Capsule formulation

Abstract

To provide a capsule formulation containing nicotinamide mononucleotide in which stability of nicotinamide mononucleotide is improved.SOLUTION: Provided is a capsule formulation containing a first capsule and a second capsule, where the first capsule contains (A) nicotinamide mononucleotide, the second capsule contains one or more kinds selected from (B1) polyhydric alcohol and (B2) sugar alcohol, and the first capsule and the second capsule are partitioned by a membrane. Therefore, a capsule formulation containing polyphenol in which insolubilization of capsule membrane is suppressed is provided, and a capsule formulation containing nicotinamide mononucleotide in which stability of nicotinamide mononucleotide is improved can be provided.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a capsule formulation. More specifically, the present invention relates to a capsule formulation containing nicotinamide mononucleotide, in which the stability of nicotinamide mononucleotide is improved. [Background technology]

[0002] Nicotinamide mononucleotide, commonly known as NMN (nicotinamide mononucleotide), is known as an intermediate metabolite involved in the biosynthesis of the coenzyme nicotinamide adenine dinucleotide (NAD). The coenzyme nicotinamide adenine dinucleotide (NAD) is an essential coenzyme for multiple cellular metabolic reactions and plays a central role in energy production. It is also thought to activate the sirtuin gene, which is related to the suppression of aging phenomena.

[0003] On the other hand, nicotinamide mononucleotide (NMN) is a precursor of NAD, and it has been revealed that the sirtuin gene is activated by the supplementation of nicotinamide mononucleotide into the body, and its anti-aging effect has been attracting attention in recent years. Therefore, research and development of medicines and foods containing nicotinamide mononucleotide has been actively carried out.

[0004] Regarding the formulation of nicotinamide mononucleotide, for example, Patent Document 1 discloses a technology relating to a nicotinamide mononucleotide derivative that suppresses hydrolysis of nicotinamide mononucleotide. Also, Patent Document 2 discloses a technology that suppresses discoloration of the contents in a formulation containing nicotinamide mononucleotide by using pullulan as a capsule base material. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2019-137625 A [Patent Document 2] Patent Publication No. 2022-085975 Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, when formulating nicotinamide mononucleotide, its stability is often a problem. The present inventors faced the problem that the content of nicotinamide mononucleotide in a capsule formulation containing nicotinamide mononucleotide was significantly reduced.

[0007] Therefore, an objective of the present invention is to provide a capsule formulation containing nicotinamide mononucleotide, which has improved stability of nicotinamide mononucleotide. [Means for solving the problem]

[0008] As a result of intensive research, the present inventors have concluded that the decrease in the content of nicotinamide mononucleotide is due to the addition of sugar alcohol and / or polyhydric alcohol. Therefore, they have found that the stability of nicotinamide mononucleotide can be improved by physically separating nicotinamide mononucleotide from sugar alcohol and / or polyhydric alcohol by using multiple capsules in the composition of a capsule formulation, and have completed the present invention.

[0009] That is, the present invention provides the following capsule formulation. [1] A capsule formulation comprising a first capsule and a second capsule, The first capsule contains (A) nicotinamide mononucleotide, The second capsule contains one or more selected from (B1) polyhydric alcohols and (B2) sugar alcohols, A capsule formulation, wherein the first capsule and the second capsule are separated by a membrane. According to the capsule formulation of the present invention, in a capsule formulation containing nicotinamide mononucleotide, by adopting a configuration consisting of multiple capsules, it is possible to provide a capsule formulation in which the stability of nicotinamide mononucleotide is improved by physically separating the polyhydric alcohol and / or sugar alcohol from the nicotinamide mononucleotide. [2] The capsule formulation according to [1], characterized in that the (B1) polyhydric alcohol contains one or more selected from glycerin, 1,3-butylene glycol, and propylene glycol, and the (B2) sugar alcohol contains one or more selected from sorbitol, mannitol, xylitol, and erythritol. According to this feature, by limiting the types of polyhydric alcohol and sugar alcohol, the effect of improving the stability of the nicotinamide mononucleotide of the present invention can be more reliably achieved. [3] The capsule formulation according to [1] or [2], characterized in that the residual rate of the (A) nicotinamide mononucleotide after storage at 50°C for one week is 90% or more. According to this feature, the effect of improving the stability of nicotinamide mononucleotide by the configuration of the present invention containing multiple capsules can be more reliably guaranteed. Effect of the Invention

[0010] According to the present invention, it is possible to provide a capsule formulation containing nicotinamide mononucleotide, in which the stability of nicotinamide mononucleotide is improved. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram showing an example of a capsule formulation having a double capsule structure in the capsule formulation of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] [Capsule formulation] The capsule formulation of the present invention is a capsule formulation comprising a first capsule and a second capsule, the first capsule containing (A) nicotinamide mononucleotide, the second capsule containing one or more selected from (B1) polyhydric alcohol and (B2) sugar alcohol, and the first capsule and the second capsule being partitioned by a membrane. Note that the "membrane" in the present invention may be anything that partitions the first capsule and the second capsule and has the function of physically separating component (A) from component (B) (component (B1) and / or component (B2)), and may be something like a partition wall with a certain thickness.

[0013] When the capsule formulation of the present invention contains nicotinamide mononucleotide, the content of nicotinamide mononucleotide is reduced by the addition of sugar alcohol and / or polyhydric alcohol, and the stability of nicotinamide mononucleotide can be improved by physically separating them using a structure having multiple capsules, thereby improving the stability of nicotinamide mononucleotide as a formulation. This makes it possible to provide a capsule formulation that can appropriately exert the expected medicinal effects of nicotinamide mononucleotide.

[0014] The capsule formulation of the present invention is composed of a plurality of capsules. The arrangement, size, and number of the first capsule and / or the second capsule constituting the plurality of capsules are not particularly limited. For example, a multi-capsule structure in which one capsule contains another capsule inside may be used, or a single capsule may be configured to have a plurality of physically separated spaces by providing a partition inside the capsule. Also, a single capsule may be configured to contain a large number of minute capsules inside, such as beads obtained by coating or microcapsules obtained by a coacervation method or the like.

[0015] Here, as an example of the configuration of the capsule formulation of the present invention, a capsule formulation 1 having a double capsule structure will be described in detail with reference to FIG. 1. First, the capsule formulation 1 of this example has a double capsule structure in which a second capsule 2b is enclosed inside a first capsule 2a. A space of a first section 6a is disposed between a first film 4a which is the outer shell of the first capsule 2a and a second film 4b which is the outer shell of the second capsule 2b, and the space of the second section 6b inside the second film 4b is partitioned via the second film 4b. The capsule contents are physically separated and enclosed in the space of the first section 6a and the space of the second section 6b.

[0016] With this configuration, nicotinamide mononucleotide and a sugar alcohol and / or a polyhydric alcohol, which are substances that affect its stability, are enclosed in the first compartment 6a and the second compartment 6b, thereby eliminating the opportunity for them to come into contact with each other at least while the coating is functioning, thereby increasing the stability of nicotinamide mononucleotide. Although the details of the phenomenon in which the coexistence of nicotinamide mononucleotide with a sugar alcohol and / or a polyhydric alcohol results in a significant decrease in the content of nicotinamide mononucleotide are unknown, a factor such as hydrolysis due to moisture is presumed to be the cause.

[0017] Furthermore, these configurations are not limited to effects related to sugar alcohols and / or polyhydric alcohols, but also make it possible to further improve the stability of nicotinamide mononucleotide by physically separating nicotinamide mononucleotide from other substances that interfere with the stability of nicotinamide mononucleotide, such as additives, dispersion media, other active ingredients, etc., via the coating.

[0018] The capsule formulations referred to in the present invention include soft capsule formulations and hard capsule formulations. A soft capsule formulation refers to a formulation in which a capsule content that is mainly liquid is encapsulated with a capsule membrane such as gelatin. A hard capsule formulation generally refers to a capsule content that is mainly powder or granular and is enclosed in a cylindrical capsule (capsule membrane), but a capsule that is filled with a liquid capsule content and then sealed to prevent leakage can also be used. The capsule formulation of the present invention is preferably a hard capsule formulation. It is preferable that a capsule containing at least nicotinamide mononucleotide is a hard capsule formulation.

[0019] In the present invention, the size of the outermost capsule is not particularly limited, and can be changed depending on the administration method, the administration subject, and the composition of the capsule contents. For example, the particle size of a spherical capsule formulation is 2 to 20 mm. The upper limit of the particle size of this spherical capsule formulation is preferably 15 mm or less, more preferably 10 mm or less. The lower limit of the particle size of the spherical capsule formulation is preferably 4 mm or more, more preferably 6 mm or more. In addition, the size of the innermost capsule is not particularly limited, and can be changed depending on the capsule preparation method, administration method, the administration subject, and the composition of the capsule contents. For example, the particle size of a spherical capsule formulation is 0.1 to 15 mm. The upper limit of the particle size of the spherical capsule formulation is preferably 10 mm or less, more preferably 5 mm or less. The lower limit of the particle size of the spherical capsule formulation is preferably 0.3 mm or more, more preferably 0.5 mm or more. In addition, when the shape of the capsule is oval or oblong, it is preferable that the average value of the minor axis and the major axis is within the above-mentioned particle size range.

[0020] <Capsule shell> The capsule preparation of the present invention has a capsule shell. The composition of the capsule shell is appropriately determined depending on the application and composition, but is roughly classified according to whether it is a soft capsule preparation or a hard capsule preparation.

[0021] Examples of the components of the capsule shell of the soft capsule preparation include polymeric components and moisturizing agents. Examples of the polymeric components include, but are not limited to, gelatin, starch, carrageenan, and the like. Among these, gelatin is preferred from the viewpoint of the suppression effect of the insolubilization of the present invention being more effectively exerted. The content of gelatin in the capsule shell is, for example, 1 to 95% by mass, and the lower limit is preferably 5% by mass or more and the upper limit is 90% by mass or less. Examples of the moisturizing agents include, but are not limited to, sugars such as glucose, and alcohols. The blending ratio of each component in the capsule shell of the soft capsule preparation is not particularly limited and can be appropriately set. The capsule shell of the soft capsule preparation is formed by filling the capsule contents into a sheet produced from the above-mentioned capsule shell components and molding it under pressure.

[0022] Examples of the components of the capsule shell of the hard capsule preparation include gelatin, pullulan, agar, carrageenan, starch, starch hydrolyzate, alginic acid, HPMC (hydroxypropyl methylcellulose), polyvinyl alcohol (PVA), starch derivatives, gellan gum, etc. Among these, gelatin is preferred from the viewpoint of the suppression effect of the insolubilization of the present invention being more effectively exerted. The content of gelatin in the capsule shell is, for example, 1 to 95 mass, and the lower limit is preferably 5 mass% or more and the upper limit is 90 mass% or less. The blending ratio of each component in the capsule shell of the hard capsule preparation is not particularly limited and can be appropriately set. The capsule shell of the hard capsule preparation is usually used by forming the above capsule shell components into a cylindrical body and cap shape. The capsule shell of the hard capsule preparation used in the present invention may be a commercially available product.

[0023] <Capsule contents> ((A) Nicotinamide mononucleotide) The capsule formulation of the present invention contains nicotinamide mononucleotide as a capsule content. Nicotinamide mononucleotide is a type of nucleotide derived from nicotinamide and ribose, and is one of the intermediate metabolites that contribute to the NAD metabolic pathway as a biochemical precursor of NAD. The nicotinamide mononucleotide that can be used in the capsule formulation of the present invention is not particularly limited. It may be industrially synthesized, or a commercially available product available in the market can be used. In addition, there are two types of optical isomers of nicotinamide mononucleotide, α-form and β-form, and either one can be used in the present invention, but the β-form can be preferably used.

[0024] The content of nicotinamide mononucleotide relative to the total amount of capsule contents is not particularly limited, but is, for example, 0.5 to 60% by mass. Here, the total amount of capsule contents refers to the total mass of the capsule contents of the first capsule and the second capsule, excluding the mass of members for holding or separating the capsule contents, such as a membrane or a barrier membrane, or for imparting other functions, from the total mass of the capsule preparation in the case of a multiple capsule formulation. The lower limit is preferably 1% by mass or more, more preferably 3% by mass or more. The upper limit is preferably 40% by mass or less, more preferably 30% by mass or less. By setting the content of nicotinamide mononucleotide within the above range, a sufficient effect of nicotinamide mononucleotide can be expected, and at the same time, the effect of improving the stability of nicotinamide mononucleotide is more effectively exhibited.

[0025] In addition, the content of nicotinamide mononucleotide relative to the total amount of the contents of the first capsule or the second capsule in which nicotinamide mononucleotide is contained is not particularly limited, and is, for example, 30 to 100% by mass. The lower limit is preferably 50% by mass or more, more preferably 60% by mass or more. The upper limit is preferably 90% by mass or less, more preferably 80% by mass or less. If the content of nicotinamide mononucleotide is close to 100% by mass (for example, 95% by mass or more), the stability of nicotinamide mononucleotide can be improved more reliably. On the other hand, by appropriately coexisting active ingredients and additives that do not affect the stability of nicotinamide mononucleotide in the same capsule as nicotinamide mononucleotide, the freedom of formulation design can be guaranteed. For example, an active ingredient different from nicotinamide mononucleotide may be contained in a different capsule, and additives that interfere with the stability of the active ingredient may be separately contained in the same capsule as nicotinamide mononucleotide.

[0026] ((B1) Polyhydric alcohol) The capsule formulation of the present invention contains a polyhydric alcohol. The (B1) polyhydric alcohol is contained in a capsule different from the (A) nicotinamide mononucleotide (if the (A) component is contained in the first capsule, it is called the second capsule, and if the (A) component is contained in the second capsule, it is called the first capsule), and is characterized in that it is physically separated from the (A) nicotinamide mononucleotide by a membrane or a partition wall. The polyhydric alcohol is not limited as long as it exhibits the effects of the present invention, and examples thereof include ethylene glycol, diethylene glycol, 1,3-butylene glycol, 1,3-propanediol, propylene glycol, dipropylene glycol, glycerin, diglycerin, triglycerin, polyglycerin, polyethylene glycol, etc. Preferred are 1,3-butylene glycol, propylene glycol, and glycerin, and more preferably glycerin. These polyhydric alcohols can be used in any blending amount by appropriately combining one or more types. In addition, these may be industrially synthesized products, or commercially available products may be used.

[0027] The content of the polyhydric alcohol relative to the total amount of the capsule contents is not particularly limited, but is, for example, 0.5 to 60% by mass. The lower limit of the polyhydric alcohol content is preferably 1% by mass or more, more preferably 3% by mass or more. The upper limit of the polyhydric alcohol content is preferably 40% by mass or less, more preferably 30% by mass or less. By setting the polyhydric alcohol content within the above range, appropriate dissolution properties and bioavailability of the active ingredient can be guaranteed, and the freedom of formulation design can be secured.

[0028] ((B2) Sugar alcohol) The capsule formulation of the present invention contains a sugar alcohol as component (B). The sugar alcohol (B) is encapsulated in a capsule different from the nicotinamide mononucleotide (A) and is physically separated from the nicotinamide mononucleotide (A) by a membrane or a partition. The sugar alcohol is not limited as long as it can achieve the effects of the present invention, and examples thereof include sorbitol, xylitol, erythritol, mannitol, maltitol, lactitol, reduced starch syrup, and the like. Preferably, it is a sugar alcohol obtained by reducing monosaccharides, more preferably sorbitol, mannitol, xylitol, erythritol, and even more preferably sorbitol. These sugar alcohols can be used in any amount by appropriately combining one or more kinds. In addition, these may be industrially synthesized products, or products distributed on the market can be used.

[0029] The content of sugar alcohol relative to the total amount of capsule contents is not particularly limited, but is, for example, 0.5 to 60% by mass. The lower limit of the sugar alcohol content is preferably 1% by mass or more, more preferably 3% by mass or more. The upper limit of the sugar alcohol content is preferably 40% by mass or less, more preferably 30% by mass or less. By keeping the sugar alcohol content within the above range, appropriate dissolution properties and bioavailability of the active ingredient can be guaranteed, and the freedom of formulation design can be ensured.

[0030] (Content of component (B)) The content of component (B) (the total content of components (B1) and (B2)) is not particularly limited, but is, for example, 5 to 80% by mass based on the total amount of the capsule contents. The lower limit is preferably 10% by mass or more, and more preferably 15% by mass or more. The upper limit is preferably 70% by mass or less, and more preferably 60% by mass or less.

[0031] Furthermore, the content of component (B) relative to the total content of the first capsule or the second capsule in which component (B) is contained is not particularly limited, and is, for example, 5 to 90% by mass. The lower limit of the content of component (B) is preferably 15% by mass or more, and more preferably 30% by mass or more. The upper limit of the content of component (B) is preferably 80% by mass or less, and more preferably 70% by mass or less. By ensuring that the content of component (B) is within the above range, appropriate dissolution properties and bioavailability of the active ingredient can be ensured, and the freedom of formulation design can be secured.

[0032] <Nicotinamide mononucleotide residual rate> In the capsule formulation of the present invention, after preparation of the capsule formulation, the capsule formulation is sealed in an aluminum pack, and after storage for one week under an environment at a temperature of 50° C., the residual rate of nicotinamide mononucleotide is preferably 90% or more compared to the initial theoretical content of nicotinamide mononucleotide. More preferably, the residual rate of nicotinamide mononucleotide is 95% or more. Although the details of the calculation method of the residual rate will be described later, when the residual rate of nicotinamide mononucleotide is 90% or more, the capsule formulation can appropriately obtain the expected effect, and the amount of nicotinamide mononucleotide blended at the time of design can be reduced, so that the capsule formulation can be made smaller.

[0033] <Other ingredients> The capsule formulation of the present invention may contain components other than nicotinamide mononucleotide, sugar alcohol, and polyhydric alcohol as capsule contents. The other components vary depending on whether the formulation is a soft capsule formulation or a hard capsule formulation, or depending on the application and formulation of the capsule formulation. In the case of a soft capsule formulation, the components include, but are not limited to, dispersants, diluent oils, surfactants, sweeteners, flavorings, colorings, preservatives, and active ingredients, while in the case of a hard capsule formulation, the components include, but are not limited to, excipients, lubricants, flow agents, surfactants, sweeteners, flavorings, colorings, and preservatives. In addition, whether each capsule content is encapsulated in the first capsule or the second capsule is preferably determined with attention paid to not affecting the effect of the present invention, i.e., not affecting the stability of nicotinamide mononucleotide. More preferably, the capsule encapsulating nicotinamide mononucleotide contains only nicotinamide mononucleotide.

[0034] (Other active ingredients) The oily composition of the present invention may contain any other active ingredient within the scope of the present invention without impairing the effects of the present invention. Examples of other active ingredients include vitamins, polysaccharides, polyhydric alcohols, amino acids, amino sugars, proteins, various nucleic acids, polyphenols, carotenoids, flavonoids, phospholipids, fatty acids, minerals, enzymes, dietary fiber, herbs, fruits and plants and their extracts, probiotic fungi, etc. These other active ingredients may be used in any amount in an appropriate combination of one or more kinds.

[0035] The vitamins are not particularly limited, but examples thereof include vitamins belonging to vitamin A group, such as retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, and pharmacologically acceptable salts thereof, thiamine, thiamine disulfide, dicethiamine, octotiamine, shikotiamine, bis-ibuthiamine, bis-bentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, panthenol, biotin, choline, inositol, pangamic acid, and pharmacologically acceptable salts thereof, vitamins belonging to vitamin B group such as ascorbic acid and its derivatives, erythorbic acid and its derivatives, and vitamins belonging to vitamin C group such as ascorbic acid and its derivatives, erythorbic acid and its derivatives, and pharmacologically acceptable salts thereof, vitamins belonging to vitamin D group such as ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, and pharmacologically acceptable salts thereof, vitamins belonging to vitamin E group such as tocopherol and its derivatives, and pharmacologically acceptable salts thereof, as well as coenzyme Q10, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin (vitamin P), eriocitrin, hesperidin, and pharmacologically acceptable salts thereof, etc. These vitamins may be blended alone or in combination of two or more.

[0036] The minerals are not particularly limited, but examples thereof include calcium, phosphorus, magnesium, potassium, iron, manganese, selenium, copper, chloride, molybdenum, chromium, zinc, silicon dioxide, and iodine salts thereof, etc. These minerals may be blended alone or in combination of two or more kinds.

[0037] Examples of the polysaccharides include agar, agarose, agaropectin, starch, amylose, amylopectin, isolichenan, laminaran, lichenan, glucan, inulin, levan, fructan, galactan, mannan, xylan, arabinan, pentosan, alginic acid, pectinic acid, fucoidan, ascophyllan, carrageenan, pectin, locust bean gum, guar gum, tara gum, and gum arabic. Examples of acidulants include citric acid, sodium citrate, acetic acid, adipic acid, fumaric acid, and malic acid. Sweeteners include, for example, sucrose and aspartame. Other flavorings include, for example, sodium chloride, monosodium glutamate, glycine, succinic acid, and sodium lactate. Ingredients that are expected to have antioxidant or anti-aging effects, such as ascorbic acids, tocopherols, glycine, coenzyme Q10, carotenoids, and resveratrol, which is a polyphenol, can be preferably used because they are expected to have a synergistic effect as the efficacy of the capsule preparation.

[0038] Among these active ingredients, ingredients with high affinity to sugar alcohols and / or polyhydric alcohols, i.e., highly hydrophilic water-soluble vitamins, polysaccharides, amino acids, aminopolysaccharides, etc., can be preferably used. By using these hydrophilic active ingredients as capsule contents in the same capsule as sugar alcohols and / or polyhydric alcohols, the sugar alcohols and polyhydric alcohols can also function as a solvent or dispersion medium for the hydrophilic active ingredients, and it is expected that the dissolution and bioavailability of the hydrophilic active ingredients can be improved. In addition, there is an advantage that the capsule preparation can further be provided with various efficacies of other active ingredients.

[0039] The content of other active ingredients of the present invention is not particularly limited and can be changed depending on the type and number of active ingredients, purpose, affinity with solvents and dispersants, etc., but is, for example, 0.5 to 30% by mass based on the total amount of capsule contents. The lower limit of the content of other active ingredients is preferably 1% by mass or more. The upper limit of the content of other active ingredients is preferably 20% by mass or less.

[0040] (dilution oil) The capsule formulation of the present invention may contain a diluent oil. The diluent oil is generally used to dilute the capsule contents. Examples of diluent oils include oils containing a lot of saturated fatty acids, such as coconut oil, coconut oil, palm oil, grapefruit oil, and medium-chain triglyceride (MCT), and oils containing a lot of unsaturated fatty acids, such as soybean oil, sesame oil, perilla oil, peanut oil, rice bran oil (rice oil, rice germ oil), wheat germ oil, corn oil, rapeseed oil, cottonseed oil, pumpkin seed oil, olive oil, guava seed oil, date palm seed oil, grape seed oil, camellia seed oil, sunflower oil, evening primrose seed oil, and safflower oil. These diluent oils can be used in any amount by combining one or more types appropriately. The amount of diluent oil in the capsule contents of the capsule formulation of the present invention is not particularly limited, but is, for example, 0.1 to 40% by mass based on the total amount of the capsule contents. The lower limit is preferably 1.0% by mass or more. The upper limit is preferably 30% by mass or less.

[0041] (Dispersant) The capsule formulation of the present invention may contain a dispersant. By including a dispersant, separation of the capsule contents is prevented, and storage stability is improved. Examples of dispersants include beeswax, glycerin fatty acid esters, condensed polyglyceryl ricinoleate, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, hydrogenated rapeseed oil, hydrogenated safflower oil, hydrogenated palm oil, sitosterol, stigmasterol, campesterol, brassicasterol, cacao butter powder, carnauba wax, rice wax, Japan wax, paraffin, and lecithin. These dispersants can be used alone or in combination of two or more. The content of the dispersant is not particularly limited, but is, for example, 0.1 to 30% by mass with respect to the total amount of the capsule contents. The lower limit is preferably 1% by mass or more. On the other hand, the upper limit is preferably 20% by mass or less.

[0042] (Excipients) Examples of excipients include crystalline cellulose, lactose, sucrose, glucose, starch and starch derivatives, aspartame, glycyrrhizic acid and its salts, saccharin and its salts, stevia and its salts, sucralose, acesulfame potassium, calcium hydrogen phosphate, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, dextrin, starch and starch derivatives, guar gum, gum arabic, tragacanth, alginic acid and its salts, pullulan, carrageenan, gelatin, agar, carboxyvinyl polymer, carmellose sodium, starch, carboxymethyl starch sodium, carmellose sodium, low-substituted hydroxypropylcellulose, etc. These excipients can be used in any amount by appropriately combining one or more of them.

[0043] Examples of lubricants include calcium stearate, magnesium stearate, talc, hydrogenated vegetable oil, etc., and among these, calcium stearate is preferred. These lubricants can be used in any amount by combining one or more of them appropriately. The flow agent may, for example, be finely divided silicon dioxide.

[0044] [Method of production of capsule formulation] The method for producing the capsule formulation of the present invention is not particularly limited as long as the compartment of the first capsule and the compartment of the second capsule can be reliably separated. For example, the method may include the steps of 1. preparing the first capsule, 2. preparing the second capsule, and 3. sealing the first capsule inside the second capsule. Note that the steps of 2. preparing the second capsule and 3. sealing the first capsule inside the second capsule may be performed simultaneously.

[0045] [Method for improving the stability of nicotinamide mononucleotide] It is possible to provide a method for stabilizing nicotinamide mononucleotide in a capsule formulation containing nicotinamide mononucleotide, a sugar alcohol and / or glycerin, characterized in that the nicotinamide mononucleotide and the sugar alcohol and / or glycerin are partitioned by a coating. EXAMPLES

[0046] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples and various modifications are possible within the technical concept of the present invention. The blending amounts in the examples are shown in mass % unless otherwise specified.

[0047] (1) Test 1: Stability test of nicotinamide mononucleotide with double capsule structure The capsule contents of the double-structured hard capsule formulations shown in Table 1 were prepared by the following method, filled into HPMC capsules, and the effect of improving the stability of nicotinamide mononucleotide in the hard capsule formulation was evaluated.

[0048] <Preparation of Capsule Contents> The capsule contents of Comparative Example 1 were prepared by the following method. 21 g of medium-chain fatty acid triglyceride (glyceryl tricaprylate; product name "Coconard RK", Kao Corporation) was heated to about 60°C, and 7 g of coenzyme Q10 (product name "Kaneka QH", Kaneka Corporation) was added and stirred until homogenized (a). In a separate container, 19 g of (B1) glycerin (Kao Corporation), 28 g of (B2) sorbitol (product name "Sorbit L-70", Mitsubishi Corporation Life Sciences), 18 g of (A) nicotinamide mononucleotide (product name "NMN", Nakahara Co., Ltd.), and 7 g of enzymatically decomposed lecithin (product name "SLP-LPC70LF", Tsuji Oil Mills) were added and stirred until homogenized (b). Then, (a) and (b) were combined and stirred for 10 minutes in a homogenizer MARK II (manufactured by Primix Corporation), and cooled to room temperature to obtain the capsule contents of the hard capsule formulation of Comparative Example 1. In addition, using the same procedure, the capsule contents of Comparative Examples 2 and 3 and the first capsule of Example 1 were obtained according to the blending ratios in Table 1.

[0049] <Preparation of Capsule Formulation> Next, about 300 mg of each of the prepared capsule contents of Comparative Examples 1 to 3 was filled into a No. 1 HPMC capsule (Vcaps Plus L, manufactured by Lonza) using Microman (manufactured by MS Equipment) to obtain a hard capsule formulation containing the capsule contents of Comparative Examples 1 to 3. In addition, 54 mg of (A) nicotinamide mononucleotide (trade name "NMN", manufactured by Nakahara Co., Ltd.) was filled into a No. 3 HPMC capsule (Vcaps Plus L, manufactured by Lonza Co., Ltd.) (second capsule), and one capsule of the second capsule and 246 mg of the capsule contents of Example 1 were filled into a No. 1 Vcaps Plus L (first capsule), to obtain a hard capsule formulation containing the capsule contents of Example 1 in the same manner except that a double capsule configuration was used.

[0050] (Stability test of nicotinamide mononucleotide) The stability of nicotinamide mononucleotide was measured for the prepared hard capsule formulation. More specifically, 10 capsule formulations of Comparative Examples 1 to 3 and Example 1 were sealed in an aluminum bag, and after preparation of the hard capsules, they were stored for one week in an environment at a temperature of 50°C. The residual rate (mass%) of nicotine aminonucleotide after one week of storage, calculated by HPLC measurement, relative to the theoretical content of nicotine aminonucleotide, was calculated from the following [Formula 1] as an index of stability. The residual rate results (average value of 10 capsules) are shown in Table 1.

[0051] (nicotinamide mononucleotide remaining rate) JPEG2025014506000002.jpg20166

[0052] The HPLC measurement conditions were as follows. Column: Inertsil HILIC, 3 μm, 3 × 100 mm Mobile phase: Solvent A (0.1% phosphoric acid aqueous solution), Solvent B (acetonitrile) Gradient conditions (B%): 0 min → 1 min (90%), 1 min → 10 min (90% → 70%), 10 min → 10.01 min (70% → 90%), 10.01 min → 13 min (90%) Detection unit: UV detector (260 nm) Flow rate: 0.4mL / min Column temperature: 40℃

[0053] (Stability evaluation criteria) The results of the stability test were evaluated based on the remaining rate of nicotinamide mononucleotide according to the following evaluation criteria, and the evaluation results are shown in Table 1. 〇: Survival rate 90% or more ×: Residual rate less than 90%

[0054] [Table 1]

[0055] These results confirmed that in the capsule formulation of the present invention, the stability of nicotinamide mononucleotide is improved by separating the sugar alcohol and / or polyhydric alcohol from the nicotinamide mononucleotide into separate capsules of the double capsule. [Industrial Applicability]

[0056] The capsule formulation of the present invention has improved stability of nicotinamide mononucleotide due to the coexistence of nicotinamide mononucleotide with a sugar alcohol and / or a polyhydric alcohol, and can stably impart the antioxidant effects, anti-aging effects, etc. expected from nicotinamide mononucleotide to the capsule formulation. The capsule formulation of the present invention can be utilized in various fields such as pharmaceuticals, quasi-drugs, cosmetics, veterinary products, foods, and supplements. [Explanation of symbols]

[0057] 1...capsule formulation, 2a...first capsule, 2b...second capsule, 4a...first coating, 4b...second coating, 6a...first compartment, 6b...second compartment

Claims

1. A capsule formulation comprising a first capsule and a second capsule, The first capsule contains (A) nicotinamide mononucleotide, The second capsule contains one or more selected from (B1) a polyhydric alcohol and (B2) a sugar alcohol, A capsule formulation, wherein the first capsule and the second capsule are separated by a membrane.

2. The capsule formulation according to claim 1, wherein the (B1) polyhydric alcohol contains one or more selected from the group consisting of glycerin, 1,3-butylene glycol, and propylene glycol, and the (B2) sugar alcohol contains one or more selected from the group consisting of sorbitol, mannitol, xylitol, and erythritol.

3. 3. The capsule formulation according to claim 1 or 2, wherein the residual rate of the nicotinamide mononucleotide (A) after storage at 50° C. for one week is 90% or more.

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