Nicotinamide riboside organic acid salt and preparation and application thereof

Abstract

The invention provides nicotinamide riboside organic acid salt as well as a preparation method and application thereof, and relates to the technical field of preparation of nicotinamide riboside salt. Organic acid basic metal salt and nicotinamide riboside react to generate the nicotinamide riboside organic salt. According to the method, high-yield nicotinamide riboside organic acid salt can be prepared, the preparation process is simple, an organic toxic reagent is almost not used, and the method is conveniently applied to the dietary supplement industry; the dietary supplement containing the nicotinamide riboside organic acid salt provided by the invention has high stability, can significantly promote the active substance nicotinamide riboside organic acid salt to play a role, and has a wide industrial application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of nicotinamide riboside salts, and in particular to a nicotinamide riboside organic acid salt and its preparation and application. Background Art

[0002] Nicotinamide riboside (NR) is an important vitamin B3 derivative. In recent years, it has garnered widespread attention in the life sciences and health fields. Within the body, NR participates in key metabolic processes, particularly the synthesis of nicotinamide adenine dinucleotide (NAD+). NAD+ is a well-known coenzyme that plays an essential role in numerous physiological processes, including cellular energy metabolism, DNA repair, and gene expression regulation. With aging or in certain disease states, NAD+ levels decrease in the body, potentially implicated in the development and progression of age-related diseases and some metabolic disorders. Therefore, NR supplementation has emerged as a potential intervention to maintain or elevate NAD+ levels, thereby improving health or preventing disease. In recent years, nicotinamide riboside has garnered significant attention as an emerging NAD+ precursor supplement. Nicotinamide riboside chloride has received GRAS designation from the US FDA, and NR chloride has been recognized by the FDA as generally recognized as safe.

[0003] However, nicotinamide riboside has some significant drawbacks and limitations in practical applications. For example, its relatively poor chemical stability may affect its storage, transportation, and effectiveness in practical applications. Furthermore, nicotinamide riboside's bioavailability is low, and there is still room for further improvement to achieve better physiological effects at lower doses.

[0004] Organic acid salts are a class of compounds widely used in medicinal chemistry and bioactive research. Forming salts of nicotinamide riboside with organic acids can improve the physicochemical properties of nicotinamide riboside to a certain extent. Given the important physiological functions of nicotinamide riboside and the limitations of existing forms, developing organic acid salts of nicotinamide riboside to enhance its stability and improve its bioavailability has important scientific significance and potential application value.

[0005] Chinese invention patent publication number CN 111454311 A discloses a method for preparing an organic acid salt of nicotinamide riboside. During the preparation process, multiple toxic organic solvents such as methanol, methyl tert-butyl ether, or ethyl acetate need to be added, making it unsuitable for application in the dietary supplement industry. Summary of the Invention

[0006] An object of the present invention is to provide a nicotinamide riboside organic acid salt having high stability. Another object of the present invention is to provide a method for preparing the nicotinamide riboside organic acid salt, which can prepare the nicotinamide riboside organic acid salt in high yield, has a simple preparation process, uses less organic toxic reagents, and is convenient for use in the dietary supplement industry. A further object of the present invention is to provide a dietary supplement and a nicotinamide riboside supplementary medicine containing the nicotinamide riboside organic acid salt, which have high stability and can better exert their efficacy.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A nicotinamide riboside organic acid salt, wherein the nicotinamide riboside organic acid salt is nicotinamide riboside alpha-ketoglutarate, and its chemical formula is shown in (I);

[0009]

[0010] Furthermore, the present invention provides a method for preparing the nicotinamide riboside organic acid salt, comprising reacting an organic acid or alkaline metal salt with nicotinamide riboside to generate the nicotinamide riboside organic salt.

[0011] Furthermore, the nicotinamide riboside is nicotinamide riboside chloride or nicotinamide riboside sulfate. Preferably, the nicotinamide riboside is nicotinamide riboside hydrochloride.

[0012] Furthermore, the organic acid is alpha-ketoglutaric acid.

[0013] Furthermore, the molar ratio of the organic acid-base metal salt to nicotinamide riboside is 1:0.9-1.1.

[0014] Furthermore, the reaction of the organic acid and alkaline metal salt with nicotinamide riboside is carried out in water and an organic solvent.

[0015] Furthermore, the organic solvent is one or any combination of ethanol, methanol, isopropanol, and acetone.

[0016] Furthermore, the preparation method comprises the following steps:

[0017] S1. Dissolve NR-Cl in anhydrous ethanol to obtain solution A;

[0018] S2. dissolving the organic acid and alkaline metal salt in anhydrous ethanol to obtain solution B;

[0019] S3. Add solution A to solution B. The reaction produces a precipitate, which is a nicotinamide riboside organic salt. The molar ratio of the organic acid and alkaline metal salt to nicotinamide riboside is 1:0.9-1.1, and the organic acid and metal salt is alpha-ketoglutarate.

[0020] The present invention provides the use of a nicotinamide riboside organic acid salt in the preparation of or as a dietary supplement or the preparation of a nicotinamide riboside supplementary medicine. The nicotinamide riboside organic acid salt is nicotinamide riboside alpha-ketoglutarate, and the nicotinamide riboside alpha-ketoglutarate is prepared by the above-mentioned preparation method.

[0021] The present invention provides a dietary supplement, which is composed of nicotinamide riboside alpha-ketoglutarate prepared by the above preparation method and edible auxiliary materials.

[0022] The present invention provides a nicotinamide riboside supplementary medicine, which is composed of the above-mentioned nicotinamide riboside alpha-ketoglutarate or the nicotinamide riboside alpha-ketoglutarate prepared by the above-mentioned preparation method and pharmaceutical excipients.

[0023] Preferably, the dietary supplement may include edible excipients.

[0024] Preferably, the dietary supplement can be prepared into various dosage forms applicable to the dietary supplement market, specifically tablets, hard capsules, soft capsules, gels, oral suspensions, and the like.

[0025] A dietary supplement comprises the above-mentioned nicotinamide riboside alpha-ketoglutarate or nicotinamide riboside alpha-ketoglutarate prepared by the above-mentioned preparation method, galactomannan, and vitamin C, wherein the weight ratio of the galactomannan to the vitamin C is 1:1-2, and the weight ratio of the galactomannan to the nicotinamide riboside alpha-ketoglutarate is 1:10-20.

[0026] Compared with the existing technology, the present invention has the following beneficial effects:

[0027] The nicotinamide riboside provided by the present invention has high stability and activity. The preparation method of the nicotinamide riboside organic acid salt can prepare nicotinamide riboside organic acid salt with high yield, and the preparation process is simple, using less organic toxic reagents, and is convenient for use in the dietary supplement industry. The dietary supplement containing the nicotinamide riboside organic acid salt provided by the present invention has high stability and significantly promotes the efficacy of the active substance nicotinamide riboside organic acid salt. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the NMR carbon spectrum of sample 1 in Example 1.

[0029] Figure 2 for Figure 1 Enlarged view of part A in the middle.

[0030] Figure 3 for Figure 1 Enlarged view of part B in the middle.

[0031] Figure 4 This is the H NMR spectrum of sample 1 in Example 1.

[0032] Figure 5 for Figure 4 Enlarged view of part C in the middle.

[0033] Figure 6 for Figure 4 Enlarged view of part D in the middle. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

[0035] Example 1

[0036] This embodiment provides a method for preparing nicotinamide riboside organic acid salt, comprising the following steps:

[0037] S1. Dissolve NR-Cl in anhydrous ethanol to obtain solution A;

[0038] S2. dissolving the organic acid and alkaline metal salt in anhydrous ethanol to obtain solution B;

[0039] S3. Add solution A to solution B. The precipitate produced by the reaction is nicotinamide riboside organic salt.

[0040] The specific preparation method is as follows: 5.0 g of NR-Cl was dissolved in 40 mL of anhydrous ethanol with stirring, allowed to react until clear, and filtered to obtain Solution A. 2.76 g of alpha-ketoglutaric acid was dissolved in 10 mL of anhydrous ethanol, 0.72 g of solid sodium hydroxide was added with stirring and ultrasonication, and the mixture was ultrasonicated and stirred for 2 hours (preventing the ingress of water during the operation). Solution B was filtered to obtain Solution A. Solution A was added dropwise to the stirring Solution B. After the addition was complete, stirring was continued until the reaction was complete, resulting in a large amount of precipitate. The solid was filtered and dried to obtain the product 1 to be tested.

[0041] Yield 98%

[0042] The nuclear magnetic resonance and infrared data of the sample 1 to be tested are measured. The subsequent other embodiments refer to this measurement. The measurement results are as follows: The nuclear magnetic resonance and infrared data of the sample 1 to be tested are as follows:

[0043] Nicotinamide riboside chloride:

[0044] 13 C NMR (101MHz, D2O) δ165.75, 145.64, 142.64, 140.38, 133.91, 128.40, 99.91, 87.63, 77.39, 69.72, 60.17.

[0045] 1 H NMR (400MHz, D2O) δ9.52 (s, 1H), 9.18 (d, J = 7.9Hz, 1H), 8.89 (d, J = 11.1Hz, 1H), 8.23–8.15 (m, 1H), 6.16 (d, J = 4. 5Hz, 1H), 4.48–4.35 (m, 2H), 4.27 (t, J=4.7Hz, 1H), 3.96 (dd, J=12.9, 2.9Hz, 1H), 3.81 (dd, J=12.9, 3.6Hz, 1H).

[0046] alpha-ketoglutarate:

[0047] 13 C NMR (101MHz, D2O) δ177.14, 173.90, 93.58, 33.13, 28.06.

[0048] 1 H NMR (400MHz, D2O) δ2.93 (s, 2H), 2.59 (t, J=6.6Hz, 2H), 2.35 (t, J=7.6Hz, 2H), 2.02 (dd, J=8.3, 7.0Hz, 2H).

[0049] Nicotinamide riboside alpha-ketoglutarate:

[0050] 13 C NMR (101MHz, D2O) δ177.95, 165.74, 145.63, 142.62, 140.37, 133.90, 128.39, 99.90, 87.62, 77.39, 69.71, 60.16, 33.94, 27.74.

[0051] 1 H NMR (400MHz, D2O) δ9.51 (d, J=1.7Hz, 1H), 9.17 (dd, J=6.4, 1.4Hz, 1H), 8.88 (dt, J=8.1, 1.5Hz, 1H), 8.17 (dd, J=8.1, 6.3Hz, 1H), 6.15 (d, J=4.4H z, 1H), 4.45–4.34 (m, 2H), 4.26 (t, J=4.6Hz, 1H), 3.95 (dd, J=12.9, 2.9Hz, 1H), 3.80 (dd, J=13.0, 3.6Hz, 1H), 2.87 (s, 2H), 2.56 (t, J=6.6Hz, 2H).

[0052] Infrared spectrum data: 112507-NRCL Batch number: IGT04HM20240519

[0053] IR(CM-1): 3304.42, 3234.70, 3146.77, 1701.38, 1666.87, 1647.96, 1510.84, 1435.57, 1398.63, 1262.45, 1178.43, 1100. 17, 1060.99, 1034.53, 986.03, 926.10, 898.45, 851.70, 830.52, 779.48, 760.63, 734.51, 667.93, 607.92, 580.58, 484.95;

[0054] 112507-a-Ketoglutaric Acid Batch Number: 20241007-2

[0055] IR(CM-1):2916.49, 2661.33, 1686.21, 1441.62, 1423.10, 1405.83, 1319.36, 1274.30, 1224.95, 1091.38, 1045.10, 871.32, 809.83, 737.40, 680.13, 640.12, 560.18, 505.80;

[0056] 112507-NRCL+-a-Ketoglutaric 1:1 Mixed Batch Number: 20241115

[0057] IR(CM-1):3234.03, 3142.06, 2964.86, 1698.28, 1666.86, 1647.48, 1581.53, 1510.58, 1397.49, 1288.97, 1262.24, 1178.0 6, 1134.35, 1095.50, 1034.18, 985.06, 925.71, 895.33, 847.95, 830.21, 759.85, 671.42, 637.60, 610.34, 528.03, 453.10;

[0058] 112507-Nicotinamide Riboside Alpha-Ket oglutarate Batch number: NRAKG241024P01

[0059] IR(CM-1):3052.40, 1694.40, 1626.46, 1445.72, 1416.73, 1319.23, 1227.65, 1102.55, 1053.87, 900.59, 869.93, 848.67, 765.95, 697.46, 672.21, 651.58;

[0060] Comparison of the C NMR data of nicotinamide riboside alpha-ketoglutarate with that of nicotinamide riboside and AKG: The chemical shift of C1" of alpha-ketoglutarate changes significantly due to the deshielding effect. Comparison of the H NMR data of nicotinamide riboside alpha-ketoglutarate with that of nicotinamide riboside and AKG: The chemical shifts of some protons around the nitrogen atom of nicotinamide riboside change significantly.

[0061] Combine Figure 1-3 and Figure 4-6 The changes in chemical shifts in the above-mentioned NMR data indicate that the chemical environment of each atom in nicotinamide riboside and AKG has changed, indicating that the two have combined to form nicotinamide riboside alpha-ketoglutarate.

[0062] Example 2

[0063] This example provides a method for preparing a nicotinamide riboside organic acid salt. The preparation method is the same as in Example 1, except that the nicotinamide riboside type is changed to nicotinamide riboside sulfate to prepare nicotinamide riboside alpha-ketoglutarate. The method comprises the following steps:

[0064] S1. Dissolve NR-Cl in anhydrous ethanol to obtain solution A;

[0065] S2. dissolving the organic acid and alkaline metal salt in anhydrous ethanol to obtain solution B;

[0066] S3. Add solution A to solution B. The precipitate produced by the reaction is nicotinamide riboside organic salt.

[0067] The specific preparation method is as follows: 5.0 g of nicotinamide riboside sulfate was dissolved in 40 mL of anhydrous ethanol with stirring, allowed to react until clear, and filtered to obtain Solution A. 2.76 g of alpha-ketoglutaric acid was dissolved in 10 mL of anhydrous ethanol, and 0.72 g of solid sodium hydroxide was added with stirring and ultrasonication, followed by ultrasonication and stirring for 2 hours (preventing the ingress of water during the operation), and filtered to obtain Solution B. Solution A was added dropwise to the stirring Solution B. After the addition was complete, stirring was continued until the reaction was complete, resulting in a large amount of precipitate. The solid was filtered and dried to obtain the test product 2. The yield was 88%.

[0068] Example 3

[0069] This example provides a method for preparing nicotinamide riboside organic acid salt. The preparation method is the same as that in Example 1, except that the molar ratio of the organic acid and alkaline metal salt to nicotinamide riboside is adjusted to 1:0.9 to prepare nicotinamide riboside organic salt. Yield: 96%

[0070] Example 4

[0071] This example provides a method for preparing nicotinamide riboside organic acid salt. The preparation method is the same as that in Example 1, except that the molar ratio of the organic acid and alkaline metal salt to nicotinamide riboside is adjusted to 1:1.1, thereby preparing nicotinamide riboside organic acid salt. Yield: 95%

[0072] Comparative Example 1

[0073] This example provides a method for preparing a nicotinamide riboside organic acid salt. The preparation method is the same as that in Example 1, except that sodium hydroxide is not used. Other steps remain unchanged, and nicotinamide riboside organic acid salt cannot be prepared.

[0074] Example 5

[0075] This example provides a method for preparing a nicotinamide riboside organic salt. The preparation method is the same as that in Example 1, except that the organic solvents are adjusted to be equal amounts of isopropanol to prepare the nicotinamide riboside organic salt.

[0076] Yield 93%

[0077] Example 6

[0078] This example provides a method for preparing a nicotinamide riboside organic acid salt. The preparation method is the same as that in Example 1, except that the organic solvent is adjusted to be equal amounts of acetone to prepare the nicotinamide riboside organic acid salt.

[0079] By statistical analysis of Examples 1-6, it can be found that nicotinamide riboside organic salt was successfully prepared. However, the yield was the highest under the conditions of Example 1, and the yields of Examples 3-6 decreased to a certain extent.

[0080] Example 7

[0081] This embodiment provides a dietary supplement comprising nicotinamide riboside alpha-ketoglutarate prepared in Example 1, galactomannan, and vitamin C; wherein the weight ratio of galactomannan to the nicotinamide riboside alpha-ketoglutarate is 1:10.

[0082] Example 8

[0083] This embodiment provides a dietary supplement comprising nicotinamide riboside alpha-ketoglutarate prepared in Example 1, galactomannan, and vitamin C; the weight ratio of galactomannan to vitamin C is 1:1, wherein the weight ratio of galactomannan to the nicotinamide riboside alpha-ketoglutarate is 1:15.

[0084] Example 9

[0085] This embodiment provides a dietary supplement comprising nicotinamide riboside alpha-ketoglutarate prepared in Example 1, galactomannan, and vitamin C; the weight ratio of galactomannan to vitamin C is 1:1, wherein the weight ratio of galactomannan to the nicotinamide riboside alpha-ketoglutarate is 1:20.

[0086] Comparative Example 2

[0087] A dietary supplement having the same components as those in Example 7, except that nicotinamide riboside alpha-ketoglutarate is replaced with equal amounts of nicotinamide riboside and alpha-ketoglutarate, and other components remain unchanged.

[0088] Comparative Example 3

[0089] A dietary supplement, having the same components as Example 7, except that it does not contain galactomannan, and other components remain unchanged.

[0090] Example 10 Stability Test

[0091] In this example, stability testing was conducted on Examples 7-9 and Comparative Examples 2-3. The testing method was as follows: the dietary supplements prepared in Examples 7-9 and Comparative Examples 2-3 were placed under accelerated conditions of 40°C and 75% RH for 0, 1, 3, and 6 months, and the accelerated stability was assessed in accordance with the Chinese Pharmacopoeia Guidelines for Stability Testing of Preparations. The test results showed that after mixing nicotinamide riboside alpha-ketoglutarate, galactomannan, and vitamin C, the active ingredient content was greater than 98% after 6 months. The highest stability, exceeding 99.56%, was achieved when the weight ratio of galactomannan to nicotinamide riboside alpha-ketoglutarate was 1:15. In contrast, the active ingredient content of Comparative Examples 2 and 3 was less than 85% after 6 months, demonstrating significantly improved stability of the dietary supplement.

[0092] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A nicotinamide riboside organic acid salt, characterized in that: The nicotinamide riboside organic acid salt is nicotinamide riboside alpha-ketoglutarate, and its chemical formula is shown in (I); 2. The method for preparing the nicotinamide riboside organic acid salt according to claim 1, characterized in that: The organic acid and alkaline metal salt reacts with nicotinamide riboside to generate a nicotinamide riboside organic salt.

3. The preparation method according to claim 2, characterized in that The nicotinamide riboside is nicotinamide riboside chloride or nicotinamide riboside sulfate; and the organic acid is alpha-ketoglutaric acid.

4. The preparation method according to claim 2, characterized in that The molar ratio of the organic acid and alkaline metal salt to nicotinamide riboside is 1:0.9-1.

1.

5. The preparation method according to claim 2, characterized in that The reaction of the organic acid and alkaline metal salt with nicotinamide riboside is carried out in water, an organic solvent or a mixture thereof.

6. The preparation method according to claim 2, characterized in that The organic solvent is one or any combination of ethanol, methanol, isopropanol, and acetone.

7. The preparation method according to claim 2, characterized in that The steps include: S1. Dissolve NR-Cl in anhydrous ethanol to obtain solution A; S2. dissolving the organic acid and alkaline metal salt in anhydrous ethanol to obtain solution B; S3. Add solution A to solution B. The reaction produces a precipitate, which is a nicotinamide riboside organic salt. The molar ratio of the organic acid and alkaline metal salt to nicotinamide riboside is 1:0.9-1.1, and the organic acid and metal salt is alpha-ketoglutarate.

8. Use of an organic acid salt of nicotinamide riboside in the preparation of or as a dietary supplement or in the preparation of a nicotinamide riboside supplementary drug, characterized in that: The nicotinamide riboside organic acid salt is nicotinamide riboside alpha-ketoglutarate, and the nicotinamide riboside alpha-ketoglutarate is prepared by the preparation method according to claim 1 or any one of claims 2-7.

9. A dietary supplement or a nicotinamide riboside supplement drug, characterized in that: The composition comprises nicotinamide riboside alpha-ketoglutarate prepared by the preparation method according to claim 1 or any one of claims 2 to 7 and an edible excipient or a medicine.

10. A dietary supplement, characterized in that The invention comprises the nicotinamide riboside alpha-ketoglutarate according to claim 1 or the nicotinamide riboside alpha-ketoglutarate prepared by the preparation method according to any one of claims 2 to 7, galactomannan, and vitamin C, wherein the weight ratio of the galactomannan to the vitamin C is 1:1-2, and the weight ratio of the galactomannan to the nicotinamide riboside alpha-ketoglutarate is 1:10-20.

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