Method for inhibiting the solidification of soft capsules and lipids

Abstract

To provide a soft capsule that includes an ascorbic acid and nicotinamide and offers improved disintegrability.SOLUTION: The present invention provides a soft capsule wherein lipids contain (A) nicotinamide and (B) an ascorbic acid represented by formula (1), the content of the component (B) being 20 mass% or less [where R1 and R2 each represent hydrogen, a metal salt or an organic group, at least one of them being selected from a metal salt or an organic group, and R3 represents hydrogen or an organic group].SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to soft capsules and a method for suppressing solidification of lipids. More specifically, it relates to a soft capsule in which ascorbic acids and nicotinamide are contained in lipids, having improved disintegration properties, and a method for suppressing solidification of lipids containing ascorbic acids and nicotinamide.

Background Art

[0002] Conventionally, soft capsules have been used for purposes such as enclosing a liquid content such as a concentrated solution, suspension, or oily substance containing a drug in an outer film and administering it to a living body.

[0003] Soft capsules usually exhibit their effects when the outer film dissolves in the living body and the capsule content containing the active ingredient is released. The outer film of soft capsules is mainly made of, for example, gelatin and is easily soluble in water. Therefore, the content is preferably hydrophobic, and soft capsules have often been used when the content is a hydrophobic substance. On the other hand, when using a hydrophilic substance such as a water-soluble vitamin, an oily suspension in which the hydrophilic component is dispersed in an oily liquid (lipid) is filled into the soft capsule.

[0004] Various problems have arisen due to such a complex composition of hydrophilic and hydrophobic substances in soft capsules. For example, it is known that the viscosity of the capsule content increases due to the interaction between hydrophilic substances in the oily suspension, making it difficult to fill the capsule content into the film.

[0005] To address these issues, for example, Patent Document 1 discloses a technique in which fine particles containing water-soluble drugs, such as microcapsules or microspheres, are mixed with an oily substance to form the capsule contents. Patent Document 2 discloses a method for producing soft capsules containing ascorbic acid and nicotinamide, in which an oily suspension containing these two components in an oily liquid is stored at 23°C or below, and then filled into soft capsules while maintaining a temperature of 23°C or below. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 5-139959 [Patent Document 2] Japanese Patent Publication No. 2002-291419 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] While the above technology has solved the formulation problems of soft capsules, it has not solved post-formulation problems, such as delayed disintegration. Specifically, in soft capsules containing ascorbic acid and nicotinamide, the problem of delayed disintegration occurred due to the solidification of the capsule contents over time after manufacturing. When disintegration is delayed, the capsule contents cannot be quickly digested and absorbed in the gastrointestinal tract, which may make it difficult to obtain the expected effect. Therefore, suppressing delayed disintegration is an important issue in formulation development.

[0008] Therefore, the object of the present invention is to provide a soft capsule containing ascorbic acid derivatives and nicotinamide with improved disintegration properties. [Means for solving the problem]

[0009] The inventors hypothesized that the ascorbic acid and nicotinamide dispersed in the suspended oily liquid as the capsule contents form a complex with the water contained in the hydrophilic coating, causing it to solidify and thus delaying disintegration.

[0010] Therefore, after diligently investigating the above issues, we discovered that by using nicotinamide and a metal salt of ascorbic acid or a chemically modified ascorbic acid derivative as the capsule contents, we can suppress the solidification of the contents and improve their disintegration properties, thus completing the present invention.

[0011] In other words, the present invention provides the following soft capsule formulations. [1] A soft capsule characterized by containing the following components (A) and (B) in a lipid. (A) Nicotinamide (B) Ascorbic acids shown in formula (1) below [ka] [In the formula, R1 and R2 are hydrogen, a metal salt, or an organic group, with at least one of them selected from a metal salt or an organic group, and R3 is hydrogen or an organic group.]

[0012] According to the soft capsule formulation of the present invention, a soft capsule containing nicotinamide and ascorbic acid derivatives can be provided in which the solidification of lipids is suppressed, thereby improving the disintegration properties of the soft capsule. [2] The soft capsule preparation according to [1], characterized in that the content of component (A) is 3 to 10% by mass relative to the contents of the capsule. According to this characteristic, by specifying the nicotinamide content, lipid solidification can be further suppressed, and the effect of improving the disintegration properties of the soft capsule of the present invention can be further enhanced. [3] The soft capsule preparation according to [1], characterized in that the content of component (B) is 20 to 50% by mass relative to the contents of the capsule. According to this characteristic, by specifying the content of ascorbic acid compounds, lipid solidification can be further suppressed, and the effect of improving the disintegration properties of the soft capsule formulation of the present invention can be further enhanced. [4] The soft capsule preparation according to any one of [1] to [3], characterized in that the component (B) is one or more selected from sodium ascorbate, calcium ascorbate, or ascorbic acid-2-glucoside. This feature allows for more reliable suppression of lipid solidification, thereby more reliably improving the disintegration properties of the soft capsule formulation of the present invention. [5] The soft capsule preparation according to any one of [1] to [3], characterized in that the lipid content is 75% by mass or less relative to the contents of the capsule. This characteristic allows the present invention to fully achieve its effects, such as suppressing lipid solidification and improving disintegration, even when the lipid content in the capsule contents is low. [6] A method for inhibiting the solidification of lipids containing nicotinamide and ascorbic acid derivatives, characterized in that it contains the following component (B). (B) Ascorbic acids shown in formula (1) below [ka] [In the formula, R1 and R2 are hydrogen, a metal salt, or an organic group, with at least one of them selected from a metal salt or an organic group, and R3 is hydrogen or an organic group.] The present invention provides a method for suppressing lipid solidification in lipids containing nicotinamide and ascorbic acid derivatives. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a soft capsule containing ascorbic acid derivatives and nicotinamide with improved disintegration properties. [Brief explanation of the drawing]

[0014] [Figure 1] SEM images of each layer of the precipitate part. [Figure 2] Comparison of IR spectra of acicular crystals in the precipitate part, ascorbic acid, and nicotinamide. [Figure 3] Comparison of IR spectra of acicular crystals in the precipitate part and yellow crystals considered to be a complex of ascorbic acid and nicotinamide. [Figure 4] A diagram showing the procedure for preparing a slurry sample in the solidification test of the present invention.

Mode for Carrying Out the Invention

[0015] [Soft Capsule Agent] When the soft capsule agent of the present invention uses nicotinamide and ascorbic acid as active ingredients in the capsule contents, solidification of the capsule contents can be suppressed by containing specific ascorbic acids. As a result, it is possible to prevent a situation where the active ingredient is not released in the body due to delayed disintegration of the soft capsule agent.

[0016] The soft capsule agent of the present invention is characterized by containing (A) nicotinamide and (B) ascorbic acids represented by the following formula (1) in a lipid.

Chemical Formula

[0017] Here, the "lipid" refers to a lipid in a broad sense, and hydrophobic substances that are allowed to be used in foods, pharmaceuticals, etc. are collectively referred to as "lipids" and are distinguished from hydrophilic substances.

[0018] Previously, a phenomenon of solidification of the capsule contents in soft capsules containing nicotinamide and ascorbic acid had been observed. This solidification of the capsule contents causes delayed disintegration in the body, leading to problems such as reduced bioavailability. To confirm this phenomenon, the inventors observed a drug solution containing nicotinamide and ascorbic acid over time. More specifically, the drug solution containing nicotinamide and ascorbic acid was poured into 10 ml and 50 ml glass screw-top bottles, left to stand at room temperature, and the changes over time were observed.

[0019] As a result, solidification was observed at the contact surface between the drug solution and air from the first day. After a few days, all of the drug solution in the 10ml bottle had solidified, and in the 50ml bottle, the top few centimeters had solidified, while the inside remained fluid. From this, it was considered possible that solidification occurred due to moisture absorption at the contact surface between the drug solution and air.

[0020] Furthermore, after sampling the fluid portion in the chemical solution and the solidified portion on the surface, both were washed with hexane and subjected to two centrifugation cycles at 1,000 rpm for 5 minutes each. The precipitate formed by centrifugation separated into 2-3 layers.

[0021] Figure 1 shows SEM image data of each layer of the precipitate. The upper left image is the fluidized portion of the upper precipitate, the upper right image is the solidified portion of the upper precipitate, the lower left image is the fluidized portion of the lower precipitate, and the lower right image is the solidified portion of the lower precipitate.

[0022] As shown in these SEM images, a large number of needle-shaped crystals were observed in the solidified portion compared to the fluid portion. Next, these formed needle-shaped crystals and the starting materials, ascorbic acid and nicotinamide, were analyzed using infrared absorption spectroscopy. Figure 2 shows these IR spectra.

[0023] Analysis of these IR spectra revealed that the IR spectrum of the needle-shaped crystals was similar to that of ascorbic acid, but it was different from that of both nicotinamide and ascorbic acid.

[0024] Here, an aqueous solution of nicotinamide dissolved in an aqueous solution of ascorbic acid instantly turns yellow, and upon drying, yellow crystals precipitate. These yellow crystals are known to be a complex formed by charge transfer between ascorbic acid and nicotinamide, as shown in the following equation (2).

[0025] [ka]

[0026] Therefore, the IR spectrum of yellow needle-shaped crystals obtained by drying an aqueous solution of nicotinamide dissolved in ascorbic acid was also analyzed and compared with the IR spectrum of the needle-shaped crystals in the solidified portion. The results are shown in Figure 3.

[0027] As shown in Figure 3, the peak positions of the IR spectra of the yellow needle-shaped crystals were almost identical to those of the needle-shaped crystals in the precipitate collected from the drug solution. Therefore, the inventors concluded that the needle-shaped crystals in the drug solution are highly likely to be a complex (reactant) of ascorbic acid and nicotinamide formed in the aqueous solution described above.

[0028] Therefore, the inventors hypothesized that moisture in the capsule's coating, or moisture that entered from the outside, formed a complex between nicotinamide and ascorbic acid in the capsule contents, and that this complex solidified the capsule contents, causing the soft capsule to fail to disintegrate properly.

[0029] Therefore, the present inventors conducted intensive research to suppress the formation of a complex between nicotinamide and ascorbic acid. As a result, they found that by using ascorbic acid derivatives described later instead of ascorbic acid as the contents of the soft capsule, this complex formation can be suppressed, and the disintegration properties of the soft capsule can be improved.

[0030] [Composition of soft capsules] The specific configuration of the soft capsule of the present invention will be described in detail below, but the present invention is not limited to these. The soft capsule of the present invention may have other components, but it mainly consists of a liquid capsule contents encased in a capsule coating made of gelatin or the like.

[0031] <Capsule contents> The contents of the capsule of the present invention are not limited as long as they achieve the effects of the present invention, but for example, they may contain an active ingredient, a solute for dissolving the active ingredient, or a lipid as a dispersion medium. Nicotinamide and ascorbic acid, which are essential components of the present invention, are hydrophilic substances and therefore exist dispersed in the lipid.

[0032] ((A) Nicotinamide) The soft capsule formulation of the present invention contains nicotinamide as the capsule contents. Nicotinamide is a type of vitamin B and is widely used in pharmaceuticals, quasi-drugs, and supplements for its expected effects in maintaining skin function and improving blood flow. The nicotinamide that can be used in the present invention is not particularly limited and can be manufactured by known methods, or commercially available products can be used.

[0033] The content of (A) nicotinamide in the soft capsule of the present invention is not particularly limited, but for example, it is 3 to 10% by mass relative to the capsule contents. The upper limit of the content of (A) nicotinamide is preferably 6% by mass or less. The lower limit of the content of (A) nicotinamide is preferably 4% by mass or more. If the content of (A) nicotinamide is 3% by mass or more, the physiological activity expected as an active ingredient can be sufficiently exhibited, and the effects of the present invention are more pronounced. If the content of (A) nicotinamide is 10% by mass or less, the degree of freedom in designing the soft capsule increases, and for example, it becomes possible to add active ingredients or add components that enhance the functions of the soft capsule, such as stability, disintegration, and dissolution. At the same time, the effect of the present invention, which is to suppress lipid solidification, can be more reliably achieved.

[0034] ((B) Ascorbic acid derivatives) The soft capsule of the present invention contains (B) ascorbic acid compounds represented by the following formula (1) as the contents of the capsule. [ka] [In the formula, R1 and R2 are hydrogen, a metal salt, or an organic group, with at least one of them selected from a metal salt or an organic group, and R3 is hydrogen or an organic group.]

[0035] Ascorbic acid is widely used in the pharmaceutical, quasi-drug, and cosmetic fields due to its expected effects such as antioxidant activity, skin whitening, and collagen production promotion. In this specification, "ascorbic acid derivatives" encompasses ascorbic acid, ascorbic acid derivatives, and their salts. On the other hand, (B) ascorbic acid derivatives of the present invention are derivatives in which the hydroxyl groups at the 2nd, 3rd, and / or 6th positions of ascorbic acid are substituted as described above. The ascorbic acid derivatives usable in the present invention are not particularly limited as long as they can be used in the pharmaceutical and food fields.

[0036] Here, R1 and R2 are not particularly limited as long as they are hydrogen, metal salts, or organic groups, as long as they achieve the effects of the present invention. Examples of metal salts include alkali metal salts and alkaline earth metal salts. Examples of organic groups include those in which the hydroxyl group has been replaced with an ester or ether of sugars, phosphoric acid, polyphosphate, sulfuric acid, fatty acids, aliphatic hydrocarbons, or other pharmaceutically acceptable compounds. Preferably, it is a sodium salt, calcium salt, glucopyranosyl group, or a branched acyl group or alkyl group having 1 to 20 carbon atoms, and more preferably, a sodium salt, calcium salt, glucopyranosyl group, or a branched acyl group or alkyl group having 1 to 3 carbon atoms. Even more preferably, it is a sodium salt, calcium salt, or glucopyranosyl group. It is believed that by substituting either the hydroxyl group at the 2nd or 3rd position of ascorbic acid with a metal salt or organic group, the chemical instability caused by the enediol bond at the 2nd and 3rd positions as shown in formula (2) can be stabilized, and complex formation can be suppressed.

[0037] R3 is not particularly limited as long as it is hydrogen or an organic group and achieves the effects of the present invention. Examples of organic groups include those in which a hydroxyl group has been converted into an ester or ether of sugars, phosphoric acid, polyphosphate, sulfuric acid, fatty acid, aliphatic hydrocarbon, or other pharmaceutically acceptable compound. Preferably, it is a branched acyl group or alkyl group having 1 to 20 carbon atoms, or a glucopyranosyl group, and more preferably, it is a branched acyl group or alkyl group having 1 to 3 carbon atoms, or a glucopyranosyl group.

[0038] (B) Specific examples of ascorbic acid compounds include, for example, potassium ascorbate, sodium ascorbate, calcium ascorbate, magnesium ascorbate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbic acid-2-phosphate ester, ascorbic acid-3-phosphate ester, ascorbic acid-2-polyphosphate ester, ascorbic acid-2-sulfate ester, ascorbic acid-2-palmitate ester, ascorbic acid-2-stearate ester, ascorbic acid-6-stearate ester, ascorbic acid-2,6-dibutyl ester, ascorbic acid-2,6-dipalmitate ester, and ascorbic acid-2-glucoside. Salts of these compounds include sodium salts, potassium salts, calcium salts, and magnesium salts. Preferably, the ascorbate is sodium ascorbate, calcium ascorbate, ascorbic acid-2-polyphosphate, ascorbic acid-2-sulfate, ascorbic acid-2,6-dibutyl, or ascorbic acid-2-glucoside, and more preferably, it is sodium ascorbate, calcium ascorbate, or ascorbic acid-2-glucoside.

[0039] Here, for example, if the hydroxyl group R1, R2, or R3 in (B) ascorbic acid is substituted with a hydrophobic functional group with a large number of carbon atoms, the affinity of the ascorbic acid to lipids increases, and the powdered (B) ascorbic acid may absorb lipids and lose fluidity, thereby promoting the solidification of lipids. Therefore, as substituents in (B) ascorbic acid, hydrophilic groups such as metal salts and sugars, or branched acyl groups or alkyl groups with 1 to 3 carbon atoms are more preferably used. In addition, the present invention can use any of the d, l, or dl forms of (B) ascorbic acid. Furthermore, metal salts of (B) ascorbic acid that are permitted in the fields of food or pharmaceuticals may also be used. Moreover, one or more types of component (B) ascorbic acid can be used in any amount as appropriate.

[0040] The content of (B) ascorbic acid derivatives in the soft capsule formulation of the present invention is not particularly limited. It can be changed depending on the intended use, the mode of administration, and the composition of other components, but for example, it is 20 to 50% by mass relative to the capsule contents. The lower limit of the content of (B) ascorbic acid derivatives is preferably 30% by mass or more relative to the capsule contents. The lower limit of the content of (B) ascorbic acid derivatives is preferably 50% by mass or less. If the content of (B) ascorbic acid derivatives is 20% by mass or more, the physiological activity expected as an active ingredient can be fully exhibited, and the effects of the present invention are more pronounced. If the content of (B) ascorbic acid derivatives is 50% by mass or less, the degree of freedom in designing the soft capsule formulation increases, and for example, it becomes possible to add an active ingredient or add a component that enhances the function of the soft capsule formulation such as stability, disintegration, and dissolution. At the same time, the effect of the present invention, which is to suppress lipid solidification, can be more reliably achieved.

[0041] The content of ascorbic acids other than (B) in the soft capsule formulation of the present invention is not particularly limited as long as the effects of the present invention are achieved. It can be changed depending on the content of nicotinamide, (B) ascorbic acid, lipid content, etc., but for example, it is contained in less than 20% by mass relative to the capsule contents. Preferably it is 10% by mass or less, more preferably 3% by mass or less, and even more preferably substantially free of ascorbic acids other than (B). Here, "substantially free" means either not contained at all or contained to the extent that it does not exert a physiological effect on the living body on its own, specifically, for example, 0.1% by mass or less. If the content of ascorbic acids other than (B) is less than 20% by mass relative to the capsule contents, the formation of complexes with nicotinamide can be suppressed, and by preventing the solidification of lipids, poor disintegration of the soft capsule formulation can be prevented.

[0042] (Other active ingredients) Other active ingredients that can be contained in the soft capsules of the present invention are any ingredients permitted for use in food and pharmaceuticals, and are not particularly limited as long as they achieve the effects of the present invention. For example, hydrophilic vitamins that can be used in the soft capsules of the present invention include vitamin B1s such as thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, dicethiamine hydrochloride, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine cetyl sulfate, thiamine thiocyanate, thiamine naphthalene-1,5-disulfonate, and thiamine lauryl sulfate; vitamin B2s such as riboflavin, riboflavin butyrate, and riboflavin sodium phosphate; vitamin B6s such as pyridoxine hydrochloride and pyridoxal phosphate; vitamin B12s such as hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, and hydroxocobalamin; pantothenic acids such as folic acid, biotin, panthenol, calcium pantothenate, and sodium pantothenate; and vitamin Ps such as methylhesperidin and rutin.

[0043] Furthermore, hydrophobic vitamins that can be used in the soft capsules of the present invention include vitamin D compounds such as vitamin D1, vitamin D2, vitamin D3, and vitamin D4; vitamin K compounds such as vitamin K1, vitamin K2, vitamin K3, vitamin K4, vitamin K5, vitamin K6, and vitamin K7; carotenoid compounds such as β-carotene, palm oil carotene, Dunaliella carotene, cryptoxanthin, zeaxanthin, canthaxanthin, β-apo-8'-carotenal, bixin, and lycopene; vitamin E compounds such as d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, and d-σ-tocopherol; and vitamin F compounds such as linoleic acid, linolenic acid, and arachidonic acid.

[0044] Furthermore, examples of yeasts that can be used in the soft capsules of the present invention include zinc yeast, selenium yeast, chromium yeast, iron yeast, magnesium yeast, manganese yeast, copper yeast, molybdenum yeast, brewer's yeast, baker's yeast, wine yeast, baker's yeast extract, brewer's yeast extract, and the like.

[0045] (Powder content) The powder content in the soft capsule of the present invention is not particularly limited. It can be changed depending on the composition of the soft capsule, the type of active ingredient, the properties of the powder, the lipid content, etc., but for example, it is 27% by mass or more relative to the capsule contents. Preferably, it is 40% by mass or more, and more preferably 55% by mass or more. When the powder content in the soft capsule is 27% by mass or more relative to the capsule contents, if ascorbic acids other than (B) ascorbic acids are used, lipid solidification may occur.

[0046] Here, an increase in the powder content leads to a relative decrease in the lipid content. This increases the probability that the lipid powder, which acts as a dispersion medium, will come into contact with moisture that has entered the capsule contents, making it easier for lipid solidification to occur due to complex formation. On the other hand, when using the (B) ascorbic acid powder of the present invention, complex formation can be suppressed even if the powder content is 27% by mass or more relative to the capsule contents, thus preventing lipid solidification. Furthermore, by increasing the content of the active ingredient powder, it becomes possible to miniaturize the soft capsule. There is no particular upper limit to the powder content in the soft capsule of the present invention, but for example, it is 65% by mass or less relative to the capsule contents. If the powder content relative to the capsule contents is 65% by mass or less, complex formation between nicotinamide and ascorbic acid can be suppressed, and lipid solidification can be suppressed.

[0047] (Diluting oil) The soft capsule formulation of the present invention may contain a diluent oil. Diluent oils are generally used to dilute the contents of the soft capsule formulation. Examples of diluent oils include oils rich in saturated fatty acids such as coconut oil, palm oil, grapefruit oil, and medium-chain triglyceride (MCT), and oils rich in 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 individually or in combination of two or more in any amount as appropriate.

[0048] The amount of diluent oil in the soft capsule formulation of the present invention is not particularly limited, but for example, it is 5 to 80% by mass relative to the capsule contents. Preferably, the lower limit is 10% by mass or more, and preferably the upper limit is 60% by mass or less.

[0049] (Dispersant) The soft capsules of the present invention may contain a dispersant. The inclusion of a dispersant prevents separation of the capsule contents and improves storage stability. Examples of dispersants include beeswax, glycerin fatty acid esters, polyglyceryl condensed 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, cocoa butter powder, carnauba wax, rice wax, Japanese wax, and paraffin. Among these, beeswax is preferred. These dispersants can be used individually or in combination of two or more as appropriate. The content of the dispersant is not particularly limited, but for example, it is 0.1 to 30% by mass or less relative to the capsule contents. The lower limit is preferably 1% by mass or more. On the other hand, the upper limit is preferably 10% by mass or less.

[0050] (Lipid content) The lipid content in the soft capsule of the present invention is not particularly limited. It can be appropriately changed depending on the type and formulation of the active ingredient, the use and size of the soft capsule, etc., but for example, it is 75% by mass or less relative to the capsule contents. The upper limit is preferably 60% by mass or less, and more preferably 50% by mass or less. It is thought that the nicotinamide and ascorbic acid dispersed in the lipids form a complex and solidify in the capsule membrane or in the moisture that migrates from the outside. If the lipid content is sufficiently high, contact between the nicotinamide and ascorbic acid and moisture can be suppressed, and the progress of solidification due to the formation of a complex between nicotinamide and ascorbic acid can also be prevented.

[0051] On the other hand, the present invention has a remarkable effect in that it can suppress the solidification of lipids due to complex formation even when the lipid content is insufficient to prevent solidification. If the lipid content is 75% by mass or less, the degree of design freedom can be increased, such as by increasing the content of the active ingredient powder, while at the same time suppressing the solidification of lipids and imparting appropriate efficacy and disintegration properties to the soft capsule. As mentioned above, lipids refer to lipids in a broad sense that are acceptable as food or pharmaceuticals, and include not only oil as a diluent or dispersant, but also hydrophobic substances as other components.

[0052] <Other ingredients> The soft capsules of the present invention may contain ingredients other than nicotinamide and ascorbic acid as the capsule contents. The other ingredients can be appropriately selected depending on the use and formulation of the soft capsules and are not particularly limited, but examples include thickeners, surfactants, sweeteners, flavorings, colorants, preservatives, and other active ingredients.

[0053] (Viscosity of capsule contents) The viscosity of the capsule contents in this invention is not particularly limited. It can be changed depending on the amount and type of powder and lipids blended, the method of administration of the soft capsule, the composition of the capsule film, etc., but for example, it is 2,000 to 30,000 mPa·s. The lower limit is preferably 5,000 mPa·s or more. The upper limit is preferably 20,000 mPa·s or less. If the viscosity of the capsule contents is 2,000 mPa·s or more, the soft capsule can be easily formed and the dispersion of powder in the lipid can be stabilized. If the viscosity of the capsule contents is 30,000 mPa·s or less, it has appropriate fluidity, so the solidification of the lipid can be suppressed. The viscosity of the capsule contents can also be adjusted by the amount of powder, the type and blending of lipids, and the selection of (B) ascorbic acid derivatives.

[0054] <Capsule coating> The soft capsules of the present invention have a capsule coating. The composition of the capsule coating is not particularly limited and can be appropriately set depending on the application and composition. Commercially available products can also be used.

[0055] The components of the capsule coating of the soft capsule include, for example, high molecular weight components, humectants, and thickening polysaccharides. While not particularly limited, high molecular weight components include, for example, gelatin, starch, and carrageenan. The content of high molecular weight components in the capsule coating is, for example, 1 to 95% by mass, with a lower limit of preferably 5% by mass or more and an upper limit of 90% by mass or less. Furthermore, while not particularly limited, humectants include sugars such as glucose, alcohols such as glycerin, and sugar alcohols such as sorbitol. Additionally, while not particularly limited, thickening polysaccharides include, for example, carrageenan, gellan gum, and alginic acid. The proportion of each component in the capsule coating of the soft capsule is not particularly limited and can be set as appropriate.

[0056] <Form of soft capsules> (Collapse-like) The soft capsule formulation of the present invention preferably has a disintegration time of 60 minutes or less, more preferably 40 minutes or less, and even more preferably 30 minutes or less. If the disintegration time is 60 minutes or less, the active ingredient is sufficiently absorbed in the gastrointestinal tract, and the required blood concentration is obtained quickly, thereby achieving the desired bioavailability.

[0057] (Size and mass) The size of the soft capsule of the present invention is not particularly limited. It can be changed depending on the intended use of the soft capsule, its form, the required disintegration properties, and the target of administration, but for example, the short diameter of the soft capsule is 3 to 10 mm and the long diameter is 7 to 20 mm. Preferably, the short diameter of the soft capsule is 6 to 10 mm and the long diameter is 9 to 15 mm. There are no particular restrictions on the mass of the soft capsule. It can be changed depending on the ratio of the active ingredient to the lipid, the required disintegration properties, or the density and size of the soft capsule, but for example, the mass of the capsule contents is 100 mg to 2,000 mg. The lower limit of the mass of the capsule contents is preferably 200 mg or more. The upper limit of the mass of the capsule contents is preferably 1,000 mg or less.

[0058] [Manufacturing method for soft capsules] The method for producing the soft capsules of the present invention is not particularly limited and can be produced using known methods. For example, they may be formed by filling a sheet made from the above-mentioned capsule coating components with the above-mentioned capsule contents and then compressing and molding it.

[0059] [Other embodiments] <Methods to improve lipid solidification> The present invention provides a method for improving lipid solidification. For example, in a formulation containing nicotinamide and / or ascorbic acid derivatives, by adding or preparing (A) nicotinamide and / or (B) ascorbic acid derivatives to the configuration of the present invention, it is possible to suppress lipid solidification in the formulation while obtaining the effects of nicotinamide and ascorbic acid as active ingredients, thereby solving problems such as reduced bioavailability. [Examples]

[0060] The present invention will be further explained below with reference to examples, but the present invention is not limited in any way to these examples, and various modifications are possible within the technical concept of the present invention. Unless otherwise specified, the amounts of ingredients in the examples are given in mass percent.

[0061] (1) Test example 1: Solidification test of capsule contents To replicate the solidification of capsule contents, slurry samples simulating capsule contents were prepared using the following method. After one week, the presence or absence of solidification in the slurry samples was evaluated. The raw materials used in the examples are shown in Table 1 below.

[0062] [Table 1]

[0063] <Solidification Test Method> (Preparation of slurry sample) Following the procedure shown in Figure 4, beeswax and diluent oil (rice bran oil) were placed in a 200 ml glass beaker in the proportions shown in Tables 2 and 3, and dissolved while being heated to 80°C. The mixture was then mixed using a stirrer. After cooling to below 40°C at room temperature, vitamins were further added to this mixture in the proportions shown in Tables 2 and 3, and the mixture was stirred and mixed using a homomixer. Subsequently, vacuum degassing was performed, and water was added to a concentration of 5% by mass relative to the chemical solution to obtain a slurry sample.

[0064] (Evaluation method) The slurry samples were evaluated based on the following criteria after being left at room temperature for one week following the addition of water. The evaluation results are shown in Tables 2 and 3. ○...Stir with a spatula, and when tilted at a 45-degree angle, it will flow out. △...It can be stirred with a spatula, but it won't flow even when tilted. ×...The spatula is stuck in the ground, making stirring impossible.

[0065] [Table 2]

[0066] [Table 3]

[0067] Table 2 shows that when the nicotinamide content is 6% by mass and the ascorbic acid content is 20% by mass or more, lipid solidification occurs. Table 3 shows that when sodium ascorbate, calcium ascorbate, or ascorbic acid-2-glucoside are used instead of ascorbic acid in the drug solution, lipid solidification can be suppressed and good fluidity can be maintained.

[0068] (2) Test example 2: Disintegration test in a manufacturing example of soft capsules In actual soft capsule manufacturing examples, to confirm the effect of improving disintegration, soft capsules of Manufacturing Example 1 and Manufacturing Comparative Example 1 were manufactured using the manufacturing method described below, and the effect of improving disintegration was examined. The capsule coating was prepared using the following formulation, and plant-coated capsules were filled using a capsule manufacturing machine. The coating was then dried to a moisture content of approximately 8% before evaluation.

[0069] (Plant-coated capsule) Main ingredients: starch, thickening polysaccharides, glycerin, water Sheet thickness: 0.5~1mm Encapsulation: Rotary capsule filling machine Filling amount: 290mg / grain Shape: Oval For the soft capsule contents, according to the formulation shown in Table 4, beeswax was added to rice bran oil, which was used as a diluent, and heated to dissolve. This solution was then allowed to cool at room temperature. Nicotinamide and ascorbic acid were then added to this solution and uniformly mixed using a homomixer. This solution was used as the capsule contents.

[0070] The contents of this capsule were filled into soft capsules at a rate of 290 mg per capsule using the aforementioned capsule coating and a soft capsule molding machine, employing a conventional method, to obtain soft capsules. The obtained soft capsules were placed in an aluminum bag, sealed, and stored at 40°C and 75% RH for 4 months. After storage, the aluminum bag was opened, and the removed soft capsules were tested for disintegration after storage using the procedure shown in the soft capsule disintegration test below.

[0071] (Evaluation method) The disintegration time of the manufactured soft capsules was measured according to "6.09 Disintegration Test Method" described in the general test methods of the "17th Edition of the Japanese Pharmacopoeia". Ion-exchanged water was used as the test solution. The disintegration tester used was a disintegration tester (NT-610 (product name), manufactured by Toyama Sangyo Co., Ltd.) manufactured by Toyama Sangyo Co., Ltd.

[0072] The test was conducted using 900 mL of test solution (purified water). The disintegration time of 6 sample capsules in water at 37°C was measured, and the average value was defined as the disintegration time. The disintegration properties were evaluated according to the following evaluation criteria.

[0073] (Criteria for evaluating disintegration) ○: Collapse time is 60 minutes or less ×: Collapse time exceeds 60 minutes The results of the collapse test are shown in Table 4.

[0074] [Table 4]

[0075] As shown in Table 4, in Comparative Example 1 of production using nicotinamide and ascorbic acid, the compound did not disintegrate even after a disintegration time of more than 60 minutes. On the other hand, in Comparative Example 1 of production using sodium ascorbate, which is the metal sodium salt of the hydroxyl group at position 2 of ascorbic acid, the disintegration time was reduced to 17 minutes, showing a significant improvement in disintegration properties.

[0076] In addition, soft capsules prepared by filling gelatin capsules with the formulation shown below, and drying the capsules to a moisture content of approximately 8%, were evaluated using the same method as in Test Example 2.

[0077] (Gelatin soft capsules) Main ingredients: Gelatin, glycerin, water Sheet thickness: 0.5~1mm Encapsulation: Rotary capsule filling machine Filling amount: 290mg / grain Shape: Oval The same effect was observed with soft capsules filled with a gelatin coating as with the case using a plant-based coating in Test Example 2.

[0078] Therefore, based on the results of Test Examples 1 and 2 described above, it was confirmed that soft capsules containing nicotinamide and ascorbic acid can have their disintegration properties improved by suppressing the formation of a complex between ascorbic acid and nicotinamide, as well as suppressing the decrease in lipid fluidity and solidification, by modifying the hydroxyl group at the 2nd or 3rd position of ascorbic acid with a metal salt or an organic group. [Industrial applicability]

[0079] The soft capsule formulation of the present invention can be used in soft capsule formulations containing nicotinamide and ascorbic acid derivatives, where the disintegration properties are improved. Furthermore, it can provide a method for maintaining fluidity and suppressing solidification in lipophilic compositions containing nicotinamide and ascorbic acid derivatives. This invention can be used in a variety of fields, including soft capsules, pharmaceuticals, quasi-drugs, veterinary products, foods, and supplements.

Claims

1. The lipid contains the following components (A) and (B): The content of component (A) is 3 to 10% by mass relative to the contents of the capsule. A soft capsule preparation characterized in that the content of component (B) is 20 to 50% by mass relative to the contents of the capsule. (A) Nicotinamide (B) Ascorbic acids shown in the following formula (1) 【Chemistry 1】 Formula (1) [In the formula, R1 and R2 are hydrogen, a metal salt, or an organic group, with at least one of them selected from a metal salt or an organic group, and R3 is hydrogen or an organic group.]

2. The soft capsule preparation according to claim 1, characterized in that the component (B) is one or more selected from sodium ascorbate, calcium ascorbate, or ascorbic acid-2-glucoside.

3. The soft capsule preparation according to claim 1 or 2, characterized in that the lipid content is 75% by mass or less relative to the contents of the capsule.

4. Contents dispersed in a suspended oily liquid, Nicotinamide in 3 to 10% by mass, A method for suppressing the solidification of contents dispersed in an oily suspension liquid containing nicotinamide and ascorbic acid derivatives, characterized by containing 20 to 50% by mass of the following component (B). (B) Ascorbic acids shown in the following formula (1) 【Chemistry 1】 Formula (1) [In the formula, R1 and R2 are hydrogen, a metal salt, or an organic group, with at least one of them selected from a metal salt or an organic group, and R3 is hydrogen or an organic group.]

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