Granule containing ascorbic acid and / or liposome

Abstract

To provide a granule containing ascorbic acids and / or liposomes, having excellent stability and aesthetic quality.SOLUTION: A granule is prepared that contains: (A) mucopolysaccharides; and (B) one or more selected from ascorbic acids and liposomes. Typically, the resulting granule has a favorable shape maintained in a well-formed spherical structure.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to granules containing ascorbic acids and / or liposomes. [Background technology]

[0002] Ascorbic acid is known to have a variety of effects, including anti-inflammatory effects, acne-fighting effects, melanin production inhibition effects, skin whitening effects, anti-aging effects, antioxidant effects, cell activation effects by promoting the synthesis of biological components such as collagen, and inhibition of cellular damage and DNA damage caused by ultraviolet rays in epidermal keratinocytes. It is an ingredient that is widely used as an external skin agent and supplement in the hope of achieving these effects.

[0003] Granules containing high concentrations of vitamin C that have good compactibility and improved disintegration properties have been proposed (Patent Document 1).

[0004] On the other hand, liposomes are single- or multi-layered closed endoplasmic reticulum of phospholipids, and can encapsulate desired components. Liposomes are composed of lipids similar to those in biological membranes, and have the property of easily binding to cell membranes and high affinity for living organisms. For this reason, liposomes are used, for example, in pharmaceuticals as a means for delivering active ingredients into the body, and as a means for delivering water-soluble ingredients that are difficult to penetrate the skin to the stratum corneum. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2021-187807 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a granule preparation which contains ascorbic acids and liposomes and has good properties. [Means for solving the problem]

[0007] The size of granules affects the appearance and sensory quality of the formulation. Furthermore, since the size of granules also affects the fluidity required in the manufacturing process, the particle size is controlled in the granulation process to improve the fluidity. However, when granulating ascorbic acids or liposomes, it is very difficult to suppress fine powder and keep the loss of raw materials during manufacturing low while maintaining a beautiful spherical appearance. In other words, problems occur in which granules are crushed and turned into fine powder during the manufacturing process.

[0008] As a result of intensive research conducted by the inventors to solve the above-mentioned problems, they discovered that by preparing a granule formulation containing ascorbic acids or mucopolysaccharides in liposomes, it is possible to produce granules containing active ingredients within a wide concentration range regardless of their concentration, with minimal fine powder, and to reduce production losses, thereby completing the present invention.

[0009] That is, the present invention provides the granules and methods described below. [1] (A) mucopolysaccharides; and (B) Granules containing one or more selected from ascorbic acids and liposomes. [2] The granule according to [1], having an average particle size of 250 μm or more. [3] The granule according to [1] or [2], wherein the total content of the component (B) is 0.02 to 95,000 parts by mass per part by mass of the component (A). [4] The granule according to any one of [1] to [3], having an aspect ratio of 1.0 to 3.5. [5] The granule according to any one of [1] to [4], wherein the particle size distribution ratio (M1 / M2) is 2.5 or more and 40 or less. [6] The granule according to any one of [1] to [5], having a surface roughness (Ra; μm) of 1 or more and 40 or less. [7] The granule according to any one of [1] to [6], which is enclosed in a package that allows the contents to be visually confirmed. [8] The granule according to any one of [1] to [7], wherein component (A) is hyaluronic acid. [9] The granule according to any one of [1] to [8], wherein the component (B) is ascorbic acid.

[10] The granule according to any one of [1] to [9], wherein component (B) is a liposome.

[11] A step of mixing one or more of (A) mucopolysaccharides and (B) ascorbic acids and liposomes to prepare a mixture; and and kneading and granulating the mixture.

[12] A method for suppressing the generation of fine powder during granulation of a mixture comprising (A) a mucopolysaccharide and (B) one or more members selected from ascorbic acids and liposomes. Effect of the Invention

[0010] According to the present invention, it is possible to provide good granules which contain ascorbic acids or liposomes and maintain a regular spherical shape. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Normally, the granulation process is controlled by adjusting the components and amounts of binders (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)) and excipients (starch, lactose). However, even when using such ordinary binders and excipients, it has been difficult to prevent pulverization in the manufacturing process of granules containing ascorbic acids or liposomes, so up until now, this has been addressed by removing the fine powder through sieving. However, production losses occur in such manufacturing processes, which also affect the quality of the product.

[0012] In the present invention, it has been clarified that the incorporation of mucopolysaccharides can suppress pulverization during the manufacturing process. As a result, even if the active ingredient is contained in a wide range of concentrations or at a high content, the granules can be manufactured without generating pulverization, and production losses can be reduced.

[0013] In the numerical ranges described in stages in this specification, the upper or lower limit of a certain numerical range can be arbitrarily combined with the upper or lower limit of another numerical range. In the numerical ranges described in this specification, the upper or lower limit of the numerical range may be replaced with a value shown in the examples. Unless otherwise specified, the components or materials exemplified in this specification may be used alone or in combination of two or more.

[0014] [Granules] ((A) Mucopolysaccharides) The mucopolysaccharides used in the present invention are polysaccharides consisting of a repeating structure of hexosamine (glucosamine, galactosamine) and uronic acid, and are also called glycosaminoglycans. Examples of mucopolysaccharides include hyaluronic acid, chondroitin, jaluronic acid, heparan, keratan, and salts thereof. Examples of these salts include alkali metal salts (sodium salts such as sodium hyaluronate, etc.), sulfated glycosaminoglycans (chondroitin sulfate I, etc.), and the like. The sulfated glycosaminoglycans may be salts such as metal salts of sodium, potassium, calcium, magnesium, iron, manganese, etc., and ammonium salts. These mucopolysaccharides may be used alone or in combination of two or more.

[0015] Among mucopolysaccharides, acidic mucopolysaccharides having an acidic group such as carboxylic acid in the structure are preferred, including hyaluronic acid or its salts (such as sodium hyaluronate), chondroitin, chondroitin sulfate or its salts (such as metal salts of chondroitin sulfate). In particular, hyaluronic acid or its salts are preferred. Although the mechanism of action is not entirely clear, mucopolysaccharides are negatively charged due to the presence of sulfate groups, uronic acid, etc., and can retain a large amount of water within the molecule, and therefore are considered to be able to achieve the effects of the invention.

[0016] The origin and molecular weight of hyaluronic acid or its salt are not limited, and it can be extracted from animal tissue or produced by fermentation method by culturing microorganisms. It can also be commercially available hyaluronic acid or its salt. The average molecular weight of hyaluronic acid or its salt may be about 2,000 to 1.7 million, about 10,000 to 1 million, or it may be hyaluronic acid with an average molecular weight of 500,000 or less. The average molecular weight of hyaluronic acid or its salt may be 2,000 to 200,000, 10,000 to 100,000, 200,000 to 2 million, 500,000 to 1.7 million, 1 million to 1.5 million, etc.

[0017] In the granules of the present invention, the total content of the (A) component relative to the total amount is preferably 0.001% by mass or more, more preferably 0.01% by mass or more, even more preferably 0.04% by mass or more, and even more preferably 0.1% by mass or more. The total content of the (A) component relative to the total amount of the granules is preferably 40% by mass or less, more preferably 30% by mass or less, even more preferably 20% by mass or less, and even more preferably 10% by mass or less.

[0018] The daily intake of the component (A) may vary depending on the condition of the individual taking it (body weight, age, sex, etc.), the formulation form of the composition, etc., but from the viewpoint of significantly exhibiting the effects of the present invention, it is, for example, preferably 1 mg or more, more preferably 5 mg or more, and even more preferably 10 mg or more. It may also be 2000 mg or less, preferably 1000 mg or less, more preferably 250 mg or less, and even more preferably 50 mg or less.

[0019] ((B) Ascorbic acids or liposomes) (B-1) Ascorbic acids The ascorbic acids used in the present invention include ascorbic acid or a salt thereof, or an ascorbic acid derivative.

[0020] Among these, although not limited thereto, from the viewpoint of significantly exhibiting the effects of the present invention, ascorbic acid or a salt thereof, or a water-soluble ascorbic acid derivative is preferably used, more preferably ascorbic acid or a salt thereof. Ascorbic acid is usually more preferably in the L-form.

[0021] In this specification, examples of the salt include salts with organic bases (e.g., salts with tertiary amines such as trimethylamine salts, triethylamine salts, monoethanolamine salts, triethanolamine salts, and pyridine salts; basic ammonium salts such as arginine); salts with inorganic bases (e.g., alkali metal salts such as ammonium salts, sodium salts, and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts); and the like.

[0022] In this specification, examples of salts of ascorbic acid include alkali metal salts, alkaline earth metal salts, and ammonium salts. Examples of alkali metal salts include sodium salts, potassium salts, and lithium salts. Examples of alkaline earth metal salts include calcium salts and magnesium salts.

[0023] Preferred salts of ascorbic acid are the sodium salt or magnesium salt.

[0024] A specific example of a preferred salt of ascorbic acid is sodium ascorbate.

[0025] Preferred ascorbic acid derivatives include ascorbic acid oxidase, L-calcium ascorbate, L-ascorbic acid 2-glucoside, L-ascorbic acid stearate, L-sodium ascorbate, L-ascorbic acid palmitate, erythorbic acid, and sodium erythorbate.

[0026] In the present invention, the ascorbic acids may be used alone or in combination of two or more thereof. For example, ascorbic acid or a salt thereof, or an ascorbic acid derivative may be used alone or in combination of two or more thereof.

[0027] In the granules of the present invention, the total content of the (B-1) component relative to the total amount is preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 10% by mass or more, and even more preferably 30% by mass or more. The total content of the (B-1) component relative to the total amount of the granules is preferably 95% by mass or less, more preferably 90% by mass or less, even more preferably 85% by mass or less, and most preferably 80% by mass or less. It may also be 40% by mass or more, 50% by mass or more, 60% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, etc.

[0028] The amount of the (B-1) component per 1 part by mass of the (A) component is not limited, but is preferably 0.025 to 95,000 parts by mass, more preferably 0.17 to 9,000 parts by mass, even more preferably 0.5 to 2,200 parts by mass, and even more preferably 3 to 800 parts by mass. The amount may be 0.1 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more, 2 parts by mass or more, 3 parts by mass or more, 5 parts by mass or more, 10 parts by mass or more, or 1,000 parts by mass or less, 800 parts by mass or less, 500 parts by mass or less, 300 parts by mass or less, 200 parts by mass or less, 100 parts by mass or less, etc.

[0029] The daily intake of the (B-1) component may vary depending on the condition of the individual taking it (body weight, age, sex, etc.), the formulation form, etc., but from the viewpoint of significantly exhibiting the effects of the present invention, for example, it is preferably 0.1 mg or more, more preferably 1 mg or more, and even more preferably 3 mg or more. It may also be 100 mg or more, 200 mg or more, 300 mg or more, or 500 mg or more. It may also be 3000 mg or less, 2000 mg or less, 1000 mg or less, or 500 mg or less.

[0030] (B-2) Liposome The liposome used in the present invention is a closed endoplasmic reticulum of a single or multiple layer of phospholipids, and can contain a desired component in the internal aqueous layer or lipid layer. In this specification, a liposome containing a desired component is also referred to as a "liposome". Such components that may be incorporated into the liposome include, but are not limited to, vitamins (e.g., vitamin A [e.g., retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.], vitamin B [e.g., 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, nicotinyl alcohol, pantothenic acid, , panthenol, biotin, choline, inositol, etc.], vitamin C [for example, ascorbic acid, salts of ascorbic acid, erythorbic acid, or derivatives thereof, etc.], vitamin D [for example, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, etc.], vitamin E [for example, tocopherol and its derivatives, ubiquinone derivatives, etc.], other vitamins [for example, hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, etc.], collagen (including hydrolyzed collagen), hyaluronic acid (including hydrolyzed hyaluronic acid), lactoferrin, polyphenols, etc. Among these, water-soluble vitamins are preferred, and ascorbic acid and / or its salts, or water-soluble vitamins including vitamin B are more preferred, and ascorbic acid and / or its salts are even more preferred.

[0031] The desired component being "encompassed" in the liposome may mean any of the following: being enclosed in the space within the liposome membrane, being present together with a component of the liposome membrane, being present between the multiple membranes that make up the liposome, or being bound to or attached to the surface of the outermost membrane that makes up the liposome.

[0032] The size of the liposome is usually about 30 to 1000 nm, preferably 30 to 600 nm, and more preferably 50 to 200 nm.

[0033] With respect to the liposomes in this specification, the components encapsulated in the liposomes may be expressed as "liposomal components of interest". For example, liposomes encapsulating vitamins may be expressed as "liposomal vitamins", "vitamin-encapsulating liposomes", "vitamin-containing liposomes", "liposomal vitamins", etc. Liposomes encapsulating ascorbic acid may be expressed as "liposomal ascorbic acid", "liposomes encapsulating ascorbic acid", "liposomes containing ascorbic acid", "liposomes containing ascorbic acid", "liposomes encapsulating ascorbic acid", "liposomes containing ascorbic acid", "liposomal ascorbic acid", etc.

[0034] Liposomes containing the desired components can be produced by a conventional method. For example, lecithin and optionally sterols are solubilized in a solvent such as ethanol, the solvent is removed under reduced pressure to prepare membrane lipids, and then a solution containing the desired components is added thereto and stirred to prepare a liposome suspension, thereby obtaining liposomes containing the components.

[0035] In addition to these methods, liposomes can also be obtained by dissolving lecithin and, optionally, a sterol in a small amount of ethanol, dispersing the mixture in an aqueous solution or buffer solution to perform pre-emulsification, and dispersing the mixture under high pressure to form a lipid bilayer to prepare a liposome suspension.

[0036] The liposome is preferably a liposome containing a water-soluble component, more preferably a liposome containing a water-soluble vitamin, and even more preferably a liposome containing ascorbic acid and / or a salt thereof. Such liposomes can be obtained by preparing the water-soluble component as the desired component by the above-mentioned method. Alternatively, a commercially available product can be used as the liposome. For example, a commercially available product of liposome containing ascorbic acid is "Vitamin C Zeal" (Aurea Bio).

[0037] In the granules of the present invention, the total content of the (B-2) component relative to the total amount is 0.1% by mass or more, more preferably 1% by mass or more, even more preferably 3% by mass or more, and even more preferably 5% by mass or more. The total content of the (B-2) component relative to the total amount of the granules is preferably 80% by mass or less, more preferably 70% by mass or less, even more preferably 50% by mass or less, and most preferably 20% by mass or less.

[0038] The content of the desired component in the liposome containing the desired component is preferably about 10 to 99% by mass, more preferably about 20 to 95% by mass, even more preferably about 25 to 90% by mass, and even more preferably 30 to 70% by mass.

[0039] For example, the content of ascorbic acid in liposomes containing ascorbic acid and / or a salt thereof is preferably about 10 to 99% by mass, more preferably about 20 to 95% by mass, even more preferably about 25 to 90% by mass, and even more preferably 30 to 70% by mass.

[0040] The amount of the (B-2) component relative to 1 part by mass of the (A) component is not limited, but is preferably 0.02 to 95,000 parts by mass, more preferably 0.2 to 9,000 parts by mass, even more preferably 0.6 to 2,100 parts by mass, and even more preferably 3.5 to 800 parts by mass. The amount may be 0.1 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more, 2 parts by mass or more, 3 parts by mass or more, 5 parts by mass or more, 10 parts by mass or more, or 1,000 parts by mass or less, 800 parts by mass or less, 500 parts by mass or less, 300 parts by mass or less, 200 parts by mass or less, 100 parts by mass or less, etc.

[0041] The amount of the (B) component relative to 1 part by mass of the (A) component is not limited, but is preferably 0.02 to 95,000 parts by mass, more preferably 0.2 to 9,000 parts by mass, even more preferably 0.6 to 2,100 parts by mass, and even more preferably 3.5 to 800 parts by mass. The amount may be 0.1 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more, 2 parts by mass or more, 3 parts by mass or more, 5 parts by mass or more, 10 parts by mass or more, or 1,000 parts by mass or less, 800 parts by mass or less, 500 parts by mass or less, 300 parts by mass or less, 200 parts by mass or less, 100 parts by mass or less, etc.

[0042] (Vitamins) The granules of the present invention may contain pharmacologically active or physiologically active ingredients other than the components (A) and (B) as long as the effects of the present invention are not impaired. The pharmacologically active or physiologically active ingredients may be used alone or in combination of two or more. Such ingredients include, but are not limited to, various vitamins and peptides.

[0043] Examples of vitamins include vitamin A [e.g., retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.], vitamin B [e.g., 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, tetrahydrofuran ... acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinyl alcohol, pantothenic acid, panthenol, biotin, choline, inositol, etc.], vitamin D group [e.g., ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, etc.], vitamin E group [e.g., tocopherol and its derivatives, ubiquinone derivatives, etc.], other vitamins [e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, etc.], etc.

[0044] Among these, water-soluble vitamins such as vitamin B are preferred, and vitamin B2 is particularly preferred. The content of such vitamin B is, for example, preferably 0.5% by mass or more, more preferably 1% by mass or more, and even more preferably 1.2% by mass or more, based on the total amount of the granule. The content of vitamin B2 is preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 1.5% by mass or less.

[0045] (Additives) The granules of the present invention may contain additives within the range that does not impair the effects of the present invention. Specific examples of such additives include binders, flow improvers / anti-caking agents, sugar alcohols, oils and fats, flavors, excipients, disintegrants, lubricants, colorants, flavorings, odorants, sugars, polyhydric alcohols, high-intensity sweeteners, emulsifiers, thickeners, acidulants, fruit juices, etc.

[0046] Examples of the binder include cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, acrylic acid polymers, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and propylene glycol alginate.

[0047] The content of the binder is, for example, preferably 1% by mass or more, more preferably 3% by mass or more, and even more preferably 5% by mass or more, based on the total amount of the granules. The content of the binder is preferably 20% by mass or less, more preferably 15% by mass or less, and even more preferably 10% by mass or less.

[0048] As the flow improver and anti-caking agent, silicon dioxide is preferred, and fine silicon dioxide is more preferred.

[0049] The content of such fine silicon dioxide is, for example, preferably 0.5% by mass or more, more preferably 0.8% by mass or more, and even more preferably 1% by mass or more, based on the total amount of the granule. The content of fine silicon dioxide is preferably 10% by mass or less, more preferably 5% by mass or less, and even more preferably 2% by mass or less.

[0050] Examples of sugar alcohols include lactose, maltose, fructose, sorbitol, maltitol, mannitol, xylitol, and trehalose.

[0051] The coloring agent may be a natural colorant, and for example, marigold color or the like is preferably used.

[0052] Of these, the additives are preferably, but not limited to, a combination of a binder, a flow improver / anti-caking agent and / or a colorant.

[0053] (Properties of granules) The granules of the present invention may have an average particle size of preferably 250 μm or more, more preferably 350 μm or more, and even more preferably 500 μm or more. The average particle size of the granules may be preferably 2000 μm or less, more preferably 1500 μm or less, and even more preferably 1200 μm or less. The average particle size is measured using a laser diffraction particle size measuring device (Malvern Panalytical Ltd. Mastersizer 3000) or according to the sieving method of the 18th Edition of the Japanese Pharmacopoeia.

[0054] The granule of the present invention may have an aspect ratio of 1 or more, preferably 3.5 or less, more preferably 3 or less, even more preferably 2.5 or less, and even more preferably 2 or less. The aspect ratio is the ratio of the minor axis to the major axis of a particle (major axis of a particle / minor axis of a particle), and is an index of sphericity. The major axis and minor axis are measured, for example, with a digital microscope (Keyence VHX-8000), and the average value of 10 measurements can be used.

[0055] Regarding the particle size of the granules of the present invention, when the ratio of granules having a size of 710 μm to 1410 μm is defined as M1 and the ratio of granules having a size of 250 to 500 μm is defined as M2, the particle size distribution ratio (M1 / M2) is preferably 40 or less, more preferably 30 or less, and further preferably 25 or less. (A / B) is preferably 2.5 or more, more preferably 2.7 or more, and even more preferably 3 or more. It may be 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, etc. The particle size distribution ratio is determined by the ratio (M1 / M2) of the proportion of granules of 710 μm to 1410 μm to the proportion of granules of 250 to 500 μm in particle size measurement of powder particles. The particle size of powder particles is measured using a laser diffraction particle size measuring device (Mastersizer 3000 manufactured by Malvern Panalytical Ltd) or according to the sieving method of the 18th revised edition of the Japanese Pharmacopoeia.

[0056] Regarding the particle size of the granules of the present invention, the particle size distribution ratio (M3 / M4) where the ratio of granules of 500 μm to 1410 μm is M3 and the ratio of granules of 250 to 355 μm is M4 may be preferably 60 or less, more preferably 50 or less, and further preferably 40 or less. The particle size distribution width (M3 / M4) may be preferably 10 or more. It may be 15 or more, 20 or more, 30 or more, etc. The particle size distribution ratio is determined by the ratio (M3 / M4) of the ratio of granules of 500 μm to 1410 μm to the ratio of granules of 250 to 355 μm in particle size measurement of powder particles.

[0057] In addition, the particle size of the granules of the present invention is preferably such that the amount of granules having a particle size of 255 to 355 μm is small. The amount is preferably 10% or less, more preferably 8% or less. It may be 6% or less, 5% or less, etc.

[0058] The particle size of the granules of the present invention is preferably such that the amount of granules of 250 μm or less is small, preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 3% by mass or less, and even more preferably 2% by mass or less.

[0059] The surface roughness (Ra) of the granule of the present invention may be preferably 40 or less, more preferably 35 or less, even more preferably 30 or less, and even more preferably 25 or less. Ra is preferably 1 or more, more preferably 3 or more, and even more preferably 7 or more. The surface roughness can be measured using a digital microscope (Keyence VHX-8000).

[0060] [Manufacturing method] The method for producing the granules of the present invention is not particularly limited, and known methods can be used. Specifically, the method includes the steps of mixing (A) mucopolysaccharides and (B) one or more of ascorbic acids and liposomes to prepare a mixture, and kneading and granulating the mixture. Here, the granulation can be performed using a granulation method that is generally used. For example, wet granulation methods such as spray granulation, stirring granulation, extrusion granulation, fluidized bed granulation, rolling granulation, and rolling fluidized bed granulation, and dry granulation methods such as compaction granulation can be used. Among these, although not limited thereto, it is preferable to use a wet granulation method, especially an extrusion granulation method or a rolling granulation method, from the viewpoint of the mechanism assumed by the inventor and enhancing the effect of the invention.

[0061] In the present invention, even when granules are produced through a normal granulation process, fine powder can be suppressed, and the obtained granules have a good appearance close to a perfect circle. The contents of each component and other conditions in the production method are in accordance with the contents described in [Granules].

[0062] [Methods for preventing fine powder generation during manufacturing] In one aspect of the present invention, the present invention relates to a method for suppressing the generation of fine powder during the production process of granules. That is, the present invention relates to a method for suppressing the generation of fine powder during granulation of a mixture by preparing a mixture containing (A) mucopolysaccharides and (B) one or more selected from ascorbic acids and liposomes. Here, fine powder refers to, for example, powder of 250 μm or less. Preferably, the amount of 250 μm powder immediately after the production of granules is suppressed to about 20% by mass or less, preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 3% by mass or less, and particularly preferably 2% by mass or less. The content of each component and other conditions in this method are the same as those described in [Granules].

[0063] [Formulation] The granules of the present invention can be used as they are or can be used after being packaged in a package. The granules of the present invention can also be molded into tablets, but in order to ensure the aesthetic appearance of the present invention, it is preferable to use them as granules. Here, the package can be SP packaging, stick packaging, or a hard capsule. Among these, it is preferable to use them as a hard capsule from the viewpoint of ease of handling and aesthetics, and it is more preferable to use a soft capsule or hard capsule packaged in a transparent or semitransparent container that allows the contents to be visually confirmed. The entire capsule may be transparent or semitransparent, or a part of the capsule (e.g., half) may be transparent or semitransparent. Here, transparency or semitransparency refers to the shape of the contents of the capsule that can be confirmed at an optimal distance by an adult with a visual acuity of 0.5 or more when visually observing the capsule from the outside.

[0064] The capsule may be a hard capsule container containing a layer containing hydroxypropylmethylcellulose. That is, the granule of the present invention may be contained in a capsule container having a layer containing hydroxypropylmethylcellulose on the surface in contact with the granule. The layer containing hydroxypropylmethylcellulose may be a layer consisting of hydroxypropylmethylcellulose only, but the ratio is not limited as long as it contains hydroxypropylmethylcellulose. The capsule may be a capsule containing one or more components selected from the group consisting of agar, carrageenan, and gelatin. Here, the capsule may be multi-layered or single-layered.

[0065] The minor axis / major axis ratio when the capsule body and cap are combined is not particularly limited, but is preferably about 0.30 to 0.42, and more preferably about 0.35 to 0.40.

[0066] [Use and dosage, etc.] The granules of the present invention can be used, for example, as ingredients of medicines, quasi-drugs, cosmetics, and food and drink (drinks, foods). The granules according to this embodiment can also be used, for example, as foods for specified health uses, nutritional functional foods, foods for the elderly, special-use foods, functional foods, dietary supplements, and food preparations (e.g., confectionery tablets) in addition to pharmaceutical preparations and quasi-drug preparations. The granules of the present invention can be useful for maintaining the moisture content of the skin, improving the firmness, moistness, and smoothness of the skin, or improving wrinkles.

[0067] The daily intake of ascorbic acid in the entire formulation of the present invention may vary depending on the condition of the individual taking it (body weight, age, sex, etc.), the formulation form of the composition, etc., but for example, it is preferably 10 mg or more, more preferably 100 mg or more, even more preferably 200 mg or more, and even more preferably 300 mg or more. It may also be 3000 mg or less, preferably 2500 mg or less, and more preferably 2000 mg or less. It may also be 400 mg or more, 500 mg or more, 600 mg or more, 1000 mg or more, 1500 mg or more, or 2000 mg or more.

[0068] The granules of the present invention may be stored and / or sold in dosage amounts including, but not limited to, 1 week or more, 10 days or more, 14 days or more, 20 days or more, or 30 days or more. EXAMPLES

[0069] The present invention will now be described in detail with reference to examples and test examples, but the present invention is not limited to the following examples and test examples. The unit of each component amount in the tables is mass % unless otherwise specified. The following reagents were used: Liposome VC: Ascorbic acid-containing liposome (Product name: Vitamin C Zeal: Alpha Link Co., Ltd., Test example 3: Product name: Liposomal PureWay-C Fine Powder: Maypro Industries Co., Ltd.) Hyaluronic acid (Product name: Low molecular weight hyaluronic acid: Chori Co., Ltd.) Original raw material: lactic acid bacteria, molecular weight: 30000~50000Da Excipients (porous silica, crystalline cellulose)

[0070] [Test Example 1. Micronization Confirmation Test] Compositions of the examples and comparative examples having the formulations shown in Table 1 below were prepared. Each component shown in the table was weighed, all components were premixed, further mixed, and kneaded in a stirring mixer while adding water to the powder, and then granulated and molded by extruding in an extrusion granulator. For the obtained granules, the particle size: tare weight of each sieve (1410, 1180, 710, 500, 355, 250 μm mesh size) was measured according to the sieving method of the Japanese Pharmacopoeia, 18th Edition. The sieves were stacked in order of the size of the mesh size so that the 1410 μm mesh size was on the top sieve, and about 10 g of granules was placed on the top sieve, covered, and the sieve set was shaken for 3 minutes. The mass of each sieve was then measured again, and the mass of the granules on the sieves was calculated.

[0071] Furthermore, the mass of the powder that passed through the 250 μm sieve was measured, and the ratio to the mass of all components was calculated. The results are shown in the table. In the table, values ​​other than "250 pass" are the measured values ​​of granules that did not pass through the 250 sieve.

[0072] [Table 1]

[0073] From the results shown in Table 1, it was confirmed that the composition of the embodiment suppresses pulverization after granulation molding and has less production loss than the composition of the comparative example. In the composition of the embodiment, the components on the 710 μm sieve and under the 1410 μm sieve accounted for about 73% to 85%, whereas in the composition of the comparative example, the components on the 710 μm sieve and under the 1410 μm sieve accounted for about 41% in the comparative example 1 and in the comparative example 2, the granules adhered to each other strongly and became coarse granules, so it was impossible to measure. In addition, it was visually confirmed that the granules obtained in the embodiment were close to a perfect circle, had a smooth and beautiful appearance on the surface, and were uniform in size. It was also confirmed that the surface roughness was actually suppressed to a low value. On the other hand, the granules obtained from the composition of the comparative example had jagged parts on the surface, even though they were produced under the same granulation conditions, and it was confirmed that the particles were not uniform or that the formation of the granules itself was difficult.

[0074] [Test Example 2. Appearance Evaluation Test] Each composition of the examples and comparative examples having the composition shown in Table 1 was prepared and encapsulated in a transparent capsule (product name: QUALI-V-N (No. 1 transparent), Qualicaps Co., Ltd.). Ten subjects who are familiar with the evaluation of capsule formulations evaluated the visual analog scale (VAS) value of the aesthetic appearance of the obtained capsule formulation. The average value (average VAS value) was used as the aesthetic value (beauty value). The maximum scale of the VAS scale was 10. The results are shown in Table 2.

[0075] <Evaluation criteria> 10 points: The granules have a glossy surface, the colors are vivid, and it feels like a high-quality product.

[0076] [Table 2]

[0077] As a result, it was confirmed that the capsule formulations containing the granules obtained from the composition of the embodiment had excellent aesthetic appearance, while the granules obtained from the composition of the comparative example were clearly inferior in aesthetic appearance. Furthermore, for each of the capsule formulations, the evaluation results of all subjects were within the range of ±1.

[0078] Granules were prepared according to the table below and filled into transparent capsules. (The excipients and capsules were the same as those used in the examples.) In all formulations, the effects of the present invention were achieved, such as suppressing pulverization after granulation and minimizing production loss, and excellent appearance. [Table 3]

Claims

1. A granule comprising (A) a mucopolysaccharide and (B) one or more members selected from ascorbic acids and liposomes.

2. 2. The granule according to claim 1, having an average particle size of 250 μm or more.

3. The granule according to claim 1, wherein the total content of the component (B) is 0.02 to 95,000 parts by mass per part by mass of the component (A).

4. The granule according to claim 1, having an aspect ratio of 1.0 to 3.

5.

5. 2. The granule according to claim 1, wherein the particle size distribution ratio (M1 / M2) is 2.5 or more and 40 or less.

6. 2. The granule according to claim 1, having a surface roughness (Ra; μm) of 1 or more and 40 or less.

7. The granule according to claim 1, which is enclosed in a package in which the contents can be visually confirmed.

8. The granule according to claim 1, wherein the component (A) is hyaluronic acid.

9. 2. The granule according to claim 1, wherein the component (B) is ascorbic acid.

10. The granule according to claim 1, wherein component (B) is a liposome.

11. A step of mixing (A) mucopolysaccharides and (B) one or more of ascorbic acids and liposomes to prepare a mixture; and and kneading and granulating the mixture.

12. A method for suppressing the generation of fine powder during granulation of a mixture comprising (A) a mucopolysaccharide and (B) one or more members selected from ascorbic acids and liposomes.

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