Delayed disintegration-type capsule and method for producing same

Abstract

An object of the present invention is to provide a technique for delaying disintegration of a capsule by blending a certain component in a core of the capsule, and to increase the degree of freedom in capsule design. The present invention relates to a delayed disintegration-type seamless capsule that is a seamless capsule including a core, one or more intermediate layers formed on the core, and an outermost layer formed on the intermediate layers, wherein the core contains an active substance, an amphoteric surfactant, and a fat having a melting point of 40°C or more, at least one layer of the intermediate layers contains a fat having a melting point of 45°C or more, and the outermost layer contains a water-soluble natural polymer. The present invention also relates to a method for producing the same.

Description

Delayed disintegration capsule and method for producing same

[0001] The present disclosure relates to a seamless capsule and a method for producing the same, and more particularly to a delayed-disintegrating seamless capsule capable of delaying capsule disintegration and a method for producing the delayed-disintegrating seamless capsule.

[0002] Seamless capsules are used in many applications due to the ease of particle size control and the simplicity of production. In particular, capsules containing beneficial bacteria such as bifidobacteria and capsules containing flavorings such as menthol are commercially available. Studies have been conducted to control the release time of the contents (also called the "core" or "core agent") in these seamless capsules.

[0003] Japanese Patent No. 5102401 (Patent Document 1) proposes a seamless capsule that disintegrates specifically in the large intestine. Furthermore, Japanese Patent Laid-Open Publication No. 2014-139200 (Patent Document 2) proposes a capsule that allows an active ingredient to reach the large intestine without being lost in the stomach or small intestine. Many other technologies exist for delaying disintegration, but all of these proposals involve improvements to the so-called coating, such as the outermost layer or middle layer of the capsule, which reduces the degree of freedom in coating design.

[0004] Japanese Patent No. 5102401 Japanese Patent Application Laid-Open No. 2014-139200

[0005] The present disclosure aims to provide a technology for delaying capsule disintegration by incorporating certain ingredients into the capsule core, thereby increasing the degree of freedom in capsule design.

[0006] As a result of extensive research to achieve the above object, the inventors have found that the above object can be achieved by incorporating an amphoteric surfactant into the capsule core.

[0007] The present disclosure provides the following aspects. [1] A delayed-disintegrating seamless capsule comprising a core, one or more intermediate layers formed on the core, and an outermost layer formed on the intermediate layer, wherein the core contains an active substance, an amphoteric surfactant, and an oil or fat having a melting point of 40°C or higher, at least one of the intermediate layers contains an oil or fat having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer. [2] The seamless capsule according to [1], wherein the amphoteric surfactant is present in an amount of 3 to 50% by weight based on the total weight of the core. [3] The seamless capsule according to [1] or [2], wherein the amphoteric surfactant is a phospholipid. [4] The seamless capsule according to [3], wherein the phospholipid is lecithin. [5] The seamless capsule according to any one of [1] to [4], wherein the active substance is selected from the group consisting of herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, microbially produced extracts, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria, essential oils, anti-inflammatory drugs, steroid drugs, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, and combinations thereof. [6] The seamless capsule according to any one of [1] to [5], wherein the water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, furcellaran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof. [7] A method for producing seamless capsules by ejecting a core liquid from the innermost nozzle of a concentric triple nozzle into a cooling liquid consisting of cooled liquid oil, and simultaneously dropping an intermediate layer liquid from a middle nozzle outside the innermost nozzle and an outermost layer liquid from the outermost nozzle to form a seamless capsule, wherein the core liquid contains an active substance, an amphoteric surfactant, and an oil or fat having a melting point of 40°C or higher, the intermediate layer liquid contains an oil or fat having a melting point of 45°C or higher, and the outermost layer liquid contains a water-soluble natural polymer. [8] A method for producing seamless capsules according to [7], wherein the amphoteric surfactant is present in an amount of 3 to 50% by weight based on the total weight of the core. [9] A method for producing seamless capsules according to [7] or [8], wherein the amphoteric surfactant is a phospholipid.

[10] The method for producing seamless capsules according to [9], wherein the phospholipid is lecithin.

[11] The method for producing seamless capsules according to [7] to

[10] , wherein the active substance is selected from the group consisting of herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, microbially produced extracts, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria, essential oils, anti-inflammatory drugs, steroid drugs, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, and combinations thereof.

[12] The method for producing seamless capsules according to [7] to

[11] , wherein the water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, furcellaran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof.

[0008] In the present disclosure, capsule disintegration can be delayed simply by incorporating an amphoteric surfactant as a core-forming compounding agent. As a result, by combining this with the previously developed disintegration delay achieved by incorporating a coating or intermediate layer, greater flexibility in capsule design can be achieved. Furthermore, the incorporation of this amphoteric surfactant allows for control of capsule disintegration time by controlling the amount incorporated and the selection of the coating. This allows for the creation of enteric-coated capsules that do not disintegrate in the stomach and colon-disintegrating capsules that do not disintegrate in the stomach or small intestine, as well as the addition of a disintegration time factor after a certain time has elapsed since ingestion, greatly simplifying seamless capsule design. In particular, the pH is not constant from the lower small intestine to the large intestine, and it has been difficult to control release (capsule disintegration) in this region using a coating composition that is resistant to acidic or alkaline conditions. However, the time control of the present disclosure enables disintegration in areas with variable pH or even beyond.

[0009] 1 is a schematic cross-sectional view of a nozzle portion of a manufacturing apparatus suitable for manufacturing a three-layer seamless capsule by a dropping method using a three-layer nozzle. It is a graph showing the change in dissolution rate versus time, showing the results of dissolution experiments of Examples and Comparative Examples.

[0010] The present disclosure provides a seamless capsule comprising a core, one or more intermediate layers formed on the core, and an outermost layer formed on the intermediate layer, wherein the core contains an active substance, an amphoteric surfactant, and an oil or fat having a melting point of 40°C or higher, at least one intermediate layer contains an oil or fat having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer.

[0011] Each component will be explained below. Note that, although two types of fats and oils are described below, one with a melting point of 40°C or higher and the other with a melting point of 45°C or higher, since both are fats and oils, the explanation of fats and oils with a melting point of 45°C or higher will include the fats and oils with a melting point of 40°C or higher.

[0012] Core The core of the seamless capsule of the present disclosure contains an active substance, an amphoteric surfactant, and an oil or fat having a melting point of 40° C. or higher. In the present disclosure, the disintegration of the capsule can be delayed by incorporating an amphoteric surfactant into the core.

[0013] The active substance incorporated into the core of the seamless capsule is a drug or functional ingredient for the living body, and is selected from one or more of the group consisting of, for example, herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, extracts produced by microorganisms, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria (e.g., beneficial intestinal bacteria), essential oils (e.g., citrus fruit-derived oils, rose-derived oils, etc.), anti-inflammatory drugs (e.g., loxoprofen sodium, acetylsalicylic acid, etc.), steroid drugs (e.g., hydrocortisone, prednisolone, etc.), omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, and combinations thereof.

[0014] In the seamless capsule of the present disclosure, the amount of the active substance in the core is usually 1 to 50% by mass, preferably 5 to 30% by mass, and more preferably 10 to 20% by mass. If it is more than 50% by mass, encapsulation becomes difficult, and if it is less than 1% by mass, the effect of the active substance will not be exerted.

[0015] The core of the seamless capsule of the present disclosure further contains 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. However, naturally occurring amphoteric surfactants are useful for use in living organisms, particularly humans. In such cases, phospholipids, specifically lecithin, are preferred. The amount of amphoteric surfactant used is not significantly different from the amount of active substance used, typically 3-50% by mass, preferably 5-30% by mass, and more preferably 10-20% by mass. Amounts greater than 50% by mass make encapsulation difficult, while amounts less than 3% by mass do not achieve the benefits of using an amphoteric surfactant. The addition of an amphoteric surfactant can control the release time of the active substance in the body independently of pH. The use of an amphoteric surfactant is likely effective due to its enhanced retention of the solid form and its increased melting point. In any case, the disintegration of seamless capsules tends to be independent of changes in pH in the body.

[0016] The core of the present disclosure may further contain additives such as excipients, stabilizers, surfactants other than amphoteric surfactants, adjuvants, or foaming agents as appropriate. The amounts of these additives are not particularly limited, but should not be in amounts that inhibit the function of the seamless capsule of the present disclosure.

[0017] In addition to the above ingredients, the core of the seamless capsule of the present disclosure contains an oil or fat having a melting point of 40°C or higher. In practice, the above ingredients are dissolved or suspended in an oil or fat having a melting point of 40°C or higher. The reason for mixing the ingredients in the oil or fat in this manner is to prevent the contents from being affected by the large amount of water, etc., present during capsule production. In the present disclosure, the oil or fat having a melting point of 40°C or higher includes edible vegetable oil, edible refined and processed oil, sucrose fatty acid ester, glycerin fatty acid ester, etc., and mixtures thereof. Among the oils or fats having a melting point of 40°C or higher, an oil or fat having a melting point of 45°C or higher can be used in at least one of the intermediate layers described below.

[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), fats and oils with a melting point of 40°C or higher are defined as animal fats and oils, vegetable fats and oils, or mixtures thereof, which have been adjusted to a melting point suitable for edible use by techniques such as "hydrogenation (adjusting the melting point by adding hydrogen and saturating unsaturated fatty acids)," "fractionation (separation by centrifugation, filtration, or dripping to separate into fractions with different melting points, hardness, and solid fat content)," and "interesterification (adjusting the melting point by changing the fatty acid composition using a catalyst)." The fats and oils used in the core of the present disclosure may be fats and oils that have not been specifically hydrogenated (referred to as "non-hydrogenated fats and oils" in this specification). As mentioned above, non-hydrogenated fats and oils mean fats and oils that have not been hydrogenated to natural fats and oils to adjust their melting point, and may be fats and oils whose melting point has been adjusted by fractionation or interesterification of the raw fats and oils. The "melting point" described in this disclosure refers to the slip melting point (the temperature at which the fat or oil softens and begins to rise when heated in a capillary tube).

[0019] Non-hydrogenated fats and oils are fats and oils that have not been subjected to hydrogenation (so-called hydrogenation), and palm oil-based fats and oils are suitable. The major fatty acids in palm oil are palmitic acid and oleic acid, with these two types of fatty acids accounting for more than 80% of the total. Palm oil is semi-solid at room temperature. When palm oil is fractionated at a specific temperature, it can be divided into low-melting-point liquid oil and high-melting-point solid oil. Low-melting-point liquid oil contains a large amount of oleic acid, while high-melting-point solid oil contains a large amount of palmitic acid. The liquid oil is commonly called palm olein, and the solid oil is commonly called palm stearin (although palmitic acid is the most abundant component, it is not called palm palmitin). Alternatively, the desired non-hydrogenated fats and oils with adjusted melting points can be obtained by interesterifying palm oil. The non-hydrogenated oils and fats used in the present disclosure may be fractionated palm oil, and interesterified palm oil or palm fractionated oil, which may be used alone or in combination.

[0020] Specific examples of non-hydrogenated fats and oils used in the present disclosure include, but are not limited to, palm stearin, palm olein, palm superolein, palm double olein, palm mid fraction, which are fractionated palm oil, and interesterified palm oil or palm fractionated oil, or mixtures thereof.

[0021] The fats and oils with a melting point of 40°C or higher used in the present disclosure 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 esterifying fatty acids to one or two of the three hydroxyl groups of glycerin and are also used as emulsifiers. Those bound to all three hydroxyl groups are fats or oils and are distinguished from glycerin fatty acid esters. The fats and oils with a melting point of 40°C or higher used in the present disclosure may be edible vegetable oils and oils, edible refined processed oils and oils, sucrose fatty acid esters, or glycerin fatty acid esters, either alone or in mixtures thereof.

[0022] Intermediate Layer In the seamless capsule of the present disclosure, one or more intermediate layers are formed on the outside of the core. That is, the intermediate layer may be a single layer or multiple layers. In the case of multiple layers, the compositions of the layers may be the same or different. For simplicity, the following description will be given assuming that there is only one intermediate layer. It is desirable for the intermediate layer to have a melting point that is 2 to 9°C, preferably 2 to 8°C, higher than the melting point of the core so that solidification during cooling can be controlled. If the melting point is lower than 2°C, the contents and the protective layer are likely to mix during cooling. Conversely, if it is higher than 9°C, the intermediate layer will not solidify, hindering the formation of the seamless capsule.

[0023] The intermediate layer is made of fats and oils having a melting point of 45° C. or higher. The fats and oils having a melting point of 45° C. or higher are selected from the fats and oils having a melting point of 40° C. or higher described above. Specific examples of fats and oils having a melting point of 45° C. or higher include the above-mentioned vegetable (fractionated) fats and oils, beeswax, highly hydrogenated oils, margarine, shortening, etc.

[0024] The intermediate layer may contain lecithin or silicon dioxide to adjust the interfacial tension, viscosity, and specific gravity. There are no particular restrictions on the amount of these ingredients, but the amount must not be such that it inhibits the function of the seamless capsule of the present disclosure.

[0025] Outermost Layer The seamless capsule of the present disclosure is further coated on the outside of the intermediate layer with an outermost layer. The outermost layer contains a water-soluble natural polymer. The water-soluble natural polymer may be selected from, for example, gelatin, casein, zein, pectin or its derivatives, alginic acid or its salts, agar, gellan gum, carrageenan, furcellaran, chitosan, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof. 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 outermost layer composition of the seamless capsule. When alginate, gellan gum, pectin, or carrageenan is used, alkali metal salts, alkaline earth metal salts, ammonium salts, etc. may be added as appropriate.

[0026] The outermost layer of the seamless capsule of the present disclosure 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% by mass, preferably 5 to 40% by mass, and more preferably 15 to 30% by mass, based on the total weight of the shell after drying. If the blending amount of the plasticizer is less than 1% by mass, 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 exceeds 50% by mass, the shell will soften and stick or melt at high temperatures.

[0027] In addition to the above-mentioned composition, the outermost layer of the seamless capsule of the present disclosure may contain, as needed, 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 will become the outermost layer of the capsule.

[0028] The outermost layer of the seamless capsule of the present disclosure after drying desirably has a thickness of 10 to 600 μm, preferably 30 to 400 μm, and more preferably 40 to 250 μm. If the thickness of the outermost layer is less than 10 μm, the shell strength tends to be low, whereas if it exceeds 600 μm, the content amount tends to be small and disintegration properties tend to be poor.

[0029] The size of the seamless capsule of the present disclosure is not particularly limited, but it is desirable that the diameter be 0.3 to 10 mm, preferably 1 to 8 mm. If the diameter of the capsule is less than 0.3 mm, the thickness of the intermediate layer in the layer structure of the seamless capsule becomes small, and the effect of preventing moisture penetration tends to be reduced, while if the diameter exceeds 8 mm, it tends to be difficult to swallow.

[0030] Method for Manufacturing Seamless Capsules The seamless capsules of the present disclosure can be manufactured by a dropping method using a multiple nozzle with three or more layers, specifically a method of dropping the capsules into a cooling liquid using a three-layer nozzle (for example, JP-A Nos. 49-59789, 51-8176, and 60-172343).

[0031] When a dropping method using a three-layer nozzle is used to produce capsules according to the present disclosure, it is preferable to eject the core liquid from the innermost nozzle, the outermost layer liquid from the outermost nozzle, and the oil or fat as the intermediate layer liquid from the middle nozzle. During ejection, the components are simultaneously extruded at a constant speed into a cooling liquid flowing downward at a steady rate to form a composite jet, which is then released into the cooling liquid. This allows the continuous production of three-layer seamless capsules by the surface tension acting between the cooling liquid and the coating composition. When using a three-layer nozzle, the resulting capsules have a three-layer structure, with a core contained in the innermost layer. In the present disclosure, adding an amphoteric surfactant to the core during the above production process can delay disintegration and also control the disintegration time.

[0032] FIG. 1 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.

[0033] 1 shows the state in which a seamless capsule jet B discharged from a three-layer nozzle A is cut in a cooling liquid 8 and becomes each seamless capsule 7. In the three-layer nozzle A, an inner nozzle 1, an intermediate nozzle 2, and an outer nozzle 3 are arranged concentrically, and a liquid 4 that will become the core of the capsule is discharged from the inner nozzle 1, a 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 a liquid that will become the outermost layer 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 a seamless capsule jet B.

[0034] 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.

[0035] As mentioned above, the seamless capsules obtained by the above method contain an amphoteric surfactant (particularly, lecithin) in the core, which delays the disintegration of the seamless capsule and also makes it possible to control the disintegration time. Furthermore, in addition to adding the amphoteric surfactant of the present disclosure to the core, the coating layer (particularly, the outermost layer) may be made acid-resistant, enteric, or colon-disintegratable. Combining these makes it possible to control the disintegration property of the seamless capsule. For example, if the seamless capsule of the present disclosure can be time-controlled to disintegrate specifically from the lower small intestine to the large intestine, it becomes possible to deliver certain drugs or functional foods to specific sites, thereby further enhancing the efficacy of the drugs.

[0036] [Examples] The present disclosure will be described in more detail with reference to examples, which are merely examples of the present disclosure.

[0037] Example 1 (a) Core liquid: 47.17 parts by weight of edible oil (JC oil manufactured by Taiyo Yushi; melting point 52±3°C), 11.79 parts by weight of edible oil (K9190 manufactured by Taiyo Yushi; melting point 49±3°C), and 3.35 parts by weight of soybean lecithin were stirred at 60°C to homogeneously dissolve, and 4.69 parts by weight of Blue No. 1 was added to form a suspension, which served as the core liquid. (b) Intermediate layer liquid: 9.30 parts by weight of edible oil (JC oil manufactured by Taiyo Yushi; melting point 52±3°C) and 0.7 parts by weight of soybean lecithin were mixed to form the intermediate layer liquid. (c) Liquid for outermost layer: 17.48 parts by weight of gelatin [jelly strength: 280 Bloom], 4.60 parts by weight of glycerin, 0.92 parts by weight of low methoxy (LM) pectin, and 85.20 parts by weight of purified water were uniformly mixed at 60°C to prepare a liquid for the outermost layer.

[0038] The core liquid was dropped from the innermost nozzle of a concentric triple nozzle, the intermediate layer liquid from the middle nozzle further outside, and the outermost layer liquid from the outermost nozzle into flowing rapeseed oil cooled to 12°C, thereby producing three-layer seamless capsules with a diameter of 6.0 mm. The resulting three-layer seamless capsules were dried by ventilation at 20°C for 8 hours. The resulting seamless capsules were subjected to a dissolution test as follows.

[0039] Dissolution Experiments: The acidic and neutralizing solutions were prepared as follows. Acidic solution: 2.0 g of sodium chloride was dissolved in 7.0 mL of 12N hydrochloric acid and water to a final volume of 1000 mL (pH 1.2). Neutralizing solution: 0.20 mol / L aqueous trisodium phosphate solution. Six seamless capsules prepared as described above were immersed in 750 mL of acidic solution for 2 hours using the paddle method (Toyama Sangyo NTR-6400A, rotation speed 50 rpm). The dye dissolution rate in the acidic solution was measured at 630 nm and the dissolution rate was calculated. Measurements were performed by sampling every hour. Next, the neutralizing solution was added to the acidic solution to adjust the pH to 6.8, and the dye dissolution rate was measured every 2 hours using the same method for a total of 26 hours. All measurements were performed at 37.5°C. The relationship between the dye dissolution rate (%) and elapsed time (h) was plotted in a graph, as shown in Figure 2.

[0040] Example 2 and Comparative Examples 1 and 2 Seamless capsules were formed using the formulations shown in Table 1 below, and a dissolution test was carried out in the same manner as in Example 1. The results are shown in Figure 2, as in Example 1.

[0041]

[0042] As is clear from the above Examples and Comparative Examples and Figure 2, in both the Examples and Comparative Examples, the pigment begins to dissolve approximately four hours after the start of the dissolution experiment. However, after eight hours from the start of the experiment, the pigment dissolution rate of the seamless capsules of the Comparative Examples is about twice that of the seamless capsules of the Examples, and the difference thereafter becomes larger. Comparative Example 1 shows a seamless capsule in which the core solution does not contain soybean lecithin, and Comparative Example 2 shows an experiment in which the amount of soybean lecithin blended is small, at 2.01 parts by weight. In Example 1, the amount of soybean lecithin blended is 3.35 parts by weight, and Figure 2 shows a significant difference compared to Comparative Example 2. From these experimental results, it can be seen that when soybean lecithin is blended in an amount exceeding 3 parts by weight, the pigment dissolution rate drops significantly, and it is thought that this can be controlled to some extent by the blend amount. For example, if a dissolution rate of 20% is taken as the standard, it is understood that in Example 1, this value is reached 12 hours after the start of the experiment, but in Example 2, this value is reached approximately 25 hours after the start of the experiment, and it is understood that the dissolution rate can be controlled by the amount of soybean lecithin added.

[0043] Example 3 (a) Core liquid: 47.17 parts by weight of JC oil, 11.79 parts by weight of edible oil (Witocan 42 / 44 manufactured by IOI Oleo, melting point 43±3°C), and 3.35 parts by weight of soybean lecithin were stirred at 60°C to homogeneously dissolve, and 4.69 parts by weight of loxoprofen sodium hydrate (CAS 80382-23-6) was added to form a suspension, which served as the core liquid. (b) Intermediate layer liquid: 4.65 parts by weight of JC oil, 4.65 parts by weight of the above Witocan 42 / 44, and 0.7 parts by weight of soybean lecithin were mixed to form the intermediate layer liquid. (c) Liquid for outermost layer: 17.48 parts by weight of gelatin [jelly strength: 280 Bloom], 4.60 parts by weight of glycerin, 0.92 parts by weight of low methoxy (LM) pectin, and 85.20 parts by weight of purified water were uniformly mixed at 60°C to prepare a liquid for the outermost layer.

[0044] The core liquid was dropped from the inner nozzle of a concentric triple nozzle, the intermediate layer liquid from the middle nozzle outside it, and the outermost layer liquid from the outermost nozzle into flowing rapeseed oil cooled to 12° C., thereby producing triple-layered seamless capsules with a diameter of 5 mm. The resulting triple-layered seamless capsules were dried under air at 20° C. for 8 hours.

[0045] A dissolution test was conducted by the paddle method in the same manner as in Example 2, and the amount of loxoprofen sodium dissolved in the test solution was measured by high-performance liquid chromatography (Shimadzu) under the following test conditions: Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 222 nm), Column: ODS (inner diameter 4.6 mm, length 15 cm), Column temperature: 40°C, Mobile phase: methanol / water / glacial acetic acid / triethylamine = 600 / 400 / 1 / 1, Flow rate: 0.5 mL / min

[0046] As a result of the above evaluation, it was found that the dissolution rate could be controlled.

[0047] Example 4 (a) Core liquid: 47.17 parts by weight of JC oil, 11.79 parts by weight of K9190, and 3.35 parts by weight of soybean lecithin were stirred at 60°C to homogeneously dissolve, and 4.69 parts by weight of lactic acid bacteria powder (lyophilized product of Lactococcus lactis subsp. lactis JCM 7638) was added to form a suspension, which served as the core liquid. (b) Intermediate layer liquid: 23.25 parts by weight of JC oil and 1.75 parts by weight of egg yolk lecithin (manufactured by Kewpie Corporation) were mixed to form the intermediate layer liquid. (c) Liquid for outermost layer: A liquid for the outermost layer was prepared by dissolving 15 parts of carrageenan (manufactured by Sansho Co., Ltd.), 50.9 parts of dextrin (manufactured by Nippon Starch Chemical Co., Ltd., DE value less than 10), 3 parts of sorbitol (manufactured by Mitsubishi Shoji Foodtech Co., Ltd.), 10 parts of LM pectin (manufactured by Unitec Foods Co., Ltd.), 1 part of potassium chloride, and 0.1 part of calcium chloride in 400 parts of purified water.

[0048] The core liquid was dropped from the inner nozzle of a concentric triple nozzle, the intermediate layer liquid from the middle nozzle outside it, and the outermost layer liquid from the outermost nozzle into flowing rapeseed oil at 20° C., thereby producing triple-layered seamless capsules with a diameter of 7 mm. The resulting triple-layered seamless capsules were dried under air at 20° C. for 8 hours.

[0049] The dissolution test was carried out by the paddle method in the same manner as in Example 2, and the number of lactic acid bacteria leaked into the test solution was evaluated using MRS agar medium (manufactured by Oxoid).

[0050] As a result of the evaluation, it was found that the dissolution rate could be controlled.

[0051] In the present disclosure, by incorporating an amphoteric surfactant into the innermost layer (core) of a seamless capsule, the disintegration of the capsule can be delayed, and this is a technology for controlling the disintegration of seamless capsules, which has high industrial applicability.

[0052] 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... Outermost layer solution 7... Three-layer seamless capsule 8... Cooling liquid

Claims

1. A delayed-disintegrating seamless capsule comprising a core, one or more intermediate layers formed on the core, and an outermost layer formed on the intermediate layer, wherein the core contains an active substance, an amphoteric surfactant, and an oil or fat having a melting point of 40°C or higher, at least one of the intermediate layers contains an oil or fat having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer.

2. The seamless capsule according to claim 1, wherein said amphoteric surfactant is present in an amount of 3 to 50% by weight based on the total weight of the core.

3. The seamless capsule according to claim 1 or 2, wherein the amphoteric surfactant is a phospholipid.

4. The seamless capsule according to claim 3, wherein the phospholipid is lecithin.

5. The seamless capsule according to any one of claims 1 to 4, wherein the active substance is selected from the group consisting of herbal extracts, tinctures, plant extracts, animal extracts, microbial extracts, extracts produced by microorganisms, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria, essential oils, anti-inflammatory drugs, steroid drugs, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, and combinations thereof.

6. The seamless capsule according to any one of claims 1 to 5, wherein the water-soluble natural polymer is selected from the group consisting of gelatin, agar, gellan gum, carrageenan, furcellaran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof.

7. A method for producing seamless capsules, comprising discharging a core liquid from the innermost nozzle of a concentric triple nozzle into a cooling liquid consisting of cooled liquid oil, simultaneously dropping an intermediate layer liquid from a middle nozzle outside the innermost nozzle and an outermost layer liquid from the outermost nozzle to form seamless capsules, wherein the core liquid contains an active substance, an amphoteric surfactant and an oil or fat having a melting point of 40°C or higher, the intermediate layer liquid contains an oil or fat having a melting point of 45°C or higher, and the outermost layer liquid contains a water-soluble natural polymer.

8. The method for producing seamless capsules according to claim 7, wherein said amphoteric surfactant is present in an amount of 3 to 50% by weight based on the total weight of the core.

9. The method for producing seamless capsules according to claim 7 or 8, wherein the amphoteric surfactant is a phospholipid.

10. The method for producing seamless capsules according to claim 9, wherein the phospholipid is lecithin.

11. The method for producing seamless capsules according to any one of claims 7 to 10, wherein the active substance is selected from the group consisting of herbal extracts, tinctures, therapeutic drugs, plant extracts, animal extracts, microbial extracts, extracts produced by microorganisms, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria, essential oils, anti-inflammatory drugs, steroid drugs, omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, and combinations thereof.

12. The method for producing seamless capsules according to any one of claims 7 to 11, wherein the water-soluble natural polymer is selected from the group consisting of gelatin, agar, gellan gum, carrageenan, furcellaran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof.