Large-intestine-delivery seamless capsule

Abstract

[Problem] The present invention provides a large-intestine-delivery seamless capsule that can easily achieve delivery of the seamless capsule to the large intestine. [Solution] The present invention provides a large-intestine-delivery seamless capsule comprising a core, an intermediate layer covering the core, and a coating covering the intermediate layer, the seamless capsule being characterized in that the intermediate layer contains an oily substance having a melting point of 50°C or higher, and satisfies the relationship of formula (1) in a stress-strain curve obtained through a compression fracture test of the intermediate layer: (1) 0.2 ≤ brittleness (B) / hardness (H) ≤ 0.6 (in the formula, the hardness (H) is the stress at the yield point of the stress-strain curve, and the brittleness (B) is the difference in stress between the yield point and the fracture point).

Description

Seamless capsule for colon delivery

[0001] The present invention relates to a seamless capsule for delivery to the large intestine, and more particularly to a seamless capsule that disintegrates upon reaching the large intestine.

[0002] Seamless capsules are used in many applications because of the ease of particle size control, simplicity of production, etc. In particular, delayed-disintegration seamless capsules in which the disintegration of seamless capsules is delayed have been proposed ( WO 2020 / 251039 A1 : Patent Document 1).

[0003] Patent Document 1 discloses a technique for delaying the disintegration of a capsule (particularly a seamless capsule) to allow the capsule to reach the large intestine. However, even with this technique, there are cases where the capsule has difficulty reaching (delivering) the large intestine.

[0004] WO2020 / 251039A1

[0005] An object of the present invention is to provide a seamless capsule for large intestine delivery, which can easily achieve large intestine delivery of the seamless capsule.

[0006] As a result of extensive research to achieve the above object, the inventors have found that the behavior of the stress-strain curve for the intermediate layer of a seamless capsule is related to the large intestine delivery property of the seamless capsule, which led to the completion of the present invention.

[0007] The present invention provides the following aspects: [1] A seamless capsule for large intestine delivery comprising a core, an intermediate layer covering the core, and a shell covering the intermediate layer, wherein the intermediate layer contains an oily substance having a melting point of 50°C or higher, and a stress-strain curve obtained by a compression-fracture test of the intermediate layer satisfies the relationship of the following formula (1): 0.2≦brittleness (B) / hardness (H)≦0.6 ... formula (1) (wherein the hardness (H) is the stress at the yield point of the stress-strain curve, and the brittleness (B) is the stress difference between the yield point and the breaking point).

[0008] According to the present invention, colon delivery of seamless capsules can be easily achieved.

[0009] Fig. 1 is a schematic explanatory diagram showing hardness and brittleness in a stress-strain curve obtained in a compression fracture test. Fig. 2 is a schematic cross-sectional view of a nozzle portion of a manufacturing apparatus suitable for manufacturing a seamless capsule according to one embodiment of the present invention. Fig. 3 is a graph showing the relationship between the caffeine concentration in the saliva of a subject and time in a human ingestion test using seamless capsules of Examples and Comparative Examples.

[0010] An embodiment of the present invention is described below. A seamless capsule for colon delivery according to this embodiment includes a core, an intermediate layer covering the core, and a shell covering the intermediate layer. In such a seamless capsule, if the intermediate layer contains an oily substance with a melting point of 50°C or higher and the ratio of brittleness to hardness of the intermediate layer is within a specific range, the seamless capsule can be delivered to the large intestine after oral administration. The hardness and brittleness of the intermediate layer satisfy the following relationship in a stress-strain curve obtained in a compression fracture test: 0.2≦brittleness (B) / hardness (H)≦0.6 (1) (wherein the hardness (H) is the stress at the yield point of the stress-strain curve, and the brittleness (B) is the stress difference between the yield point and the fracture point). Although the mechanism of disintegration of seamless capsules in this embodiment has not been fully elucidated, it is believed that the ratio of hardness to brittleness of the intermediate layer is more closely related to disintegration time than the shell, which is directly exposed to the dissolution environment of the seamless capsule. In this specification, "colon delivery" means that few seamless capsules disintegrate before reaching the large intestine.

[0011] This embodiment provides a seamless capsule comprising a core, one or more intermediate layers formed on the core, and a coating formed on the intermediate layers. The core, intermediate layer, and coating will be described in this order.

[0012] Core The core of the seamless capsule of this embodiment contains components generally contained in seamless capsules and an oily substance. The components generally contained in seamless capsules include functional components that impart desired functions to the seamless capsule. The oily substance contained in the core is an oily substance with a melting point of 30°C or higher.

[0013] In the seamless capsule according to the present embodiment, when the core contains a functional component, the functional component is a component that is effective in the vital activities of a living organism (e.g., a human), including maintaining the health of the organism or mitigating harmful substances. Examples of such functional components include, but are not limited to, caffeine, organic acids, organic acid salts, plant extracts, animal extracts, microbial extracts, microbially produced extracts, microbially fermented extracts, fruit juices, functional polysaccharides, dietary fiber, polyphenols, vitamins, vitamin derivatives, vitamin-like substances, amino acids, microorganisms, microbial organelles, plant organelles, essential oils, anti-inflammatory drugs, omega-3 fatty acids, omega-6 fatty acids, and omega-9 fatty acids. The functional component is not limited to the above-mentioned examples, and any component can be used. In this specification, "organelle" refers to a structure other than the cytoplasm that constitutes a cell, and examples include the nucleus, mitochondria, endoplasmic reticulum, lysosomes, Golgi apparatus, centrosomes, cell membranes, and cell walls. Examples of organic acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, lactic acid, citric acid, chlorogenic acid, ferulic acid, orotic acid, and succinic acid. Organic acid salts, also known as organic acid derivatives, have a structure in which the carboxyl group of an organic acid is neutralized. Examples of such organic acid salts include alkali metal salts, alkaline earth metal salts, ammonium salts, and alkyl esters of organic acids. Examples of plant extracts include rosehip extract, blackcurrant extract, salacia extract, and peony extract. Examples of animal extracts include beef extract, fish extract, and placenta extract. Microbial extracts are compositions containing components extracted from microbial flora, such as lactic acid bacteria, bifidobacteria, Bacillus subtilis var. natto, filamentous fungi, actinomycetes, and yeast. Microbial extracts are compositions containing components produced by microorganisms during growth, such as in culture. Examples of such microorganisms include those listed above. The microbial fermentation extract is a composition containing a material that has been fermented by a microorganism, and examples of such microorganisms include those mentioned above. An example of the microbial fermentation extract is fermented soybean extract.Fruit juice is juice obtained by squeezing fruit, such as lemon, lime, mandarin orange, apple, strawberry, peach, grape, cranberry, and pineapple. Functional polysaccharides include neutral mucopolysaccharides such as chitin and chitosan; and acidic mucopolysaccharides such as chondroitin sulfate and hyaluronic acid. Dietary fiber is a material that is difficult for humans to assimilate but is easily assimilated by bacteria in the large intestine. Examples of dietary fiber include inulin, indigestible dextrin, cellulose, and pectin. Examples of vitamins include thiamine, ascorbic acid, and tocopherol. Examples of vitamin-like substances include inositol, carnitine, and biotin. Examples of essential oils include lemon oil, eucalyptus oil, fennel oil, and peppermint oil. Anti-inflammatory drugs include, for example, celecoxib, Voltaren, ibuprofen, loxoprofen, acetaminophen, and diclofenac.

[0014] In the seamless capsule of this embodiment, the amount of the functional ingredient is usually 1 to 50% by weight, preferably 5 to 40% by weight, and more preferably 10 to 35% by weight, relative to the weight of the core. When the amount of the functional ingredient is within the above range, the effect of the functional ingredient can be easily obtained, and the seamless capsule can be easily produced.

[0015] In the seamless capsule of this embodiment, the core can further contain an amphoteric surfactant. Amphoteric surfactants contain both cationic and anionic structures in the molecule, exhibiting amphoteric surface activity. Examples of amphoteric surfactants include amidobetaine and imidazoline types, but naturally occurring amphoteric surfactants are useful for use in living organisms, particularly humans. Phospholipids are preferred as naturally occurring amphoteric surfactants. The phospholipid may be at least one component selected from the group consisting of lecithin, lysolecithin, hydrogenated lecithin, and hydrogenated lysolecithin. Lecithin is a diacyl ester-type glycerophospholipid having two acyl groups, and lysolecithin is a component of lecithin in which one of the two acyl groups has been removed. Lysolecithin is, for example, a component obtained by treating lecithin with phospholipase A2, and has a structure in which the acyl group at the second position is missing. The amount of amphoteric surfactant is not particularly limited, but may be, for example, 0.5% by weight or more relative to the weight of the core. Specific examples of the amount of amphoteric surfactant include 0.5 wt%, 1 wt%, 5 wt%, 7 wt%, 10 wt%, 20 wt%, 30 wt%, and 50 wt%, and may be within a range between any two of these values. Note that in this embodiment, the core may not contain an amphoteric surfactant.

[0016] The core of this embodiment may further contain ingredients such as flavorings, excipients, stabilizers, surfactants other than amphoteric surfactants, thickeners, adjuvants, foaming agents, etc. The content of the ingredients in the core is not particularly limited and can be set as desired depending on the function to be imparted to the core of this embodiment.

[0017] In addition to the above components, the core of the seamless capsule of this embodiment contains an oily substance with a melting point of 30°C or higher. In practice, the above components are dissolved or suspended in the oily substance with a melting point of 30°C or higher. The reason for mixing the oily substance in this manner is to prevent the core from being affected by the large amount of water present during capsule production. In this embodiment, the oily substance with a melting point of 30°C or higher is, for example, at least one substance selected from the group consisting of edible vegetable oils and fats, edible animal oils and fats, edible refined and processed oils and fats, sucrose fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, higher alcohols, and higher fatty acids. Among oily substances with a melting point of 30°C or higher, those with a melting point of 50°C or higher can be used in the intermediate layer described below. The upper limit of the melting point of the oily substance used in the core of this embodiment is not particularly limited as long as it has a melting point of 30°C or higher, but the melting point of the oily substance may be 90°C or lower, 80°C or lower, or 70°C or lower. The melting point of the oily substance may be 35°C or higher, or 40°C or higher. Seamless capsules are often edible, and substances that are harmful to the human body often cannot be used. The higher alcohol may contain at least one component selected from the group consisting of myristyl alcohol, cetanol, stearyl alcohol, arachidyl alcohol, and ceryl alcohol. The higher fatty acid may contain at least one component selected from the group consisting of capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and arachidic acid.

[0018] According to the Japanese Agricultural Standards for Edible Refined and Processed Oils and Fats (Ministry of Agriculture, Forestry and Fisheries Notification No. 3115, December 24, 2013), oily substances with a melting point of 30°C or higher are oils and fats that have been adjusted to a melting point suitable for edible use by techniques such as "hydrogenation (adjusting the melting point by adding hydrogen to saturate unsaturated fatty acids)," "fractionation (separating by centrifugation, filtration, or dripping to separate into parts with different melting points, hardness, and solid fat content)," and "transesterification (adjusting the melting point by changing the fatty acid composition using a catalyst)" to animal oils and fats, vegetable oils, or mixed oils and fats. Note that the "melting point" used in this specification refers to the slip melting point (the temperature at which an oil or fat begins to soften and rise when heated in a capillary tube).

[0019] In this embodiment, fats and oils that have been subjected to hydrogenation (hydrogenation treatment) (referred to as "hydrogenated fats and oils" in this specification) may be used as the oily substance having a melting point of 30°C or higher. Such hydrogenated fats and oils may have a melting point adjusted by the degree of hydrogenation applied to the raw fats and oils. The hydrogenated fats and oils may be partially hydrogenated fats and oils, fully hydrogenated fats and oils, or a mixture of partially hydrogenated fats and oils, fully hydrogenated fats and oils.

[0020] The hydrogenated oils and fats are, for example, at least one oil and fat selected from the group consisting of hydrogenated rapeseed oil, hydrogenated jojoba oil, hydrogenated soybean oil, hydrogenated palm oil, hydrogenated palm kernel oil, and hydrogenated coconut oil. The hydrogenated oil and fat is not limited to the above and may be any component.

[0021] Furthermore, in this embodiment, fats and oils that have not been subjected to hydrogenation (hydrogenation treatment) (referred to as "non-hydrogenated fats and oils" in this specification) may be used as the oily substance having a melting point of 30°C or higher. Such non-hydrogenated fats and oils may be obtained by adjusting the melting point of raw fats and oils, for example, by fractionating or interesterifying the raw fats and oils. An example of a non-hydrogenated fat and oil is palm oil-based fat and oil. In fats and oils such as palm oil, fatty acids generally exist as triacylglycerols, which are esters with glycerin. In palm oil, the main fatty acids are palmitic acid and oleic acid, and these two types of fatty acids account for 80% or more of the total fat and oil, and the palm oil is semi-solid at room temperature. When palm oil is fractionated at a specific temperature, it can be separated into low-melting-point liquid oils and high-melting-point solid oils. Low-melting-point liquid oils contain a large amount of oleic acid, while high-melting-point solid oils contain a large amount of palmitic acid. The liquid oil is commonly called palm olein, and the solid oil is commonly called palm stearin (paltimic acid is the most abundant component in the composition, but it is not called palm palmitic). Alternatively, a desired non-hydrogenated oil with an adjusted melting point can be obtained by interesterifying palm oil. The non-hydrogenated oil may be a palm fractionated oil, or an interesterified palm oil or palm fractionated oil, either alone or in combination.

[0022] Specific examples of non-hydrogenated fats and oils include, but are not limited to, palm stearin, palm olein, palm superolein, palm double olein, palm mid-fraction, and interesterified fats and oils of palm oil or palm fractionated oils, or mixtures thereof.

[0023] Furthermore, the non-hydrogenated fats and oils may be fats and oils other than palm oil-based fats, as long as they have a melting point of 30°C or higher. Examples of non-hydrogenated fats and oils other than palm oil-based fats and oils include vegetable fats such as carnauba wax, rice wax, sunflower wax, candelilla wax, sunflower butter, almond butter, and avocado butter; and animal fats and oils such as beeswax, privet wax, butter (cow's dairy), lard, and beef tallow, and one or more of these can be used. Of course, the present invention is not limited to these, and any non-hydrogenated fats and oils can be used. If the vegetable fats and oils and animal fats are edible, they are the same as the edible vegetable fats and oils and animal fats described above.

[0024] The oily substance with a melting point of 30°C or higher used in this embodiment may include sucrose fatty acid esters or glycerin fatty acid esters. Sucrose fatty acid esters are formed by reacting the hydroxyl groups of sucrose with fatty acids (e.g., stearic acid or oleic acid) and are typically used as emulsifiers. Glycerin fatty acid esters are formed by ester-bonding fatty acids to one or two of the three hydroxyl groups of glycerin and are also used as emulsifiers. Those bonded to all three hydroxyl groups are fats or oils, and are distinguished from glycerin fatty acid esters.

[0025] Intermediate Layer The seamless capsule of this embodiment includes an intermediate layer covering the core. The intermediate layer is a layer interposed between the shell and the core, and its melting point is the same as or higher than that of the core. Having such a melting point facilitates solidification between the shell and the core during the production of the seamless capsule (particularly during cooling), and also facilitates the maintenance of the presence of the intermediate layer even after the seamless capsule is produced. When the melting point of the intermediate layer is higher than that of the core, the difference in melting point between the intermediate layer and the core is not particularly limited. However, the melting point of the intermediate layer may be, for example, 2 to 9°C higher or 2 to 8°C higher than that of the core. The intermediate layer is typically a single layer, but multiple layers can also be formed. Even such multiple layers are understood to be encompassed within this embodiment as long as they satisfy the requirements of this embodiment. In the case of multiple layers, the compositions of the layers may be the same or different. When the intermediate layer is a single layer, the seamless capsule of this embodiment has a three-layer structure.

[0026] An oily substance having a melting point of 50° C. or higher is used for the intermediate layer. The oily substance having a melting point of 50° C. or higher is selected from the above-mentioned oily substances having a melting point of 30° C. or higher. Examples of oily substances having a melting point of 50° C. or higher include the above-mentioned vegetable (fractionated) oils and fats, vegetable oils and fats, animal fats and fats, highly hydrogenated oils, margarine, shortening, sucrose fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, higher alcohols, and higher fatty acids, and one or more of these may be used.

[0027] When an oily substance having a melting point of 50°C or higher is the main component of the intermediate layer, the blending amount of the oily substance having a melting point of 50°C or higher is usually 50% by weight or more and 90% by weight or less, based on the weight of the intermediate layer. The blending amount of the oily substance having a melting point of 50°C or higher may be 60% by weight or more, 70% by weight or more, or 80% by weight or more.

[0028] The intermediate layer may further contain an amphoteric surfactant. The description of the amphoteric surfactant is the same as above, and the amphoteric surfactant may be, for example, at least one phospholipid selected from the group consisting of lecithin, lysolecithin, hydrogenated lecithin, and hydrogenated lysolecithin. The amount of the amphoteric surfactant is not particularly limited, but may be, for example, 0.5 wt% or more relative to the weight of the intermediate layer. Specific examples of the amount of the amphoteric surfactant include 0.5 wt%, 1 wt%, 5 wt%, 7 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, and 50 wt%, and may be within a range between any two of these values. In this embodiment, the intermediate layer does not necessarily contain an amphoteric surfactant.

[0029] The intermediate layer of the seamless capsule of this embodiment can further contain, in addition to the oily substance having a melting point of 50° C. or higher, an oily substance having a melting point of 30° C. or higher and lower than 50° C. Such an oily substance having a melting point of 30° C. or higher and lower than 50° C. can be any oily substance that satisfies the melting point range from the above-mentioned oily substances having a melting point of 30° C. or higher.

[0030] When the intermediate layer contains an oily substance with a melting point of 50°C or higher and an oily substance with a melting point of 30°C or higher but lower than 50°C, the amount of the oily substance with a melting point of 50°C or higher is preferably 5 wt% or higher relative to the weight of the oily substance with a melting point of 30°C or higher but lower than 50°C. There is no particular upper limit to the amount of the oily substance with a melting point of 50°C or higher, but the amount of the oily substance with a melting point of 50°C or higher may be, for example, 35 wt% or lower. Specific examples of the amount of the oily substance with a melting point of 50°C or higher include 5 wt%, 5.2 wt%, 5.3 wt%, 5.5 wt%, 5.6 wt%, 6 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 12.1 wt%, 12.5 wt%, 13 wt%, 14 wt%, and 15 wt%, and the amount may be within a range between any two of these values. The blend amount of the oily substance having a melting point of 30° C. or higher and lower than 50° C. is preferably 50 wt % or higher relative to the weight of the intermediate layer. Furthermore, the blend amount of the oily substance having a melting point of 30° C. or higher and lower than 50° C. is preferably 95 wt % or lower. Specific examples of the blend amount of the oily substance having a melting point of 30° C. or higher and lower than 50° C. include 50 wt %, 60 wt %, 70 wt %, 75 wt %, 80 wt %, 83 wt %, 84.5 wt %, 85 wt %, 88 wt %, 90 wt %, 93 wt %, 94 wt %, and 95 wt %, and may be within a range between any two of these values.

[0031] The intermediate layer according to the present embodiment is not limited to the above components, and may further contain compounding agents such as excipients, stabilizers, surfactants other than amphoteric surfactants, thickeners, adjuvants, or foaming agents. When the intermediate layer contains compounding agents, the content of the compounding agents in the intermediate layer is not particularly limited and can be set as desired as long as it does not affect the effects of the present invention.

[0032] In the seamless capsule of this embodiment, as described above, the ratio of hardness to brittleness of the intermediate layer must satisfy the relationship of the following formula (1) in the stress-strain curve obtained in the compression fracture test: 0.2≦brittleness (B) / hardness (H)≦0.6 ... formula (1) (wherein the hardness (H) is the stress at the yield point of the stress-strain curve, and the brittleness (B) is the stress difference between the yield point and the breaking point.) When the requirement of formula (1) is satisfied, high colonic delivery can be achieved. In the above formula (1), the unit of brittleness (B) is N (Newton), and the unit of hardness (H) is also N (Newton). Specific examples of the brittleness (B) / hardness (H) ratio include 0.2, 0.25, 0.3, 0.35, 0.37, 0.41, 0.45, 0.5, 0.55, 0.57, and 0.6, and the ratio may be within a range between any two of these values.

[0033] In the compression fracture test for the intermediate layer, a molten composition for the intermediate layer (intermediate layer liquid described below) was poured into a 10 mm square silicone ice cube tray, cooled in a refrigerator (4°C) for 1 hour to solidify, and then kept at 37°C for 1 hour to prepare a test specimen (10 mm deep x 10 mm wide x 9 mm thick), the thickness of which corresponds to the compression direction in the compression fracture test. The test specimen was then compressed using a texture analyzer (manufactured by Shimadzu Corporation) equipped with a plunger with a diameter of 20 mm on the compression surface. Immediately after the stress reached 1 N (Newton), the test specimen was compressed at 0.1 mm / s (second) with a stroke of 5 mm, thereby obtaining a stress-strain curve as shown in Figure 1.

[0034] In FIG. 1 , the vertical axis represents the stress of the test specimen relative to the compressive force, and the horizontal axis represents the strain of the test specimen due to compression. The point at which the curve reaches a maximum is the yield point. In a compression fracture test, after the yield point, the stress decreases with increasing strain, and cracks appear in the test specimen. As cracks appear in the test specimen, the stress relative to the compressive force reaches a minimum. In other words, the point at which the curve reaches a minimum after the yield point is the break point. After the break point, the stress increases with increasing strain, as if the test specimen is crushed by compression. In this embodiment, the stress at the yield point is the hardness (H), and the difference between the stress at the yield point and the stress at the break point is the brittleness (B). When the ratio of brittleness (B) / hardness (H) is within a predetermined range, the seamless capsule can have large intestine delivery properties.

[0035] The thickness of the intermediate layer may be, for example, 100 μm or more. When the thickness of the intermediate layer is 100 μm or more, it is thought that even if the shell peels off after oral ingestion of the seamless capsule, the intermediate layer is more likely to have impact resistance, and the seamless capsule is more likely to be delivered to the large intestine. Specific examples of the thickness of the intermediate layer include 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, and 800 μm, and the thickness may be within a range between any two of these values.

[0036] Coating The seamless capsule of this embodiment is further coated with a coating on the outside of the intermediate layer. The coating contains a water-soluble natural polymer. The water-soluble natural polymer is, for example, at least one component selected from the group consisting of gelatin, casein, zein, pectin, pectin derivatives, alginic acid, alginate, agar, gellan gum, carrageenan, furcellaran, chitosan, curdlan, starch, modified starch, pullulan, and mannan. Of course, the water-soluble natural polymer is not limited to these. These water-soluble natural polymers preferably account for 50% to 90% by weight of the total solids weight of the seamless capsule coating. When alginate, gellan gum, pectin, or carrageenan is used as the water-soluble natural polymer, alkali metal salts, alkaline earth metal salts, ammonium salts, etc. may be added as appropriate.

[0037] The shell of the seamless capsule of this embodiment may further contain a plasticizer to impart flexibility in a dry state, and examples of such plasticizers include glycerin and sorbitol. The blending amount of the plasticizer is 1 to 50 wt %, preferably 5 to 40 wt %, and more preferably 15 to 30 wt %, based on the total weight of the shell after drying. If the blending amount of the plasticizer is less than 1 wt %, the shell will not be able to withstand vacuum drying or will not be able to maintain sufficient flexibility in a dry state, resulting in cracks. If the blending amount of the plasticizer is more than 50 wt %, the shell will soften and stick or melt at high temperatures.

[0038] In addition to the above-mentioned composition, the shell of the seamless capsule of this embodiment may contain, as necessary, various additives commonly used in this field, such as flavorings, sweeteners, coloring agents, preservatives such as parabens, etc. When such additives are used, the total content of all additives is, for example, 0.01% by weight to 10% by weight, and preferably 0.1% by weight to 5% by weight, based on the total solid weight of the composition that becomes the capsule shell.

[0039] The thickness of the shell after drying of the seamless capsule of this embodiment is not particularly limited, but may be, for example, 10 μm or more, 30 μm or more, or 40 μm or more. If the thickness of the shell after drying is 10 μm or more, the shell can have a strength sufficient to maintain the outer shape of the seamless capsule. Furthermore, from the viewpoint of easily ensuring the volume inside the seamless capsule, the thickness of the shell after drying may be, for example, 600 μm or less, 400 μm or less, or 250 μm or less.

[0040] The seamless capsule of this embodiment may be delivered to the large intestine after oral ingestion. While the particle size (diameter) of the seamless capsule is not particularly limited, it is preferably within the range of 0.3 to 10 mm, and more preferably within the range of 1 to 8 mm. If the diameter of the capsule is less than 0.3 mm, the thickness of the intermediate layer of the seamless capsule's layer structure becomes small, reducing its effectiveness in preventing moisture penetration. If the diameter exceeds 8 mm, the capsule is likely to be difficult to swallow. On the other hand, if the particle size of a conventional capsule is small (e.g., approximately 2.5 mm), the capsule tends to disintegrate before being delivered to the large intestine after oral ingestion. While the mechanism of disintegration is not yet clearly understood, it is thought that the capsule is susceptible to the influence of contents other than the capsule in the stomach or small intestine, causing the capsule to break down into small pieces before delivery to the large intestine. However, since the seamless capsule of this embodiment has the ability to be delivered to the large intestine, it is thought to be less susceptible to the influence of contents of the stomach or small intestine. Therefore, a particle size of 5 mm or less is also suitable for the seamless capsule of this embodiment. The particle size of the seamless capsule of this embodiment may be 3 mm or less.

[0041] Manufacturing Method of Seamless Capsules A manufacturing method of seamless capsules according to one embodiment will be described below. The manufacturing method according to this embodiment is a method for manufacturing the seamless capsules described above. Therefore, for the parts corresponding to the seamless capsules, refer to the description of the seamless capsules described above, and detailed description will be omitted. Furthermore, the manufacturing method according to this embodiment will be described using the manufacturing apparatus shown in FIG. 2 as an example, but as described above, the intermediate layer may have multiple layers, and therefore, the manufacturing method is not limited to a manufacturing method for obtaining seamless capsules with a three-layer structure.

[0042] When the dropping method using a three-layer nozzle with a concentric cross section is used to produce capsules according to this embodiment, the core liquid is discharged from the innermost nozzle, the coating liquid is discharged from the outermost nozzle, and the intermediate layer liquid is discharged from the middle nozzle. During discharge, the liquids are simultaneously extruded at a constant rate into a cooling liquid flowing downward at a steady rate to form a composite jet, which is then released into the cooling liquid. By utilizing the surface tension acting between the cooling liquid and the coating liquid, three-layer seamless capsules can be continuously produced. When using a three-layer nozzle, the resulting capsules have a three-layer structure, with the core contained in the innermost layer. In this embodiment, seamless capsules with colon delivery properties can be obtained by controlling the brittleness (B) / hardness (H) ratio of the intermediate layer in a compression fracture test to 0.2 to 0.6 during the above production process.

[0043] FIG. 2 shows a schematic cross-sectional view of a nozzle portion of a production apparatus suitable for producing three-layer structure seamless capsules by the dropping method using a three-layer nozzle.

[0044] 2 shows the state in which the seamless capsule jet B discharged from the three-layer nozzle A is cut in the cooling liquid 8 and becomes each seamless capsule 7. The three-layer nozzle A has an inner nozzle 1, an intermediate nozzle 2, and an outer nozzle 3 arranged concentrically, and the liquid 4 that will become the capsule core is discharged from the inner nozzle 1, the liquid that will become the intermediate layer is discharged from the intermediate nozzle 2 (specifically, between the intermediate nozzle 2 and the inner nozzle 1), and the liquid that will become the coating is discharged from the outer nozzle 3 (specifically, between the outer nozzle 3 and the intermediate nozzle 2), and the three types of liquid are discharged simultaneously to form the seamless capsule jet B.

[0045] The seamless capsules 7 obtained as described above are subjected to ventilation drying at 5°C to 30°C for 2 to 12 hours. If it is necessary to further reduce the moisture content in the capsules 7, vacuum drying or vacuum freeze drying may be further performed after ventilation drying. In vacuum drying, the degree of vacuum is maintained at 0.002 to 0.5 MPa or less, and in vacuum freeze drying, the capsules are frozen and dried at -20°C or less. There are no particular restrictions on the time required for vacuum drying or vacuum freeze drying. It is generally 5 to 60 hours, preferably 24 to 48 hours. If it is less than 5 hours, drying will be insufficient, and the water present in the capsules 7 may have an adverse effect on the contents.

[0046] As described above, the seamless capsule obtained by the above method can control the ratio of brittleness (B) / hardness (H) of the intermediate layer in the compression fracture test within a predetermined range, thereby ensuring large intestine delivery of the seamless capsule. Moreover, even seamless capsules with small particle sizes can ensure large intestine delivery. In this embodiment, by controlling the brittleness (B) / hardness (H) of the intermediate layer in the compression fracture test and adding an amphoteric surfactant to the core or the intermediate layer, not only can large intestine delivery be ensured, but also disintegration of the seamless capsule in the large intestine can be made easier.

[0047] [Examples] The present invention will be described in more detail with reference to examples, which are merely illustrative of the present invention.

[0048] In explaining each example and comparative example, the details of the components shown in Tables 1 to 3 below are as follows: WITOCAN-H: fully hydrogenated oil and fat with a melting point of 34°C (hardened palm oil) WITOCAN-42 / 44: fully hydrogenated oil and fat with a melting point of 43°C (hardened palm oil) Beeswax: beeswax with a melting point of 64°C Lecithin: soybean lecithin Hydrogenated lysolecithin: hydrogenated soybean lysolecithin Lysolecithin: soybean lysolecithin JC oil: non-hydrogenated oil and fat with a melting point of 50°C (derived from palm oil) Gelatin: porcine-derived gelatin (jelly strength 240 bloom) Pectin: low methoxyl (LM) pectin

[0049] Examples 1 to 4 and Comparative Examples 1 and 2 A core liquid (Table 1), an intermediate layer liquid (Table 2), and a shell liquid (Table 3) were prepared according to the composition ratios shown in Tables 1 to 3 below. The core liquid was dropped from the innermost nozzle of a concentric triple nozzle, the intermediate layer liquid from the outermost nozzle, and the shell liquid from the outermost nozzle into flowing rapeseed oil cooled to 12°C, thereby producing three-layer seamless capsules. The obtained three-layer seamless capsules were dried by ventilation at 20°C for 8 hours. After drying, the seamless capsules had a diameter of 2.5 mm, a shell thickness of 110 µm, and an intermediate layer thickness of 300 µm.

[0050] Furthermore, a compression fracture test was carried out using the intermediate layer solution as follows, and the brittleness (B) value, hardness (H) value and their ratio (B / H) are shown in Table 2.

[0051] Compression fracture test: The above intermediate layer liquid was poured into a 10 mm square silicone ice cube tray in a molten state, cooled in a refrigerator (4°C) for 1 hour to solidify, and then kept at 37°C for 1 hour to prepare a test specimen (10 mm deep x 10 mm wide x 9 mm thick). The test specimen was then placed on a test stand with its thickness aligned with the compression direction of the compression fracture test. The test specimen was then compressed using a texture analyzer (manufactured by Shimadzu Corporation) equipped with a plunger with a 20 mm diameter compression surface. Immediately after the stress reached 1 N (Newton), the specimen was compressed at 0.1 mm / s (seconds) with a 5 mm stroke, thereby obtaining a stress-strain curve. From this stress-strain curve, the brittleness (B) and hardness (H) values ​​were measured, and the brittleness (B) / hardness (H) ratio was calculated.

[0052] Using the obtained seamless capsules, the disintegration behavior was estimated by a quantitative test of caffeine in saliva as follows.

[0053] Test for Quantitative Analysis of Caffeine in Saliva The subjects (four individuals) were placed in a caffeine-free state from 9:00 AM on the day before the test. From 9:00 PM on the day before the test, they consumed only designated meals (water and white rice). At 9:00 AM on the day of the test, they ingested one type of seamless capsule, and saliva samples were collected hourly. The test was completed eight hours after ingestion of the seamless capsule. After the test, the caffeine concentration in each saliva sample was quantified using high-performance liquid chromatography. The above series of procedures was repeated for Examples 1-4 and Comparative Examples 1-2, resulting in the graph shown in Figure 3. The average value (Tmax) was calculated for each subject from the time at which the salivary caffeine concentration reached its maximum, and this Tmax is listed in Table 4. In this test, if Tmax was 5 hours or longer, the seamless capsule was considered to have been delivered to the large intestine.

[0054]

[0055]

[0056]

[0057]

[0058] Examples 5 to 16 A core liquid (Table 1), an intermediate layer liquid (Table 2), and a shell liquid (Table 3) were prepared, and three-layer seamless capsules were prepared in the same manner as in Example 1.

[0059] As is clear from the above results, in Examples 1 to 4, which satisfy the range of the present invention, the Tmax was 5 hours or more, and the caffeine concentration in saliva did not decrease even 5 to 8 hours after ingestion, so it is thought that the seamless capsules disintegrated more in the large intestine than in the stomach or small intestine. On the other hand, in Comparative Examples 1 and 2, the Tmax was less than 5 hours, and the caffeine concentration in saliva decreased 4 hours or more after ingestion, so it is thought that the seamless capsules mostly disintegrated before reaching the large intestine (duodenum or small intestine). Furthermore, the seamless capsules of Examples 5 to 16 also have intermediate layers that satisfy the relationship 0.2≦friability (B) / hardness (H)≦0.6, so they can be expected to disintegrate more in the large intestine.

[0060] The present invention controls the large intestine delivery property of a seamless capsule, i.e., the ability to reach the large intestine by making it less likely to disintegrate in the digestive tract upstream of the large intestine, by the physical properties of the middle layer of the seamless capsule.

[0061] The present invention also provides the following aspects. [1] A seamless capsule for large intestine delivery comprising a core, an intermediate layer covering the core, and a coating covering the intermediate layer, wherein the intermediate layer contains an oily substance having a melting point of 50°C or higher, and a stress-strain curve obtained in a compression-rupture test of the intermediate layer satisfies the relationship of the following formula (1): 0.2≦brittleness (B) / hardness (H)≦0.6 ... formula (1) (wherein the hardness (H) is the stress at the yield point of the stress-strain curve, and the brittleness (B) is the stress difference between the yield point and the breaking point.) [2] The seamless capsule for large intestine delivery according to [1], wherein the intermediate layer further contains an oily substance having a melting point of 30°C or higher but lower than 50°C. [3] The seamless capsule for large intestine delivery according to [1] or [2], wherein the core contains an oily substance having a melting point of 30°C or higher. [4] The seamless capsule for large intestine delivery according to any one of [1] to [3], wherein the core further contains a functional ingredient. [5] The seamless capsule for large intestine delivery according to any one of [1] to [4], wherein the functional ingredient is at least one component selected from the group consisting of caffeine, organic acids, organic acid salts, plant extracts, animal extracts, microbial extracts, microbially produced extracts, microbial fermentation extracts, fruit juices, functional polysaccharides, dietary fiber, polyphenols, vitamins, vitamin derivatives, vitamin-like substances, amino acids, microorganisms, microbial organelles, plant organelles, essential oils, anti-inflammatory drugs, omega-3 fatty acids, omega-6 fatty acids, and omega-9 fatty acids. [6] The seamless capsule for large intestine delivery according to any one of [1] to [5], wherein at least one of the core and the intermediate layer contains an amphoteric surfactant. [7] The seamless capsule according to any one of [1] to [6], wherein the amphoteric surfactant is a phospholipid. [8] The seamless capsule according to any one of [1] to [7], wherein the phospholipid is at least one component selected from the group consisting of lecithin, lysolecithin, hydrogenated lecithin, and hydrogenated lysolecithin. [9] The seamless capsule according to any one of [1] to [8], wherein the phospholipid is lecithin.

[0062] A... Nozzle cross section B... Seamless capsule jet 1... Inner nozzle 2... Intermediate nozzle 3... Outer nozzle 4... Capsule core solution 5... Intermediate layer solution 6... Coating solution 7... Three-layer seamless capsule 8... Cooling liquid

Claims

1. A seamless capsule for large intestine delivery comprising a core, an intermediate layer covering said core, and a shell covering said intermediate layer, wherein said intermediate layer contains an oily substance having a melting point of 50°C or higher, and a stress-strain curve obtained in a compression-rupture test of said intermediate layer satisfies the relationship of the following formula (1): 0.2≦brittleness (B) / hardness (H)≦0.6 ... formula (1) (wherein said hardness (H) is the stress at the yield point of said stress-strain curve, and said brittleness (B) is the stress difference between the yield point and the breaking point).

2. The seamless capsule for colon delivery according to claim 1, wherein the intermediate layer further contains an oily substance having a melting point of 30°C or higher but lower than 50°C.

3. A seamless capsule for colon delivery according to claim 1 or 2, wherein the core contains an oily substance having a melting point of 30°C or higher.

4. A seamless capsule for colon delivery according to any one of claims 1 to 3, wherein the core further contains a functional ingredient.

5. The colon-deliverable seamless capsule according to claim 4, wherein the functional ingredient is at least one ingredient selected from the group consisting of caffeine, organic acids, organic acid salts, plant extracts, animal extracts, microbial extracts, microbially produced extracts, microbially fermented extracts, fruit juices, functional polysaccharides, dietary fiber, polyphenols, vitamins, vitamin derivatives, vitamin-like substances, amino acids, microorganisms, microbial organelles, plant organelles, essential oils, anti-inflammatory drugs, omega-3 fatty acids, omega-6 fatty acids, and omega-9 fatty acids.

6. A seamless capsule for colon delivery according to any one of claims 1 to 5, wherein at least one of the core and the intermediate layer contains an amphoteric surfactant.

7. The seamless capsule according to claim 6, wherein the amphoteric surfactant is a phospholipid.

8. The seamless capsule according to claim 7, wherein the phospholipid is at least one component selected from the group consisting of lecithin, lysolecithin, hydrogenated lecithin, and hydrogenated lysolecithin.

9. The seamless capsule according to claim 7 or 8, wherein the phospholipid is lecithin.

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