Reduced β-nicotinamide mononucleotide salt and composition thereof, preparation method therefor and use thereof

Abstract

Provided is a reduced β-nicotinamide mononucleotide salt-type compound as represented by formula (I), and particularly provided are a reduced β-nicotinamide mononucleotide salt and a composition thereof, a preparation method therefor, and a use thereof. The salt-type compound may serve as an active ingredient in a pharmaceutical composition for enhancing NAD+ to delay aging and / or for preventing or treating diseases or symptoms induced or caused by NAD+ deficiency and for preventing and / or treating diseases or symptoms induced or caused by deficiencies in essential elements and / or essential amino acids of the human body. In addition, compared with NMNH disodium salt crystalline and amorphous forms, the reduced β-nicotinamide mononucleotide salt-type compound exhibits long-term stability and moisture absorption resistance and is more beneficial to long-term storage and market promotion.

Description

Reduced β-nicotinamide mononucleotide salt and its composition, preparation method and use Technical Field

[0001] The present invention relates to the field of chemical raw materials for medicines, health products, cosmetics and food additives, and in particular to a reduced β-nicotinamide mononucleotide salt and a composition, preparation method and use thereof. Background Art

[0002] As one of the most popular molecules in the anti-aging field, nicotinamide adenine dinucleotide (NAD + ) has become the core of anti-aging substances throughout the ages. + It 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 + Equivalent doses can significantly improve multiple organ functions, including liver function, kidney function, heart function, and skeletal muscle function (Canto et al., 2012; Mills et al., 2016; Rajman et al., 2018). + It can be synthesized using tryptophan in the de novo biosynthesis pathway, nicotinic acid (NA) in the preiss-handler pathway, and nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) in the salvage pathway (Canto et al., 2015; Chiarugi et al., 2012; Johnson and Imai, 2018). In particular, as NAD + The key intermediates, 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 currently considered the most suitable NAD + Precursor, and currently NMN is hot-selling in the global market and is highly favored by consumers.

[0003] NMNH (molecular structure as shown in formula (A)) is called "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide" in Chinese. It is the reduced form of NMN and is a supplement to NAD. + A new precursor of NAD with better NMN properties +The promoting effect and other biological functions such as increasing cellular antioxidant capacity, reducing fat accumulation, reducing inflammatory response and inhibiting tumor cell growth are considered to be health-promoting agents with significant commercial potential (WO2021098725A1).

[0004] Human elements refer to the chemical components that make up the human body. The human body is composed of over 60 chemical elements. In the elemental composition of a typical healthy adult, magnesium (Mg) accounts for 0.05% and potassium (K) for 0.35%, both exceeding 0.01%, making them considered constant elements in the human body. Zinc (Zn), iron (Fe), copper (Cu), and manganese (Mn) are essential trace elements for the human body. Deficiencies in these elements can affect growth and development, and can even lead to various clinical symptoms and illnesses.

[0005] D-Glucosamine, also known as glucosamine, glucosamine, glucosamine, 2-deoxyglucosamine, is a common amino sugar and a natural substance that stimulates the body's production of glycosaminoglycans to repair and form cartilage. It is often used to treat osteoarthritis. L-Arginine is an amino acid encoded in protein synthesis and is one of the eight essential amino acids for the human body. L-Lysine is an essential amino acid for the human body that promotes human development, enhances immune function, and improves the function of central nervous system tissues. L-Histidine is a semi-essential amino acid for the human body used to treat gastric ulcers, anemia, and cardiovascular diseases such as angina pectoris, aortitis, and heart failure.

[0006] NMNH is the reduced form of NMN. It is air-sensitive, easily oxidized, and unstable, making it unsuitable for long-term storage and market promotion. WO2023160405(A1) reports on the disodium salt of NMNH and its crystalline and amorphous forms. Other salt forms have not yet been reported.

[0007] In addition, the current usage of NMNH is relatively simple and cannot complement other elements or compounds needed by the human body.

[0008] Therefore, there is an urgent need in this field to develop new salt types to improve product stability, facilitate market promotion, and also supplement different essential elements and essential amino acids for the human body.

[0009] Summary of the Invention

[0010] The present invention aims to develop a new NMNH salt form that has good product stability, is easy to store and market, and can also 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 invention, a reduced β-nicotinamide mononucleotide salt compound (NMNH-M) is provided, represented by formula (I):

[0012] Where,

[0013] M is independently selected from the group consisting of Mg 2+ 、Zn 2+ 、Fe 3+ 、Cu 2+ 、Mn 2+ , organic matter;

[0014] When M is Mg 2+ When X=1, Y=1;

[0015] When M is Zn 2+ When X=1, Y=1;

[0016] When M is Fe 3+ When X=2, Y=3;

[0017] When M is Cu 2+ When X=1, Y=1;

[0018] When M is Mn 2+ When X=1, Y=1;

[0019] The organic matter is selected from the following group: D-glucosamine, L-arginine, L-lysine, and L-histidine.

[0020] In another preferred embodiment, the M is further selected from the following group of metal ions: calcium and selenium.

[0021] In another preferred embodiment, M in the compound of formula (I) is Mg 2+ When Mg is Mg-NMNH-Mg, the compound of formula (I) is recorded as NMNH-Mg.

[0022] In another preferred embodiment, the compound of formula (I) is selected from the following group: 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 salt, NMNH-di(L-lysine), NMNH-L-lysine, NMNH-di(L-histidine), NMNH-L-histidine.

[0023] In another preferred embodiment, the compound is an amorphous substance.

[0024] In another preferred embodiment, M is Mg 2+ , X=1, Y=1.

[0025] In a second aspect of the present invention, there is provided a method for preparing the compound of the first aspect, comprising the steps of:

[0026] (1) adding reduced β-nicotinamide mononucleotide disodium salt to a 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 a reaction;

[0027] (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 the mixture to obtain a solution B;

[0028] (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.

[0029] In another preferred embodiment, the first solvent is selected from the group consisting of water, methanol, and ethanol.

[0030] In another preferred embodiment, the inorganic salt is selected from the following group: MgCl2, KCl, CaCl2, ZnCl2, FeCl3, CuCl2, MnCl2, Mg(OH)2, KOH, Ca(OH)2, NaOH, Cu(OH)2.

[0031] 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, and L-histidine hydrochloride.

[0032] In another preferred embodiment, the organic matter is selected from D-glucosamine, L-arginine, L-lysine, and L-histidine.

[0033] In another preferred embodiment, the molar ratio of the reduced β-nicotinamide mononucleotide to the corresponding organic matter is 1:1-2.5, preferably 1:1-2.

[0034] In another preferred embodiment, the molar ratio of the reduced β-nicotinamide mononucleotide to the inorganic salt is 1:0.5-1.1.

[0035] In another preferred embodiment, the molar ratio of the reduced β-nicotinamide mononucleotide to the organic salt is 1:0.8-2.5, preferably 1:1-2.

[0036] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising the reduced β-nicotinamide mononucleotide salt compound described in the first aspect or a pharmaceutically acceptable carrier thereof.

[0037] 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.

[0038] In another preferred embodiment, the pharmaceutical composition is a tablet, capsule, lyophilized powder, solution, injection, dressing, etc.

[0039] In a fourth aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising the steps of:

[0040] The reduced β-nicotinamide mononucleotide salt compound described in the first aspect is mixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

[0041] In the fifth aspect of the present invention, there is provided a use of the reduced β-nicotinamide mononucleotide salt compound as described in the first aspect or the pharmaceutical composition as described in the third aspect for preparing a method for increasing the activity of nicotinamide adenine dinucleotide (NAD + ) to delay aging, and / or for the prevention or treatment of NAD deficiency + Products that cause or contribute to illness or symptoms.

[0042] In another preferred embodiment, the disease or symptom is selected from the following group: symptoms or diseases related to aging phenomena, symptoms or diseases related to decreased immunity, metabolic diseases or symptoms, neurodegeneration, etc.

[0043] In another preferred embodiment, the diseases or symptoms related to the aging phenomenon are selected from the following group: atrophy and collapse of skin tissue, dry, rough, loose, wrinkled skin, pellagra, lack of energy, muscle weakness, sarcopenia, fatigue, cognitive decline, memory decline, cognitive decline, Alzheimer's disease, etc.

[0044] In another preferred embodiment, the disease or symptom associated with decreased immunity is selected from the following group: weakness, immune system disorder, arthritis, cancer, etc.

[0045] In another preferred embodiment, the metabolic disease or symptom is selected from the following group: endocrine disorders, metabolic disorders, diabetes, obesity, atherosclerosis, hypertension, metabolic dysfunction, etc.

[0046] In a sixth aspect of the present invention, there is provided a use of the reduced β-nicotinamide mononucleotide salt compound as described in the first aspect or the pharmaceutical composition as described in the third aspect for preparing a product for preventing and / or treating diseases or symptoms caused or resulting from a deficiency of essential elements in the human body.

[0047] In another preferred embodiment, the product is selected from the group consisting of medicines, dietary supplements, health products, nutritional supplements, or food additives.

[0048] In another preferred embodiment, the essential elements include magnesium, calcium, zinc, iron, copper, manganese, and selenium.

[0049] In another preferred embodiment, the disease or symptom is selected from the following group: diseases or symptoms related to magnesium deficiency, diseases or symptoms related to calcium deficiency, diseases or symptoms related to zinc deficiency, diseases or symptoms related to iron deficiency, diseases or symptoms related to copper deficiency, diseases or symptoms related to manganese deficiency, and diseases or symptoms related to selenium deficiency.

[0050] In another preferred embodiment, the disease or symptom of magnesium deficiency is selected from the group consisting of anorexia, nausea, vomiting, weakness, apathy, memory loss, mental tension, irritability, confusion, restlessness, athetoid movements, and epileptic seizures.

[0051] In another preferred embodiment, the diseases or symptoms associated with calcium deficiency are selected from the following group: muscle cramps, weakness in the limbs, body aches, loose teeth, sweating, fatigue, tracheal spasm leading to dry cough without sputum, bone spurs, joint pain, fear of wind, high blood pressure, constipation, dysmenorrhea, short stature, bow legs and bow legs.

[0052] In another preferred embodiment, the diseases or symptoms associated with zinc deficiency are selected from the group consisting of growth retardation, decreased immunity, slow wound healing, dermatitis, sexual dysfunction, loss of appetite, abnormal taste, geophagia, slowed dark adaptation, narcolepsy, depression and stress symptoms, chronic diarrhea, hair loss and dermatitis.

[0053] In another preferred embodiment, the diseases or symptoms related to iron deficiency are selected from the following group: waking up from sleep, mental depression, anorexia, picky eating, growth retardation, frequent dizziness, insomnia, colds, fever, cough, diarrhea, poor concentration, comprehension, memory, pale complexion, sallow complexion, pale lips, dull hair, insomnia and dreaminess, weakness in the limbs, chills, scanty menstruation, amenorrhea or heavy menstruation, dysmenorrhea, skin prone to wrinkles and spots, oral ulcers, iron deficiency anemia, fatigue, fear of cold, and decreased resistance.

[0054] In another preferred embodiment, the diseases or symptoms associated with copper deficiency are selected from the following group: fatigue and weakness caused by decreased red blood cell count (anemia), increased risk of infection caused by decreased white blood cell count, osteoporosis, nerve damage causing tingling and loss of sensation in the hands and feet, muscle weakness, impaired consciousness, irritability, mild depression, impaired coordination, etc.

[0055] In another preferred embodiment, the manganese deficiency-related diseases or symptoms are selected from the following group: growth and reproductive disorders, abnormal development of children, movement disorders, tardive dyskinesia, osteoporosis, bone insufficiency, high blood cholesterol, easy cramps, abnormal fat metabolism, and central nervous system disorders.

[0056] In another preferred embodiment, the diseases or symptoms related to selenium deficiency are selected from the following group: decreased human immune ability, severe hair loss and nail loss, some patients may experience skin symptoms, nervous system diseases and tooth damage, and long-term severe selenium deficiency can lead to serious chronic diseases such as Keshan disease and Kashin-Beck disease.

[0057] In another preferred embodiment, the essential elements for the human body are selected from the following group: magnesium (Mg), zinc (Zn), iron (Fe), copper (Cu), and manganese (Mn).

[0058] In another preferred embodiment, the essential elements further include calcium (Ca) and selenium (Se).

[0059] In a seventh aspect, the present invention provides a use of the reduced β-nicotinamide mononucleotide salt compound of the first aspect or the pharmaceutical composition of the third aspect for preparing a product for preventing and / or treating diseases or symptoms caused or resulting from symptoms such as malnutrition, loss of appetite, and developmental failure.

[0060] In another preferred embodiment, the disease or symptom associated with D-glucosamine deficiency is selected from the following group: joint inflammation and swelling, cartilage damage, and osteoarthritis.

[0061] In another preferred embodiment, the disease or symptom associated with L-arginine deficiency 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.

[0062] In another preferred embodiment, the diseases or symptoms associated with L-lysine deficiency are selected from the following group: delayed height development, low immunity, inattention, fatigue, loss of appetite, osteoporosis, and hypoproteinemia.

[0063] In another preferred embodiment, the diseases or symptoms associated with L-histidine deficiency are selected from the following groups: anemia and decreased 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, allergies, hypertension, cognitive decline, gastric ulcers, symptoms caused by renal failure or renal dialysis, poor growth and development in infants and young children, heart disease and other health problems.

[0064] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIG1 shows the XRPD pattern of the amorphous form of NMNH magnesium salt.

[0066] FIG2 shows the XRPD pattern of the amorphous form of NMNH dipotassium salt.

[0067] FIG3 shows the XRPD pattern of the amorphous form of NMNH zinc salt.

[0068] FIG4 shows the XRPD pattern of the amorphous form of NMNH ferric salt.

[0069] FIG5 shows the XRPD pattern of the amorphous form of NMNH ferrous salt.

[0070] FIG6 shows the XRPD pattern of the amorphous form of NMNH divalent copper salt.

[0071] FIG7 shows the XRPD pattern of the amorphous form of NMNH manganese divalent salt.

[0072] Figure 8 shows the NMNH inorganic salt 1 H NMR spectrum.

[0073] FIG9 shows the XRPD pattern of the amorphous form of NMNH-di(D-glucosamine) salt.

[0074] FIG10 shows the XRPD pattern of the amorphous form of NMNH-D-glucosamine salt.

[0075] FIG11 shows the XRPD pattern of the amorphous form of NMNH-di(L-arginine) salt.

[0076] FIG12 shows the XRPD pattern of the amorphous form of NMNH-L-arginine salt.

[0077] FIG13 shows the XRPD pattern of the amorphous form of NMNH-di(L-lysine) salt.

[0078] FIG14 shows the XRPD pattern of the amorphous form of NMNH-L-lysine salt.

[0079] FIG15 shows the XRPD pattern of the amorphous form of NMNH-di(L-histidine) salt.

[0080] FIG16 shows the XRPD pattern of the amorphous form of NMNH-L-histidine salt.

[0081] Figure 17 shows the NMNH-di(D-glucosamine) salt 1 H NMR spectrum.

[0082] FIG18 shows the NMNH-D-glucosamine salt 1 H NMR spectrum.

[0083] FIG19 shows the NMNH-di(L-arginine) salt 1 H NMR spectrum.

[0084] Figure 20 shows the NMNH-L-arginine salt 1 H NMR spectrum.

[0085] FIG21 shows the NMNH-di(L-lysine) salt 1 H NMR spectrum.

[0086] Figure 22 shows the NMNH-L-lysine salt 1 H NMR spectrum.

[0087] FIG23 shows the NMNH-di(L-histidine) salt 1 H NMR spectrum.

[0088] Figure 24 shows the NMNH-L-histidine salt 1 H NMR spectrum. DETAILED DESCRIPTION

[0089] Through extensive and in-depth research, the present inventors unexpectedly developed a reduced β-nicotinamide mononucleotide salt compound (NMNH-M) for the first time, wherein M is independently selected from the following group: Mg 2+ 、Zn 2+ 、Fe 3+ 、Cu 2+ 、Mn 2+ The compounds of the present invention or the active ingredients of pharmaceutical compositions are used to increase NAD + To slow down aging, and / or for the prevention or treatment of NAD deficiency + The invention can also be used to prevent and / or treat diseases or symptoms caused or resulting from a deficiency of essential elements and / or essential amino acids. Research conducted by the present invention has shown that the reduced β-nicotinamide mononucleotide salt compound of the present invention exhibits long-term stability and hygroscopic resistance compared to the crystalline and amorphous forms of the NMNH disodium salt, making it more suitable for long-term storage and market promotion. Furthermore, the compound of the present invention meets the shelf life requirements of commercial products and is suitable for use in pharmaceutical compositions, health products, cosmetics, food additives, and the like. Based on this, the inventors completed the present invention.

[0090] Terminology

[0091] As used herein, the term NMNH is the Chinese name for "reduced nicotinamide mononucleotide" or "reduced β-nicotinamide mononucleotide", which is the reduced form of β-NMN and is a supplement to NAD. + new precursors.

[0092] The "NMNH", "reduced nicotinamide mononucleotide" and its salts mentioned herein all refer to the "β configuration".

[0093] In the present invention, the compound of formula (I)

[0094] M is Mg 2+ When, the compound of formula (I) is recorded as NMNH-Mg;

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

[0096] M is K 1+ When, the compound of formula (I) is recorded as NMNH-K2;

[0097] M is Na 1+ When, the compound of formula (I) is recorded as NMNH-Na2;

[0098] M is Zn 2+ When, the compound of formula (I) is recorded as NMNH-Zn;

[0099] M is Fe 3+ When , the compound of formula (I) is recorded as NMNH-Fe(III);

[0100] M is Fe 2+ When, the compound of formula (I) is recorded as NMNH-Fe(II);

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

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

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

[0104] As used herein, the terms "reduced β-nicotinamide mononucleotide salt compound," "NMNH-M," and "compound of the present invention" are used interchangeably. The NMNH-M of the present invention is a salt formed by reduced β-nicotinamide mononucleotide and a corresponding metal ion or organic compound. Unless otherwise specified, the term "compound of the present invention" herein refers to the compound in the β configuration.

[0105] Preparation method of reduced β-nicotinamide mononucleotide salt compound

[0106] In the present invention, the preparation method of the compound comprises the steps of:

[0107] (1) adding reduced β-nicotinamide mononucleotide disodium salt to a 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 a reaction;

[0108] (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 the mixture to obtain a solution B;

[0109] (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.

[0110] Preferably, the first solvent is selected from the group consisting of water, methanol, and ethanol.

[0111] Preferably, the inorganic salt is selected from the following group: MgCl2, KCl, CaCl2, ZnCl2, FeCl3, CuCl2, MnCl2, Mg(OH)2, KOH, Ca(OH)2, NaOH, Cu(OH)2.

[0112] Preferably, the organic matter is selected from the group consisting of D-glucosamine, L-arginine, L-lysine, and L-histidine.

[0113] Preferably, the organic salt is selected from the group consisting of magnesium acetate, zinc acetate, D-glucosamine hydrochloride, L-arginine hydrochloride, L-lysine hydrochloride, and L-histidine hydrochloride.

[0114] Pharmaceutical composition

[0115] The reduced β-nicotinamide mononucleotide salt compound of the present invention can be used to increase NAD + To slow down aging, and / or for the prevention or treatment of NAD deficiency + 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.

[0116] 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.

[0117] 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).

[0118] Preferably, the amino acid is selected from the group consisting of L-arginine, L-lysine, and L-histidine.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] A preferred pharmaceutical composition comprises NMNH-Na2, NMNH-Mg, NMNH-Ca, NMNH-Zn, NMNH-Fe(III), NMNH-Cu(II), NMNH-Mn(II), NMNH-di(D-glucosamine), NMNH-D-glucosamine salt, NMNH-di(L-arginine), NMNH-L-arginine, NMNH-di(L-lysine), NMNH-L-lysine, NMNH-di(L- The present invention relates to one or more of: amino acid, 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.

[0123] More preferably, in the composition, Na content ≤138 mg, K content ≤234 mg, Mg content ≤73 mg, Ca content ≤120 mg, Zn content ≤15.0 mg, Fe content ≤20.0 mg, Cu content ≤1.5 mg, Mn content ≤4.0 mg, D-glucosamine content ≤1000 mg, L-arginine content ≤1000 mg, L-lysine content ≤870 mg, and L-histidine content ≤20 mg.

[0124] More preferably, in the composition, Na content ≤83 mg, K content ≤140 mg, Mg content ≤44 mg, Ca content ≤72 mg, Zn content ≤15.0 mg, Fe content ≤20.0 mg, Cu content ≤1.5 mg, Mn content ≤4.0 mg, D-glucosamine content ≤640 mg, L-arginine content ≤620 mg, L-lysine content ≤520 mg, and L-histidine content ≤20 mg.

[0125] More preferably, the composition has a Na content of 55 to 83 mg, a K content of 94 to 140 mg, a Mg content of 29 to 44 mg, a Ca content of 48 to 72 mg, a Zn content of 0.8 to 15.0 mg, a Fe content of 1.5 to 20.0 mg, a Cu content of 0.1 to 1.5 mg, a Mn content of 0.3 to 4.0 mg, a D-glucosamine content of 200 to 640 mg, a L-arginine content of 200 to 620 mg, a L-lysine content of 170 to 520 mg, and a L-histidine content of 6 to 15 mg.

[0126] Such carriers include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical formulation should be compatible with the mode of administration. The pharmaceutical composition of the present invention can be prepared in the form of an injection, for example, by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount, for example, about 1 microgram / kg body weight to about 5 mg / kg body weight per day.

[0127] In addition, other chemical agents without pharmacological effects may or may not be added to the pharmaceutical composition of the present invention as compounding ingredients such as pH regulators, stabilizers, and solubilizers.

[0128] The pharmaceutical composition of the present invention can be prepared into a unit dosage form or a multiple dosage form, and can be administered alone or in combination, and can be applied to + The drug and / or drug potentiator that causes or contributes to the disease or symptom.

[0129] As used herein, the term "treating" refers to the administration of a compound of the present invention to alleviate a disease or condition in a host. Thus, the term "treating" includes preventing the onset of a condition in a host, particularly where 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 cases where the methods of the present invention are used to prevent a condition, it should be understood that the term "preventing" does not require complete inhibition of the disease. As used herein, the term "preventing" encompasses the ability of one skilled in the art to identify a population susceptible to a disease so that a compound of the present invention can be administered before the onset of the disease. The term does not imply that a condition can be completely avoided. Compounds identified using the screening methods of the present invention can be used in conjunction with other compounds.

[0130] Compared with the prior art, the present invention has the following beneficial effects:

[0131] (1) The compounds of the present invention can be used to increase NAD + To slow down aging, and / or for the prevention or treatment of NAD deficiency + The invention can be used to prevent and / or treat diseases or symptoms caused or resulted from the lack of essential elements or essential amino acids for the human body.

[0132] (2) Compared with the NMNH disodium salt crystal form and amorphous solid, the reduced β-nicotinamide mononucleotide salt compound of the present invention has better stability, lower hygroscopicity, and is more conducive to long-term storage and market promotion.

[0133] (3) The preparation method of the reduced β-nicotinamide mononucleotide salt compound of the present invention is simple and suitable for industrial production.

[0134] (4) The reduced β-nicotinamide mononucleotide salt compound of the present invention can be used in pharmaceutical compositions, health products, cosmetics, food additives, etc.

[0135] 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.

[0136] Example 1. Preparation of NMNH magnesium salt

[0137] 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 shown in Figure 1. 1 The H NMR spectrum is shown in Figure 8.

[0138] Example 2. Preparation of NMNH dipotassium salt

[0139] 1.7 kg of β-NMN and 0.94 kg of sodium dithionite were added to 10 L of saturated sodium bicarbonate aqueous solution, stirred at room temperature overnight, and filtered to obtain a 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 dropped to 50-100 μS. 0.57 kg of potassium hydroxide or 0.76 kg of potassium chloride were added, and the pH of the solution was adjusted to 10 with aqueous ammonia. The resulting NMNH dipotassium salt aqueous solution was added dropwise to 30 L of stirring ethanol to precipitate the NMNH dipotassium salt solid. The solid was filtered and washed with a mixed solvent (1 L of water and 3 L of ethanol). The filter cake was vacuum dried at 20-30°C to obtain 1.57 kg of NMNH dipotassium salt as a yellow solid, with a yield of 75.3%. The purity was 99.7% as determined by HPLC, the moisture content was 3.8%, and the K content was 18.9% by weight. XRPD analysis showed that the solid was an amorphous solid. The XRPD spectrum is shown in Figure 2.

[0140] Example 3. Preparation of NMNH zinc salt

[0141] 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 solution conductivity dropped to 50-100μS. 81.6g zinc chloride was added, and the pH of the solution was adjusted to 10 with aqueous ammonia to obtain an aqueous solution of NMNH zinc salt. This was added dropwise to 2L of stirred methanol to precipitate NMNH zinc salt solid. The solid was filtered and the filter cake was washed with a mixed solvent (200ml water and 400ml methanol). The filter cake was vacuum dried at 20-30°C to obtain 214.0kg of yellow solid NMNH zinc salt, with a yield of 89.5%, a moisture content of 0.2%, and a Zn content of 16.3% wt. XRPD analysis showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 3.

[0142] Example 4. Preparation of NMNH ferric salt

[0143] 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 solution conductivity dropped to 50-100μS. 64.7g iron (III) chloride was added and the pH of the solution was adjusted to 10 with ammonia water to obtain an aqueous solution of NMNH trivalent iron salt. This was added dropwise to 2L of stirred methanol to precipitate NMNH trivalent iron salt solid, filtered, and the filter cake was washed with a mixed solvent (200ml water and 400ml methanol). The filter cake was vacuum dried at 20-30°C to obtain 199.6g NMNH trivalent iron salt as a brown solid, with a yield of 89.8%, a moisture content of 0.3%, and an Fe content of 10.0% wt. XRPD test showed that it was an amorphous solid, and the XRPD spectrum is shown in Figure 4.

[0144] Example 5. Preparation of NMNH divalent iron salt

[0145] 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 solution conductivity dropped to 50-100μS. 75.8g iron (II) chloride was added and the pH of the solution was adjusted to 10 with ammonia water to obtain an aqueous solution of NMNH divalent iron salt. This was added dropwise to 2L of stirred methanol to precipitate NMNH divalent iron salt solid. The solid was filtered and washed with a mixed solvent (200ml water and 400ml methanol). The filter cake was vacuum dried at 20-30°C to obtain 206.3g of NMNH divalent iron salt as a light green solid, with a yield of 88.4%, a moisture content of 0.3%, and an Fe content of 14.3% wt. XRPD analysis showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 5.

[0146] Example 6. Preparation of NMNH divalent copper salt

[0147] Add 200g of β-NMN and 110g of sodium dithionite to 1.2L of saturated sodium bicarbonate aqueous solution, stir at room temperature overnight, 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 50-100μS. 58.4 g of copper (II) hydroxide or 80.5 g of copper (II) chloride was added, and the pH of the solution was adjusted to 10 with sodium hydroxide to obtain an aqueous solution of NMNH divalent copper salt, which was added dropwise to 2 L of stirred methanol to precipitate NMNH divalent copper salt solid. The solid was filtered and the filter cake was washed with a mixed solvent (200 ml of water and 400 ml of methanol). The filter cake was vacuum dried at 20-30° C. to obtain 211.1 g of NMNH divalent copper salt as a green solid with a yield of 88.7%, a moisture content of 0.2%, and a Cu content of 15.9% wt. XRPD analysis showed that the solid was an amorphous solid. The XRPD spectrum is shown in FIG6 .

[0148] Example 7. Preparation of NMNH divalent manganese salt

[0149] 200g of β-NMN and 110g of sodium dithionite were added to 1.2L of saturated sodium bicarbonate aqueous solution, stirred at room temperature overnight, and filtered to obtain a 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 solution conductivity dropped to 50-100μS. 75.3g of manganese (II) chloride was added, and the pH of the solution was adjusted to 10 with aqueous ammonia to obtain an aqueous solution of NMNH manganese salt. This was added dropwise to 2L of stirring ethanol to precipitate NMNH manganese salt solid. The solid was filtered and washed with a mixed solvent (200ml of water and 400ml of ethanol). The filter cake was vacuum dried at 20-30°C to obtain 200.5g of NMNH manganese salt as a yellow solid, with a yield of 86.1%, a moisture content of 0.6%, and a Mn content of 14.1% wt. XRPD analysis showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 7.

[0150] Example 8. Preparation of NMNH-di(D-glucosamine) salt (1:2)

[0151] 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. 193.0g D-glucosamine was added to obtain NMNH-di(D-glucosamine) salt aqueous solution, which was added dropwise to 2L of stirred ethanol to precipitate NMNH-di(D-glucosamine) salt solid, filtered, and washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 325.0g NMNH-di(D-glucosamine) salt solid, with a yield of 78.2%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 9. 1 The H NMR spectrum is shown in Figure 17 .

[0152] Example 9. Preparation of NMNH-D-glucosamine salt (1:1)

[0153] 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. 96.5g D-glucosamine was added to obtain NMNH-D-glucosamine salt aqueous solution, which was added dropwise to 2L of stirred ethanol to precipitate NMNH-D-glucosamine salt solid, filtered, and washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 229.1g NMNH-D-glucosamine salt solid, with a yield of 74.3%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 10. 1 The H NMR spectrum is shown in Figure 18.

[0154] Example 10. Preparation of NMNH-di(L-arginine) salt (1:2)

[0155] 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. 187.6g L-arginine was added to obtain an NMNH-di(L-arginine) salt aqueous solution, which was added dropwise to a stirred 2L ethanol to precipitate NMNH-di(L-arginine) salt solid, filtered, and washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 260.1g NMNH-di(L-arginine) salt solid, with a yield of 63.5%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 11. 1 The H NMR spectrum is shown in Figure 19.

[0156] Example 11. Preparation of NMNH-L-arginine salt (1:1)

[0157] 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. 93.8g L-arginine was added to obtain an aqueous solution of NMNH-L-arginine salt, which was added dropwise to a stirred 2L ethanol to precipitate NMNH-L-arginine salt solid, filtered, and washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 200.7g NMNH-L-arginine salt solid, with a yield of 65.7%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 12. 1 The H NMR spectrum is shown in Figure 20.

[0158] Example 12. Preparation of NMNH-di(L-lysine) salt (1:2)

[0159] 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 washed with a mixed solvent (200ml water and 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 shown in Figure 13. 1 The H NMR spectrum is shown in Figure 21.

[0160] Example 13. Preparation of NMNH-L-lysine salt (1:1)

[0161] 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 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 shown in Figure 14. 1 The H NMR spectrum is shown in Figure 22.

[0162] Example 14. Preparation of NMNH-di(L-histidine) salt (1:2)

[0163] 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. 167.1g L-histidine was added to obtain an NMNH-di(L-histidine) salt aqueous solution, which was added dropwise to a stirred 2L ethanol to precipitate the NMNH-di(L-histidine) salt solid, filtered, and the filter cake was washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 277.0g NMNH-di(L-histidine) salt solid, with a yield of 71.6%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 15. 1 The H NMR spectrum is shown in FIG23 .

[0164] Example 15. Preparation of NMNH-L-histidine salt (1:1)

[0165] 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. 83.6g L-histidine was added to obtain an NMNH-L-histidine salt aqueous solution, which was added dropwise to a stirred 2L ethanol to precipitate NMNH-L-histidine salt solid, filtered, and the filter cake was washed with a mixed solvent (200ml water and 400ml ethanol). The filter cake was vacuum dried at 20-30°C to obtain 216.1g NMNH-L-histidine salt solid, with a yield of 73.5%. XRPD test showed that it was an amorphous solid. The XRPD spectrum is shown in Figure 16. 1 The H NMR spectrum is shown in FIG24 .

[0166] Example 16. Screening of NMNH salt forms and their performance evaluation

[0167] The performance of various salt forms of NMNH was investigated through accelerated experiments. The results are shown in Table 1 below:

[0168] Table 1: Properties of various NMNH salt forms

[0169] From the data in the above table we can see that:

[0170] The performance of amorphous NMNH-K2 salt is similar to that of amorphous NMNH-Na2 salt reported in WO2023160405A1. When left open at 25°C, 65% RH and for one day, the powder absorbs water and turns into oil, and the purity drops from 99.61% to 99.24%.

[0171] When NMNH-Mg salt was exposed to the air at 25°C and 65% RH for 30 days, the yellow solid powder remained unchanged, with no change in purity (99.53%) or moisture content (0.23%). The NMNH-Na2 salt form A reported in WO2023160405A1 has a moisture content of 19%-30%. Compared to NMNH-Na2 salt, the amorphous NMNH-Mg salt exhibits improved stability, lower moisture content, and stronger antioxidant and hygroscopic properties, demonstrating significant performance advantages.

[0172] NMNH-Zn salt, NMNH-Fe(III) salt, NMNH-Cu(II) salt, and NMNH-Mn(II) salt remain unchanged in appearance, color, and moisture content when placed in an open environment at 25°C and 65% RH for 30 days. They also have higher stability, antioxidant properties, and hygroscopic resistance than NMNH-Na2 salt.

[0173] 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), and NMNH-L-histidine salt (1:1) are all organic salts of NMNH (formed with organic compounds). Compared to inorganic salts (such as Na and K), these organic salts have a certain degree of hydrophobicity and therefore have stronger resistance to moisture absorption, which is consistent with the data in the table above.

[0174] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A reduced β-nicotinamide mononucleotide salt compound (NMNH-M) represented by formula (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 organic matter is selected from the following group: D-glucosamine, L-arginine, L-lysine, and L-histidine.

2. The compound according to claim 1, wherein The compound is an amorphous substance.

3. A method for preparing the compound according to claim 1, characterized in that: Including steps: (1) adding reduced β-nicotinamide mononucleotide disodium salt to a 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 a 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 the mixture 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.

4. The method according to claim 3, wherein The organic matter is selected from D-glucosamine, L-arginine, L-lysine and L-histidine.

5. The method according to claim 3, wherein The molar ratio of the reduced β-nicotinamide mononucleotide to the corresponding organic matter is 1:1-2.5, preferably 1:1-2.

6. 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.

7. 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.

8. A use of the reduced β-nicotinamide mononucleotide salt compound according to claim 1 or the pharmaceutical composition according to claim 6, characterized in that: For the preparation of nicotinamide adenine dinucleotide (NAD + ) to delay aging, and / or for the prevention or treatment of NAD deficiency + Products that cause or contribute to illness or symptoms.

9. A use of the reduced β-nicotinamide mononucleotide salt compound according to claim 1 or the pharmaceutical composition according to claim 6, characterized in that: Used to prepare products for preventing and / or treating diseases or symptoms caused or resulting from the lack of essential elements for the human body.

10. Use of the reduced β-nicotinamide mononucleotide salt compound according to claim 1 or the pharmaceutical composition according to claim 6, characterized in that: Used to prepare products for preventing and / or treating diseases or symptoms caused by or resulting from malnutrition, loss of appetite, and developmental failure.

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