A ketone body sustained-release material and its application

Abstract

The present invention relates to a ketone body sustained-release material, comprising compound I and / or compound II, wherein the compound I is in the form of a ketoacid dimer and a salt or ester thereof, and the compound II is in the form of an R-3-hydroxybutyric acid dimer and a salt or ester thereof, and the mass ratio of compound I to compound II is between 0-100%, and the mass ratio with the best sustained-release effect is 62:38. The ketone body sustained-release material can slowly release ketone bodies in a subject's body, prolong the action time of ketone bodies in the blood, and can be used for the treatment of metabolic disorders.

Description

Technical Field

[0001] The invention belongs to the field of health care product / drug synthesis, and specifically relates to a ketone body sustained-release material and application thereof. Background Art

[0002] Ketone bodies are intermediate metabolites in the process of fat oxidation metabolism, including acetoacetate, 3-hydroxybutyrate (3-HB) and acetone. In healthy humans, a small amount of ketone bodies exists in the blood in the proportion of 78% 3-hydroxybutyrate, 20% acetoacetate and 2% acetone. 3-Hydroxybutyrate is the monomer form of the natural polymer poly 3-hydroxybutyrate (PHB), and exists in a pure R configuration in the natural state. R-3HB has been proven to play a very important role in organisms and has a variety of physiological and medicinal values. R-3-hydroxybutyrate and its salts can be used as direct ketone body supply. It is not only a FDA-approved nutritional supplement, but also plays a beneficial role in the treatment of metabolic disorders. However, direct ketone body supply has the risk of instantly increasing the ketone body concentration in the subject's blood and is accompanied by the risk of ketone body poisoning in the subject.

[0003] In the patent application document of the published patent CN112779297A, the preparation method of keto acid dimer and R-3-hydroxybutyric acid dimer and their derivatives has been disclosed. The present invention creates keto acid dimer and R-3-hydroxybutyric acid dimer and their derivatives based on the aforementioned disclosed preparation method, and further develops a new ketone body sustained-release material to solve the short-term effects in the direct supply of ketone bodies and the adverse effects of ketone poisoning on subjects when high-concentration ketone bodies are directly used. Summary of the invention

[0004] In view of the problems faced by the direct use of ketone bodies by the subjects, the purpose of the present invention is to provide a ketone body sustained-release material, which can slowly release ketone bodies in the body of the patient and prolong the action time of ketone bodies in the blood.

[0005] Another object of the present invention is to provide the application of the ketone body sustained-release material in treating metabolic disorders.

[0006] The content of the invention is as follows:

[0007] A ketone body sustained-release material, comprising compound I and / or compound II, wherein compound I is in the form of a keto acid dimer and a salt or ester thereof, and compound II is in the form of an R-3-hydroxybutyric acid dimer and a salt or ester thereof

[0008] .

[0009] For the ketone body sustained-release material of the present invention, the mass ratio of compound I and compound II can be selected between 0-100%. Simple compound I or compound II also has the effect of ketone body sustained-release. However, when the mass ratio of compound I: compound II is 62:38, the ketone body concentration and duration in the subject's blood are optimal.

[0010] The compound I in the ketone body sustained-release material is a keto acid dimer salt, which may be one or more of sodium, magnesium, potassium, calcium, and zinc. The form of an organic salt can make the form of the compound I more stable and facilitate industrial production.

[0011] The compound II in the ketone body sustained-release material is an R-3-hydroxybutyric acid dimer salt, and the R-3-hydroxybutyric acid dimer salt can be one or more of sodium, magnesium, potassium, calcium and zinc.

[0012] The compound I in the ketone body sustained-release material is a keto acid dimer ester, and the keto acid dimer ester can be one or more of its methyl ester, ethyl ester, isopropyl ester and butyl ester.

[0013] The compound II in the ketone body sustained-release material is R-3-hydroxybutyric acid dimer ester, and the R-3-hydroxybutyric acid dimer ester can be one or more of its methyl ester, ethyl ester, isopropyl ester and butyl ester.

[0014] The R-3-hydroxybutyric acid dimer and its salt or ester in the compound II in the ketone body sustained-release material are of chiral configuration.

[0015] The ketone body sustained-release material provided by the invention can be used as a medical food and / or a food for special medical purposes or a nutrient / food supplement.

[0016] The ketone body sustained-release material provided by the present invention can be used to treat at least one metabolic disorder.

[0017] The ketone body sustained-release composition has been verified through animal experiments to achieve a ketone body sustained-release effect and reduce the excessive concentration of immediate ketone bodies during ketone body supplementation. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Ketone body concentration curve under the action of ketoacid dimer sodium salt.

[0019] Figure 2 Ketone body concentration curve under the action of R-3-hydroxybutyrate dimer sodium salt.

[0020] Figure 3 Ketone body concentration curve under DD1 and 3-HB control.

[0021] Figure 4 Ketone body concentration curve under DD2 and 3-HB control. Implementation

[0022] In order to further illustrate the technical effects of the present invention, the ketone body sustained-release material provided by the present invention is described in detail below in conjunction with the examples. Example 1

[0023] 0.01 g, 0.1 g, 1 g and 10 g of keto acid dimer sodium salt were weighed respectively, added into 10 ml of deionized water, mixed and completely dissolved, to form keto acid dimer sodium salt aqueous solutions with final concentrations of 0.1% (w / v), 1% (w / v), 10% (w / v) and 100% (w / v) in sequence.

[0024] Mice were fed 1 ml of 0.1% (w / v), 1% (w / v), 10% (w / v) and 100% (w / v) ketoacid dimer sodium salt aqueous solutions, and then venous blood was drawn from the experimental mice at 0, 0.5, 1, 2, 3, 4, 8, 12, 24, 36 and 48 hours, and the 3-HB content in the venous blood was tested. The 3-HB value can reflect the changes in ketone body concentration in the experimental mice. Figure 1 It can be seen that after the experimental mice were fed with the ketoacid dimer sodium salt aqueous solution, 3-HB was still detectable in the blood for a long period of time, indicating that feeding the ketoacid dimer sodium salt aqueous solution alone can prolong the release of ketone bodies in the body. Example 2

[0025] 0.01 g, 0.1 g, 1 g and 10 g of R-3-hydroxybutyric acid dimer sodium salt were weighed respectively, added into 10 ml of deionized water, mixed and completely dissolved, to form R-3-hydroxybutyric acid dimer sodium salt aqueous solutions with final concentrations of 0.1% (w / v), 1% (w / v), 10% (w / v) and 100% (w / v) in sequence.

[0026] Mice were fed 1 ml of 0.1% (w / v), 1% (w / v), 10% (w / v) and 100% (w / v) R-3-hydroxybutyric acid dimer sodium salt aqueous solution, and then venous blood was drawn from the experimental mice at 0, 0.5, 1, 2, 3, 4, 8, 12, 24, 36 and 48 hours, and the 3-HB content in the venous blood was tested. The value of 3-HB can reflect the changes in ketone body concentration in the experimental mice. Figure 2 It can be seen that after the experimental mice were fed with the R-3-hydroxybutyric acid dimer sodium salt aqueous solution, 3-HB was still detectable in the blood for a long period of time, indicating that feeding the R-3-hydroxybutyric acid dimer sodium salt aqueous solution alone can prolong the release of ketone bodies in the body. Example 3

[0027] 10 g of R-3-hydroxybutyric acid dimer sodium salt was weighed and added into 10 ml of deionized water, mixed and completely dissolved to prepare an R-3-hydroxybutyric acid dimer sodium salt aqueous solution (DD1) with a final concentration of 100% (w / v).

[0028] Weigh 10g of 3-HB and add it to 10ml of deionized water, mix and completely dissolve to make a 3-HB aqueous solution with a final concentration of 100% (w / v). Feed the mice in the experimental group with 1ml of DD1, and feed the mice in the control group with 1ml of 3-HB aqueous solution. Then, at 0, 0.5, 1, 2, 3, 4, 8, 12, 24, 36 and 48 hours, blood was collected from the mice in the experimental group and the control group, and the concentration of 3-HB in the blood was tested. Figure 3 It can be seen that within 4 hours, the 3HB content in the blood of mice fed with 3HB dropped to 0.5mM. However, after 4 hours of feeding DD1, the 3HB content in the blood basically remained between 1.5mM-2mM. Within 4-24 hours, the 3HB content in the blood continued to decrease, but remained at around 1 mM, achieving the effect of maintaining a high level of 3HB in the blood. Figure 3 It can be seen that after the experimental mice were fed with the sodium salt aqueous solution of R-3-hydroxybutyric acid dimer, the peak level of 3HB in the blood was lower than that of the control group fed with 3HB, the risk of ketoacidosis was reduced, and 3HB could be slowly released within 24 hours to maintain the appropriate concentration of 3HB in the blood. Example 4

[0029] 6.2 g of keto acid dimer sodium salt and 3.8 g of R-3-hydroxybutyric acid dimer sodium salt were weighed and added into 10 ml of deionized water, mixed and completely dissolved to prepare a mixed solution (DD2) with a mass ratio of keto acid dimer sodium salt to R-3-hydroxybutyric acid dimer sodium salt of 62:38.

[0030] Weigh 10g of 3-HB and add it to 10ml of deionized water, mix and completely dissolve to make a 3-HB aqueous solution with a final concentration of 100% (w / v). Feed the mice in the experimental group with 1ml of DD2, and feed the mice in the control group with 1ml of 3-HB aqueous solution. Then, at 0, 0.5, 1, 2, 3, 4, 8, 12, 24, 36 and 48 hours, blood was collected from the mice in the experimental group and the control group, and the concentration of 3-HB in the blood was tested. Figure 4 It can be seen that within 4 hours, the 3-HB content in the blood of mice fed with 3-HB dropped to 0.5mM. However, after 4 hours of feeding DD2, the 3-HB content in the blood basically remained between 1mM and 2mM. Within 4-24 hours, the 3HB content in the blood continued to decrease, but remained at around 1 mM, achieving the effect of maintaining a high level of 3HB in the blood. Figure 4It can be seen that after the experimental group of mice were fed with the combination of ketoacid dimer sodium salt aqueous solution and R-3-hydroxybutyric acid dimer sodium salt aqueous solution, the peak level of 3-HB in the blood was greatly reduced compared with the control group fed with 3-HB. At the same time, compared with the use of R-3-hydroxybutyric acid dimer salt alone, the risk of ketotoxicity was further reduced, and 3-HB could be slowly released within 24 hours to maintain an appropriate concentration of 3-HB in the blood.

[0031] The description of the above embodiments is only used to help understand the implementation and effect of the invention. It should be noted that, for those skilled in the art, without departing from the principles of the invention, the invention can also be improved and modified, and these improvements and modifications also fall within the scope of protection of the claims of the invention.

Claims

1. A ketone body sustained-release material, comprising compound I and compound II, wherein compound I is a keto acid dimer and a salt or ester thereof, and compound II is an R-3-hydroxybutyric acid dimer and a salt or ester thereof, characterized in that: The mass ratio of compound I to compound II is 62:38 When compound I is a keto acid dimer ester, the keto acid dimer ester is one or more of its methyl ester, ethyl ester, isopropyl ester, and butyl ester; when compound II is an R-3-hydroxybutyric acid dimer ester, the R-3-hydroxybutyric acid dimer ester is one or more of its methyl ester, ethyl ester, isopropyl ester, and butyl ester; the ketone body sustained-release material can slowly release ketone bodies in the body of a patient and prolong the action time of ketone bodies in the blood.

2. The ketone body sustained-release material according to claim 1, wherein the compound I is a keto acid dimer salt.

3. The ketone body sustained-release material according to claim 2, wherein the ketoacid dimer salt is one or more of sodium, magnesium, potassium, calcium, and zinc.

4. The ketone body sustained-release material according to claim 1, wherein the compound II is an R-3-hydroxybutyric acid dimer salt.

5. The ketone body sustained-release material according to claim 4, wherein the R-3-hydroxybutyric acid dimer salt is one or more of sodium, magnesium, potassium, calcium, and zinc.

6. Use of the sustained-release ketone body material according to any one of claims 1 to 5 in the preparation of a drug for treating metabolic disorders.

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