Method and composition for increasing or maintaining ketone body levels and improving metabolic functions

Abstract

A method and composition for increasing or maintaining ketone body levels and improving metabolic functions, and use thereof. The method comprises administering to a subject in need thereof a composition comprising an effective amount of 3-acetoxybutyric acid or a pharmaceutically acceptable salt thereof, an ester thereof, or a derivative thereof. The composition further comprises an effective amount of 3-hydroxybutyric acid or a pharmaceutically acceptable salt thereof, an ester thereof, or a derivative thereof. Also provided is use of the composition in the preparation of a dietary supplement, food, beverage, or animal feed.

Description

Methods and compositions for increasing or maintaining ketone body levels, improving metabolic function TECHNICAL FIELD

[0001] The present application belongs to the technical field of nutritional products or dietary supplements, and particularly relates to a method and composition for increasing or maintaining ketone body levels, improving metabolic function, and application thereof. BACKGROUND

[0002] Currently, there is a growing demand for dietary or nutritional supplements aimed at improving the health status of individuals and reducing the risk of disease; athletes also use dietary or nutritional supplements to improve strength and performance.

[0003] Generally, the human body relies on glucose to obtain energy, but when the supply of glucose is insufficient to meet the body's energy needs, such as during long-term exercise, hunger or lack of dietary carbohydrates, the body will turn to consuming fat as fuel. Since the brain and central nervous system cannot directly use fat as energy, the liver produces ketone bodies from fatty acids as an alternative fuel, which is then released into the blood / plasma. Ketone bodies not only provide fuel for the brain, but are also used by skeletal muscle and cardiac muscle. The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, protection of muscle characteristics, and improved cognitive and physical performance. Based on the improvement of cell metabolic efficiency, the management of ketone supplementation can have beneficial effects on physical, cognitive and mental health, and have long-term effects on health in terms of common avoidable diseases such as obesity, cardiovascular disease, neurodegenerative disease, diabetes and cancer.

[0004] Although there are many health advantages to pursuing a ketogenic diet or lifestyle and maintaining a nutritional ketosis state, there are still significant barriers to pursuing and maintaining a ketogenic state. One of these barriers is the difficulty of transitioning to a ketogenic state. The fastest endogenous route to enter ketosis by depleting the body's glucose reserves is through fasting and exercise. This is physically and emotionally demanding and extremely challenging even for the most motivated and disciplined individuals.

[0005] A large number of studies on exogenous ketones have shown that the intake of compounds that can increase the level of ketone bodies in the blood can bring various clinical benefits, including enhancing physical and cognitive abilities and treating cardiovascular disease, diabetes, neurodegenerative disease and epilepsy. Therefore, it is desirable to directly provide ketone bodies as energy to humans or animals. The present inventors have found that 3-acetyloxybutyric acid has a high conversion activity due to the presence of an acetyl structure that can be utilized by the human body, and it can increase or maintain ketone body levels, improve metabolic function, has a faster ketogenesis rate, better ketogenesis effect, and other characteristics. It can better maintain a state of ketosis and be better used as a ketogenic substance in dietary or nutritional supplements, and the ketogenesis effect is much better than existing ketogenic products. SUMMARY

[0006] In one aspect, the present application provides a method of increasing or maintaining ketone body levels, improving metabolic function, the method comprising administering to a subject in need thereof a composition comprising an effective amount of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof.

[0007] In some embodiments, increasing or maintaining ketone body levels, improving metabolic function comprises elevating blood ketone levels, promoting fat-oxidative utilization, improving insulin sensitivity, reducing glycemic excursions, reducing blood glucose, weight loss.

[0008] In some embodiments, improving metabolic function comprises anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle protective properties, improved cognitive and physical performance, and epigenetic effects (positive or beneficial gene expression).

[0009] In some embodiments, increasing or maintaining ketone body levels, improving metabolic function is achieved through replacement of oxidative energy sources, i.e., through fatty acid oxidation to reduce or replace glucose for energy. By replacing or reducing glucose for energy dependence through fatty acid oxidation, ketone body levels can be significantly increased or maintained, achieving metabolic optimization. The liver converts fatty acids into ketone bodies (such as beta-hydroxybutyrate), as a highly efficient energy source for tissues such as the brain, muscle, etc., reducing dependence on glucose. This process can promote mitochondrial biogenesis and autophagy, enhancing cellular energy efficiency, while reducing chronic inflammation and oxidative stress. Ketone body metabolism can improve insulin sensitivity, conserve glucose for energy and red blood cell utilization, and maintain energy homeostasis under conditions of starvation or disease. This mechanism not only optimizes metabolic function, but also provides a potential therapeutic strategy for diabetes, neurodegenerative diseases, etc.

[0010] In some embodiments, 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is administered at a dose of 1 to 200 g per day. In some embodiments, 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof can be administered at a dose of 1.5 to 150 g, 2 to 100 g, 3 to 80 g, 4 to 60 g, 5 to 40 g, 8 to 30 g, 10 to 20 g, 12.5 to 17.5 g, 13 to 18.5 g per day.

[0011] In some embodiments, the composition further comprises an effective amount of 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof.

[0012] In some embodiments, the ratio of 3-acetoxylbutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof is 1:200 to 200:1. In some embodiments, the ratio of 3-acetoxylbutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof can be 1:200 to 200:1, 1:180 to 180:1, 1:150 to 150:1, 1:120 to 120:1, 1:100 to 100:1, 1:80 to 80:1, 1:60 to 60:1, 1:40 to 40:1, 1:20 to 20:1, 1:10 to 10:1, 1:5 to 5:1, 1:3 to 3:1.

[0013] In some embodiments, the composition is formulated as a suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0014] In some embodiments, the composition is prepared as a dietary supplement, food, beverage, or animal feed.

[0015] In some embodiments, the composition is administered orally, intravenously, intramuscularly, intraperitoneally, or sublingually.

[0016] In another aspect, the present application provides a composition comprising 3-acetoxylbutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof for use in increasing or maintaining ketone body levels, improving metabolic function.

[0017] In some embodiments, the composition further comprises 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester, or derivative thereof.

[0018] In some embodiments, increasing or maintaining ketone body levels, improving metabolic function comprises elevating blood ketone levels, promoting fat-oxidative utilization, improving insulin sensitivity, reducing blood glucose fluctuations, reducing blood glucose, weight loss.

[0019] In some embodiments, improving metabolic function comprises anticonvulsant effects, enhanced brain metabolism, neuroprotective, muscle protective properties, improved cognitive and physical performance, and epigenetic effects (positive or beneficial gene expression).

[0020] In some embodiments, increasing or maintaining ketone body levels, improving metabolic function is achieved through fatty acid oxidation to reduce or replace glucose for energy.

[0021] In some embodiments, 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is administered at a dose of 1 to 200 g per day. In some embodiments, 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof can be administered at a dose of 1.5 to 150 g, 2 to 100 g, 3 to 80 g, 4 to 60 g, 5 to 40 g, 8 to 30 g, 10 to 20 g, 12.5 to 17.5 g, 13 to 18.5 g per day.

[0022] In some embodiments, the ratio of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is 1:200 to 200:1. In some embodiments, the ratio of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof can be 1:100 to 100:1, 1:80 to 80:1, 1:60 to 60:1, 1:40 to 40:1, 1:20 to 20:1, 1:10 to 10:1, 1:5 to 5:1, 1:3 to 3:1.

[0023] In some embodiments, the composition is formulated into a suppository, tablet, pill, granule, powder, film, capsule, beverage, aerosol, spirit, tincture, tonic, liquid suspension, syrup.

[0024] In some embodiments, the composition is prepared as a dietary supplement, food, beverage or animal feed.

[0025] In another aspect, the present application provides use of a composition as described above in the preparation of a dietary supplement, food, beverage or animal feed.

[0026] The 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof and / or 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof of the present application and the composition comprising the same can be in a non-racemic, racemic, pure R or S configuration.

[0027] Compared with other exogenous ketones, the composition of the present application has excellent adaptability; as a ketogenic substance, it can have wide application prospects in the field of dietary supplements or foods. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is a graph of blood ketone content of each group at different time points.

[0029] Figure 2 is the area under the curve (AUC) of blood ketone content of each group.

[0030] Figure 3 is a graph of body weight change of mice in each group after 6 weeks of gavage.

[0031] Figure 4 is a chart of the change in fasting blood glucose in each group of mice before and after gavage intervention. DETAILED DESCRIPTION

[0032] Reference will now be made in detail to the preferred embodiments of the application, examples of which are illustrated in the accompanying drawings. While the application will be described in conjunction with the preferred embodiments, it will be understood that they are not intended to limit the application to these embodiments. On the contrary, the application is intended to cover alternatives, modifications, and equivalents, which can be included within the spirit and scope of the application as defined by the claims.

[0033] As used herein, the term "or" is intended to mean "and" and "or". In other words, the term "or" shall not be interpreted in the exclusive or sense.

[0034] As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0035] As used herein, the term "comprising" or "including" or variations thereof, means that the compositions or methods described include, but are not limited to, those stated or the equivalent thereof. Further, the terms "comprise", "comprising", "comprises" or "comprising" when used in this specification and in claims of this patent specification shall not specify the presence of only the features or components listed in the specification, but shall also permit the implication of additional features or components.

[0036] As used herein, the term "administering" refers to the process of delivering the disclosed compositions or active ingredients to a subject. The compositions of the present application can be administered to exert the desired effect by various suitable means, including orally, intragastrically, and parenterally (i.e., intravenously and intra-arterially, as well as other suitable parenteral routes), and the like. The compositions of the present application can be administered to a subject in an effective dose and / or at a frequency that induces or maintains ketosis. In some embodiments, multiple doses of the composition are administered over a period of time.

[0037] As used herein, the term "effective amount" refers to the amount necessary to achieve the effect as taught herein. The amount to be administered can vary depending on factors such as the sensitivity of the individual, the age, sex, and weight of the individual, the specific reaction of the individual, and the like. According to the present disclosure, a suitable single dose size is a dose that is capable of achieving the above-mentioned effect when administered one or more times over a suitable period of time.

[0038] As used herein, the term "pharmaceutically acceptable" means pharmaceutically, physiologically, dietetically, and / or nutritionally acceptable and refers to those compositions or agents, materials, or components that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals, compatible with other ingredients used in the composition, not unduly toxic, irritating, allergic, or otherwise now or hereafter known to be a problem in the art, and commensurate with a reasonable benefit / risk ratio.

[0039] The compositions of the present application can be used to prepare ketogenic substances for elevating or maintaining blood ketone levels in a subject, elevating ketone body levels in a subject, including inducing and / or maintaining elevated ketone body levels at a desired level (e.g., ketosis) in a subject to which it is administered. "Ketosis" refers to blood ketone levels in a subject that are in the range of about 0.5 mmol / L to about 16 mmol / L. Ketosis can improve mitochondrial function, reduce production of reactive oxygen species, reduce inflammation, and increase activity of neurotrophic factors. "Ketoadaptation" refers to long-term nutritional ketosis (>1 week) to achieve sustained non-pathological "mild ketosis" or "therapeutic ketosis." In some cases, "elevated ketone body levels" can not mean that the subject is in a "clinical ketosis" state, but still has an elevated ketone supply for energy production and / or other beneficial effects of ketones.

[0040] Administration of the compositions of the present application can elevate or maintain blood ketone levels in a subject as ketogenic substances to produce one or more desired effects, including but not limited to appetite suppression, weight loss, fat reduction, reduced blood glucose levels, improved mental alertness, increased physical performance, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

[0041] In the present application, the form of administration of the compositions involves a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject, i.e., suitable for ingestion or nutritionally acceptable. The above carriers include those commonly used in health foods and dietary supplements as well as pharmaceutical preparations, such as nontoxic compatible substances such as sugars, starches, cellulose and its derivatives, powdered tragacanth, malt, gelatin, talc, oil, diols, polyols, esters, agar, alginic acid, pyrogen-free water, isotonic saline, and the like.

[0042] In some embodiments, the compositions of the present application can be administered with other supplements, such as vitamins, minerals, nootropics, and other supplements known in the art.

[0043] The compositions of the present application can be prepared into food and beverage products for human consumption as well as nutritional supplements, energy treatments, medical treatments, or strength and / or endurance exercise supplements as ketogenic substances to provide a dietary source of exogenous ketones to elevate or maintain blood ketone levels in a subject.

[0044] The following examples are illustrative of selected embodiments of the application, and are not meant to limit the scope of the application. Example 1

[0045] The compositions 1-13 were prepared according to the formulation components of the following table:

[0046]

[0047] In addition to the examples of the above table, the composition of the present application can be prepared by selecting appropriate amounts or ratios of amounts as needed. The ratio of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof can be 1:100 to 100:1, 1:80 to 80:1, 1:60 to 60:1, 1:40 to 40:1, 1:20 to 20:1, 1:10 to 10:1, 1:5 to 5:1, 1:3 to 3:1. The composition of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof can be administered at a dose of 1 to 200 g per day. Example 2

[0048] 24 ICR mice were divided into 3 groups (blank control group, 3-hydroxybutyric acid group, 3-acetyloxybutyric acid group) respectively. The mice were fasted overnight before the experiment. Before the experiment, the mice were intragastrically administered (3-hydroxybutyric acid: 1624 mg / kg; 3-acetyloxybutyric acid: 2279.8 mg / kg) with a volume of 0.1 ml / 10 g. The blood ketone content was detected by tail tip blood sampling before intragastric administration, 15, 30, 60, 90, 120, 180 and 240 minutes after intragastric administration.

[0049] Figure 1 is a graph of the blood ketone content of each group at different time points. As shown in Figure 1, in this experiment, the rate of ketone production in the body reached a maximum at 0-15 minutes, and peaked at 15 minutes. The blood ketone content of 3-acetyloxybutyric acid was higher than that of 3-hydroxybutyric acid at 15 minutes, and remained at a higher level within 240 minutes. Figure 2 is the area under the curve (AUC) of the blood ketone content of each group. As shown in Figure 2, 3-acetyloxybutyric acid has the highest effect on increasing blood ketones, which is 42.9% better than 3-hydroxybutyric acid. Example 3

[0050] 24 C57BL6 / J mice fed with high-fat diet for 10 weeks were randomly divided into 3 groups (blank control group, 3-hydroxybutyric acid group, 3-acetyloxybutyric acid group). The fasting blood glucose of the mice was determined by tail tip blood sampling before the experiment. During the experiment, the mice in the 3 groups continuously received high-fat diet, but were intragastrically administered distilled water, 3-hydroxybutyric acid (1624 mg / kg) and 3-acetyloxybutyric acid (2279.8 mg / kg) respectively for 6 consecutive weeks, with a volume of 0.1 ml / 10 g. The body weight of the mice was recorded once a week, and the fasting blood glucose of the mice was determined again after 6 weeks.

[0051] Figure 3 is a graph of the body weight change of mice in each group after 6 weeks of gavage. As shown in Figure 3, during the experiment, the mice continuously received a high-fat diet, and the body weight of the mice in the blank group continuously increased. Compared with the blank group, the body weight of the mice in the 3-hydroxybutyric acid group was significantly reduced, and the body weight of the mice in the 3-acetyloxybutyric acid group was reduced more obviously, showing a more excellent weight loss effect, which was 8.4% better than that of the 3-hydroxybutyric acid. Figure 4 is a graph of the change of fasting blood glucose of mice in each group before and after gavage intervention. As shown in Figure 4, before the experiment, the 3 groups of mice all had high fasting blood glucose levels induced by a high-fat diet, and after 6 weeks of intervention, compared with the blank group, the fasting blood glucose level of the mice in the 3-hydroxybutyric acid group was significantly reduced, and the fasting blood glucose level of the mice in the 3-acetyloxybutyric acid group was reduced more obviously, which was 32.7% better than that of the 3-hydroxybutyric acid.

[0052] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any person skilled in the art can make various changes, modifications, replacements and variations to these embodiments without departing from the principles and purposes of the present application, and the scope of the present application is defined by the claims and their equivalents.

Claims

1. A method of increasing or maintaining ketone body levels, improving metabolic function, characterized by, The method comprises administering to a subject in need thereof a composition comprising an effective amount of 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof.

2. The method of claim 1, wherein, The increasing or maintaining ketone body levels, improving metabolic function comprises increasing blood ketone levels, promoting fat oxidation utilization, improving insulin sensitivity, reducing blood glucose fluctuations, reducing blood glucose, weight loss.

3. The method according to claim 1 or 2, characterized in that, The increasing or maintaining ketone body levels, improving metabolic function is achieved by fatty acid oxidation to reduce or replace glucose energy supply.

4. The method according to any one of claims 1 to 3, characterized in that, The 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is administered at a dose of 1 to 200 g per day.

5. The method according to any one of claims 1 to 4, characterized in that, The composition further comprises an effective amount of 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof.

6. The method of claim 5, wherein, The ratio of the 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to the 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is 1:200 to 200:

1.

7. The method according to any one of claims 1 to 6, characterized in that, The composition is formulated into suppositories, tablets, pills, granules, powders, films, capsules, beverages, aerosols, spirits, tinctures, tonics, liquid suspensions, syrups.

8. The method according to any one of claims 1 to 7, characterized in that, The composition is prepared as a dietary supplement, food, beverage or animal feed.

9. The method according to any one of claims 1 to 8, characterized in that, The composition is administered orally, intravenously, intramuscularly, intraperitoneally or sublingually.

10. A composition comprising 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof, characterized in that, The composition is used for increasing or maintaining ketone body levels, improving metabolic function.

11. The composition according to claim 10, characterized in that, The composition further comprises 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof.

12. The composition according to claim 10 or 11, characterized in that, The increasing or maintaining ketone body levels, improving metabolic function comprises increasing blood ketone levels, promoting fat oxidation utilization, improving insulin sensitivity, reducing blood glucose fluctuations, reducing blood glucose, weight loss.

13. The composition according to any one of claims 11 to 13, characterized in that, The increasing or maintaining ketone body levels, improving metabolic function is achieved by fatty acid oxidation to reduce or replace glucose energy supply.

14. The composition according to any one of claims 11 to 13, characterized in that, The 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is administered at a dose of 1 to 200 g per day.

15. The composition according to any one of claims 11 to 14, characterized in that, The ratio of the 3-acetyloxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof to the 3-hydroxybutyric acid or a pharmaceutically acceptable salt, ester or derivative thereof is 1:200 to 200:

1.

16. The composition according to any one of claims 10 to 15, characterized in that, The composition is formulated into suppositories, tablets, pills, granules, powders, films, capsules, beverages, aerosols, spirits, tinctures, tonics, liquid suspensions, syrups.

17. The composition according to any one of claims 10 to 16, characterized in that, The composition is prepared as a dietary supplement, food, beverage or animal feed.

18. Use of the composition of any one of claims 10 to 17 in the preparation of a dietary supplement, food, beverage or animal feed.

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