Composition containing NAD < + > precursor and nano polyphenol compound, medicine capsule and preparation method thereof

Abstract

The invention discloses a composition containing an NAD < + > precursor and a polyphenol compound, and the composition is obtained by nanocrystallizing the polyphenol compound and then mixing the nanocrystallized polyphenol compound with the NAD < + > precursor and an optional vitamin B group derivative, wherein the NAD < + > precursor is nicotinamide riboside; the polyphenol compound comprises at least one of curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol and soy isoflavone, and preferably any two to four of the curcumin, the quercetin, the dihydroquercetin, the pterostilbene, the resveratrol and the soy isoflavone. The invention further provides a medicine capsule containing the composition and a preparation method of the medicine capsule. According to the composition containing the NAD < + > precursor and the polyphenol compound provided by the invention, by utilizing the special properties of the nano polyphenol compound raw material, the absorption of nicotinamide riboside in a body is increased, and the oral bioavailability of the nicotinamide riboside is improved, so that the concentration of the NAD < + > in the body is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a composition containing NAD+ precursors and nano-polyphenol compounds, a pharmaceutical capsule and a preparation method thereof. Background Art

[0002] NAD+ is an important biological substance, the full name of which is Nicotinamide adenine dinucleotide (NAD for short). In cell metabolism, NAD+ is involved in many key reactions, such as glycolysis, citric acid cycle, and oxidative phosphorylation. It plays a role in transferring hydrogen and electrons in these reactions, enabling cells to generate energy and maintain life activities. NAD+ is also involved in many other biochemical reactions, such as DNA repair, signal transduction, and gene expression. Studies have found that the level of NAD+ is closely related to the aging process. With age, the content of NAD+ in cells gradually decreases, leading to the decline of cell function and weakened metabolic capacity. Increasing NAD+ levels is considered to be an effective means to delay aging and maintain cell vitality. Some studies have shown that increasing NAD+ levels may have potential benefits in the treatment of neurodegenerative diseases, metabolic diseases, and immune system diseases. Some scientists are also exploring the possibility of using NAD+ to improve cognitive function, enhance physical strength, and improve quality of life.

[0003] Nicotinamide riboside (NR, or nicotinamide riboside) is a precursor of NAD+. Supplementing with NR can effectively increase NAD+ levels and has many health benefits. It can slow down signs of aging and prolong life, improve mitochondrial function, promote cognitive health, and may reduce the risk of cardiovascular disease.

[0004] Nicotinamide riboside (NR) is easily decomposed in gastric acid. Most NAD+ precursor products on the market are usually swallowed, but the problem with this method is that most NAD+ precursor products are difficult to stably exist in the gastric acid environment and are easily decomposed by gastric acid, resulting in poor absorption. Nicotinamide riboside (NR) has a low bioavailability in the human body. According to research, when a large amount of NR is taken orally, NR will be converted into nicotinamide (Niacinamide, referred to as NAM) in the intestine through CD157, and converted into nicotinic acid (Niacin, referred to as NA) under the action of intestinal microorganisms. NR can enter the blood in its natural form and quickly become NAM in the blood (half-life is about 3 minutes). The bioavailability of nicotinamide riboside (NR) in the human body is very low.

[0005] Chinese patent CN111838669B discloses a nanocomposition, preparation, preparation method and use for treating and improving vulnerable organs, and specifically discloses that by compounding nicotinamide riboside (NR) and / or nicotinamide nucleotide (NMN) with synergistic active substances, and by changing the microstructure of the formed composition, while strengthening the effect, the absorption rate and utilization rate of the composition are fundamentally changed. In the embodiment, the active ingredient nicotinamide riboside (NR) of the composition is mixed with one or two of resveratrol, catechins, pterostilbene, curcumin, fisetin, kaempferol and quercetin, and prepared into nano powder by spraying with a nano spray dryer (the nozzle temperature is set to 75-105°C). Compared with the composition made by simple mixing, the nano powder increases the NAD+ / NADH ratio of organ tissues, indicating that the nano powder increases the absorption rate and utilization rate of the active ingredient (NR). This patented technology does not investigate the stability of the active ingredient (NR) during the process of preparing the nano powder by spraying with a nano spray dryer. We found that the active ingredient nicotinamide riboside (NR) was mixed with one or two of pterostilbene, resveratrol, curcumin, and quercetin, and after nano spray drying (the nozzle temperature was set at 75-95°C), the content of the active ingredient nicotinamide riboside (NR) was reduced by 20-25%. The active ingredient is unstable and the content is low. The quality of the product cannot meet the quality standards required for commercial production and cannot be truly marketed as a drug or health food. Therefore, patent CN111838669B is unlikely to have substantial application value. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a composition containing NAD+ precursors and polyphenol compounds, which utilizes the special properties of nano-polyphenol compound raw materials to increase the absorption of nicotinamide riboside in the body, improve the oral bioavailability of nicotinamide riboside, and thus increase the concentration of NAD+ in the body.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0008] The first aspect of the present invention provides a composition containing an NAD+ precursor and a polyphenol compound, wherein the composition is obtained by nano-forming the polyphenol compound and then mixing it with an NAD+ precursor and an optional vitamin B derivative; wherein the NAD+ precursor is nicotinamide riboside (NR); and the polyphenol compound includes at least one of curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol, and soy isoflavones.

[0009] Furthermore, the method for nano-forming the polyphenolic compound includes any one of the following:

[0010] (a) preparing a polyphenol compound into a nano suspension, and obtaining a nano powder after spray drying;

[0011] (b) preparing the polyphenol compound into a nano suspension, and granulating the suspension by a fluidized bed to obtain nanoparticles;

[0012] Wherein, the particle size D90 value of the nano suspension is less than 1000 nm, preferably 300-500 nm.

[0013] In the present invention, the inventor surprisingly found that after nano-grinding natural polyphenols such as curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol, and soy isoflavones, the nano suspension was mixed with nicotinamide riboside (NR) after fluidized bed granulation or spray drying, which can significantly increase the half-life and bioavailability of nicotinamide riboside (NR) in the body, thereby facilitating the increase of the concentration of NAD+ in the body. After experimental verification, the nicotinamide riboside (NR) of the mixture composed of nano-polyphenol compounds and nicotinamide riboside (NR) remained stable after being placed at room temperature for 12 months, with a content of more than 99% and no change in quality, meeting the quality standard requirements for commercial production. Compared with the method disclosed in Chinese patent CN111838669B, the present invention does not need to mix nicotinamide riboside (NR) with natural polyphenol compounds such as curcumin, quercetin, and pterostilbene for nano-spray drying or fluidized bed granulation, thereby avoiding the decomposition of the active ingredient nicotinamide riboside (NR) under high temperature conditions to cause product quality problems. In this way, the product can be commercially produced, the product can meet the quality standards and be marketed, and truly achieve a better human therapeutic effect.

[0014] Further, the polyphenolic compound is preferably any two to four of curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol, and soy isoflavones; more preferably, the polyphenolic compound is selected from any three of curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol, and soy isoflavones. For example, the polyphenolic compound may be: (1) curcumin, quercetin, and resveratrol; (2) curcumin, dihydroquercetin, and pterostilbene; (3) curcumin, dihydroquercetin, and resveratrol. There is no limit to their ratio, for example, it may be 1:1:1.

[0015] Furthermore, the preparation method of the nano suspension is:

[0016] S1. dispersing the polyphenol compound in a liquid solvent to obtain a suspension;

[0017] S2. Adding grinding balls to the suspension, and after grinding, obtaining a nano suspension with a particle size D90 less than 1000 nm.

[0018] In the above step S1, the liquid solvent includes but is not limited to at least one of water, polyethylene glycol, glycerol, and propylene glycol. Preferably, the liquid solvent is water, so that no organic solvent is needed in the entire preparation process.

[0019] In the above step S2, the polyphenol compound raw material can be ground to nanometer level by wet grinding, thus achieving nano-scale.

[0020] Furthermore, in step S1, the liquid solvent further includes at least one stabilizer, which is beneficial to improving the stability of the suspension. The stabilizer may be a cellulose derivative and / or a surfactant. The cellulose derivative includes but is not limited to at least one of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose. The surfactant includes but is not limited to at least one of polyoxyethylene ether, poloxamer, polyglycolized glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate, and sodium cholate.

[0021] In some preferred embodiments, the stabilizer includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, and poloxamer, more preferably hydroxypropyl methylcellulose.

[0022] Furthermore, the dosage ratio of the polyphenol compound to the stabilizer is 2:1 to 20:1 (w / w), for example, it can be 2:1 (w / w), 4:1 (w / w), 5:1 (w / w), 6:1 (w / w), 7:1 (w / w), 10:1 (w / w), 12:1 (w / w), 15:1 (w / w), 16:1 (w / w), 18:1 (w / w), 20:1 (w / w), etc., preferably 5:1 (w / w).

[0023] Furthermore, the inventors have also found that adding a small amount of vitamin B derivatives to the composition can further increase the NAD+ concentration in the body. The vitamin B derivatives include but are not limited to at least one of the following vitamins, preferably any two or three: vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9 and vitamin B12. Preferably, the vitamin B derivatives include vitamin B3 and vitamin B6. More preferably, in the vitamin B derivatives, the ratio of vitamin B3 to vitamin B6 is 6:1.

[0024] Furthermore, the composition may also include auxiliary materials, including but not limited to at least one of fillers and lubricants. The fillers include but are not limited to at least one of starch, sucrose, dextrin, lactose, mannitol, microcrystalline cellulose, and pregelatinized starch, preferably microcrystalline cellulose. The lubricants include but are not limited to at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, micropowdered silica gel, talc, and hydrogenated vegetable oil, preferably magnesium stearate.

[0025] Furthermore, since nicotinamide riboside (NR) is easily decomposed by gastric acid after oral administration, thereby reducing the bioavailability of NR in the body and the concentration of NAD+ in the body, the present invention also provides a drug capsule, which is obtained by filling the above-mentioned composition into enteric-coated capsules or compressing tablets into enteric-coated tablets. This drug capsule can prevent nicotinamide riboside (NR) from dissolving in gastric juice, but can release active ingredients in intestinal juice, thereby further improving the concentration and bioavailability of nicotinamide riboside (NR) in the body.

[0026] Furthermore, in the pharmaceutical capsule, the content of NAD+ precursor can be 200-450 mg, such as 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, etc., preferably 250 mg. The content of polyphenol compounds can be 100-400 mg, such as 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, etc.

[0027] Furthermore, in the pharmaceutical capsule, the content of vitamin B derivatives does not exceed 10.5 mg, for example, it can be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 10.5 mg, etc.

[0028] Vitamin B3 contains two components, nicotinic acid (NA) and nicotinamide (NAM). Nicotinic acid (NA) and nicotinamide (NAM) can be converted into NAD+ in the body, but taking excessive amounts of vitamin B3 directly can cause serious side effects, including skin problems such as redness, burning, stinging, and itching, digestive system problems such as nausea, vomiting, and activation of ulcer surfaces, as well as liver damage, cardiovascular risks and other side effects. Therefore, the present invention controls the content of vitamin B3 in the drug capsule to not more than 9 mg, and the content of vitamin B6 to not more than 1.5 mg, which will not cause side effects caused by overdose and can further increase the concentration of NAD+ in the body.

[0029] The present invention also provides a method for preparing the drug capsule, comprising the following steps:

[0030] The polyphenol compound is formulated into a nano suspension, spray-dried or fluidized-bed granulated, and then mixed with a NAD+ precursor and an optional vitamin B derivative; then filled into enteric-coated capsules or compressed into tablets with enteric coating to obtain the drug capsule.

[0031] Furthermore, the composition provided by the present invention can increase the NAD+ concentration in the body, delay aging, maintain cell vitality, promote cognitive health, and possibly reduce the risk of cardiovascular disease.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] 1. The composition containing NAD+ precursor and polyphenolic compounds provided by the present invention is prepared by wet grinding the particle size of the polyphenolic compound raw material to nanometer level without using an organic solvent, and then drying and removing water, total mixing, and filling into enteric-coated capsules to prepare an improved NAD+ precursor preparation. The special properties of the nano-polyphenolic raw materials are utilized to increase the absorption of nicotinamide riboside in the body, improve the oral bioavailability of nicotinamide riboside, and thus increase the concentration of NAD+ in the body.

[0034] 2. The composition containing NAD+ precursors and polyphenol compounds provided by the present invention also contains a small amount of vitamin B derivatives, which can further increase the NAD+ concentration in the body.

[0035] 3. The composition containing NAD+ precursors and polyphenol compounds provided by the present invention can prevent nicotinamide riboside (NR) from dissolving in gastric juice by filling enteric-coated capsules or compressing tablets with enteric coatings, but can release active ingredients in intestinal juice, thereby further improving the concentration and bioavailability of nicotinamide riboside (NR) in the body.

[0036] 4. In the composition containing NAD+ precursors and polyphenolic compounds provided by the present invention, nicotinamide riboside (NR) does not need to be mixed with natural polyphenolic compounds such as curcumin, quercetin, and pterostilbene for nano-spray drying or fluidized bed granulation, thereby avoiding the decomposition of the active ingredient nicotinamide riboside (NR) under high temperature conditions to cause product quality problems. In this way, the product can be commercially produced, the product can meet the quality standards and be marketed, and truly achieve a better human therapeutic effect.

[0037] 5. The composition containing NAD+ precursors and polyphenol compounds provided by the present invention can increase the NAD+ concentration in the body, delay aging, maintain cell vitality, promote cognitive health, and may reduce the risk of cardiovascular disease. DETAILED DESCRIPTION

[0038] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0039] The present invention is further described below in conjunction with specific embodiments and comparative examples.

[0040] Example 1

[0041] This embodiment provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 1.

[0042] Table 1 Prescription of Example 1 Nicotinamide Riboside Nano-polyphenol Enteric-coated Capsules

[0043]

[0044] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0045] 1) Nanosuspension preparation

[0046] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the auxiliary material solution in the above stirring, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0047] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 2.

[0048] Table 2

[0049] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241001 3000 3 121.46 219.62 397.09

[0050] 2) Spray drying granulation

[0051] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2210.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0052] 3) Preparation of enteric-coated capsules by total mixing

[0053] According to the prescription, the active ingredients, B vitamins (vitamin B3: vitamin B6 = 6: 1) and other excipients are accurately weighed, the prepared polyphenol spray-dried powder and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0054] Example 2

[0055] This embodiment provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 3.

[0056] Table 3 Prescription of Example 2 Nicotinamide Riboside Nano-polyphenol Enteric-coated Capsules

[0057]

[0058] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0059] 1) Nanosuspension preparation

[0060] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 2 (curcumin: dihydroquercetin: pterostilbene = 1:1:1) raw material, slowly add it to the auxiliary material solution in the above stirring, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, grind for 3h, and obtain a polyphenol suspension.

[0061] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 4.

[0062] Table 4

[0063] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241002 3000 3 125.12 221.23 399.65

[0064] 2) Spray drying granulation

[0065] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2210.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0066] 3) Preparation of enteric-coated capsules by total mixing

[0067] According to the prescription, the active ingredients, B vitamins (vitamin B3: vitamin B6 = 6: 1) and other excipients are accurately weighed, the prepared polyphenol spray-dried powder and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0068] Example 3

[0069] This example provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 5.

[0070] Table 5 Prescription of Example 3 Nicotinamide Riboside Nano-polyphenol Enteric-coated Capsules

[0071]

[0072] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0073] 1) Nanosuspension preparation

[0074] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 3 (curcumin: dihydroquercetin: resveratrol = 1:1:1) raw material, slowly add it to the stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0075] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 6.

[0076] Table 6

[0077] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241003 3000 3 125.21 219.55 398.89

[0078] 2) Spray drying granulation

[0079] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2210.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0080] 3) Preparation of enteric-coated capsules by total mixing

[0081] According to the prescription, the active ingredients, B vitamins (vitamin B3: vitamin B6 = 6: 1) and other excipients are accurately weighed, the prepared polyphenol spray-dried powder and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0082] Example 4

[0083] This example provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 7.

[0084] Table 7 Prescription table of Example 4 Nicotinamide Riboside Nano-polyphenol Enteric-coated Capsules

[0085]

[0086] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0087] 1) Nanosuspension preparation

[0088] Weigh 40g of hydroxypropyl methylcellulose E3, add it to 2160g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the auxiliary material solution in the above stirring, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0089] The above nano-polyphenol mixture was re-dissolved with a diluent and tested. The results are shown in Table 8.

[0090] Table 8

[0091] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241004 3000 3 110.16 210.13 400.81

[0092] 2) Spray drying granulation

[0093] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2400.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0094] 3) Preparation of enteric-coated capsules by total mixing

[0095] According to the prescription, the active ingredients, B vitamins (vitamin B3: vitamin B6 = 6: 1) and other excipients are accurately weighed, the prepared polyphenol spray-dried powder and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0096] Example 5

[0097] This example provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 9.

[0098] Table 9 Prescription table of Example 5 Nicotinamide Riboside Nano-polyphenol Enteric-coated Capsules

[0099]

[0100]

[0101] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0102] 1) Nanosuspension preparation

[0103] Weigh 40g of hydroxypropyl methylcellulose E3, add it to 2700g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the auxiliary material solution in the above stirring, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, grind for 3h, and obtain a polyphenol suspension.

[0104] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 10.

[0105] Table 10

[0106] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241005 3000 3 131.95 231.29 405.42

[0107] 2) Spray drying granulation

[0108] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 3000.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0109] 3) Preparation of enteric-coated capsules by total mixing

[0110] According to the prescription, the active ingredients, B vitamins (vitamin B3: vitamin B6 = 6: 1) and other excipients are accurately weighed, the prepared polyphenol spray-dried powder and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0111] Example 6

[0112] This example provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 11.

[0113] Table 11 Prescription of Example 6 Nicotinamide Riboside Nano-Polyphenol Enteric-Coated Capsules

[0114]

[0115]

[0116] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0117] 1) Nanosuspension preparation

[0118] Weigh 40g of hydroxypropyl methylcellulose E3, add it to 2160g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0119] 2) Fluidized bed granulation:

[0120] Add 285g of nicotinamide riboside chloride and 10g of microcrystalline cellulose PH101 into the fluidized bed, set the air inlet temperature to 55°C and the air volume to 30m 3 / h to preheat the material temperature to 40°C, take the above nano-polyphenol suspension for fluidized bed top spray granulation, the granulation process spray pressure is 1000mbar, the spray speed is 8.0rpm / min, the air volume is 30-50m 3 / h, product temperature 30-35°C, inlet air temperature 55-60°C, after granulation is completed, continue drying until the moisture content of the particles is less than 3% and then stop drying to obtain nano-polyphenol particles.

[0121] 3) Preparation of enteric-coated capsules by total mixing

[0122] According to the prescription, vitamin B group (vitamin B3: vitamin B6 = 6: 1) and other auxiliary materials are accurately weighed, the prepared polyphenol particles and the weighed materials are passed through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder is then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside nano-polyphenol enteric capsules.

[0123] Example 7

[0124] This embodiment provides a nicotinamide riboside nano-polyphenol enteric-coated tablet (batch: 1000 tablets), the contents of which are shown in Table 12.

[0125] Table 12 Prescription table of Example 7 Nicotinamide Riboside Nano-polyphenol Enteric-coated Tablets

[0126]

[0127]

[0128] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated tablets of this embodiment is as follows:

[0129] 1) Nanosuspension preparation

[0130] Weigh 40g of hydroxypropyl methylcellulose E3, add it to 2160g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0131] 2) Fluidized bed granulation:

[0132] Add 285g of nicotinamide riboside chloride and 10g of microcrystalline cellulose PH101 into the fluidized bed, set the air inlet temperature to 55°C and the air volume to 30m 3 / h to preheat the material temperature to 40°C, take the above nano-polyphenol suspension for fluidized bed top spray granulation, the granulation process spray pressure is 1000mbar, the spray speed is 8.0rpm / min, the air volume is 30-50m 3 / h, product temperature 30-35°C, air inlet temperature 55-60°C. After granulation, continue drying until the moisture content of the granules is less than 3%, then stop drying to obtain nano-polyphenol granules.

[0133] 3) Total mixing and tableting

[0134] According to the prescription, vitamin B complex (vitamin B3: vitamin B6 = 6:1) and other auxiliary materials were accurately weighed, the prepared polyphenol particles and the weighed materials were sieved through a 40-mesh sieve, and then loaded into a three-dimensional mixer. After mixing evenly, they were pressed into tablets. The weight of the plain tablets was 555.0 mg.

[0135] 4) Enteric coating

[0136] Add 555 mg into the coating pan, set the inlet air temperature to 50°C, and after the outlet air temperature reaches 35°C, take a 10% solid content of hydroxypropyl methylcellulose acetate succinate ethanol-water solution (90:10) for coating. After the coating increases to 10%, stop coating and dry for 2.0 hours to prepare nicotinamide riboside nano-polyphenol enteric-coated tablets.

[0137] Example 8

[0138] This example provides a nicotinamide riboside nano-polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 13.

[0139] Table 13 Prescription of Example 8 Nicotinamide Riboside Nano-Polyphenol Enteric-Coated Capsules

[0140]

[0141] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this embodiment is as follows:

[0142] 1) Nanosuspension preparation

[0143] Weigh 40g of hydroxypropyl methylcellulose E3, add it to 2160g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material, slowly add it to the stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, and grind for 3h to obtain a polyphenol suspension.

[0144] The above nano-polyphenol mixture was re-dissolved with a diluent and tested. The results are shown in Table 14.

[0145] Table 14

[0146] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241008 3000 3 113.13 212.24 399.88

[0147] 2) Spray drying granulation

[0148] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2400.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0149] 3) Preparation of enteric-coated capsules by total mixing

[0150] The active ingredients and other excipients were accurately weighed according to the prescription, the prepared polyphenol spray-dried powder and the weighed materials were sieved through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder was then loaded into the hopper of a capsule filling machine for filling into enteric-coated capsules to prepare nicotinamide riboside nano-polyphenol enteric-coated capsules.

[0151] Comparative Example 1

[0152] This comparative example provides enteric-coated capsules (batch: 1000 capsules) formulated with commercially available nicotinamide riboside polyphenols as the main ingredient, the contents of which are shown in Table 15.

[0153] Table 15 Prescription table of comparative example 1 Nicotinamide riboside nano-polyphenol enteric-coated capsules

[0154]

[0155] The preparation method of the nicotinamide riboside nano-polyphenol enteric-coated capsules of this comparative example is as follows:

[0156] According to the prescription, 200g of the raw materials, polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1), 285g of nicotinamide riboside chloride, vitamin B group (vitamin B3: vitamin B6 = 6:1) and other materials were accurately weighed, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder was then loaded into the hopper of the capsule filling machine for filling into enteric capsules to prepare nicotinamide riboside polyphenol comparison enteric capsules.

[0157] Comparative Example 2

[0158] This comparative example provides a nano nicotinamide riboside polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 16.

[0159] Table 16 Prescription table of comparative example 2 Nano Nicotinamide Riboside Polyphenol Enteric-coated Capsules

[0160]

[0161] The preparation method of the nano nicotinamide riboside polyphenol enteric-coated capsules of this comparative example is as follows:

[0162] 1) Nanosuspension preparation

[0163] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 1 (curcumin: quercetin: resveratrol = 1:1:1) raw material and 285g of nicotinamide riboside chloride, slowly add the above stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, grind for 3h, and obtain a polyphenol suspension.

[0164] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 17.

[0165] Table 17

[0166] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241012 3000 3 140.55 245.47 435.12

[0167] 2) Spray drying granulation

[0168] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2495.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0169] 3) Preparation of enteric-coated capsules by total mixing

[0170] According to the prescription, vitamin B group (vitamin B3: vitamin B6 = 6: 1) and other excipients were accurately weighed, the prepared spray-dried powder and the weighed excipients were sieved through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder was then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nano-nicotinamide riboside polyphenol comparison enteric capsules.

[0171] Comparative Example 3

[0172] This comparative example provides a nano nicotinamide riboside polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 18.

[0173] Table 18 Prescription table of comparative example 3 nano nicotinamide riboside polyphenol enteric-coated capsules

[0174]

[0175] The preparation method of the nano nicotinamide riboside polyphenol enteric-coated capsules of this comparative example is as follows:

[0176] 1) Nanosuspension preparation

[0177] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 2 (curcumin: dihydroquercetin: pterostilbene = 1:1:1) raw material and 285g of nicotinamide riboside chloride, slowly add the above stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, grind for 3h, and obtain a polyphenol suspension.

[0178] The above nano-polyphenol mixture was re-dissolved in a diluent and tested. The results are shown in Table 19.

[0179] Table 19

[0180] batch number Speed ​​(rpm) Grinding time (h) D10(nm) D50(nm) D90(nm) CJ201241013 3000 3 148.25 242.11 432.21

[0181] 2) Spray drying granulation

[0182] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2495.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0183] 3) Preparation of enteric-coated capsules by total mixing

[0184] According to the prescription, vitamin B group (vitamin B3: vitamin B6 = 6: 1) and other excipients were accurately weighed, the prepared spray-dried powder and the weighed excipients were sieved through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder was then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nano-nicotinamide riboside polyphenol comparison enteric capsules.

[0185] Comparative Example 4

[0186] This comparative example provides a nano nicotinamide riboside polyphenol enteric-coated capsule (batch: 1000 capsules), the contents of which are shown in Table 20.

[0187] Table 20 Prescription table of comparative example 4 nano nicotinamide riboside polyphenol enteric-coated capsules

[0188]

[0189] The preparation method of the nano nicotinamide riboside polyphenol enteric-coated capsules of this comparative example is as follows:

[0190] 1) Nanosuspension preparation

[0191] Weigh 10g of hydroxypropyl methylcellulose E3, add it to 2000g of pure water, stir until the solution is clear, and obtain an auxiliary material solution. Weigh 200g of polyphenol combination 3 (curcumin: dihydroquercetin: resveratrol = 1:1:1) raw material and 285g of nicotinamide riboside chloride, slowly add the above stirring auxiliary material solution, and disperse it in the auxiliary material solution to obtain a pre-grinding suspension. Add grinding beads to the grinding chamber, add the suspension to the grinder feed funnel, set the speed to 3000rpm, grind for 3h, and obtain a polyphenol suspension.

[0192] The above nano-polyphenol mixture was re-dissolved with a diluent and tested. The results are shown in Table 21.

[0193] Table 21

[0194]

[0195]

[0196] 2) Spray drying granulation

[0197] The spray drying air inlet temperature was set to 130° C., the air outlet temperature was set to 90° C., and the spray speed was set to 30.0 rpm / min. 2495.0 g of the above nanosuspension was taken and spray-dried for granulation.

[0198] 3) Preparation of enteric-coated capsules by total mixing

[0199] According to the prescription, vitamin B group (vitamin B3: vitamin B6 = 6: 1) and other excipients were accurately weighed, the prepared spray-dried powder and the weighed excipients were sieved through a 40-mesh sieve, and then loaded into a three-dimensional mixer and mixed evenly. The mixed powder was then loaded into the hopper of a capsule filling machine for filling into enteric capsules to prepare nano-nicotinamide riboside polyphenol comparison enteric capsules.

[0200] 1. Stability evaluation

[0201] According to the guidelines for formulation stability experiments in the 2020 edition of the Chinese Pharmacopoeia, the dosage forms obtained in Examples 1 to 8 and Comparative Examples 1 to 4 were respectively placed in sealed brown vials and placed under test conditions of temperature 25°C ± 2°C and humidity 60% ± 10% for long-term stability tests. The results are shown in Table 22.

[0202] Table 22 Stability test results

[0203]

[0204] It can be seen from the stability test results in Table 22 that the nicotinamide riboside nano-polyphenol enteric-coated capsules or enteric-coated tablets prepared in Examples 1 to 8 of the present invention have good stability under normal temperature and humidity conditions; the commercially available simple mixture in Comparative Example 1 also has good stability.

[0205] Comparative Examples 2 to 4 adopt the method in patent CN111838669B to nano-spray-dry nicotinamide riboside (NR) and polyphenols. The stability is significantly reduced compared with the examples, and the NR content is reduced to 84-86%. The product does not meet the quality standard requirements.

[0206] 2. Animal Experimental Plan and Results

[0207] In this experiment, the nano-polyphenol enteric capsules of Example 2, the nano-polyphenol enteric tablets of Example 7, the nano-polyphenol enteric capsules 8 without vitamin B of Example 8 and the simple mixed comparative enteric capsules of Comparative Example 1 were used for NAD+ test in rats. 16 SD rats weighing about 250g were selected, and the experiment was carried out after one week of adaptive feeding. The 16 rats were divided into 4 groups, with 4 rats in each group (half male and half female). The first group was gavaged with microcapsules of Example 2, the second group was gavaged with microtablets of Example 7, the third group was gavaged with microcapsules of Example 8, and the fourth group was gavaged with microcapsules of Comparative Example 1. Each rat in each group was gavaged with the same dose of nicotinamide riboside (NR), and the NR gavage dose was 50 mg / kg.

[0208] Blood was collected from the tail vein of each group of rats at 0.5h, 1h, 2h, 12h, and 24h after gavage with the corresponding microcapsules or microtablets, and the blood volume was 0.1ml each time. The venous blood taken from each group of rats at each time point was processed and the NAD+ content in the blood samples was detected by liquid chromatography-mass spectrometry (HPLC-MS). The test results of 4 rats in each group were averaged, and the results are shown in Table 23.

[0209] Table 23 Animal test results

[0210]

[0211] From the test results in Table 23, it can be seen that when rats orally take the nicotinamide riboside nano-polyphenol enteric-coated capsules in Example 2 or the enteric-coated tablets in Example 7, the NAD+ content in the blood at 0.5h, 2h and 12h is 2.9 to 3.2 times, 2.1 to 2.4 times and 4.1 times that of the simple mixture enteric-coated capsules, respectively, and the NAD+ content in the blood at 24h is 2.0 to 2.6 times that of the simple mixture enteric-coated capsules. This shows that compared with the commercially available simple mixed nicotinamide riboside products, the nicotinamide riboside nano-polyphenol enteric-coated capsules or enteric-coated tablets of the present invention improve the intestinal absorption of nicotinamide riboside (NR), improve the bioavailability of NR in the body, and thus maintain a higher and sustained NAD+ concentration in the body.

[0212] In addition, when rats orally took the nicotinamide riboside nano-polyphenol enteric-coated capsules containing vitamin B in Example 2, the NAD+ content in the blood at 0.5h and 24h was 1.4 times that of the nicotinamide riboside nano-polyphenol enteric-coated capsules without vitamin B in Example 8. This shows that the addition of vitamin B in the nicotinamide riboside nano-polyphenol enteric-coated capsules or enteric-coated tablets of the present invention improves the intestinal absorption of nicotinamide riboside (NR) and improves the bioavailability of NR in the body, thereby maintaining a higher and sustained NAD+ concentration in the body.

[0213] In summary, the present invention provides a composition containing NAD+ precursors and polyphenol compounds, which utilizes the special properties of nano-polyphenol raw materials to increase the absorption of nicotinamide riboside in the body, improve the oral bioavailability of nicotinamide riboside, and thus increase the concentration of NAD+ in the body; and the composition has high stability, and the product can meet the quality standards and be marketed. Since nicotinamide riboside (NR) is a precursor of NAD+, supplementing NR can effectively increase the level of NAD+ and has many health benefits, so the product of the present invention can more effectively slow down aging, improve mitochondrial function, promote cognitive health, and reduce the risk of cardiovascular disease.

[0214] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A composition containing NAD+ precursors and polyphenol compounds, characterized in that: The composition is obtained by nano-forming a polyphenol compound and mixing it with an NAD+ precursor and an optional vitamin B derivative; wherein the NAD+ precursor is nicotinamide riboside; and the polyphenol compound includes at least one of curcumin, quercetin, dihydroquercetin, pterostilbene, resveratrol, and soy isoflavones, preferably any two to four of them.

2. A composition containing NAD+ precursors and polyphenol compounds according to claim 1, characterized in that: The method for nano-forming the polyphenolic compound comprises any one of the following: (a) preparing a polyphenol compound into a nano suspension, and obtaining a nano powder after spray drying; (b) preparing the polyphenol compound into a nano suspension, and granulating the suspension by a fluidized bed to obtain nanoparticles; Wherein, the particle size D90 value of the nano suspension is less than 1000 nm, preferably 300-500 nm.

3. A composition containing NAD+ precursors and polyphenol compounds according to claim 2, characterized in that: The preparation method of the nano suspension is: S1. dispersing the polyphenol compound in a liquid solvent to obtain a suspension; the liquid solvent comprises at least one of water, polyethylene glycol, glycerol, and propylene glycol; S2. Adding grinding balls to the suspension, and after grinding, obtaining a nano suspension with a particle size D90 less than 1000 nm.

4. A composition containing NAD+ precursors and polyphenol compounds according to claim 3, characterized in that: In step S1, the liquid solvent further comprises at least one stabilizer, wherein the stabilizer is a cellulose derivative and / or a surfactant; and / or, The usage ratio of the polyphenol compound to the stabilizer is 2:1 to 20:1 (w / w), preferably 5:1 (w / w).

5. A composition containing NAD+ precursors and polyphenol compounds according to claim 4, characterized in that: The cellulose derivative is selected from at least one of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose; the surfactant is selected from at least one of polyoxyethylene ether, poloxamer, polyglycolized glyceride, polyethoxylated hydrogenated castor oil, sodium lauryl sulfate and sodium cholate; and / or, The stabilizer includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, and poloxamer; preferably hydroxypropyl methylcellulose.

6. The composition containing NAD+ precursor and polyphenolic compounds according to claim 1, characterized in that: The vitamin B derivatives are selected from any two or three of the following vitamins: vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9 and vitamin B12; Preferably, the vitamin B derivatives include vitamin B3 and vitamin B6.

7. The composition containing NAD+ precursor and polyphenol compounds according to claim 1, characterized in that: The composition further includes auxiliary materials, wherein the auxiliary materials include at least one of a filler and a lubricant; and / or, The filler comprises at least one of starch, sucrose, dextrin, lactose, mannitol, microcrystalline cellulose, and pregelatinized starch, preferably microcrystalline cellulose; and / or, The lubricant includes at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, micro powder silica gel, talc, and hydrogenated vegetable oil, preferably magnesium stearate.

8. A drug capsule, characterized in that: The drug capsule is obtained by filling the composition according to any one of claims 1 to 7 into enteric-coated capsules or compressing tablets into enteric-coated tablets.

9. A drug capsule according to claim 8, characterized in that: In the drug capsule, the content of NAD+ precursor is 200-450 mg, preferably 250 mg; and / or, The content of polyphenol compounds in the drug capsule is 100-400 mg; and / or, In the drug capsule, the content of vitamin B derivatives is 1 to 10.5 mg.

10. A method for preparing the drug capsule according to claim 8, characterized in that: The following steps are involved: The polyphenol compound is formulated into a nano suspension, spray-dried or fluidized-bed granulated, and then mixed with a NAD+ precursor and an optional vitamin B derivative; then filled into enteric-coated capsules or compressed into tablets with enteric coating to obtain the drug capsule.

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