Reduced beta-nicotinamide mononucleotide salts and compositions, methods of making and uses thereof

Abstract

The present application provides a reduced beta-nicotinamide mononucleotide salt compound shown in formula (I), especially relates to reduced beta-nicotinamide mononucleotide and its composition, preparation method and use. The salt compound of the present application or as an active ingredient of a pharmaceutical composition is used to improve NAD + in order to delay aging, and / or for preventing or treating diseases or symptoms caused or resulted from lack of NAD + , and / or for preventing and / or treating diseases or symptoms caused or resulted from lack of essential elements and / or essential amino acids in human body. In addition, compared with NMNH disodium salt crystal form and amorphous phase, the reduced beta-nicotinamide mononucleotide salt compound of the present application shows long-term sustained stability, anti-hygroscopicity, and is more beneficial to long-term storage and market promotion.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical raw materials for medicine and cosmetics, in particular to reduced β-nicotinamide mononucleotide and its composition, preparation method and use. BACKGROUND

[0002] As one of the hottest molecules in the anti-aging field, nicotinamide adenine dinucleotide (NAD + ) has become the center of anti-aging substances of all ages without exception. NAD + is an important coenzyme required for more than 500 enzymatic reactions, and is well known for its role in oxidation and reduction (Ansari and Raghava, 2010; Rajman et al., 2018; Stein and Imai, 2012). More and more studies indicate that increasing NAD + equivalents can significantly improve multi-organ function, including liver function, kidney function, heart function and skeletal muscle function (Canto et al., 2012; Mills et al., 2016; Rajman et al., 2018). NAD + can be synthesized in the de novo biosynthesis pathway using tryptophan, in the preiss-handler pathway using nicotinic acid (NA), and in the salvage pathway using nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) (Canto et al., 2015; Chiarugi et al., 2012; Johnson and Imai, 2018). In particular, as a key intermediate of NAD + , NAM, NR and NMN have been extensively studied for their potential therapeutic effects in many mouse disease models (Mills et al., 2016), among which NMN is considered the most suitable NAD + precursor at present, and NMN is currently in hot sales on the global market and is favored by consumers.

[0003] NMNH (molecular structure as shown in formula (A)) is named "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide" in Chinese, which is the reduced form of NMN, a new precursor of NAD + , has better NAD + promoting effect than NMN and other biological functions such as increasing cell antioxidant capacity, reducing fat accumulation, reducing inflammatory response and inhibiting tumor cell growth, etc., is a health-promoting reagent with significant commercial potential (WO2021098725A1).

[0004]

[0005] Human elements refer to chemical elements that make up the human body. The human body is composed of chemical elements, and there are more than 60 elements that make up the human body. In the element composition of a standard healthy adult, magnesium (Mg) accounts for 0.05%, and potassium (K) accounts for 0.35%, both of which are greater than 0.01%, and belong to human constant elements. Zinc (Zn), iron (Fe), copper (Cu) and manganese (Mn) are essential trace elements for the human body. When these elements are lacking, the growth and development of the human body will be affected, and even various clinical symptoms and diseases will be caused.

[0006] D-glucosamine, also known as glucosamine, glucosamine, aminoglucose, aminoglucose, 2-deoxyglucose, is a common amino sugar, which is a natural substance that can stimulate the human body to produce glycosaminoglycans to repair and form cartilage, and is often used to treat osteoarthritis. L-arginine is an encoding amino acid in protein synthesis, and is one of the eight essential amino acids for the human body. L-lysine is one of the essential amino acids for the human body, which can promote human development, enhance immune function, and improve the function of central nervous tissue. L-histidine is a semi-essential amino acid for the human body, which is used to treat gastric ulcers, anemia, and cardiovascular system diseases such as angina pectoris, aortitis, and heart failure.

[0007] NMNH is the reduced form of NMN, which is sensitive to air and easy to be oxidized, and is unstable, which makes it difficult to store for a long time and promote in the market. WO2023160405(A1) reports NMNH disodium salt compound and its crystal form, amorphous. There is no literature report on other salt types.

[0008] In addition, the current use of NMNH is relatively single, and cannot complement other human body required elements or compounds.

[0009] Therefore, there is an urgent need in the art to develop new salt types to improve product stability, facilitate market promotion, and also to supplement different essential elements, essential amino acids and the like for the human body. SUMMARY

[0010] The purpose of the present application is to develop a new salt type of NMNH with good product stability, convenient storage and market promotion, and also to supplement different essential elements and essential amino acids for the human body. Specifically, it relates to a reduced β-nicotinamide mononucleotide salt and its composition, preparation method and use.

[0011] In the first aspect of the present application, a reduced β-nicotinamide mononucleotide salt compound (NMNH-M) represented by formula (I) is provided:

[0012]

[0013] In the formula,

[0014] M is independently selected from the group consisting of Mg 2+ , Zn 2+ , Fe 3+ , Cu 2+ , Mn 2+ , and an organic substance;

[0015] when M is Mg 2+ , X = 1 and Y = 1 ;

[0016] when M is Zn 2+ , X = 1 and Y = 1 ;

[0017] when M is Fe 3+ , X = 2 and Y = 3 ;

[0018] when M is Cu 2+ , X = 1 and Y = 1 ;

[0019] when M is Mn 2+ , X = 1 and Y = 1 ;

[0020] said organic substance is selected from the group consisting of D-glucosamine, L-arginine, L-lysine, L-histidine.

[0021] In another preferred embodiment, M is further selected from the group consisting of ions of calcium and selenium.

[0022] In another preferred embodiment, M in the compound of formula (I) is Mg 2+ , and the compound of formula (I) is designated NMNH-Mg.

[0023] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of NMNH-Mg, NMNH-Zn, NMNH-Fe(III), NMNH-Cu(II), NMNH-Mn(II), NMNH-di(D-glucosamine), NMNH-D-glucosamine, NMNH-di(L-arginine), NMNH-L-arginine, NMNH-di(L-lysine), NMNH-L-lysine, NMNH-di(L-histidine), NMNH-L-histidine.

[0024] In another preferred embodiment, the compound is in amorphous form.

[0025] In another preferred embodiment, M is Mg 2+ , X = 1 and Y = 1.

[0026] In a second aspect of the present application, a method for preparing the compound of the first aspect is provided, comprising the steps of:

[0027] (1) adding reduced β-nicotinamide mononucleotide disodium salt into a first solvent, stirring and adjusting pH to 3-4 to obtain solution A, or generating reduced β-nicotinamide mononucleotide solution A in situ;

[0028] (2) adding a solution of inorganic salt or organic substance or organic salt into solution A obtained in step (1), adjusting pH, and stirring to obtain solution B;

[0029] (3) removing solvent from solution B obtained in step (2) and drying to obtain reduced β-nicotinamide mononucleotide salt compound.

[0030] In another preferred embodiment, the first solvent is selected from the group consisting of water, methanol, ethanol.

[0031] In another preferred embodiment, the inorganic salt is selected from the group consisting of MgCl2, KCl, CaCl2, ZnCl2, FeCl3, CuCl2, MnCl2, Mg(OH)2, KOH, Ca(OH)2, NaOH, Cu(OH)2.

[0032] In another preferred embodiment, the organic salt is selected from the group consisting of magnesium acetate, zinc acetate, D-glucosamine hydrochloride, L-arginine hydrochloride, L-lysine hydrochloride, L-histidine hydrochloride.

[0033] In another preferred embodiment, the organic substance is selected from D-glucosamine, L-arginine, L-lysine, L-histidine.

[0034] In another preferred embodiment, the molar ratio of reduced β-nicotinamide mononucleotide to the corresponding organic substance is 1:1-2.5, preferably 1:1-2.

[0035] In another preferred embodiment, the molar ratio of reduced β-nicotinamide mononucleotide to the inorganic salt is 1:0.5-1.1.

[0036] In another preferred embodiment, the molar ratio of reduced β-nicotinamide mononucleotide to the organic salt is 1:0.8-2.5, preferably 1:1-2.

[0037] In a third aspect of the present application, a pharmaceutical composition is provided, which contains the reduced β-nicotinamide mononucleotide salt compound of the first aspect or a pharmaceutically acceptable carrier thereof.

[0038] In another preferred embodiment, the pharmaceutically acceptable carrier is selected from the group consisting of saline, buffer, glucose, water, glycerol, ethanol, or a combination thereof.

[0039] In another preferred embodiment, the pharmaceutical composition is a tablet, capsule, lyophilized powder, solution, injection, dressing, etc.

[0040] In a fourth aspect of the present application, there is provided a method of preparing a pharmaceutical composition, comprising the steps of:

[0041] mixing the reduced β-nicotinamide mononucleotide salt-type compound of the first aspect with a pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition.

[0042] In a fifth aspect of the present application, there is provided use of the reduced β-nicotinamide mononucleotide salt-type compound of the first aspect or the pharmaceutical composition of the third aspect, for the manufacture of a product for elevating nicotinamide adenine dinucleotide (NAD + ) to delay aging, and / or for preventing or treating a disease or a symptom caused or resulted from the deficiency of NAD + .

[0043] In another preferred embodiment, the disease or symptom is selected from the group consisting of a symptom or a disease associated with aging, a symptom or a disease associated with decreased immunity, a metabolic disease or symptom, neurodegeneration, etc.

[0044] In another preferred embodiment, the disease or symptom associated with aging is selected from the group consisting of atrophy and collapse of skin tissue, dry, rough, slack, wrinkled, and leathery skin, lack of energy, muscle weakness, sarcopenia, easy fatigue, decreased cognitive ability, decreased memory, decreased cognitive ability, senile dementia, etc.

[0045] In another preferred embodiment, the disease or symptom associated with decreased immunity is selected from the group consisting of weakness, immune system disorder, arthritis, cancer, etc.

[0046] In another preferred embodiment, the metabolic disease or symptom is selected from the group consisting of endocrine disorder, metabolic disorder, diabetes, obesity, atherosclerosis, hypertension, metabolic dysfunction, etc.

[0047] In a sixth aspect of the present application, there is provided use of the reduced β-nicotinamide mononucleotide salt-type compound of the first aspect or the pharmaceutical composition of the third aspect, for the manufacture of a product for preventing and / or treating a disease or a symptom caused or resulted from the deficiency of an essential element for a human body.

[0048] In another preferred embodiment, the product is selected from the group consisting of a drug, a dietary supplement, or a nutritional supplement.

[0049] In another preferred embodiment, the essential element includes magnesium, calcium, zinc, iron, copper, manganese, selenium.

[0050] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0051] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0052] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0053] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0054] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0055] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0056] In another preferred embodiment, the disease or condition is selected from the group consisting of a magnesium deficiency related disease or condition, a calcium deficiency related disease or condition, a zinc deficiency related disease or condition, an iron deficiency related disease or condition, a copper deficiency related disease or condition, a manganese deficiency related disease or condition, a selenium deficiency related disease or condition.

[0057] In another preferred embodiment, the selenium deficiency related disease or symptom is selected from the group consisting of: decreased immunity, severe hair loss, skin symptoms, nervous system diseases, and dental damage, and long-term severe selenium deficiency can cause Keshan disease, Kashin-Beck disease and other serious diseases.

[0058] In another preferred embodiment, the essential element for human body is selected from the group consisting of: magnesium (Mg), zinc (Zn), iron (Fe), copper (Cu), and manganese (Mn).

[0059] In another preferred embodiment, the essential element further comprises calcium (Ca) and selenium (Se).

[0060] In a seventh aspect of the present application, there is provided a use of the reduced form of beta-nicotinamide mononucleotide salt compound according to the first aspect or the pharmaceutical composition according to the third aspect for the manufacture of a product for preventing and / or treating a disease or symptom caused or resulted from malnutrition, anorexia, and developmental failure.

[0061] In another preferred embodiment, the D-glucosamine deficiency related disease or symptom is selected from the group consisting of: joint inflammation and swelling, cartilage damage, and osteoarthritis.

[0062] In another preferred embodiment, the L-arginine deficiency related disease or symptom is selected from the group consisting of: congestive heart failure, cystitis, male erectile dysfunction, infertility, cardiovascular and cerebrovascular diseases, diabetes, hypertension, arteriosclerosis, and angina pectoris.

[0063] In another preferred embodiment, the L-lysine deficiency related disease or symptom is selected from the group consisting of: delayed height development, low immunity, lack of concentration, fatigue and weakness, anorexia, osteoporosis, and hypoproteinemia.

[0064] In another preferred embodiment, the L-histidine deficiency related disease or symptom is selected from the group consisting of: anemia and reduced hemoglobin, joint pain, rheumatoid arthritis, symptoms of anxiety and depression, fatigue and dizziness, inflammation of the skin and mucous membranes and dry or scaly skin lesions, poor kidney and liver function, eczema, allergy, hypertension, decreased cognitive ability, gastric ulcers, symptoms caused by kidney failure or kidney dialysis, poor growth and development in infants, and heart disease.

[0065] It should be understood that, within the scope of the present application, the above technical features of the present application and the technical features specifically described in the following (e.g., the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0066] Figure 1XRPD pattern of NMNH magnesium salt amorphous form is shown.

[0067] Figure 2 XRPD pattern of NMNH dipotassium salt amorphous form is shown.

[0068] Figure 3 XRPD pattern of NMNH zinc salt amorphous form is shown.

[0069] Figure 4 XRPD pattern of NMNH ferric salt amorphous form is shown.

[0070] Figure 5 XRPD pattern of NMNH ferrous salt amorphous form is shown.

[0071] Figure 6 XRPD pattern of NMNH cupric salt amorphous form is shown.

[0072] Figure 7 XRPD pattern of NMNH manganous salt amorphous form is shown.

[0073] Figure 8 XRPD pattern of NMNH inorganic salt amorphous form is shown. 1 H NMR pattern.

[0074] Figure 9 XRPD pattern of NMNH-di(D-glucosamine) salt amorphous form is shown.

[0075] Figure 10 XRPD pattern of NMNH-D-glucosamine salt amorphous form is shown.

[0076] Figure 11 XRPD pattern of NMNH-di(L-arginine) salt amorphous form is shown.

[0077] Figure 12 XRPD pattern of NMNH-L-arginine salt amorphous form is shown.

[0078] Figure 13 XRPD pattern of NMNH-di(L-lysine) salt amorphous form is shown.

[0079] Figure 14 XRPD pattern of NMNH-L-lysine salt amorphous form is shown.

[0080] Figure 15 XRPD pattern of NMNH-di(L-histidine) salt amorphous form is shown.

[0081] Figure 16 XRPD pattern of NMNH-L-histidine salt amorphous form is shown.

[0082] Figure 17 shows the H NMR spectrum of NMNH-D-glucosamine salt 1 H NMR spectrum.

[0083] Figure 18 shows the H NMR spectrum of NMNH-D-glucosamine salt 1 H NMR spectrum.

[0084] Figure 19 shows the H NMR spectrum of NMNH-di(L-arginine) salt 1 H NMR spectrum.

[0085] Figure 20 shows the H NMR spectrum of NMNH-L-arginine salt 1 H NMR spectrum.

[0086] Figure 21 shows the H NMR spectrum of NMNH-di(L-lysine) salt 1 H NMR spectrum.

[0087] Figure 22 shows the H NMR spectrum of NMNH-L-lysine salt 1 H NMR spectrum.

[0088] Figure 23 shows the H NMR spectrum of NMNH-di(L-histidine) salt 1 H NMR spectrum.

[0089] Example 1. Preparation of NMNH magnesium salt shows the H NMR spectrum of NMNH-L-histidine salt 1 H NMR spectrum. DETAILED DESCRIPTION

[0090] The present inventors, through extensive and intensive research, have for the first time unexpectedly developed a reduced form of β-nicotinamide mononucleotide salt type compound (NMNH-M), wherein M is independently selected from the group consisting of Mg 2+ , Zn 2+ , Fe 3+ , Cu 2+ , Mn 2+ . The compound of the present invention or as an active ingredient of a pharmaceutical composition for elevating NAD + for delaying aging, and / or for preventing or treating diseases due to the lack of NAD +The disease or symptom caused or induced can also be used for preventing and / or treating the disease or symptom caused or induced by lack of essential elements and / or essential amino acids in human body. The research of the present application shows that the reduced β-nicotinamide mononucleotide salt type compound of the present application shows long-term sustained stability, anti-hygroscopicity, and is more beneficial for long-term storage and market promotion compared with NMNH disodium salt crystal form and amorphous phase. In addition, the compound of the present application meets the shelf life of commodity and is suitable for use in pharmaceutical compositions, cosmetics and the like. On this basis, the inventors complete the present application.

[0091] Term explanation

[0092] As used herein, the term NMNH is named as "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide" in Chinese, which is a reduced form of β-NMN and is a new precursor of supplementing NAD + .

[0093] The "NMNH" "reduced nicotinamide mononucleotide" and its salts described herein all refer to "β configuration".

[0094] In the present application, the compound of formula (I) is

[0095] M is Mg 2+ , the compound of formula (I) is recorded as NMNH-Mg;

[0096] M is Ca 2+ , the compound of formula (I) is recorded as NMNH-Ca;

[0097] M is K 1+ , the compound of formula (I) is recorded as NMNH-K2;

[0098] M is Na 1+ , the compound of formula (I) is recorded as NMNH-Na2;

[0099] M is Zn 2+ , the compound of formula (I) is recorded as NMNH-Zn;

[0100] M is Fe 3+ , the compound of formula (I) is recorded as NMNH-Fe(III);

[0101] M is Fe 2+ , the compound of formula (I) is recorded as NMNH-Fe(II);

[0102] M is Cu 2+ , the compound of formula (I) is recorded as NMNH-Cu(II);

[0103] M is Mn 2+ , the compound of formula (I) is recorded as NMNH-Mn(II);

[0104] M is Se 2+ When M is Se, the compound of formula (I) is noted as NMNH-Se (II).

[0105] As used herein, the terms "reduced β-nicotinamide mononucleotide salt type compound", "NMNH-M", "compound of the present invention" are used interchangeably. The NMNH-M of the present invention is a salt of reduced β-nicotinamide mononucleotide with a corresponding metal ion or organic. If not otherwise specified, "compound of the present invention" herein refers to the compound in β configuration.

[0106] Process for preparing a reduced β-nicotinamide mononucleotide salt type compound

[0107] In the present invention, the process for preparing the compound comprises the steps of:

[0108] (1) adding reduced β-nicotinamide mononucleotide disodium salt into a first solvent, stirring to adjust pH to 3-4 to obtain solution A, or generating reduced β-nicotinamide mononucleotide solution A in situ through reaction;

[0109] (2) adding a solution of inorganic salt or organic or organic salt into solution A obtained in step (1), adjusting pH, and stirring to obtain solution B;

[0110] (3) removing the solvent from solution B obtained in step (2) and drying to obtain the reduced β-nicotinamide mononucleotide salt type compound.

[0111] Preferably, the first solvent is selected from the group consisting of water, methanol, ethanol.

[0112] Preferably, the inorganic salt is selected from the group consisting of MgCl2, KCl, CaCl2, ZnCl2, FeCl3, CuCl2, MnCl2, Mg(OH)2, KOH, Ca(OH)2, NaOH, Cu(OH)2.

[0113] Preferably, the organic is selected from the group consisting of D-glucosamine, L-arginine, L-lysine, L-histidine.

[0114] Preferably, the organic salt is selected from the group consisting of magnesium acetate, zinc acetate, D-glucosamine hydrochloride, L-arginine hydrochloride, L-lysine hydrochloride, L-histidine hydrochloride.

[0115] Pharmaceutical composition

[0116] The reduced β-nicotinamide mononucleotide salt type compound of the present invention can be used to elevate NAD + for delaying aging, and / or for preventing or treating diseases caused by lack of NAD +Diseases or symptoms caused or resulting from the use of the reduced β-nicotinamide mononucleotide salt compound of the present invention can generally be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium. The formulated pharmaceutical composition can be administered by conventional routes, including (but not limited to): intramuscular, intraperitoneal, intravenous, subcutaneous, intradermal, or topical administration.

[0117] The reduced β-nicotinamide mononucleotide salt compound of the present invention can be directly used to treat diseases, such as NAD deficiency. + Diseases or symptoms caused or resulting from the lack of essential elements or essential amino acids for the human body.

[0118] Preferably, the essential elements for the human body are selected from the following group: magnesium (Mg), calcium (Ca), potassium (K), zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), and selenium (Se).

[0119] Preferably, the amino acid is selected from the group consisting of L-arginine, L-lysine, and L-histidine.

[0120] The organic substance in the reduced β-nicotinamide mononucleotide organic salt compound is selected from the following group: D-glucosamine, L-arginine, L-lysine, and L-histidine.

[0121] The present invention also provides a pharmaceutical composition, which is formed by mixing the reduced β-nicotinamide mononucleotide salt compound represented by formula (I) with a pharmaceutically acceptable carrier.

[0122] The pharmaceutical composition of the present invention contains a safe and effective amount (eg, 0.001-99.9 wt%, more preferably 0.01-90 wt%) of the reduced β-nicotinamide mononucleotide salt compound of the present invention and a pharmaceutically acceptable carrier or excipient.

[0123] A preferred pharmaceutical composition comprises one or more of NMNH-Na2, NMNH-Mg, NMNH-Ca, NMNH-Zn, NMNH-Fe(III), NMNH-Cu(II), NMNH-Mn(II), NMNH-di(D-glucosamine), NMNH-D-glucosamine, NMNH-di(L-arginine), NMNH-L-arginine, NMNH-di(L-lysine), NMNH-L-lysine, NMNH-di(L-histidine), NMNH-L-histidine, etc., wherein the Na content is ≤ 3000 mg, the K content is ≤ 2400 mg, the Mg content is ≤ 400 mg, the Ca content is ≤ 1000 mg, the Zn content is ≤ 15.0 mg, the Fe content is ≤ 20.0 mg, the Cu content is ≤ 1.5 mg, the Mn content is ≤ 4.0 mg, the D-glucosamine content is ≤ 1500 mg, the L-arginine content is ≤ 4000 mg, the L-lysine content is ≤ 2500 mg, and the L-histidine content is ≤ 20 mg.

[0124] More preferably, in the composition, the Na content is ≤ 138 mg, the K content is ≤ 234 mg, the Mg content is ≤ 73 mg, the Ca content is ≤ 120 mg, the Zn content is ≤ 15.0 mg, the Fe content is ≤ 20.0 mg, the Cu content is ≤ 1.5 mg, the Mn content is ≤ 4.0 mg, the D-glucosamine content is ≤ 1000 mg, the L-arginine content is ≤ 1000 mg, the L-lysine content is ≤ 870 mg, and the L-histidine content is ≤ 20 mg.

[0125] More preferably, in the composition, the Na content is ≤ 83 mg, the K content is ≤ 140 mg, the Mg content is ≤ 44 mg, the Ca content is ≤ 72 mg, the Zn content is ≤ 15.0 mg, the Fe content is ≤ 20.0 mg, the Cu content is ≤ 1.5 mg, the Mn content is ≤ 4.0 mg, the D-glucosamine content is ≤ 640 mg, the L-arginine content is ≤ 620 mg, the L-lysine content is ≤ 520 mg, and the L-histidine content is ≤ 20 mg.

[0126] More preferably, in the composition, the Na content is 55 to 83 mg, the K content is 94 to 140 mg, the Mg content is 29 to 44 mg, the Ca content is 48 to 72 mg, the Zn content is 0.8 to 15.0 mg, the Fe content is 1.5 to 20.0 mg, the Cu content is 0.1 to 1.5 mg, the Mn content is 0.3 to 4.0 mg, the D-glucosamine content is 200 to 640 mg, the L-arginine content is 200 to 620 mg, the L-lysine content is 170 to 520 mg, and the L-histidine content is 6 to 15 mg.

[0127] Such carriers include, but are not limited to, saline, buffers, dextrose, water, glycerol, ethanol, and combinations thereof. Pharmaceutical formulations should be matched to the mode of administration. The pharmaceutical compositions of the present application can be prepared in the form of injectable solutions, for example, by conventional methods using physiologically acceptable diluents or carriers such as saline or aqueous dextrose and other auxiliary agents. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injectable solutions, tablets, and capsules are preferably manufactured under aseptic conditions. The amount of active ingredient administered is a therapeutically effective amount, for example, from about 1 microgram per kilogram of body weight to about 5 milligrams per kilogram of body weight per day.

[0128] In addition, other chemical agents having no pharmacological effects can be added or not added in the pharmaceutical composition of the present application as compounding ingredients such as pH adjusters, stabilizers, and solubilizers.

[0129] The pharmaceutical composition of the present application can be prepared in unit dosage or multiple dosage forms, and can be administered alone or in combination, and can be applied to agents and / or drug potentiators for diseases or symptoms caused or resulted from the lack of NAD + in the human body.

[0130] The term "treatment" as used herein refers to the administration of a compound of the present application to reduce a disease or condition in a host. Thus, the term "treatment" includes preventing the onset of a condition in a host, especially when the host is predisposed to the disease but has not yet been diagnosed with the disease; inhibiting the condition; and / or alleviating or curing the condition. In the case of using the method of the present application for preventing a condition, it is understood that the term "prevention" does not require complete inhibition of the disease. The term "prevention" as used herein includes the ability of a person skilled in the art to identify a population susceptible to the disease, so that the compound of the present application can be used before the onset of the disease. The term does not mean that the condition can be completely avoided. The compound determined by the screening method of the present application can be used in combination with other compounds.

[0131] Compared with the prior art, the present application has the following advantages:

[0132] (1) The compound of the present application can be used to increase NAD + in the human body to delay aging, and / or to prevent or treat diseases or symptoms caused or resulted from the lack of NAD + in the human body, and can also be used to prevent and / or treat diseases or symptoms caused or resulted from the lack of essential elements or essential amino acids in the human body.

[0133] (2) The reduced β-nicotinamide mononucleotide salt compound of the present application has better stability, lower hygroscopicity, and is more conducive to long-term storage and market promotion compared with the crystalline and amorphous solid forms of NMNH disodium salt.

[0134] (3) The reduced β-nicotinamide mononucleotide salt compound of the present application has a simple preparation method and is suitable for industrial production.

[0135] (4) The reduced β-nicotinamide mononucleotide salt compound of the present invention can be used in pharmaceutical compositions, cosmetics, and the like.

[0136] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0137] Figure 1

[0138] Add 1.7 kg of β-NMN and 0.94 kg of sodium dithionite to 10 L of saturated sodium bicarbonate aqueous solution, stir overnight at room temperature, filter the clear solution, and adjust the pH of the clear solution to 3-4 with 37% hydrochloric acid. Desalt the solution by electrodialysis until the conductivity drops to 50-100 μS. 0.30 kg of magnesium hydroxide was added; alternatively, 0.49 kg of magnesium chloride and 0.83 kg of ammonium chloride were added, and the pH of the solution was adjusted to 10 with sodium hydroxide; the obtained NMNH magnesium salt aqueous solution was added dropwise to 20 L of stirred ethanol to precipitate NMNH magnesium salt solid, which was filtered and the filter cake was washed with a mixed solvent (1 L of water and 2 L of ethanol). The filter cake was vacuum dried at 20-30 ° C to obtain 1.51 kg of NMNH magnesium salt yellow solid with a yield of 82.8%. The purity was 99.6% as measured by HPLC, the moisture content was 0.8%, and the Mg content was 6.7% wt. XRPD test showed that it was an amorphous solid. The XRPD spectrum is as shown below. Figure 8 As shown, 1 H NMR spectrum Example 2. Preparation of NMNH dipotassium salt shown.

[0139] Figure 2

[0140] 10 L saturated sodium bicarbonate aqueous solution was added with 1.7 kg β-NMN, 0.94 kg sodium hydrosulfite, stirred at room temperature overnight, filtered to get the clear solution, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 0.57 kg potassium hydroxide was added; or 0.76 kg potassium chloride was added, and the pH of the solution was adjusted to 10 with ammonia water; the obtained NMNH dipotassium salt aqueous solution was added dropwise into 30 L stirring ethanol, and the NMNH dipotassium salt solid was precipitated, filtered, the filter cake was washed with mixed solvent (1 L water and 3 L ethanol), and the filter cake was vacuum dried at 20-30 °C to obtain 1.57 kg NMNH dipotassium salt yellow solid, the yield was 75.3%, the purity was 99.7% by HPLC, the moisture was 3.8%, the K content was 18.9% wt, and it was tested by XRPD to be an amorphous solid, the XRPD spectrum is shown in Example 3. Preparation of NMNH zinc salt .

[0141] Figure 3

[0142] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium hydrosulfite, stirred at room temperature overnight, filtered to get the clear solution, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 81.6 g zinc chloride was added, and the pH of the solution was adjusted to 10 with ammonia water to obtain an NMNH zinc salt aqueous solution, which was added dropwise into 2 L stirring methanol, and the NMNH zinc salt solid was precipitated, filtered, the filter cake was washed with mixed solvent (200 ml water and 400 ml methanol), and the filter cake was vacuum dried at 20-30 °C to obtain 214.0 kg NMNH zinc salt yellow solid, the yield was 89.5%, the moisture was 0.2%, the Zn content was 16.3% wt, and it was tested by XRPD to be an amorphous solid, the XRPD spectrum is shown in Example 4. Preparation of NMNH ferric salt .

[0143] Figure 4

[0144] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 64.7 g of iron (III) chloride was added, the pH of the solution was adjusted to 10 with ammonia water, to obtain a NMNH ferric salt aqueous solution, which was added dropwise into 2 L stirring methanol, NMNH ferric salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml methanol), the filter cake was dried at 20-30 °C under vacuum to obtain 199.6 g of NMNH ferric salt brownish solid, the yield was 89.8%, the moisture content was 0.3%, the Fe content was 10.0% wt, which was tested by XRPD to be an amorphous solid, the XRPD spectrum is shown in Example 5. Preparation of NMNH ferrous salt .

[0145] Figure 5

[0146] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 64.7 g of iron (III) chloride was added, the pH of the solution was adjusted to 10 with ammonia water, to obtain a NMNH ferric salt aqueous solution, which was added dropwise into 2 L stirring methanol, NMNH ferric salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml methanol), the filter cake was dried at 20-30 °C under vacuum to obtain 199.6 g of NMNH ferric salt brownish solid, the yield was 89.8%, the moisture content was 0.3%, the Fe content was 10.0% wt, which was tested by XRPD to be an amorphous solid, the XRPD spectrum is shown in Example 6. Preparation of NMNH cupric salt .

[0147] Figure 6

[0148] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium hydrosulfite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 58.4 g copper (II) hydroxide was added; or 80.5 g copper (II) chloride was added, the pH of the solution was adjusted to 10 with sodium hydroxide; NMNH bivalent copper salt aqueous solution was obtained, which was added dropwise into 2 L stirring methanol, NMNH bivalent copper salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml methanol), the filter cake was dried at 20-30 °C under vacuum, 211.1 g NMNH bivalent copper salt green solid was obtained, the yield was 88.7%, the moisture was 0.2%, the Cu content was 15.9% wt, which was tested by XRPD and showed that it was an amorphous solid, the XRPD spectrum was shown in Example 7. Preparation of NMNH manganous salt .

[0149] Figure 7

[0150] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium hydrosulfite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 58.4 g copper (II) hydroxide was added; or 80.5 g copper (II) chloride was added, the pH of the solution was adjusted to 10 with sodium hydroxide; NMNH bivalent copper salt aqueous solution was obtained, which was added dropwise into 2 L stirring methanol, NMNH bivalent copper salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml methanol), the filter cake was dried at 20-30 °C under vacuum, 211.1 g NMNH bivalent copper salt green solid was obtained, the yield was 88.7%, the moisture was 0.2%, the Cu content was 15.9% wt, which was tested by XRPD and showed that it was an amorphous solid, the XRPD spectrum was shown in Example 8. Preparation of NMNH-di(D-glucosamine) salt (1:2) .

[0151] Figure 9

[0152] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium hydrosulfite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 96.5 g D-glucosamine was added to obtain NMNH-D-glucosamine salt aqueous solution, which was added dropwise into 2 L stirring ethanol, NMNH-D-glucosamine salt solid was precipitated, filtered, the filter cake was washed with mixed solvent (200 ml water and 400 ml ethanol), the filter cake was dried at 20-30 °C under vacuum to obtain 229.1 g NMNH-D-glucosamine salt solid, the yield was 74.3%, which was tested by XRPD and showed that it was an amorphous solid, the XRPD spectrum is shown in Figure 17 , 1 The H NMR spectrum is shown in Example 9. Preparation of NMNH-D-glucosamine salt (1:1) .

[0153] Figure 10

[0154] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium hydrosulfite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 96.5 g D-glucosamine was added to obtain NMNH-D-glucosamine salt aqueous solution, which was added dropwise into 2 L stirring ethanol, NMNH-D-glucosamine salt solid was precipitated, filtered, the filter cake was washed with mixed solvent (200 ml water and 400 ml ethanol), the filter cake was dried at 20-30 °C under vacuum to obtain 229.1 g NMNH-D-glucosamine salt solid, the yield was 74.3%, which was tested by XRPD and showed that it was an amorphous solid, the XRPD spectrum is shown in Figure 18 , 1 The H NMR spectrum is shown in Example 10. Preparation of NMNH-di(L-arginine) salt (1:2) .

[0155] Figure 11

[0156] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 187.6 g L-arginine was added to obtain NMNH-di(L-arginine) salt aqueous solution, which was added dropwise into 2 L stirring ethanol, NMNH-di(L-arginine) salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml ethanol), the filter cake was dried at 20-30 °C under vacuum to obtain 260.1 g NMNH-di(L-arginine) salt solid, the yield was 63.5%, which was tested by XRPD to be amorphous solid, the XRPD spectrum is shown in Figure 19 , 1 The H NMR spectrum is shown in Example 11. Preparation of NMNH-L-arginine salt (1:1) .

[0157] Figure 12

[0158] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, the clear solution was obtained by filtration, the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 187.6 g L-arginine was added to obtain NMNH-di(L-arginine) salt aqueous solution, which was added dropwise into 2 L stirring ethanol, NMNH-di(L-arginine) salt solid was precipitated, the filter cake was washed with mixed solvent (200 ml water and 400 ml ethanol), the filter cake was dried at 20-30 °C under vacuum to obtain 260.1 g NMNH-di(L-arginine) salt solid, the yield was 63.5%, which was tested by XRPD to be amorphous solid, the XRPD spectrum is shown in Figure 20 , 1 The H NMR spectrum is shown in Example 12. Preparation of NMNH-di(L-lysine) salt (1:2) .

[0159] Figure 13

[0160] 200g β-NMN and 110g sodium dithionite were added to 1.2L saturated sodium bicarbonate aqueous solution, stirred at room temperature overnight, filtered to obtain a clear solution, and the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution dropped to 50-100μS. 157.5g L-lysine was added to obtain an NMNH-di(L-lysine) salt aqueous solution, which was added dropwise to a stirred 2L ethanol to precipitate NMNH-di(L-lysine) salt solid, filtered, and the filter cake was washed with a mixed solvent (200ml water mixed with 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 259.9g NMNH-di(L-lysine) salt solid, with a yield of 69.1%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is as shown below. Figure 21 As shown, 1 H NMR spectrum Example 13. Preparation of NMNH-L-lysine salt (1:1) shown.

[0161] Figure 14

[0162] 200g β-NMN and 110g sodium dithionite were added to 1.2L saturated sodium bicarbonate aqueous solution, stirred at room temperature overnight, filtered to obtain a clear solution, and the pH of the clear solution was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution dropped to 50-100μS. 78.7g L-lysine was added to obtain an aqueous solution of NMNH-L-lysine salt, which was added dropwise to a stirred 2L ethanol to precipitate NMNH-L-lysine salt solid, filtered, and the filter cake was washed with a mixed solvent (200ml water mixed with 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 197.5g NMNH-L-lysine salt solid, with a yield of 68.4%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is as shown below. Figure 22 As shown, 1 H NMR spectrum Example 14. Preparation of NMNH-di(L-histidine) salt (1:2) shown.

[0163] Figure 15

[0164] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, and the filtrate was obtained by filtration. The pH of the filtrate was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 167.1 g L-histidine was added to obtain an aqueous solution of NMNH-di(L-histidine) salt, which was added dropwise into 2 L stirring ethanol to precipitate NMNH-di(L-histidine) salt solid. The filter cake was washed with a mixed solvent (200 ml water and 400 ml ethanol) and dried at 20-30 °C under vacuum to obtain 277.0 g NMNH-di(L-histidine) salt solid, with a yield of 71.6%. XRPD test showed that it was an amorphous solid, and the XRPD spectrum is shown in Figure 23 , 1 The H NMR spectrum is shown in Example 15. Preparation of NMNH-L-histidine salt (1:1) .

[0165] Figure 16

[0166] 1.2 L saturated sodium bicarbonate aqueous solution was added with 200 g β-NMN, 110 g sodium dithionite, stirred at room temperature overnight, and the filtrate was obtained by filtration. The pH of the filtrate was adjusted to 3-4 with 37% hydrochloric acid. The solution was desalted by electrodialysis until the conductivity of the solution was reduced to 50-100 μS. 167.1 g L-histidine was added to obtain an aqueous solution of NMNH-di(L-histidine) salt, which was added dropwise into 2 L stirring ethanol to precipitate NMNH-di(L-histidine) salt solid. The filter cake was washed with a mixed solvent (200 ml water and 400 ml ethanol) and dried at 20-30 °C under vacuum to obtain 277.0 g NMNH-di(L-histidine) salt solid, with a yield of 71.6%. XRPD test showed that it was an amorphous solid, and the XRPD spectrum is shown in Figure 24 , 1 The H NMR spectrum is shown in Example 16. Screening of NMNH salt forms and investigation of their properties .

[0167] ​

[0168] The performance of NMNH various salt types was investigated by accelerated experiment, and the results are shown in Table 1 below:

[0169] Table 1: Performance of NMNH various salt types

[0170]

[0171] From the above data, it can be seen that:

[0172] The amorphous NMNH-K2 salt has similar properties as the amorphous NMNH-Na2 salt reported in WO2023160405A1, at 25℃, 65% RH, open for 1 day, the powder absorbs water and becomes oil, the purity decreases from 99.61% to 99.24%.

[0173] The NMNH-Mg salt remains unchanged in appearance, purity (99.53%) and moisture (0.23%) at 25℃, 65% RH, open for 30 days. The NMNH-Na2 salt reported in WO2023160405A1 has a moisture content as high as 19%-30%. Compared with the NMNH-Na2 salt, the amorphous NMNH-Mg salt has better stability, lower moisture, stronger anti-oxidation and anti-hygroscopicity, and has significant superior performance.

[0174] The NMNH-Zn salt, NMNH-Fe(III) salt, NMNH-Cu(II) salt, NMNH-Mn(II) salt remain unchanged in appearance, color, and moisture at 25℃, 65% RH, open for 30 days, and also have higher stability, anti-oxidation and anti-hygroscopicity than the NMNH-Na2 salt.

[0175] The NMNH-di(D-glucosamine) salt (1:2), NMNH-D-glucosamine salt (1:1), NMNH-di(L-arginine) salt (1:2), NMNH-L-arginine salt (1:1), NMNH-di(L-lysine) salt (1:2), NMNH-L-lysine salt (1:1), NMNH-di(L-histidine) salt (1:2), NMNH-L-histidine salt (1:1) all belong to the organic salts of NMNH (salts with organic compounds). Compared with inorganic salts (Na, K, etc.), these salted organic compounds have certain hydrophobicity, so they have stronger anti-hygroscopicity and show consistency with the data in the above table.

[0176] All the documents mentioned in the present application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that, after reading the above teaching of the present application, those skilled in the art can make various modifications or amendments to the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A reduced β-nicotinamide mononucleotide salt compound (NMNH-M) represented by formula (I): (Ⅰ) Where, M is independently selected from the group consisting of Mg 2+ 、Zn 2+ 、Fe 3+ 、Cu 2+ 、Mn 2+ , organic matter; When M is Mg 2+ When X=1, Y=1; When M is Zn 2+ When X=1, Y=1; When M is Fe 3+ When X=2, Y=3; When M is Cu 2+ When X=1, Y=1; When M is Mn 2+ When X=1, Y=1; The compound of formula (I) is selected from the group consisting of NMNH-Mg, NMNH-Zn, NMNH-Fe(III), NMNH-Cu(II), NMNH-Mn(II), NMNH-di(D-glucosamine) salt, NMNH-D-glucosamine salt, NMNH-di(L-arginine) salt, NMNH-L-arginine salt, NMNH-di(L-lysine) salt, NMNH-L-lysine salt, NMNH-di(L-histidine) salt, and NMNH-L-histidine salt; the compound is an amorphous substance; The XRPD spectrum of NMNH-Mg is shown in Figure 1 ; The XRPD spectrum of NMNH-Zn is shown in Figure 3; The XRPD spectrum of NMNH-Fe(III) is shown in Figure 4 ; The XRPD spectrum of NMNH-Cu(II) is shown in Figure 6 ; The XRPD spectrum of NMNH-Mn(II) is shown in Figure 7 The XRPD spectrum of NMNH-di(D-glucosamine) is shown in Figure 9; The XRPD spectrum of NMNH-D-glucosamine is shown in Figure 10; The XRPD spectrum of NMNH-di(L-arginine) is shown in Figure 11; The XRPD spectrum of NMNH- L-arginine salt is shown in Figure 12; The XRPD spectrum of NMNH-di(L-lysine) is shown in Figure 13; The XRPD spectrum of NMNH- L -lysine is shown in Figure 14; The XRPD spectrum of NMNH-di(L-histidine) is shown in Figure 15; The XRPD spectrum of NMNH-L-histidine is shown in FIG16 .

2. The compound according to claim 1, wherein The compound of formula (I) is selected from the group consisting of NMNH-Mg, NMNH-Zn, NMNH-Fe(III), NMNH-Cu(II), and NMNH-Mn(II).

3. The compound according to claim 1, wherein The compound of formula (I) is selected from the following group: NMNH-di(D-glucosamine) salt, NMNH-D-glucosamine salt, NMNH-di(L-arginine) salt, NMNH-L-arginine salt, NMNH-di(L-lysine) salt, NMNH-L-lysine salt, NMNH-di(L-histidine) salt, NMNH-L-histidine salt.

4. A method for preparing the compound according to claim 1, characterized in that: Including steps: (1) adding reduced β-nicotinamide mononucleotide disodium salt to the first solvent, stirring and adjusting the pH to 3-4 to obtain solution A, or generating reduced β-nicotinamide mononucleotide solution A in situ through reaction; (2) adding an inorganic salt or an organic substance or a solution of an organic salt to the solution A obtained in step (1), adjusting the pH, and stirring to react to obtain a solution B; (3) removing the solvent from the solution B obtained in step (2) and drying the solution to obtain a reduced β-nicotinamide mononucleotide salt compound; The inorganic salt is selected from the group consisting of MgCl2, ZnCl2, FeCl3, CuCl2, MnCl2, Mg(OH)2, and Cu(OH)2; The organic matter is selected from the group consisting of D-glucosamine, L-arginine, L-lysine, and L-histidine; The organic salt is selected from the following group: magnesium acetate, zinc acetate, D-glucosamine hydrochloride, L-arginine hydrochloride, L-lysine hydrochloride, and L-histidine hydrochloride.

5. The method according to claim 4, wherein The first solvent is selected from the group consisting of water, methanol, and ethanol.

6. The method according to claim 4, wherein The molar ratio of the reduced β-nicotinamide mononucleotide to the corresponding organic matter is 1:1-2.

5.

7. The method according to claim 4, wherein The molar ratio of the reduced β-nicotinamide mononucleotide to the corresponding organic matter is 1:1-2.

8. The method according to claim 4, wherein The molar ratio of the reduced β-nicotinamide mononucleotide to the inorganic salt is 1:0.5-1.

1.

9. A pharmaceutical composition, characterized in that It contains the reduced β-nicotinamide mononucleotide salt compound according to claim 1 or a pharmaceutically acceptable carrier thereof.

10. A method for preparing a pharmaceutical composition, characterized in that: It includes the steps: The reduced β-nicotinamide mononucleotide salt compound according to claim 1 is mixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

11. A use of the reduced β-nicotinamide mononucleotide salt compound according to claim 1 or the pharmaceutical composition according to claim 9, characterized in that: For use in preparations for the prevention or treatment of NAD deficiency + Products that cause or contribute to diseases or symptoms associated with aging.

12. The use according to claim 11, characterized in that The diseases or symptoms associated with aging phenomena are selected from the following group: atrophy and collapse of skin tissue, dryness, roughness, sagging, wrinkles, pellagra, lack of energy, and fatigue.

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