also be taken between or after meals. The key is that it is painless and inconvenient, and can be continued daily. The ultimate goal is to restore smiles, motivation, and appetite to those suspected of dementia. This will lead to the happiness of their families and make a significant contribution to solving social problems. The biggest challenge facing dementia is the lack of new dementia drugs, preventative medications, or diagnostic biomarkers. This invention provides a solution (delay and prevention) to the rapidly increasing progression of dementia and Alzheimer's disease with medical and scientific evidence. 9. Insulin secretion deficiency, caused by genetic factors and lifestyle habits, is particularly prevalent in Japanese and East Asians. However, the purpose of this invention is to restore insulin function and response to normal in elderly and mature people who have developed insulin resistance due to excessive fasting insulin secretion caused by aging, thereby slowing the progression of dementia and enabling its alleviation or prevention, thereby maintaining or restoring the health and happiness of these individuals and their families. At the same time, the invention will be applied to the development of mixing solvents and devices that can be ingested via nasal suction to prevent swallowing disorders and accidental ingestion, and to provide safe, inexpensive, and large-scale delivery to protect the elderly, mature people, and their families from the rapidly increasing incidence of dementia and Alzheimer's disease. [Means for solving the problem]

[0040] Preferred methods include distribution as a daily food, prescription at hospitals, over-the-counter sales at drugstores, and online shopping via social media. If corosolic acid could be easily ingested as a daily food, it could potentially be a dream new drug or daily food effective against a wide range of common elderly conditions, including adult diseases, lifestyle-related diseases, and dementia. Above all, corosolic acid, its related compounds, and extracts containing them are inexpensive to produce and, unlike synthetic drugs, are safe and free of side effects. Adding it to daily foods such as tea, candy, honey, and yogurt is also a desirable solution to specific problems. Corosolic acid and its derivatives are safe plant-derived compounds with a long history of traditional dietary use and no reported side effects. There is no risk of accidents or side effects even when taken in large amounts or as addictive properties. The diseases that cause deaths in modern people are adult diseases, such as cancer, heart disease, diabetes, high blood pressure, and pneumonia, which increase in risk with age, or lifestyle-related diseases, which are caused by high blood concentrations and blood clots due to "an easily digestible, nutritious diet" and "lack of exercise," which have never been seen before in human history. The next most important disease is dementia. Proposing specific solutions to these problems, along with evidence, is an urgent issue and the subject of this invention. As a third means of solving the problem, corosolic acid has already been successfully nano-sized, made transparent, and made water-soluble. It can also be made into a liquid that is colorless, transparent, tasteless, and odorless, and dissolves in anything, just like water, making its range of uses limitless. [Effects of the Invention]

[0041] The effects achieved by the invention are as follows: 1. Creation of a new industry. Corosolic acid mass production facilities. Callus factories, processing facilities, extraction facilities, simple purification columns, etc. 2. Increase in working elderly people. Resolving problems for individuals, their families, and society by slowing and preventing the progression of adult diseases, dementia, and Alzheimer's disease. 3. Resolving the issue of social insurance premium burden. Maintaining the health of the elderly and resolving the problem of a shortage of caregivers. 4. Proposing a simple and affordable method of preventing dementia in everyday life. Just take three small tablets. 5. Creation of a new market. Countermeasures against lifestyle-related diseases, creation of products to prevent and cure dementia, and creation of new industries and jobs. 6. Promote the industry, including exporting dementia prevention and treatment products, equipment, and know-how originating in Japan. 7. Contribute to regular diagnosis and early detection of adult diseases, dementia, and Alzheimer's disease progression and drug efficacy. 8. Add simple medical checkups, dementia diagnosis, and smartphone usage items to the list, and collaborate with VR technology. 9. Improve biomarker technology for the early detection of adult diseases and dementia during general health checkups using blood samples. 10. Add insulin response values ​​and insulin resistance values ​​as biomarkers to response-based adult diseases and dementia items during blood samples to serve as a reference for early detection. 11. Promote the entry of IoT and AI technologies into the dementia market, and create a new high-tech dementia industry. [Brief explanation of the drawings]

[0042] [Figure 1]This is the chemical formula for corosolic acid. [Figure 2] Comparison of fasting insulin levels before and after one month of corosolic acid intake [Figure 3] Comparison of insulin levels 30 minutes after eating before and after one month of corosolic acid intake [Figure 4] A comparative study of insulin resistance after one month of second corosolic acid intake

[0043] Comparison of fasting insulin levels before and after one month of corosolic acid intake DETAILED DESCRIPTION OF THE INVENTION

[0044] The first step in implementing this invention is to make corosolic acid widely known to the public. This will lead to the emergence of new developers and partners, accelerating commercialization. Spreading the word means gaining exposure on social media and in the media, and it is important to ensure that it generates the news it deserves. Calculating the relationship between corosolic acid and insulin through computer simulations would also be a cost-effective approach. The inventor has already crystallized corosolic acid and determined its 3D structure. Furthermore, the 3D structure of insulin has been widely published, making computer simulations (digital simulation experiments) possible. The second mode for carrying out the present invention is to utilize corosolic acid and its analogues in all aspects of the daily lives of people with adult diseases, lifestyle-related diseases, dementia, and suspected dementia (MCI), and to develop products such as medicines, foods, beverages, environmental (spray), and IoT products based on resolving insulin resistance.

[0045] One mode of carrying out the present invention is to solve the problem of postprandial insulin bolus in Japanese people. The postprandial insulin bolus secretion patterns of Asians and Westerners are different. This is thought to be due to the historical difference in diet between agricultural and hunter-gathering peoples. Corosolic acid and its analogs of the present invention are more preferably used in elderly people from ethnic groups whose staple diet is grains. Japanese and other Asians are agricultural peoples (since the Paleolithic period), and their DNA begins to secrete insulin slowly. However, they continue to secrete insulin even when blood sugar levels drop. This delayed insulin response is one of the causes of insulin resistance. Taking corosolic acid before meals or as part of a daily diet can solve the above problems and is a concrete example of how this invention can be implemented.

[0046] This is one explanation of insulin, the main target of this invention. In the human body, there is no other hormone other than insulin that takes up sugar into cells, so insulin secretion is extremely important. Therefore, it is the most important and unique hormone for maintaining human life.

[0047] One of the aims of this invention is to understand the concept of dementia and Alzheimer's disease, which are rapidly increasing among the elderly as adult diseases. Let's take insulin resistance as an example. 1) Dementia and Alzheimer's disease are characterized by brain atrophy, but this is a result that can only be confirmed through imaging. 2) Brain atrophy is thought to be caused by neurodegenerative disorders (destruction of the central nervous system). 3) Most of the brain is made up of approximately 1 trillion glial cells and 100 billion nerve cells, making normal metabolism important. 4) The brain receives its only nutrition from glucose (sugar), not protein or fat, and insulin is crucial in the brain. 5) Brain cells require more energy than other cells (comparable to liver cells). 6) For these reasons, glucose metabolism is essential for healthy brain function. 7) The brain has a barrier known as the blood-brain barrier, which has been thought to make it difficult for drugs to reach it. However, it has been confirmed that insulin, a large-molecular-weight hormone, can pass through this barrier. 8) Insulin is likely the key player in brain metabolism. 9) Weakened insulin function can easily lead to diabetes, even in the brain. This is why dementia and Alzheimer's disease have come to be called the third form of diabetes. 10) If insulin function in the brain can be normalized or brought closer to normal, dementia and Alzheimer's disease may be alleviated and prevented.

[0048] As a second example, diabetes is a condition where high blood sugar and high blood viscosity cause the destruction of capillaries and the resulting toxicity. In recent years, there has been a rapid increase in diabetes among the elderly due to longevity (aging) and lifestyle habits. The main cause is thought to be insulin resistance. Insulin resistance refers to a state in which insulin function is reduced, or it is thought to be a decrease in the insulin sensitivity of cells that absorb nutrients.

[0049] Because insulin is ineffective, blood sugar levels do not decrease, leading to excessive insulin secretion. Insulin response also becomes insensitive, and the highly viscous blood in the brain cannot flow smoothly through the tiny brain capillaries, preventing nutrients from reaching brain cells. Furthermore, residual insulin in the weakened brain blood vessels binds to proteins (amyloid beta precursor proteins) and produces the substance that causes amyloid beta peptide. Amyloid beta → phosphorylation of tau protein → production of senile plaques, resulting in dementia and Alzheimer's disease. This is the general pharmacological mechanism behind the onset of dementia.

[0050] To summarize the thesis of the invention, corosolic acid can alleviate and improve insulin resistance, which is a major cause of adult diseases, cancer, diabetes, hypertension, diabetes, erectile dysfunction, and other diseases that affect the elderly. (1) To alleviate and prevent dementia and Alzheimer's disease, (2) it is important to normalize blood glucose metabolism in the brain, (3) restore insulin function to normal, and (4) it is not enough to simply increase insulin secretion levels and lower blood glucose levels. (5) Timing is important; that is, insulin must work normally when needed and quickly lower insulin levels in the blood once its role has been completed (normalizing total insulin secretion and timing). It is important to discover a composition that makes this possible, and at the same time, there must be numerical and physicochemical proof that it alleviates and prevents dementia and Alzheimer's disease.

[0051] At the same time, it must have a noticeable effect on cognitive function (memory, language, judgment, calculation, executive function, etc.) in elderly adults and those suspected of having dementia, Alzheimer's disease, or mild cognitive impairment (MCI). Side effects and stress would be counterproductive, and these must be verified. Health promotion is the ultimate goal. Furthermore, it is desirable for the ingested composition to be inexpensive, mass-produced, and ingestible in a way that is relevant to daily life. A single prescription costing tens, hundreds, or even millions of yen would be unrealistic and impossible to prescribe to the masses. For the hundreds of millions of people who will suffer from depression, dementia, or mild cognitive impairment in the future, it would have to cost less than a tenth of a monthly salary. Specifically, a single prescription should cost a few thousand yen, preferably less than a few hundred yen.

[0052] The following is an example of the process leading up to the onset of dementia and Alzheimer's disease, and the order of alleviation and prevention achieved by this invention. This demonstrates the significance of corosolic acid in solving the problem of insulin resistance. [Dementia and Alzheimer's disease] ← [destruction of brain neurons] ← [poor glucose metabolism in the brain] ← [destruction and toxicity of brain capillaries] ← [hyperglycemia in the brain, high viscosity of blood, and residual insulin in brain vessels] ← [insulin resistance]. Corosolic acid intake = [improvement of insulin resistance] → [improvement of brain metabolism] → [reduction of residual insulin] → [resulting in amyloid beta → phosphorylation of tau protein → reduction in senile plaque production] → [alleviation and prevention of neurodegenerative diseases (central nervous system)] → [alleviation and prevention of dementia and Alzheimer's disease].

[0053] The present invention realizes the above steps with supporting evidence. The data proving the claims of the invention are attached below. The claims are: (1) Intake of corosolic acid alleviates and prevents dementia and mild cognitive impairment (MCI), (2) this is due to improvement of brain metabolism, (3) this physicochemical evidence has been substantiated by clinical trials, (4) improvement of brain metabolism is important for improving insulin response and resistance, (5) this has resulted in alleviation and prevention of dementia and mild cognitive impairment (MCI), (6) this evidence has been substantiated by the MMSE test, which is widely recognized worldwide, and (7) therefore, it has been proven that intake of corosolic acid alleviates and prevents dementia and mild cognitive impairment (MCI).

[0054] The target population for whom this invention is thought to be effective can be roughly defined (imaged): 1. Elderly people or adults who have insulin secretion but suspect insulin response and resistance are: 2. Fasting blood insulin levels are within the range of 1-12 micro / mL (insulin is being secreted), and the HOMA-IR value, which indicates insulin resistance, is considered normal (≤1.6-2.6 points or more, indicating insulin resistance). 3. Or, if your INSLIN-OGENIC, which is an indicator of insulin response or secretion insufficiency, is 0.4 or less (problems with insulin response), and at the same time your MMSE test score is 26 points or less (suspected dementia / MCI mild cognitive impairment), 4. Elderly people aged 65 and over and adults aged 20 to 65. In other words, people with insulin resistance.

[0055] The present invention aims to improve memory impairment, depression, loss of appetite, loss of motivation, forgetfulness, etc. in people suspected of dementia, an adult disease or lifestyle-related disease, by administering a certain amount of corosolic acid or its analogous compounds, thereby relieving anxiety and pain for the patient and their family and providing a sense of security and relaxation. The general mechanism of action is the discovery of a method and composition that alleviates insulin resistance and enables the alleviation and prevention of brain capillary damage and neurofibrillary tangles and destruction, which are believed to be major causes of dementia.

[0056] The compositions of the present invention include extracts containing corosolic acid compounds extracted from various plants, extracts and reagents obtained by plant culture, related compounds and semi-synthesized compounds of related compounds, compounds modified with sugar chains, and compounds obtained by cleaving the carboxylic acid moiety. All of the above are presumed to involve or partially involve corosolic acid. Furthermore, corosolic acid at a purity of 99.5% or higher as a reagent or compositions containing it may restore the original function of insulin in response to the slowed insulin response and insulin resistance caused by aging and lifestyle habits, which are believed to be the main causes of dementia. They may also function as a ligand or agonist with insulin in the brain or in vivo within the human signaling network, effectively delaying and preventing the progression of dementia and Alzheimer's disease. Further research is needed to determine the mechanism of action in the brain. Furthermore, the development of ingestion methods, volatile substances, mass production methods, simple methods and biomarkers for dementia diagnosis, genetically modified and genome-edited plants, as well as feed and meat, using this invention will lead to the creation and development of new dementia prevention products, industries, and markets.

[0057] 5. Effects of long-term intake of corosolic acid (1) After one month of corosolic acid supplementation, cognitive function (memory, language, judgment, calculation, executive function, etc.) of elderly people aged 80 years and older improved significantly by 9.8 points. (2) After one month of corosolic acid supplementation, scores of elderly people in their 70s also improved by 5.8 points. (3) Medium- to long-term (2 weeks to 1 month) corosolic acid supplementation restored cognitive function in most subjects. Smiles, appetite, calmness, and motivation were significantly restored. (4) The subjects were healthy elderly people in their 70s and 80s. (5) All subjects had mild cognitive impairment (MCI) before the study began. (6) A total of 22 elderly subjects ultimately participated in the study. (7) Cognitive function improved significantly, especially in elderly people aged 80 years and older. (8) A total of 10 subjects participated in the clinical trial, including 8 subjects and 2 subjects with high precision. (9) Informed consent (participation and disclosure consent forms) was obtained from all participants and their guardians. (10) Participants experienced mild depression, but this improved after one month, and their smiles and appetites returned. (11) Interviews were conducted after one month of corosolic acid supplementation, and no side effects were reported. (12) After one month of corosolic acid supplementation, cognitive function (memory, language ability, judgment, calculation, executive function, etc.) in elderly people aged 80 and over improved significantly by 9.8 points. (13) After one month of corosolic acid supplementation, scores in elderly people in their 70s also improved by 5.8 points. (14) Long-term corosolic acid supplementation (2 weeks to 1 month) improved cognitive function in most subjects. (15) The subjects selected were physically healthy elderly people in their 70s and 80s. (16) All subjects had mild cognitive impairment (MCI) before the study began. (17) A total of 22 elderly people ultimately participated in the study. (18) Cognitive function improved significantly, especially in elderly people aged 80 and over. (19) Eight of these participants and two others with high prescribing skills participated in the clinical trial, for a total of 10 participants. (20) Informed consent (participation and disclosure consent form) was obtained from all participants and their guardians. (21) Participants experienced mild depression, but this was alleviated after one month, and their smiles and appetites returned. (22) Interviews were conducted after one month of corosolic acid intake, and no side effects were reported.(23) Adults, mainly between 30 and 50 years old, who were overly dependent on smartphones and suspected of suffering from brain fatigue were also given corosolic acid for two weeks, and MMSE tests were performed before and after the intake. [Industrial Applicability]

[0058] The present invention is considered to be industrially applicable to the following industries, business sectors, and products as a creation of a new industry. 1. Mass production of corosolic acid: Plant and mushroom cultivation industry, such as wood ear mushroom and king oyster mushroom 2. Biomarkers: testing equipment manufacturers, reagent companies, Japanese Red Cross, hospitals 3. Dementia prevention: Pharmaceutical companies, health food companies, tea companies, mail-order companies, nursing homes 4. In-car volatile cassettes: disposable air fresheners, jet printer equipment industry 5. Stationary sprayers: Home appliance manufacturers, medical device manufacturers, telecommunications companies, mobile phone companies 6. 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, restaurants

Claims

1. Claim 1 of the present invention is a corosolic acid-containing composition which is based on the basic principle of activating insulin function using a corosolic acid reagent with a purity of 95% or more, or an extract containing corosolic acid at a concentration of 0.01% or more, and is used for the purposes of improving and alleviating insulin resistance, suppressing and curing chronic inflammation, normalizing the immune system, suppressing blood sugar rise and activating metabolism such as anti-diabetes, improving the effectiveness of various drugs, and using insulin as a linker to transport insulin to target cells such as solid cancer cells, or using insulin and corosolic acid as an alternative to antibodies in an antibody-drug conjugate drug development method.

2. A corosolic acid-containing composition for use in medicines and foods, containing 0.01% to 99.9% corosolic acid, for the purpose of activating insulin function and alleviating insulin resistance, as a dependent claim of claim 1.

3. As a dependent claim of claim 1, a corosolic acid-containing composition is used for the purpose of preventing the onset of dementia, recovering or improving cognitive function, and alleviating and curing smartphone dementia in young children, mild cognitive impairment due to information overload, and forgetfulness syndrome in adults.

4. As a dependent claim of claim 1, a corosolic acid-containing composition containing 0.01% to 99.9% corosolic acid is used to reduce the total amount of insulin secreted, thereby suppressing amyloid beta production, and at the same time passing through the blood-brain barrier to improve brain metabolism, alleviate chronic inflammation in the temporofrontal lobe, and improve cognitive function.

5. As a dependent claim of claim 1, a corosolic acid-containing composition is provided which is used to alleviate and cure various diseases and maintain health by taking 0.01% to 99.9% corosolic acid composition, or its related compounds, or extracts containing them, at a daily dose of 0.001 milligrams to 1,000 milligrams per 50 kilograms of body weight, thereby improving insulin sensitivity.

6. As a dependent claim of claim 1, a compound synthesized for the purpose of treating dementia or chronic inflammation by cleaving the molecular structure of corosolic acid around the carboxyl group (COOH group) of corosolic acid, or a compound decorated with sugar chains, etc., or a synthetic composition based on corosolic acid obtained by genetic manipulation for the same purpose as above.

7. As a dependent claim of claim 1, a corosolic acid-containing composition produced by extraction, isolation and purification using plant callus species developed for the purpose of industrialization that contains 2 to 1,000 times the normal amount of corosolic acid, or callus species developed from colored banana leaves other than green, colored loquat leaves, colored guava leaves, colored persimmon leaves, colored mulberry leaves, and colored shiso.

8. As a dependent claim of claim 1, a corosolic acid-containing composition prescribed for preventing, alleviating, or curing dementia such as Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal lobar degeneration, which are alleviated by improving cerebral metabolism by utilizing the insulin linker function of corosolic acid, or for use in enhancing the effects of prescribed drugs.

9. As a dependent claim of claim 1, there is provided a corosolic acid-containing composition for oral health foods, daily foods, tablets, powders, liquids, sprays, foods, beverages, and liquids for nasal inhalation or as a general food ingredient for preventing dementia, alleviating mild dementia, recovering from mild cognitive impairment, preventing chronic inflammation, preventing cancer, various adult diseases, and preventing lifestyle-related diseases.

10. As a dependent claim of claim 1, there is provided a corosolic acid-containing composition in the form of a liquid to be used with a nebulizer or a powder to be dissolved and used, which is combined with a transparent aqueous solution and a fragrance to moisten the pores by humidifying the airways to avoid the risk of swallowing disorders and make it easier for elderly people to ingest foods and medicines for preventing and alleviating dementia, and which is used to prevent colds and improve cognitive function.

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