NMN-containing composition as well as preparation method and application thereof

Abstract

The invention discloses a composition containing NMN and a preparation method and application thereof. The composition provided by the invention comprises any two or more of NMN, coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber and glutathione. The invention unexpectedly discovers that the combination of two or more of NMN, coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber, glutathione and gamma-butylamine shows a beneficial synergistic effect in improving the NAD + level in vivo compared with a single component only applying pure NMN. Moreover, this synergy may result in additional benefits in therapy, such as anti-aging, enhancing immunity, resisting oxidation, protecting nerves, improving sub-health status, improving patient compliance, and the like. Meanwhile, no side effect is generated after long-term taking, and the conditions of body tolerance, drug effect absorption reduction and the like caused by long-term taking are also avoided.

Description

Technical Field

[0001] The present invention relates to the technical fields of pharmaceuticals and health products, and particularly relates to a composition containing nicotinamide mononucleotide (NMN) and a preparation method and application of a capsule thereof. Background Art

[0002] NMN, namely β-nicotinamide mononucleotide, is an intermediate in the synthesis pathway of nicotinamide adenine dinucleotide (NAD+) in mammals, and exists in two different forms, α and β, among which the β isomer is the active form. The molecular formula of β-nicotinamide mononucleotide is: C11H15N2O8P; molecular weight: 334.22. Scientific research shows that NMN participates in the synthesis of NAD (nicotinamide adenine dinucleotide), an important coenzyme for intracellular energy conversion in cells, and plays an important role in human cell energy metabolism and cell signal transduction.

[0003] The human body can continuously synthesize β-nicotinamide mononucleotide (NMN). With the increase of age, the ability of the human body to synthesize NMN by itself continuously decreases, and it is necessary to supplement NMN artificially. Nicotinamide mononucleotide W+NMN can increase NAD in organs, thereby being able to repair brain damage, improve islet function, protect the heart from ischemia-reperfusion injury, and repair brain mitochondrial respiratory defects, and has a certain therapeutic effect on senile degenerative diseases, retinal degenerative diseases, type 2 diabetes, cerebral hemorrhage, etc. Therefore, taking NMN preparations orally is a relatively feasible method.

[0004] There is no scientific and effective recommended standard for the dosage of orally taken NMN. Also, due to the unsatisfactory effect of taking pure NMN, there is currently no product with verified good curative effect on the market. Existing technical research proves that an adult weighing 60 kg needs to take 1000 mg to barely achieve the effect of improving symptoms. Taking NMN in a large dose may have side effects on the human body, and considering economic factors, taking pure NMN is not recommended.

[0005] Therefore, it is urgent to develop an NMN composition with good antioxidant effect and low dosage for solving the technical defects in the prior art that anti-aging and antioxidant products are difficult to take into account good antioxidant effect, no harm to the human body and stable product quality.

[0006] Studies have shown that the NAMPT activator P7C3, the classic SIRT1 activator resveratrol, and the CD38 inhibitor 78C, an NAD+-consuming enzyme, may also act in concert with NMN mechanistically to increase the NAD+ pool. Resveratrol binds to nicotinamide mononucleotide, an intermediate metabolite involved in the biosynthesis of coenzyme NAD (nicotinamide adenine dinucleotide), and can reduce total blood cholesterol, and normalize elevated levels of low-density lipoprotein cholesterol, triglycerides, and uric acid beyond the appropriate reference ranges.

[0007] In addition, β-nicotinamide mononucleotide (NMN) is chemically unstable and highly sensitive to light, oxygen, and moisture. It has been oxidized in air to form inactive oxidation products. Moreover, NMN is easily decomposed under the action of gastric juice, and simply taking NMN preparations actually has little effect. Therefore, NMN cannot be directly applied, and β-nicotinamide mononucleotide (NMN) must be formulated. For this purpose, NMN has been made into various tablets or capsules.

[0008] The inventors found that the NMN composition of the present invention is very effective in preventing, improving, and maintaining a healthy physical condition, and developed a method for preparing it into hard capsules, thus completing the present invention. Summary of the Invention

[0009] In view of the current technical situation, the technical problem to be solved by the present invention is to overcome the problems of instability and large dosage of existing NMN products, and provide a composition containing NMN and a method for preparing its capsules. The hard capsules obtained by this preparation method have good stability. The components in the NMN composition provided by the present invention are scientifically and rationally formulated, synergistically enhance the effect, and have stable efficacy.

[0010] The object of the present invention is to provide a composition containing NMN.

[0011] Another object of the present invention is to provide a method for preparing the composition containing NMN into hard capsules.

[0012] Another object of the present invention is to provide the application of the composition containing NMN in the preparation of antioxidant products.

[0013] The above objects of the present invention are achieved by the following technical solutions:

[0014] A composition containing NMN, comprising nicotinamide mononucleotide NMN as the first active ingredient and having a second active ingredient with antioxidant properties.

[0015] Using the above composition of the present invention, composition products with different effects can be developed;

[0016] For example, the second active ingredient can be any one or more of coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber, glutathione, and γ-aminobutyric acid.

[0017] The above NMN composition can play roles such as anti-aging, immune enhancement, antioxidant, nerve protection, and improvement of sub-healthy state. At the same time, taking it for a long time will not produce any side effects, nor will there be situations such as reduced body tolerance and drug efficacy absorption due to long-term use.

[0018] The present invention unexpectedly discovers that, compared with only applying a single component of pure NMN, a combination of two or more of NMN, coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber, glutathione, and γ-aminobutyric acid shows beneficial synergistic effects in increasing the level of NAD+ in the body. Moreover, this synergy can produce additional benefits in treatment, such as anti-aging, immune enhancement, antioxidant, nerve protection, improvement of sub-healthy state, and improvement of patient compliance.

[0019] Preferably, the mass ratio of the NMN to the second active ingredient is 300:2 to 60; the NMN accounts for 83.3% to 99.3% of the total mass of the active ingredients of the composition.

[0020] In addition, the composition containing NMN of the present invention can also be compounded with pharmaceutically or health care acceptable excipients to form different dosage forms. The excipients can be selected from sucrose, lactose, microcrystalline cellulose, modified starch, silica, magnesium stearate, talc powder, HPC, etc.

[0021] Preferably, the excipients contained in the present invention are microcrystalline cellulose and magnesium stearate.

[0022] The dosage form of the preparation unit in the composition of the present invention can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including aqueous injection, powder injection and infusion), an eye drop, a nasal drop, a lotion and a liniment, etc.; the solid dosage form can be a tablet (including ordinary tablet, enteric-coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pill, a suppository, a film, a patch, an aerosol (powder aerosol), a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc.

[0023] The dosage form is preferably a solid dosage form, more preferably a capsule, and even more preferably a hard capsule.

[0024] As a reference implementation method, the following provides a method for preparing a composition containing nicotinamide mononucleotide NMN into a hard capsule:

[0025] The first active ingredient nicotinamide mononucleotide (NMN) is formulated into a powder mixture with a second active ingredient and excipients; after the powder mixture is filled into a capsule shell, locked, and polished, a high-molecular enteric coating material is directly coated outside the capsule shell.

[0026] As a reference implementation method, a method for preparing the locking shell material is provided as follows: a mixed solution of 20 parts by weight of gelatin, 40 parts by weight of water, and 40 parts by weight of ethanol is transferred to a dispensing tank and stirred at room temperature for 1 hour to obtain the locking shell gelatin solution.

[0027] As a reference implementation method, a method for preparing a coating solution is provided as follows:

[0028] 4 - 20 parts by weight of polyacrylic resin II and 4 - 20 parts by weight of polyacrylic resin III are soaked in ethanol for 24 hours, and then transferred to a dispensing tank together with 4 - 20 parts by weight of castor oil, 4 - 20 parts by weight of diethyl phthalate, 1 - 20 parts by weight of polysorbate 80, and 1 - 20 parts by weight of polyethylene glycol 6000 and stirred at room temperature for 1 hour to obtain the enteric coating solution. Description of the Drawings

[0029] Attached Figure 1 is an NMN composition according to an embodiment of the present invention. Detailed Description of the Invention

[0030] The embodiments of the present invention are described in detail below. The embodiments provided by the present invention are exemplary and are intended to explain the present invention, but should not be construed as a limitation to the present invention.

[0031] The term "nicotinamide mononucleotide" used in the present invention is usually referred to as NMN (Nicotinamidemononucleotide), which includes α-isomers and β-isomers or is a β-isomer. In the context of this application, "nicotinamide mononucleotide" and "NMN" can be used interchangeably.

[0032] The term "active ingredient" used in the present invention refers to molecules and reagents of biological, physiological, or pharmaceutical active substances that play a role in increasing the NAD+ level in the body. This term is used relative to terms such as "pharmaceutically acceptable carrier", "excipient", "adjuvant", etc.

[0033] It should be understood that all mentions of various active ingredients include solvate addition forms (solvates, such as hydrates, ethanol solvates, acetone solvates, etc.) of the same active ingredient or its various crystal forms (such as amorphous, polymorphs, etc.).

[0034] The composition according to the present invention may contain only the specified active ingredients, or may additionally contain other medicaments and / or one or more pharmaceutically acceptable solid or liquid carriers, excipients, and / or adjuvants, etc.

[0035] As used herein, the term "preparation unit" refers to a unit dosage form of a pharmaceutical preparation, which may be a pure product containing nicotinamide mononucleotide without a second active ingredient, or a composition containing any one or more of coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber, glutathione, and γ-butyric acid.

[0036] The composition containing NMN has the following components:

[0037] Table 1 Active ingredient table of the composition containing NMN

[0038]

[0039] Example 1 Composition A containing NMN, comprising the following components:

[0040]

[0041] Example 2 Composition B containing NMN, comprising the following components:

[0042]

[0043]

[0044] Example 3 Composition C containing NMN, comprising the following components:

[0045]

[0046] Example 4 Composition D containing NMN, comprising the following components:

[0047]

[0048] Example 5 Composition E containing NMN, comprising the following components:

[0049]

[0050] Example 6 Composition F containing NMN, comprising the following components:

[0051]

[0052] Example 7 Composition G containing NMN, comprising the following components:

[0053]

[0054]

[0055] Example 8: Composition H containing NMN, comprising the following components:

[0056]

[0057] The substances of Examples 1 to 5 were ground into a powder mixture, and the density and fluidity were inspected in accordance with "Determination of Bulk Density and Tap Density in Chinese Pharmacopoeia - 0993". It met the requirements for capsule filling and was reserved.

[0058] The above powders were mixed by a mixer. The mixing speed was 5 - 8 rpm, preferably 6 rpm; the mixing time was 10 - 60 min, preferably 30 min.

[0059] The above powder mixture to be filled has very strict requirements for the environment. The relative critical humidity should be controlled within 56%. If it exceeds 56%, the powder will quickly absorb moisture from the air and cause caking, seriously affecting capsule filling. The environmental humidity should be controlled below 56%, preferably 56%; the environmental temperature should be controlled to meet the requirements of the GMP workshop, that is, 16°C - 26°C, preferably 25°C.

[0060] Example 9: Preparation of hard capsules

[0061] (1) Through a fully automatic capsule filling machine, the prepared powder of Composition A of the NMN active ingredient was pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules were filled, finally the capsule caps were put on for shell locking; the prepared capsules were placed in a coating pan, and the coating solution was sprayed to increase the weight by 4% - 6%, and then dried to obtain hard capsules A.

[0062] (2) Through a fully automatic capsule filling machine, the prepared powder of Composition B of the NMN active ingredient was pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules were filled, finally the capsule caps were put on for shell locking; the prepared capsules were placed in a coating pan, and the coating solution was sprayed to increase the weight by 4% - 6%, and then dried to obtain hard capsules B.

[0063] (3) Through a fully automatic capsule filling machine, the prepared powder of Composition C of the NMN active ingredient was pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules were filled, finally the capsule caps were put on for shell locking; the prepared capsules were placed in a coating pan, and the coating solution was sprayed to increase the weight by 4% - 6%, and then dried to obtain hard capsules C.

[0064] (4) Using a fully automatic capsule filling machine, the prepared composition D powder of NMN active ingredient is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain hard capsules D.

[0065] (5) Using a fully automatic capsule filling machine, the prepared composition E powder of NMN active ingredient is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain hard capsules E.

[0066] (6) Using a fully automatic capsule filling machine, the prepared composition F powder of NMN active ingredient is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain hard capsules F.

[0067] (7) Using a fully automatic capsule filling machine, the prepared composition G powder of NMN active ingredient is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain hard capsules G.

[0068] (8) Using a fully automatic capsule filling machine, the prepared composition H powder of NMN active ingredient is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain hard capsules H.

[0069] (9) Using a fully automatic capsule filling machine, the pure NMN active ingredient powder is pressed into hydroxypropyl methylcellulose capsules. After multiple operations until the capsules are filled, finally, capsule caps are put on and the capsules are locked; the prepared capsules are placed in a coating pan, coating liquid is sprayed, the weight is increased by 4% - 6%, and then dried to obtain pure NMN hard capsules.

[0070] The speed of preparing the above hard capsules is 1200 - 2000 capsules / min, and preferably the preparation speed is 1600 capsules / min.

[0071] A gelatin solution is prepared using a mixed solution of 20 parts by weight of gelatin, 40 parts by weight of water, and 40 parts by weight of ethanol to lock the shells of the above-prepared hard capsules.

[0072] Product monitoring of Example 10

[0073] The hard capsules prepared in Examples 1 to 10 were subjected to product monitoring, including disintegration time limit and light exposure index. The test method was carried out with reference to the corresponding method in Appendix II of the 2005 Edition of the Pharmacopoeia of the People's Republic of China.

[0074] (1) Disintegration time limit

[0075] In hydrochloric acid solution for 2 hours, the hard capsules shall not rupture or disintegrate, and the disintegration time limit in intestinal solution shall not exceed 30 minutes.

[0076] Table 2 Long-term stability study of hard capsules in hydrochloric acid solution for 2 hours

[0077]

[0078]

[0079] The hanging basket was suspended on the metal bracket through the upper stainless steel shaft, immersed in a 1000 ml beaker, and the position of the hanging basket was adjusted so that the sieve was 25 mm from the bottom of the beaker when it descended. The beaker was filled with water (or the specified solution) at a temperature of 37 ± 1 °C, and the liquid level was adjusted so that the sieve was 15 mm below the liquid level when the hanging basket rose. Unless otherwise specified, 6 hard capsules were taken and placed in the glass tubes of the above-mentioned hanging basket, 1 capsule was added to each tube, and the disintegrator was immediately started for inspection.

[0080] All capsules should disintegrate completely within 30 minutes. If 1 capsule fails to disintegrate completely, another 6 capsules should be taken for retest, and all should meet the requirements.

[0081] Table 3 Disintegration time limit of hard capsules prepared in Examples 1 to 6 in intestinal fluid in long-term stability study

[0082]

[0083] Overall disintegration time limit ranking: pure NMN > D > B > A > E > F > C > G > H. Except for the D and F hard capsules at 24 months, and the pure NMN products at 18 months and 24 months that do not meet the disintegration time limit, the hard capsule products prepared from other compositions all meet the disintegration time limit requirements within 24 months.

[0084] (2) Explore the stability of NMN under light

[0085] Take 10 portions of the product of Example 9, each with a mass of 0.4 g, and place them in simulated environments such as outdoor strong light, indoor strong light, indoor weak light, and light avoidance conditions respectively to conduct a light stability test (under the condition of 4 °C). The test time lasts for 24 hours, and the HPLC method (using a Shim-pack VP-ODS (150L×2.0 mm, 5 μm) chromatographic column for chromatographic separation, with the mobile phase being methanol and 0.1% acetic acid aqueous solution, gradient elution for 12 min, and the flow rate being 0.3 mL / min) is used to detect the content changes of 9 products. The results are shown in Table 4 below:

[0086] Table 4 Investigation of the light stability of the hard capsules prepared in Example 9

[0087] Group Outdoor strong light Indoor strong light Indoor weak light Light-avoiding condition A 51.3％ 71.2％ 82.4％ 92.8％ B 49.6％ 68.9％ 80.3％ 91.3％ C 67.8％ 85.4％ 93.2％ 99.4％ D 48.5％ 67.8％ 79.5％ 90.3％ E 57.7％ 74.3％ 89.4％ 97.2％ F 53.3％ 72.3％ 85.6％ 95.4％ G 64.4％ 82.8％ 91.6％ 99.5％ H 65.9％ 84.4％ 93.1％ 99.6％ Pure NMN 49.3％ 68.9％ 90.4％ 99.3％

[0088] The light stability results are shown in the table. It can be seen from the data analysis that NMN has relatively high stability under light avoidance conditions, and increasing the light intensity has a greater impact on the stability of NMN. Overall light stability: H>G>C>E>F>A>B>D>pure NMN.

[0089] Test Example 1 Anti-inflammatory effect of the NMN composition

[0090] Take the compositions A, B, C, D, E, F, G, H and pure NMN respectively, and prepare aqueous solutions of 80 mg / mL, 60 mg / mL, 50 mg / mL and 30 mg / mL with physiological saline. Hydrocortisone is used as a positive control drug and is prepared into an aqueous solution of 1.5 mg / mL. Prepare a croton oil mixed inflammatory solution composed of 0.2 ml of croton oil, 2 ml of absolute ethanol and 7.8 ml of ether.

[0091] Male mice weighing 27 - 30 g are provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0092] Weigh the mice that have fasted for 16 h and randomly divide them into 28 groups, with 4 dose groups for each NMN drug mixture, namely 800 mg / kg, 60 mg / kg, 50 mg / kg and 30 mg / kg.

[0093] Hydrocortisone at 15 mg / kg is used as a positive control, and the above are all administered by intragastric gavage once. The blank control group is intragastrically gavaged with 10 ml / kg (NS) once. 1 hour after intragastric administration, apply 0.05 mL of the croton oil mixed inflammatory solution to both sides of the left ear of each mouse. 4 h after inflammation induction, the animals are sacrificed by decapitation, and the left and right ear discs of the mice are removed with a corneal ring, weighed, and processed for the drug group and the blank control group.

[0094] Inflammatory inhibition rate (%) = [(swelling degree of the control group - swelling degree of the administration group) / swelling degree of the control group]×100%.

[0095] Table 5 Anti-inflammatory effects of NMN-containing compositions

[0096]

[0097] As shown in the above table, the overall inflammation inhibition rate: hydrocortisone > H > G > C > E > F > A > B > D > pure NMN. For the NMN compositions of the present invention and hydrocortisone, both have obvious inhibitory effects on mouse ear swelling. The inhibitory effect of the NMN compositions of the present invention increases with the increase of the dose, and the anti-inflammatory effect is better than that of pure NMN. Among them, the anti-inflammatory effect of composition H is slightly higher than that of other compositions, showing the synergistic anti-inflammatory effect among the NMN compositions of the present invention.

[0098] Test Example 2 Improvement of the growth status of mice by NMN compositions

[0099] Taking pure NMN as a control, 10 adult mice were fed with each of the NMN compositions A - E of the present invention for 10 weeks, and the growth status of the mice was observed.

[0100] Table 6 Improvement of the growth status of mice by NMN-containing compositions

[0101]

[0102]

[0103] As shown in the above table, the overall improvement in growth status: H > G > C > E > F > A > B > D > pure NMN > blank control group. The NMN compositions of the present invention have obvious improvement effects on the growth status of mice, and the improvement effect is better than that of pure NMN. Among them, the anti-inflammatory effect of composition H is slightly higher than that of other compositions, showing the synergistic effect of improving the growth status among the NMN compositions of the present invention.

[0104] Results: There were no significant differences in the body weight, thymus and spleen indices of the mice in the NMN group compared with the control group. In the blood cell detection, there were no significant differences in each index. The results of the spontaneous activity analysis showed that the total movement distance and the percentage of movement time of the mice in the NMN group within 5 minutes were extremely significantly increased compared with the control group (P < 0.01). In the results of the forced swimming experiment, the immobile time of the mice in the NMN group was extremely significantly decreased compared with the control group (P < 0.01). Conclusion: NMN has no significant effect on the immunity of naturally aged mice, but has certain pharmacodynamic effects of improving anxiety and increasing activity.

[0105] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation manners of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation manners here. Any modifications, equivalent replacements, improvements, etc. derived from the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. A composition containing NMN, characterized in that: It contains nicotinamide mononucleotide as the first active ingredient and a second active ingredient with antioxidant properties.

2. The composition containing NMN according to claim 1, wherein: The second active ingredient is any one or more of coenzyme Q10, pyrroloquinoline quinone, resveratrol, plant fiber, glutathione, and γ-aminobutyric acid.

3. The composition containing NMN according to claim 1 or 2, characterized in that: Among them, the weight ratio of the active ingredients is (150 - 3):

1.

4. The composition comprising NMN according to claim 3, characterized in that, It also contains an excipient, and the excipient, NMN, and the second active ingredient are mixed by a mixer to form a powder mixture; the weight percentage of NMN in the effective ingredients of the composition is 81.0% - 98.0%; The excipient contains any one or two of sucrose, lactose, microcrystalline cellulose, modified starch, silicon dioxide, magnesium stearate, talcum powder, and HPC; Preferably, the excipient is microcrystalline cellulose and magnesium stearate.

5. The composition containing NMN according to claim 4, characterized in that, The mixing speed is 5 - 8 rpm, preferably 6 rpm; the mixing time is 10 - 60 min, preferably 30 min.

6. The NMN composition according to any one of claims 1 to 5, characterized in that, The dosage form of the preparation unit of this composition can be a liquid dosage form, a solid dosage form, or a semi-solid dosage form; Preferably, the liquid dosage form can be a solution, an emulsion, a suspension, an injection, an eye drop, a nasal drop, a lotion, a liniment, etc.; Preferably, the solid dosage form can be a tablet, a capsule, a granule, a powder, a pill, a suppository, a film, a patch, an aerosol, a spray, etc.; Preferably, the semi-solid dosage form can be an ointment, a gel, a paste, etc.

7. The preparation unit of the NMN composition according to claim 6, characterized in that The dosage form is preferably a solid dosage form, more preferably a capsule, and even more preferably a hard capsule.

8. A method for preparing a hard capsule of a composition containing NMN, characterized in that, This method includes: grinding the first active ingredient NMN, the second active ingredient, and the auxiliary materials into a powder mixture; filling the powder mixture into a capsule shell, locking the shell, and polishing it, and then directly coating a high-molecular enteric coating material outside the capsule shell; For the step of locking the shell, the composition of the shell-locking material is: a mixture of 20 - 30 parts by weight of gelatin, 40 - 50 parts by weight of water, and 40 - 50 parts by weight of ethanol; The composition of the enteric coating material is: 4 - 20 parts by weight of polyacrylic resin II, 4 - 20 parts by weight of polyacrylic resin III, 4 - 20 parts by weight of castor oil, 4 - 20 parts by weight of diethyl phthalate, 1 - 20 parts by weight of polysorbate 80, and 1 - 20 parts by weight of polyethylene glycol 6000.

9. The method for preparing a hard capsule according to claim 8, wherein The production speed is 1200 - 2000 capsules / min, the environmental temperature is 18 - 26°C, and the environmental humidity is 45% - 65%; Preferably, the production speed is 1200 - 1600 capsules / min; the temperature is 25°C; the environmental humidity is 56%.

10. The application of the NMN composition according to any one of claims 1 - 9 in the preparation of an antioxidant product, specifically in products such as enhancing immunity, protecting nerves, and improving the sub-healthy state.

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