Delayed disintegration capsule and method of manufacturing the same

Abstract

The present invention provides a technology that delays the disintegration of a capsule by incorporating certain components into the core of the capsule, with the aim of greatly increasing the degree of freedom in capsule design. The invention relates to a seamless capsule comprising 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, a cationic surfactant, and an oil having a melting point of 40°C or higher, at least one layer of the intermediate layer contains an oil having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer, and a method for manufacturing the same.

Description

Technology Field

[0001] The present disclosure relates to a seamless capsule and a method for manufacturing the same, and more specifically, to a delayed-decay type seamless capsule capable of delaying the decay of the capsule and a method for manufacturing the delayed-decay type seamless capsule. Background Technology

[0002] Seamless capsules are used for many purposes, considering factors such as ease of controlling particle size and simplicity of manufacturing. In particular, capsules containing beneficial bacteria such as Bifidobacteria and capsules containing flavorings such as menthol are commercially available. In these seamless capsules, controlling the release timing of the contents (also referred to as the "nucleus" or "nucleating agent") has been investigated.

[0003] Japanese Patent No. 5102401 (Patent Document 1) proposes a seamless capsule that specifically disintegrates in the large intestine. Additionally, Japanese Patent Publication No. 2014-139200 (Patent Document 2) proposes a capsule capable of delivering the active ingredient to the large intestine without the active ingredient being lost in the stomach or small intestine. While there are many other techniques to slow down disintegration, 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 the coating design. Prior art literature

[0004] Japanese Patent No. 5102401 and Japanese Patent Publication No. 2014-139200 The problem to be solved

[0005] The present disclosure aims to provide a technology that delays the disintegration of a capsule by incorporating a certain component into the core of the capsule, thereby greatly increasing the degree of freedom in capsule design. means of solving the problem

[0006] As a result of repeated research to solve the above objective, the inventors discovered that the objective could be achieved by incorporating an amphoteric surfactant into the core of the capsule.

[0007] The present disclosure provides the following aspects.

[0008] [1] A seamless capsule comprising a nucleus, one or more intermediate layers formed on the nucleus, and an outermost layer formed on the intermediate layers,

[0009] A delayed-disintegration seamless capsule in which the nucleus contains an active substance, a cationic surfactant, and an oil having a melting point of 40°C or higher, at least one layer of the intermediate layer contains an oil having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer.

[0010] [2] Seamless capsule described in [1], in which the above positive surfactant is present in an amount of 3 to 50% by weight relative to the total weight of the nucleus.

[0011] [3] Seamless capsules described in [1] or [2], wherein the positive surfactant is a phospholipid.

[0012] [4] Seamless capsule described in [3], in which the above phospholipid is lecithin.

[0013] [5] A seamless capsule described in 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, microbial product 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.

[0014] [6] A seamless capsule described in any one of [1] to [5], wherein the above water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, purceleran, pectin, chitosan, alginic acid, curdran, starch, modified starch, pullulan, mannan, and mixtures thereof.

[0015] [7] A method for manufacturing a seamless capsule, wherein a core liquid is discharged from the innermost nozzle of a concentric triple nozzle, an intermediate layer liquid is simultaneously dropped from the middle nozzle outside the innermost nozzle, and an outermost layer liquid is simultaneously dropped from the outermost nozzle to form a seamless capsule, wherein a core liquid is discharged from the innermost nozzle of a coolant consisting of cooled liquid oil, and an intermediate layer liquid is simultaneously dropped from the outermost nozzle.

[0016] A method for manufacturing a delayed-disintegration type seamless capsule, characterized in that the core liquid contains an active substance, a cationic surfactant, and an oil having a melting point of 40°C or higher, the middle layer liquid contains an oil having a melting point of 45°C or higher, and the outermost layer liquid contains a water-soluble natural polymer.

[0017] [8] A method for manufacturing a seamless capsule of [7] in which the above positive surfactant is present in an amount of 3 to 50% by weight relative to the total weight of the nucleus.

[0018] [9] A method for manufacturing a seamless capsule of [7] or [8] in which the positive surfactant is a phospholipid.

[0019]

[10] A method for manufacturing seamless capsules of [9] in which the above phospholipid is lecithin.

[0020]

[11] A method for manufacturing seamless capsules of [7] to

[10] in which the active substance is selected from the group consisting of herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, microbial product 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.

[0021]

[12] A method for manufacturing seamless capsules of [7] to

[11] in which the above water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, purceleran, pectin, chitosan, alginic acid, curdran, starch, modified starch, pullulan, mannan and mixtures thereof. Effects of the invention

[0022] In the present disclosure, the disintegration of a capsule can be delayed simply by incorporating a cationic surfactant as a nucleation agent. As a result, the degree of freedom in capsule design can be greatly increased by combining this with disintegration delays achieved through the formulation of coatings or intermediate layers developed previously. Furthermore, the formulation of this cationic surfactant allows for the control of the capsule disintegration time through the control of the formulation amount or the selection of the coating. This enables the addition of a time factor for disintegration occurring after a certain period following ingestion, in addition to enteric capsules that do not disintegrate in the stomach and colonic capsules that do not disintegrate in the stomach and small intestine. Consequently, the design of seamless capsules becomes very easy. In particular, since the pH is inconsistent from the lower small intestine to the large intestine, it was difficult to control release (capsule disintegration) in that region using a coating composition that withstands acidity or alkalinity; however, the time control of the present disclosure makes it possible to disintegrate in the region where the pH is inconsistent or to disintegrate beyond that region. Brief explanation of the drawing

[0023] Figure 1 is a schematic cross-sectional view of the nozzle section of a manufacturing device suitable for manufacturing a three-layer seamless capsule by the dropping method using a three-layer nozzle. Figure 2 is a graph showing the change in dissolution rate and time, representing the results of the dissolution experiments of the examples and comparative examples. Specific details for implementing the invention

[0024] 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 layers, wherein the core contains an active substance, a cationic surfactant, and an oil having a melting point of 40°C or higher, at least one layer of the intermediate layer contains an oil having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer.

[0025] Each composition is described below. Meanwhile, regarding the fats below, two types of fats with melting points of 40°C or higher and 45°C or higher are described; however, since both are fats, the fat with a melting point of 45°C or higher is included in the description of the fat with a melting point of 40°C or higher.

[0026] nucleus

[0027] In the core of the seamless capsule of the present disclosure, an active substance, an amphoteric surfactant, and an oil having a melting point of 40°C or higher are used. In the present disclosure, the disintegration of the capsule can be delayed by incorporating an amphoteric surfactant into the core.

[0028] The active substance incorporated into the core of the seamless capsule is selected from one or more of the group consisting of, for example, herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, microbial product extracts, fruit juices, functional polysaccharides, polyphenols, vitamin C, vitamin B, amino acids, microorganisms, bacteria (e.g., beneficial intestinal bacteria), essential oils (e.g., citrus-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.

[0029] In the seamless capsule of the present disclosure, the amount of the active substance in the core is typically 1 to 50 mass%, preferably 5 to 30 mass%, and more preferably 10 to 20 mass%. If it is more than 50 mass%, encapsulation becomes difficult, and if it is less than 1 mass%, the effect of the active substance does not occur.

[0030] The core of the seamless capsule of the present disclosure further comprises an amphoteric surfactant. The amphoteric surfactant comprises both a cationic structure and an anionic structure within the molecule exhibiting the amphoteric surfactant. Examples of amphoteric surfactants include the amidobetaine type and the imidazoline type; however, amphoteric surfactants derived from natural products are useful when used in living organisms, particularly humans, and in such cases, phospholipids, specifically lecithin, are suitably used. The amount of amphoteric surfactant used is not significantly different from the amount of active substance used, and is typically 3 to 50 mass%, preferably 5 to 30 mass%, and more preferably 10 to 20 mass%. If it is more than 50 mass%, encapsulation becomes difficult, and if it is less than 3 mass%, the effect of using the amphoteric surfactant does not occur. By adding an amphoteric surfactant, the release time of the active substance in the body can be controlled independently of pH. It is thought that the effect of using an amphoteric surfactant is exerted because the retention of the solid form is increased or the melting point is raised. In any case, the breakdown of seamless capsules tends to be independent of changes in body pH.

[0031] In addition to the core of the present disclosure, compounding agents such as excipients, stabilizers, surfactants other than cationic surfactants, adjuvants, or foaming agents may be appropriately incorporated. The amounts of these compounding agents are not particularly limited, but must not be an amount that impairs the function of the seamless capsule of the present disclosure.

[0032] The core of the seamless capsule of the present disclosure comprises, in addition to the above components, an oil having a melting point of 40°C or higher. In practice, the above components are dissolved or suspended in an oil having a melting point of 40°C or higher. The reason for mixing with the oil in this way is that the contents are not affected by a large amount of water, etc. present during capsule manufacturing. In the present disclosure, the oil having a melting point of 40°C or higher is used as edible vegetable oil, edible refined processed oil, sucrose fatty acid ester, glycerin fatty acid ester, etc., and mixtures thereof. Meanwhile, among the oils having a melting point of 40°C or higher, an oil having a melting point of 45°C or higher may be used in at least one of the intermediate layers described below.

[0033] According to the Japanese Agricultural and Forestry Standards for Refined and Processed Oils and Fats for Edible Use (Notice No. 3115 of the Ministry of Agriculture, Forestry and Fisheries dated December 24, 2019), oils and fats with a melting point of 40°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 (dividing into parts with different melting points, hardness, or solid fat content by performing separation operations by centrifugation, filtration, or dripping),” and “ester exchange (adjusting the melting point by changing the composition of fatty acids using a catalyst)” on animal oils, vegetable oils and fats, or mixed oils and fats. The oil used in the core of the present disclosure may be an oil that has not been hydrogenated (referred to as “non-hydrogenated oil” in this specification). As previously stated, non-hydrogenated oils refer to oils that are not natural oils with a melting point adjusted by hydrogenation, and may be oils from which the melting point has been adjusted by fractionation or ester exchange. Meanwhile, the term "melting point" as described in this disclosure refers to the rising melting point (the temperature at which the oil softens and begins to rise when heated in a capillary tube).

[0034] Non-hydrogenated oils are oils that have not undergone hydrogenation treatment (so-called hydrogenation treatment), and palm oil-based oils are suitable. The major fatty acids in palm oil are palmitic acid and oleic acid, and these two types of fatty acids make up more than 80% of the composition; at room temperature, it is semi-solid. When this palm oil is fractionated at a specific temperature, it can be divided into a low-melting point liquid oil and a high-melting point solid oil. The low-melting point liquid oil contains a large amount of oleic acid, while the high-melting point solid oil contains a large amount of palmitic acid. The liquid oil is conventionally called palm olein, and the solid oil is conventionally called palm stearin (although palmitic acid is the most abundant component, it is not called palm palmitin). In addition, desired non-hydrogenated oils with adjusted melting points can also be obtained by esterifying palm oil. In addition, the non-hydrogenated oil used in the present disclosure may be a fractionated palm oil and an ester-exchanged oil of palm oil or said fractionated palm oil, used individually or in combination.

[0035] The non-hydrogenated oils used in the present disclosure, specifically, may include palm stearin, palm olein, palm super olein, palm double olein, palm mid fractionation, and ester exchange oils of palm oil or said palm fraction oil, or mixtures thereof. Of course, they are not limited to these.

[0036] The oils used in the present disclosure having a melting point of 40°C or higher may include sucrose fatty acid esters or glycerin fatty acid esters. Sucrose fatty acid esters are formed by the reaction of a fatty acid (e.g., stearic acid or oleic acid) with the hydroxyl group of sucrose and are commonly used as emulsifiers. Glycerin fatty acid esters are formed by ester bonding a fatty acid 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. The oils used in the present disclosure having a melting point of 40°C or higher may be edible vegetable oils, edible refined processed oils, sucrose fatty acid esters, or glycerin fatty acid esters alone, or a mixture thereof.

[0037] middle layer

[0038] In the seamless capsule of the present disclosure, one or more intermediate layers are formed on the outer side of the core. That is, the intermediate layer may be a single layer or multiple layers. In the case of multiple layers, the composition of each layer may be the same or different. For simplicity, the intermediate layer will be described as a single layer below. In order to control solidification during cooling, it is preferable for the intermediate layer to have a melting point 2 to 9°C, preferably 2 to 8°C, higher than the melting point of the core. 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, solidification of the intermediate layer does not occur, which hinders the formation of the seamless capsule.

[0039] In the intermediate layer, a fat with a melting point of 45°C or higher is used. Among the aforementioned fats with a melting point of 40°C or higher, one with a melting point of 45°C or higher is selected. Specific examples of fats with a melting point of 45°C or higher include the above vegetable (fragmented) oil, beeswax, highly hydrogenated oil, margarine, shortening, etc.

[0040] In the intermediate layer, lecithin or silicon dioxide may be added to adjust interfacial tension, viscosity, or specific gravity. The amount of these additives is not particularly limited, but must not be an amount that impairs the function of the seamless capsule of the present disclosure.

[0041] outermost layer

[0042] The seamless capsule of the present disclosure has the outer surface of the intermediate layer additionally coated with an outermost layer. The outermost layer comprises a water-soluble natural polymer. The water-soluble natural polymer is selected from, for example, gelatin, casein, zein, pectin or its derivatives, alginic acid or its salt, agar, gellan gum, carrageenan, purceleran, chitosan, curdran, starch, modified starch, pullulan, mannan, and mixtures thereof. Of course, the water-soluble natural polymer is not limited to these. It is preferable that the water-soluble natural polymer be in the range of 50% to 90% by weight based on the total solid weight of the outermost layer composition of the seamless capsule. When using alginate, gellan gum, pectin, or carrageenan, alkali metal salts, alkaline earth metal salts, ammonium salts, etc. may be appropriately added.

[0043] The outermost layer of the seamless capsule of the present disclosure may additionally contain a plasticizer to impart flexibility in a dry state, and examples of said plasticizers include glycerin, sorbitol, etc. The amount of said plasticizer is 1 to 50 mass%, preferably 5 to 40 mass%, more preferably 15 to 30 mass%, based on the total weight of the film after drying. If the amount of said plasticizer is less than 1 mass%, the film cannot withstand vacuum drying or cannot maintain sufficient flexibility in a dry state, causing cracking, and if it exceeds 50 mass%, the film softens and adhesion or melting occurs at high temperatures.

[0044] The outermost layer of the seamless capsule of the present disclosure may, if necessary, include various additives commonly used in the field, such as flavorings, sweeteners, coloring agents, and preservatives such as parabens, in addition to the composition. When such additives are used, the total content of all additives is, for example, 0.01% to 10% by weight, and preferably 0.1% to 5% by weight, with respect to the total weight of the solids in the composition forming the outermost layer of the capsule.

[0045] The outermost layer of the seamless capsule of the present disclosure after drying preferably 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 film strength is likely to decrease, and if it exceeds 600 μm, the content volume decreases and the disintegration resistance is also likely to deteriorate.

[0046] The size of the seamless capsule of the present disclosure is not particularly limited, but it is preferable to have a diameter of 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 middle layer of the layer structure of the seamless capsule decreases, and the effect of preventing moisture intrusion tends to decrease, and if it exceeds 8 mm, it tends to become difficult to swallow.

[0047] Method for manufacturing seamless capsules

[0048] The seamless capsule of the present disclosure may be described by a dropping method using three or more multiple nozzles, specifically a method of dropping into a cooling liquid using three nozzles (e.g., Japanese Patent Publication No. Sho 49-59789, Japanese Patent Publication No. Sho 51-8176, and Japanese Patent Publication No. Sho 60-172343).

[0049] In the manufacture of the capsule of the present disclosure, when using a dropping method utilizing a three-layer nozzle, it is preferable to discharge the nucleus liquid from the innermost nozzle, discharge the outermost layer liquid from the outermost nozzle, and discharge oil as an intermediate layer liquid from the middle nozzle. During discharge, a three-layer seamless capsule can be continuously manufactured by extruding simultaneously at a constant speed into a cooling liquid flowing at a normal speed to form a composite jet and releasing it into the cooling liquid, thereby utilizing the surface tension acting between the cooling liquid and the film composition. In the case of a three-layer nozzle, the obtained capsule has a three-layer structure, and the innermost layer contains a nucleus. In the present disclosure, during the above manufacturing process, by adding a cationic surfactant to the nucleus, the decay can be delayed and the decay time can be controlled.

[0050] FIG. 1 shows a schematic cross-sectional view of the nozzle part of a manufacturing apparatus suitable for manufacturing a three-layer seamless capsule in a dropping method using a three-layer nozzle.

[0051] FIG. 1 illustrates a state in which a seamless capsule jet (B) discharged from a three-layer nozzle (A) is broken 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) existing concentrically. A liquid (4) that becomes the core of the capsule is discharged from the inner nozzle (1), a liquid that becomes 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 becomes the outermost layer is discharged from the outer nozzle (3) (specifically, between the outer nozzle (3) and the intermediate nozzle (2)), so that three types of liquids are discharged simultaneously to form a seamless capsule jet (B).

[0052] For the seamless capsule (7) obtained as described above, ventilation drying is performed at 5°C to 30°C for 2 to 12 hours. Additionally, if it is necessary to lower the moisture content in the capsule (7), vacuum drying or vacuum freeze-drying may be performed after ventilation drying. In vacuum drying, the vacuum level is maintained at 0.002 to 0.5 MPa or less, and in vacuum freeze-drying, the method involves freezing and drying at -20°C or lower. The time required for vacuum drying or vacuum freeze-drying is not particularly limited. Generally, it is 5 to 60 hours, preferably 24 to 48 hours. If it is less than 5 hours, drying is insufficient, and the water present in the capsule (7) may have an adverse effect on the contents.

[0053] As previously mentioned, the seamless capsule obtained by the above method contains a cationic surfactant (particularly lecithin) in the core, thereby delaying the disintegration of the seamless capsule and further controlling the disintegration time. In addition, not only is the cationic surfactant of the present disclosure added to the core, but acid resistance, enteric properties, or colonic disintegration properties may also be imparted to the coating layer (particularly the outermost layer). By combining these, it becomes possible to control the disintegration properties of the seamless capsule. In the seamless capsule of the present disclosure, for example, if the time is controlled so that it disintegrates specifically from the lower small intestine to the large intestine, it is possible to deliver a certain drug or functional food to a specific site, thereby making it possible to further enhance the effect of the drug.

[0054] [Example]

[0055] The present disclosure is explained in more detail by way of examples. The present disclosure, and these examples, are merely illustrative of the invention.

[0056] Example 1

[0057] (a) Core solution: 47.17 parts by weight of edible oil (JC oil from Taiyo Oil: melting point 52±3℃), 11.79 parts by weight of edible oil (K9190 from Taiyo Oil: melting point 49±3℃), and 3.35 parts by weight of soybean lecithin were stirred and uniformly dissolved at 60℃, and 4.69 parts by weight of Blue No. 1 were mixed and suspended to make the core solution.

[0058] (b) Liquid for the intermediate layer: 9.30 parts by weight of edible oil (JC oil from Daiyo Oil: melting point 52±3℃) and 0.7 parts by weight of soybean lecithin were mixed to make the liquid for the intermediate layer.

[0059] (c) Liquid for the 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 make the liquid for the outermost layer.

[0060] A three-layer seamless capsule with a diameter of 6.0 mm was produced by simultaneously dropping the liquid for the core from the innermost nozzle of a concentric triple nozzle, the liquid for the middle layer from the outermost intermediate nozzle, and the liquid for the outermost layer from the outermost nozzle into rapeseed oil that is cooled to 12°C and flowing. The obtained three-layer seamless capsule was air-dried at 20°C for 8 hours. A dissolution test was performed using the obtained seamless capsule according to the following method.

[0061] Dissolution experiment

[0062] The acidic solution and neutralizing solution were prepared as follows.

[0063] Acidic solution: 2.0 g of sodium chloride dissolved in 7.0 mL of 12N hydrochloric acid and water to make 1000 mL (pH 1.2)

[0064] Neutralizing solution: 0.20 mol / L aqueous solution of trisodium phosphate

[0065] Six seamless capsules prepared above were immersed in 750 mL of acidic solution for 2 hours using the paddle method (Toyama Sangyo NTR·6400A, rotation speed 50 rpm), and the pigment elution rate in the acidic solution was measured at 630 nm and calculated. Measurements were taken by sampling every hour. Subsequently, the above neutralizing solution was added to the acidic solution to adjust the pH to 6.8, and the pigment elution rate was measured by sampling every 2 hours in the same manner up to a total of 26 hours. All measurements were performed at 37.5°C. The relationship between the pigment elution rate (%) and elapsed time (h) was plotted on a graph and is shown in Fig. 2.

[0066] Example 2 and Comparative Examples 1-2

[0067] Using the formulation shown in Table 1 below, seamless capsules were formed in the same manner as in Example 1, and a dissolution experiment was performed in the same manner. The results are shown in Figure 2, in the same manner as in Example 1.

[0068]

[0069] As is evident from the above examples and comparative examples and Figure 2, in both the examples and comparative examples, the pigment begins to be released approximately 4 hours after the start of the elution experiment. However, 8 hours after the start of the experiment, the pigment release rate of the seamless capsule of the comparative example becomes about twice that of the seamless capsule of the example, and thereafter, the difference widens significantly. Comparative Example 1 is a seamless capsule that does not contain soybean lecithin in the nucleus liquid, and Comparative Example 2 shows an experiment in which the amount of soybean lecithin added is quantitatively low at 2.01 parts by weight. In Example 1, the amount of soybean lecithin added is 3.35 parts by weight, and as can be seen from Figure 2, there is a significant difference compared to Comparative Example 2. From these experimental results, it appears that when soybean lecithin is added in excess of 3 parts by weight, the pigment release rate decreases significantly, suggesting that it can be controlled to some extent by the amount added. For example, if the extraction rate is taken as a standard of 20%, it can be seen that in Example 1, the value is reached 12 hours after the start of the experiment, but in Example 2, the value is reached about 25 hours after the start of the experiment, so it can be seen that the extraction rate can be controlled by the amount of soybean lecithin.

[0070] Example 3

[0071] (a) Core solution: 47.17 parts by weight of JC oil, 11.79 parts by weight of edible oil (Witocan 42 / 44, IOI Oleo: melting point 43±3℃), and 3.35 parts by weight of soybean lecithin were uniformly dissolved by stirring at 60℃, and 4.69 parts by weight of loxoprofen sodium hydrate (CAS80382-23-6) were mixed and suspended to make the core solution.

[0072] (b) Liquid for the intermediate layer: 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 make the liquid for the intermediate layer.

[0073] (c) Liquid for the 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 make the liquid for the outermost layer.

[0074] A triple-layer seamless capsule with a diameter of 5 mm was produced by simultaneously dropping the liquid for the core from the inner nozzle of the concentric triple nozzle, the liquid for the middle layer from the outer intermediate nozzle, and the liquid for the outermost layer from the outermost nozzle into rapeseed oil that is cooled to 12°C and flowing. The obtained triple-layer seamless capsule was air-dried at 20°C for 8 hours.

[0075] As in Example 2, an elution test was performed using the paddle method, and the sodium loxoprofen eluted in the test solution under the following test conditions was measured by high-speed liquid chromatography (Shimadz).

[0076] Detector: UV absorption spectrophotometer (measurement wavelength: 222 nm)

[0077] Column: ODS (Inner diameter 4.6mm, length 15cm)

[0078] Column temperature: 40℃

[0079] Mobile phase: Methanol / Water / Glacial Acetic Acid / Triethylamine = 600 / 400 / 1 / 1

[0080] Flow rate: 0.5 mL / min

[0081] As a result of the evaluation above, it was found that the dissolution rate could be controlled.

[0082] Examples 4

[0083] (a) Core solution: 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 uniformly dissolved by stirring at 60°C, and 4.69 parts by weight of lactic acid bacteria powder (freeze-dried product of Lactococcus lactis subsp. lactis JCM 7638) were mixed and suspended to make the core solution.

[0084] (b) Liquid for the intermediate layer: 23.25 parts by weight of JC oil and 1.75 parts by weight of egg yolk lecithin (manufactured by Qewie) were mixed to make the liquid for the intermediate layer.

[0085] (c) Liquid for the outermost layer: The liquid for the outermost layer was prepared by dissolving 15 parts of carrageenan (Sansho Co., Ltd.), 50.9 parts of dextrin (Nichiden Chemical Co., Ltd., DE value less than 10), 3 parts of sorbitol (Mitsubishi Corporation Food Tech Co., Ltd.), 10 parts of LM pectin (Unitech Foods Co., Ltd.), 1 part of potassium chloride, and 0.1 parts of calcium chloride in 400 parts of purified water.

[0086] A triple-layer seamless capsule with a diameter of 7 mm was produced by simultaneously dropping the liquid for the core from the inner nozzle of the concentric triple nozzle, the liquid for the middle layer from the outer intermediate nozzle, and the liquid for the outermost layer from the outermost nozzle into rapeseed oil flowing at 20°C. The obtained triple-layer seamless capsule was air-dried at 20°C for 8 hours.

[0087] As in Example 2, an elution test was performed using the paddle method, and the number of lactic acid bacteria leaked into the test solution was evaluated using MRS agar medium (Oxoid).

[0088] As a result of the evaluation, it was found that the dissolution rate could be controlled. Industrial applicability

[0089] In the present disclosure, by incorporating a cationic surfactant into the innermost layer (core) of a seamless capsule, the disintegration of the capsule can be delayed, and as a technique for controlling the disintegration of a seamless capsule, it has high industrial applicability. Explanation of the symbols

[0090] A… Nozzle cross-section B… Seamless Capsule Jet 1… inner nozzle 2… middle nozzle 3… outer nozzle 4… Capsule nuclear solution 5… Intermediate layer solution 6… outermost solution 7… 3-layer seamless capsule 8… coolant

Claims

Claim 1 A seamless capsule comprising 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 an oil having a melting point of 40°C or higher, at least one layer of the intermediate layer contains an oil having a melting point of 45°C or higher, and the outermost layer contains a water-soluble natural polymer, wherein the active substance and the amphoteric surfactant are dissolved or suspended in an oil having a melting point of 40°C or higher, wherein the amphoteric surfactant is present in an amount of 5 to 50% by weight relative to the total weight of the core, and wherein the amphoteric surfactant is lecithin. Claim 2 A seamless capsule according to claim 1, wherein the active substance is selected from the group consisting of herbal medicine extracts, tinctures, plant extracts, animal extracts, microbial extracts, microbial product 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. Claim 3 A seamless capsule according to claim 1 or 2, wherein the water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, purceleran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof. Claim 4 A method for manufacturing a seamless capsule comprising a cooling liquid consisting of a cooled liquid phase, wherein a core liquid is discharged from the innermost nozzle of a concentric triple nozzle, an intermediate layer liquid is simultaneously dropped from an intermediate nozzle outside the innermost nozzle, and an outermost layer liquid is dropped from the outermost nozzle to form a seamless capsule, wherein the core liquid contains an active substance, a cationic surfactant, and an oil having a melting point of 40°C or higher, the intermediate layer liquid contains an oil having a melting point of 45°C or higher, and the outermost layer liquid contains a water-soluble natural polymer, wherein the active substance and the cationic surfactant are dissolved or suspended in an oil having a melting point of 40°C or higher, the cationic surfactant is present in an amount of 5 to 50% by weight relative to the total weight of the core liquid, and the cationic surfactant is lecithin. Claim 5 A method for manufacturing a seamless capsule according to claim 4, wherein the active substance is selected from the group consisting of herbal medicine extracts, tinctures, therapeutic drugs, plant extracts, animal extracts, microbial extracts, microbial product 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. Claim 6 A method for manufacturing a seamless capsule according to claim 4 or 5, wherein the water-soluble natural polymer is selected from gelatin, agar, gellan gum, carrageenan, purceleran, pectin, chitosan, alginic acid, curdlan, starch, modified starch, pullulan, mannan, and mixtures thereof. Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete

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