JPWO2019198835A1 - Soft capsule aggregate and composition for oral administration containing it - Google Patents

Abstract

It is an object of the present invention to provide a soft capsule assembly having a particle size of less than 1 mm on the order of microns and which can be used by blending with other materials. An aggregate of soft capsules in which the contents are encapsulated with a film, the average particle size is 900 μm or less, irregularities are formed on the surface of the film, and the average circularity represented by the formula (1) is 0. A soft capsule assembly of .95 or less. Circularity = 4πS / L2 (1) (In equation (1), S represents the projected area of the projected image of the soft capsule particles, and L represents the peripheral length of the projected image.)

Description

The present invention relates to a soft capsule aggregate having an average particle size of 900 μm or less and having irregularities formed on the surface of the film, and a composition for oral administration containing the soft capsule aggregate.

Soft capsules are widely used in the fields of pharmaceuticals, foods, cosmetics, pesticides and the like. If the particle size of the soft capsule is reduced, it is expected that the texture and the feeling of taking the soft capsule will be improved when it is blended into powders, granules and high-viscosity substances. Therefore, in recent years, the particle size is particularly high in foods and pharmaceuticals. There is a demand for micron-order soft capsules having a particle size smaller than that of the conventional one, such as less than 1 mm or 900 μm or less. As a method for manufacturing soft capsules, a rotary method in which two film-forming sheets are punched out to form a soft capsule, or a coating solution in which a content liquid to be filled into a capsule from an inner nozzle using a double nozzle is formed from an outer nozzle to form a capsule film. Is known at the same time and dropped into the curing liquid (Patent Document 1). However, in the rotary method, it is difficult to reduce the particle size because the sheet is punched out and molded. Although the dropping method can produce soft capsules having a smaller particle size than the rotary method, the particle size of the soft capsules that can be produced can be produced. Is about 1 to 10 mm, and it has been difficult to produce micron-order soft capsules having a particle size of less than 1 mm. Further, in order to manufacture a soft capsule having a three-layer structure as a dropping method, a triple nozzle is used to simultaneously discharge the content liquid from the inner nozzle, the protective liquid from the intermediate nozzle, and the coating liquid from the outer nozzle into the curing liquid. Although a method of dropping is proposed (Patent Document 2), the particle size of the obtained soft capsule was the same as that of the double nozzle. Under such circumstances, it has been desired to develop a micron-order soft capsule that can be blended with other materials and used.

International Publication 2013/100013 Pamphlet Japanese Unexamined Patent Publication No. 2016-74615

An object of the present invention is to solve the above problems and to provide a soft capsule assembly having a particle size of less than 1 mm on the order of microns and which can be used by blending with other materials.

The present inventors have started to study soft capsules having a particle size on the order of microns. In the course of the study, the present inventors discharge a carrier liquid such as medium-chain fatty acid triglyceride (MCT) from the outside of the coating liquid forming the outermost layer of the soft capsule, and further discharge the flow rate of the coating liquid per unit time. , And the flow rate of the content liquid discharged inside the coating liquid per unit time is very small compared to the flow rate of the carrier liquid per unit time, and the flow rate of each liquid is set to a specific range. It has been found that the droplets can be miniaturized and soft capsules having a fine particle size of less than 1 mm (hereinafter, also referred to as Microsoft capsules) can be manufactured. Normally, when the flow rate of the internal content liquid and the coating liquid is reduced compared to the flow rate of the carrier liquid in the outermost layer, the liquid flow of the content liquid and the coating liquid is disturbed, and it seems that uniform droplets are not formed. The aggregate of soft capsules thus obtained was an aggregate of soft capsules having a sharp particle size distribution and a uniform particle size. According to this method, a soft capsule assembly having a fine particle size such as 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less is produced. Becomes possible. Further, according to this manufacturing method, not only soft capsules having a smooth surface but also soft capsules having irregularities on the surface can be manufactured. The present inventors have studied the Microsoft capsules thus obtained, and found that the Microsoft capsules have a small particle size and a smooth surface, so that it is difficult to uniformly mix them with other materials such as powder. In addition, when molded with other powder materials and used as tablets, for example, a new problem has been found in which Microsoft capsules on the surface are missing due to the small particle size. Conventionally, soft capsules are often used alone, and there is no particular problem even when they are used together with other materials. Therefore, the above-mentioned problems due to miniaturization have not been predicted. However, Microsoft capsules are expected to be used in combination with other materials rather than used alone, so if these problems cannot be solved, even if the particle size can be reduced to the order of microns. It cannot be put into practical use. Therefore, when various Microsoft capsules were prepared and further studied, surprisingly, the Microsoft capsules having irregularities on the surface were excellent in mixing with other materials such as powder and could be mixed uniformly, and tablets. Even when it was molded into a uniform shape, it did not come off from the surface. Conventionally, it has been considered that soft capsules should be close to a true sphere and have a smooth surface. This is the common sense of those who are involved in soft capsules, and it is said that capsules with irregularities are not soft capsules and have been treated as defective products. Forming irregularities on the surface was contrary to such common general technical knowledge, but the present inventors formed specific irregularities on the surface of Microsoft capsules having different particle sizes and usage methods from the conventional ones. By doing so, it has been found that a soft capsule which is excellent in mixing with other powders and the like and can prevent chipping when molded into tablets and the like can be obtained. The present invention has been completed based on the above findings.

That is, the present invention is specified by the following matters.
[1] An aggregate of soft capsules in which the contents are encapsulated with a film, the average particle size is 900 μm or less, irregularities are formed on the surface of the film, and the circularity represented by the formula (1) is formed. A soft capsule aggregate having an average of 0.95 or less.
Circularity = 4πS / L ² (1)
(In the formula (1), S represents the projected area of the projected image of the soft capsule particles, and L represents the peripheral length of the projected image.)
[2] An aggregate of soft capsules in which the contents are encapsulated with a film, the average particle diameter is 900 μm or less, unevenness is formed on the surface of the film, and the degree of unevenness indicating the degree of the unevenness is determined. Observe the cross section of the soft capsule and touch the radius of the circle in contact with the convex portion located farthest from the center of gravity in the cross section and the concave portion closest to the center of gravity centered on the center of gravity. A soft capsule aggregate having the unevenness of 20 μm or more when defined by the difference from the radius of the circle.
[3] The soft capsule aggregate according to the above [1] or [2], wherein the average of the lengths and shortnesses represented by the formula (2) is 0.04 or more.
Long / short diameter = 1-minor / major (2)
[4] The soft capsule aggregate according to any one of the above [1] to [3], wherein the ratio of the film thickness to the particle size of the soft capsule is 0.08 to 0.15.
[5] The soft capsule aggregate according to any one of the above [1] to [4], wherein the average particle size is 700 μm or less.
[6] The soft capsule aggregate according to any one of the above [1] to [5], wherein the average particle size is 300 μm or more.
[7] A composition for oral administration, which comprises the soft capsule aggregate according to any one of the above [1] to [6].
[8] The composition for oral administration according to the above [7], which contains 0.1 to 50% by mass of a soft capsule aggregate.
[9] The composition for oral administration according to the above [7] or [8], which is a tablet.
Further, another aspect of the present invention is a method of producing a soft capsule aggregate by discharging a raw material from a nozzle, and discharges a content liquid containing a capsule filling component from the innermost side at a discharge rate of 0.1 to 5 mL / min. Then, the film liquid containing the film-forming component is discharged from the outside at a discharge rate of 0.1 to 10 mL / min, and the carrier liquid is discharged from the outside at a discharge rate of 1500 to 30000 mL / min to form droplets. A method for producing a soft capsule aggregate having an average particle diameter of 900 μm or less, which is characterized by curing the coating liquid of droplets, or an aggregate of soft capsules in which the contents are encapsulated with a coating, and the average particle diameter is 900 μm. The present invention relates to a soft capsule aggregate characterized by the following, and the soft capsule aggregate characterized in that irregularities are formed on the surface of the film.

Since the soft capsule aggregate of the present invention has an average particle size of 900 μm or less and irregularities formed on the surface, mixing uniformity when blended with other materials such as powders, granules, and high-viscosities. Excellent for. Since it has a small particle size and is excellent in mixing uniformity with other materials, it has an excellent texture and ingestion feeling when used in foods and pharmaceuticals. In addition, it is possible to prevent chipping when molded into a molded product such as a tablet. In the composition for oral administration of the present invention, the soft capsule aggregate to be blended has an average particle size of 900 μm or less and irregularities are formed on the surface, so that the composition is excellent in texture and ingestion feeling, and even in the form of tablets. There is no missing soft capsule.

It is a schematic diagram which shows one Embodiment of the nozzle part used in this manufacturing method. It is a figure which shows the particle size distribution of the soft capsule obtained in Example 1. FIG. It is a figure which shows the particle size distribution of the soft capsule obtained in Reference Example 1. FIG. It is a figure which shows the particle size distribution of the soft capsule obtained in Example 2. It is an X-ray CT image of the soft capsule obtained in Reference Example 1. It is an X-ray CT image of the soft capsule obtained in Example 2. It is an image by the optical microscope of the soft capsule obtained in Example 1. It is an image by the optical microscope of the soft capsule obtained in Reference Example 1. It is a cross-sectional image of the soft capsule obtained in Comparative Example 1. It is a cross-sectional image of the soft capsule obtained in Comparative Example 2. It is a cross-sectional image of the soft capsule obtained in Example 3. It is a cross-sectional image of the soft capsule obtained in Example 4. It is a cross-sectional image of the soft capsule obtained in Example 5. 6 is a cross-sectional image of the soft capsule obtained in Example 6. It is a cross-sectional image of the soft capsule obtained in Example 7. 6 is a cross-sectional image of the soft capsule obtained in Example 8. 6 is a cross-sectional image of the soft capsule obtained in Example 9. It is a cross-sectional image of the soft capsule obtained in Example 10. It is a cross-sectional image of the soft capsule obtained in Example 11. It is a photograph of a state in which microcapsules and silica are mixed. From the left, the microcapsules obtained in Comparative Example 1, Comparative Example 2, Example 3, Example 4, and Example 5 are used. (A) is an SEM image of the surface of a tablet tableted using the microcapsules obtained in Example 5 (using a scanning electron microscope manufactured by KEYENCE Corporation; the same applies hereinafter), and (b) is Comparative Example 1. It is an SEM image of the surface of a tablet tableted using the microcapsules obtained in. (A) is an SEM image of the surface of a tablet tableted using the microcapsules obtained in Example 3, and (b) is a tablet tableted using the microcapsules obtained in Comparative Example 1. It is an SEM image of the surface of (a) and (b), and the magnification is 30 times. FIG. 21 is a 200-fold SEM image obtained by further enlarging FIG. 21. It is a schematic diagram which shows the state which the soft capsule close to a sphere is missing from a tablet.

The soft capsule aggregate of the present invention is an aggregate of soft capsules whose contents are covered with a film, has an average particle diameter of 900 μm or less, and has irregularities formed on the surface of the film, and is represented by the formula (1). The average circularity to be formed is 0.95 or less.
Circularity = 4πS / L ² (1)
(In the formula (1), S represents the projected area of the projected image of the soft capsule particles, and L represents the peripheral length of the projected image.)
The average particle size in the present invention can be determined by a known method for measuring the average particle size, but the number of samples (N number) is 100 or more using a particle image analyzer (device name: Moforogi G3, Malvern). It is preferable to perform the analysis in. Further, the average circularity (hereinafter, also referred to as average circularity) in the present invention is obtained by determining the projected area of the projected images of a plurality of soft capsule particles and the peripheral length of the projected images by using a known method. The circularity calculated from the values can be obtained by averaging, but it can be obtained by performing an analysis with a sample number (N number) of 100 or more using a particle image analyzer (device name: Moforogi G3, Malvern). Is preferable. The average circularity in the present invention is preferably 0.85 or more from the viewpoint of maintaining the strength of the soft capsule, from the viewpoint of improving the mixing property with other materials, from the viewpoint of preventing chipping during molding, and maintaining the strength of the soft capsule. From the viewpoint of this, 0.85 to 0.95 is preferable. The average particle size of the soft capsule aggregate of the present invention is preferably 700 μm or less from the viewpoint of further improving the texture and the feeling of ingestion, and preferably 300 μm or more from the viewpoint of ease of handling. The average particle size of the soft capsule aggregate of the present invention is preferably 300 to 900 μm, more preferably 300 to 700 μm.

The soft capsule aggregate of the present invention is an aggregate of soft capsules whose contents are covered with a film, has an average particle diameter of 900 μm or less, and has irregularities formed on the surface of the film to indicate the degree of the irregularities. Observe the cross section of the soft capsule and check the degree of unevenness with the radius of the circle in contact with the convex portion located farthest from the center of gravity in the cross section and the position closest to the center of gravity with the center of gravity as the center. It is characterized in that the degree of unevenness is 20 μm or more when defined by the difference from the radius of the circle in contact with the concave portion in. Here, the center of gravity is the position of the point of action of the resultant force of gravity acting on each part. Further, as a method for observing the cross section, any known method such as a method of cutting soft capsule particles and observing the cross section of the particles with a scanning electron microscope (SEM), a method of observing an image of the cross section of the particles using a 3DX ray microscope, or the like. However, it is preferable to place the soft capsule particles on a plane and observe a cross section parallel to the plane at a position approximately intermediate between the bottom and the top of the particles using a 3DX scanning microscope. In the case of the observation method using the 3DX ray microscope, the cross-sectional shape of the intermediate position differs depending on the direction in which the particles are placed, but in the present invention, the degree of unevenness observed in either direction is 20 μm or more. All you need is. If such irregularities are formed on the surface of the soft capsule particles, the effect of the present invention can be achieved. The degree of unevenness in the soft capsule assembly of the present invention is the radius of the sphere in contact with the convex portion located farthest from the center of gravity of the soft capsule and the position closest to the center of gravity of the center of gravity. It may be defined by the difference from the radius of the sphere in contact with the concave portion, and the degree of unevenness thus obtained may be 20 μm or more. Further, the degree of unevenness in the present invention is preferably 30 μm or more from the viewpoint of further improving the mixing property with other materials and further improving the effect of preventing chipping during molding, and 150 μm or less from the viewpoint of maintaining the strength of the soft capsule. Is preferable, 100 μm or less is more preferable, and 80 μm or less is further preferable. As a preferable range of the degree of unevenness of the soft capsule assembly of the present invention, 20 to 150 μm, 20 to 100 μm, 20 to 80 μm, 30 to 150 μm, 30 to 100 μm, 30 to 80 μm and the like can be exemplified. In the soft capsule assembly of the present invention, the average circularity may be 0.95 or less and the unevenness may be 20 μm or more, the unevenness may be 20 μm or more, and the average circularity may be 0.95 or less. There may be.

Further, the soft capsule aggregate of the present invention preferably has an average of long and short degrees represented by the formula (2) (hereinafter, also referred to as average long and short degrees) of 0.04 or more.
Long / short diameter = 1-minor / major (2)
The length represented by the formula (2) can be determined by using any known method, but the number of samples (device name: Moforogi G3, Malvern) is used by using a particle image analyzer (device name: Moforogi G3, Malvern). It is preferable to perform analysis with N number) 100 or more. The length of the present invention is more preferably 0.05 or more from the viewpoint of improving the mixing property with other materials and improving the effect of preventing chipping during molding. Further, the long and short degree in the present invention is preferably 0.15 or less, more preferably 0.1 or less, from the viewpoint of maintaining the strength of the soft capsule. Preferred ranges of long and short length of the soft capsule assembly of the present invention exemplify 0.04 to 0.15, 0.04 to 0.1, 0.05 to 0.15, 0.05 to 0.1 and the like. be able to.

In the soft capsule assembly of the present invention, the ratio of the film thickness to the particle size of the soft capsule is preferably 0.08 to 0.15. Here, the thickness of the film is a known method such as a method of cutting soft capsule particles and observing the particle cross section with a scanning electron microscope (SEM), a method of observing an image of the particle cross section using a 3DX beam microscope, and the like. The particle size can also be determined by observation with a scanning electron microscope (SEM), etc., but as with the measurement of unevenness, soft capsule particles are placed on a flat surface and 3DX rays are used. Using a microscope, observe a cross section parallel to the plane at a position approximately halfway between the bottom and the top of the particles, and let the thickness of the film at the thickest part of the film be the thickness of the film, and pass through the center of gravity of the cross section. It is preferable that the longest diameter is the particle diameter. When the ratio of the film thickness to the particle size is in the above range, it is possible to secure a filling space for the contents while maintaining the strength of the soft capsule even though it is a minute soft capsule on the order of microns. Similar to the measurement of the degree of unevenness, the cross-sectional shape of the intermediate position differs depending on the direction in which the particles are placed, but the ratio of the thickness of the film to the particle size observed in either direction is 0.08 to 0. It may be .15. In the case of soft capsules produced by the dropping method, the thickness of the film varies depending on the location, but it does not differ significantly. Therefore, if the value observed in either direction is within the above range, it is almost within the range as a whole. is there.

The soft capsule aggregate of the present invention is a method for producing a soft capsule aggregate by ejecting a raw material from a nozzle, and a content liquid containing a capsule filling component is provided from the innermost side, and a film liquid containing a film forming component is provided from the outer side. The carrier liquid is discharged from the outside to form droplets, and the coating liquid of the droplets is cured. Further, the content liquid is discharged at a discharge speed of 0.1 to 5 mL / min to discharge the coating liquid. It can be produced by a method for producing a soft capsule aggregate having an average particle diameter of 900 μm or less, which comprises discharging at a discharge rate of 0.1 to 10 mL / min and discharging a carrier liquid at a discharge rate of 1500 to 30000 mL / min. it can. As a method of discharging each liquid in the present manufacturing method, for example, a nozzle (outer nozzle) for discharging the coating liquid is provided outside the nozzle (inner nozzle) for discharging the content liquid so as to surround the inner nozzle, and the outer nozzle is provided. The upper end (opening) of the forming tube for allowing the carrier liquid to flow into the forming tube is provided so as to surround the outer nozzle on the outside, the content liquid is discharged from the inner nozzle, and the coating liquid is discharged from the outer nozzle to form. Examples thereof include a method in which a composite droplet of the coating liquid and the content liquid is passed through the carrier liquid that has flowed into the forming pipe from the upper end of the pipe. In this case, the shape of each nozzle is not particularly limited, but from the viewpoint that the contents are not unevenly distributed and the thickness of the film is made uniform, the shape of the discharge port of each nozzle is preferably annular, and each nozzle is arranged concentrically. It is more preferable to have. The flow rate of the liquid discharged from each nozzle in this manufacturing method is 0.1 to 1 for the flow rate of the content liquid discharged from the inner nozzle from the viewpoint of miniaturizing the formed droplets and stably forming the droplets. The flow rate of the coating liquid discharged from the outer nozzle is 0.1 to 10 mL / min, and the flow rate of the carrier liquid flowing into the inside of the forming tube is 1500 to 30000 mL / min. Flow rate of the content liquid The flow rate of the content liquid included in the range of 0.1 to 5 mL / min is 0.5 to 5 mL / min, 1 to 5 mL / min, 1.5 to 5 mL / min, and 2 to 5 mL / min. , 0.1 to 4 mL / min, 0.5 to 4 mL / min, 1 to 4 mL / min, 1.5 to 4 mL / min, 2 to 4 mL / min, 0.1 to 3 mL / min, 0.5 to 3 mL Examples include / min, 1 to 3 mL / min, 1.5 to 3 mL / min, 2 to 3 mL / min, and the like. Flow rate of film solution The flow rate of film solution included in the range of 0.1 to 10 mL / min is 0.5 to 10 mL / min, 1 to 10 mL / min, 1.5 to 10 mL / min, 2 to 10 mL / min. 3, 10 mL / min, 3.5 to 10 mL / min, 4 to 10 mL / min, 0.1 to 8 mL / min, 0.5 to 8 mL / min, 1 to 8 mL / min, 1.5 to 8 mL / min , 2-8 mL / min, 3-8 mL / min, 3.5-8 mL / min, 4-8 mL / min, 0.1-6 mL / min, 0.5-6 mL / min, 1-6 mL / min, 1 .5 to 6 mL / min, 2 to 6 mL / min, 3 to 6 mL / min, 3.5 to 6 mL / min, 4 to 6 mL / min, and the like are exemplified. Carrier liquid flow rate The carrier liquid flow rate included in the range of 1500 to 30000 mL / min is 17000 to 30000 mL / min, 19000 to 30000 mL / min, 2000 to 30000 mL / min, 1500 to 28000 mL / min, 17000 to 28000 mL / min. 1,900-28000 mL / min, 20000-28000 mL / min, 1500-25000 mL / min, 17000-25000 mL / min, 19000-25000 mL / min, 20000-25000 mL / min, 1500-23000 mL / min, 17000-23000 mL / min, 19000 Examples thereof include ~ 23000 mL / min, 20000-23000 mL / min, 1500-21000 mL / min, 17000-21000 mL / min, 19000-21000 mL / min, 20000-21000 mL / min, and the like. The flow rate of the content liquid and the coating liquid is the flow rate discharged from each nozzle per unit time, and the flow rate of the carrier liquid is the flow rate of the carrier liquid flowing into the forming tube per unit time. In the book, these flow rates are also called discharge rates.

The flow rate of the carrier liquid flowing into the forming tube is preferably larger than the flow rate of the content liquid discharged from the inner nozzle and the flow rate of the coating liquid discharged from the outer nozzle, and the flow rate of the liquid and the carrier liquid discharged from both nozzles. The ratio of the flow rate (discharge rate) is preferably 0.8 to 8 as the ratio of the flow rate of the coating liquid to the flow rate of the content liquid. The ratio of the flow rate of the coating liquid to the flow rate of the content liquid included in this range is 0.8 to 6, 0.8 to 5, 0.8 to 4, 0.8 to 3, 1 to 8, 1 to 6. , 1-5, 1-4, 1-3, 1.5-8, 1.5-6, 1.5-5, 1.5-4, 1.5-3, 2-8, 2-6 , 2-5, 2-4, 2-3 and the like. The ratio of the flow rate of the carrier liquid to the flow rate of the coating liquid is preferably 2000 to 7000. The ratio of the flow rate of the carrier liquid to the flow rate of the coating liquid included in this range is 2000 to 6000, 2000 to 5500, 2000 to 5000, 2000 to 4000, 3000 to 7000, 3000 to 6000, 3000 to 5500, 3000 to 5000. , 3000-4000 and the like are exemplified. The area of the discharge port opening of the inner nozzle in the present manufacturing method is preferably ^{0.03 to 3 mm 2} , more preferably 0.05 to 2 mm 2. Area of the opening of the discharge port of the outer nozzle is preferably 0.03~8mm ^2, 0.05~7mm ² is more preferable. The area of the opening at the upper end of the forming tube is preferably ^{70 to 750 mm 2.} Further, the area of the opening of the discharge port of the outer nozzle is preferably 1 to 3 times the area of the opening of the discharge port of the inner nozzle. In this manufacturing method, when each liquid is discharged from the nozzle, minute droplets in which the content liquid is covered with the coating liquid are formed by the action of the carrier liquid. In this manufacturing method, the flow rate of the content liquid discharged from the inner nozzle is 0.1 to 5 mL / min, the flow rate of the coating liquid discharged from the outer nozzle is 0.1 to 10 mL / min, and the flow rate of the forming tube is 0.1 to 10 mL / min. When the flow rate of the carrier liquid flowing into the forming tube from the upper end is 1500 to 30000 mL / min, the average particle diameter is 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, Alternatively, it is suitably used for producing soft capsules having a size of 100 μm or less. Further, the average particle size is 400 to 900 μm, 400 to 800 μm, 400 to 700 μm, 400 to 600 μm, 450 to 900 μm, 450 to 800 μm, 450 to 700 μm, 450 to 600 μm, 500 to 900 μm, 500 to 800 μm, 500 to 700 μm, It is suitably used for producing soft capsules of 500 to 600 μm, 550 to 900 μm, 550 to 800 μm, 550 to 700 μm or 600 to 700 μm.

In this production method, after forming droplets, a soft capsule is produced by curing the coating liquid of the formed droplets. The coating liquid may be cured by dropping the droplets into a curing liquid in which the coating liquid gels. Further, in this production method, the carrier liquid and the curing liquid remaining attached to the film can be removed by washing as necessary, and the microcapsules are assembled as a dry powder by drying the liquid. The body is obtained. In this production method, the particle size can be controlled by appropriately adjusting the flow rate, flow velocity, viscosity, etc. of the content liquid, the coating liquid, and the carrier liquid, and microcapsules of less than 1 mm can be manufactured. Further, according to this production method, it is possible to produce a microcapsule aggregate having an average particle size of 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less. it can. Further, the average particle size is 400 to 900 μm, 400 to 800 μm, 400 to 700 μm, 400 to 600 μm, 450 to 900 μm, 450 to 800 μm, 450 to 700 μm, 450 to 600 μm, 500 to 900 μm, 500 to 800 μm, 500 to 700 μm, Microcapsule aggregates having a particle size of 500 to 600 μm, 550 to 900 μm, 550 to 800 μm, 550 to 700 μm or 600 to 700 μm can be produced. Particles having a particle size on the order of microns are usually treated as aggregates, so-called powders, rather than being treated individually, and in this case, the particle size is generally expressed by the average particle size. The soft capsule aggregate in the present invention means a collection of a plurality of soft capsules, and does not mean an integrated one or an arrangement according to a specific rule. Further, it does not mean only the state in which the soft capsules constituting the aggregate are in contact with each other, and even when the soft capsules constituting the aggregate are dispersed in other materials, the aggregate of the dispersed soft capsules is called an aggregate. .. Here, the average particle size can be obtained by performing an analysis with a sample number (N number) of 100 or more using a particle image analyzer (device name: Moforogi G3, Malvern). Further, in this production method, another liquid between the content liquid and the coating liquid, for example, a liquid containing a capsule filling component having a component different from that of the innermost content liquid, protection for protecting the coating component from the content liquid. A liquid or the like containing a component may be discharged. According to this production method, a soft capsule aggregate having an average particle size of 900 μm or less can be produced, and a soft capsule aggregate having a sharp particle size distribution and a uniform particle size can be produced. In addition, the particle size and surface shape of the manufactured soft capsule aggregate can be adjusted. According to the production method of the present invention, soft capsules having a spherical shape and a smooth surface can be produced. In addition, soft capsules having irregularities on the surface can be manufactured. Since the soft capsule aggregate of the present invention is an aggregate of soft capsules having an average particle size of 900 μm or less, it has excellent mixing uniformity when blended into powders, granules and high-viscosity substances, and is also suitable for foods and pharmaceuticals. Excellent texture and ingestion when used. In particular, when blended in a granulated product, the uniformity can be further improved by aligning the particle size of the granulated product with the particle size of the soft capsule aggregate. Further, when the soft capsule having an uneven surface is used for locking, it is difficult to come off from the locked product, and the shape stability of the locked product can be improved.

The soft capsule aggregate of the present invention can be used for various purposes such as pharmaceuticals, foods, cosmetics, pesticides, etc., and the composition of the content liquid in the present invention is appropriately determined according to the use. Hereinafter, the capsule contents contained in the content liquid of the present invention and filled in the capsule will be illustrated, but the present invention is not limited to these, and a solvent may be contained as necessary. The content liquid may be in the form of a solution or a suspension.

As fats and oils, avocado oil, almond oil, flaxseed oil, sardine oil, egoma oil, olive oil, olive squalane, orange oil, orange raffer oil, sesame oil, garlic oil, cacao fat, pumpkin seed oil, chamomile oil, carrot oil, cucumber Oil, beef fat fatty acid, kukui nut oil, cranberry seed oil, brown rice germ oil, rice oil, wheat germ oil, saflower oil, shea butter, liquid shea butter, perilla oil, soybean oil, evening primrose oil, camellia oil, corn oil, rapeseed Oil, sawtooth oil, honeybee oil, persic oil, parsley seed oil, sunflower oil, sunflower oil, grape seed oil, borage oil, macadamia nut oil, meadow home oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, Fish oil, palm oil, palm kernel oil, mokuro, palm oil, long-chain, medium-chain, short-chain fatty acid triglycerides, diacylglyceride, beef fat, pork fat, squalane, squalane, pristan, and hydrogenated additives for these fats and oils, etc. Can be contained.

As waxes and waxes, shelac wax, honey wax, carnauba wax, whale wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, cyclic lanolin, lanolin wax, candelilla wax, mokuro, montan wax, cellac wax, rice wax and the like can be contained. Is. As the hydrogenated oil, it can contain a hydrogenated vegetable oil, a hydrogenated beef tallow oil, a hydrogenated lard oil, and the like obtained by hydrogenating vegetable oils and fats.

Examples of lecithins include egg yolk lecithin, soybean lecithin, enzymatically decomposed lecithin (lysolecithin), phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin, disetylphosphate, stearylamine, phosphatidylglycerol, phosphatidylate, phosphatidylinositolamine, and cardiolipin. It can contain ceramide phosphoryl ethanolamine, ceramide phosphoryl glycerol and the like. Enzymatically decomposed lecithin, for example egg yolk lecithin, it is obtained by the action of soy lecithin phospholipase A _2.

As the mineral oil, liquid paraffin, petrolatum, paraffin, ozokelide, selecin, microcrystalline wax and the like can be contained.

As fatty acids, lauric acid, myristic acid, palmitic acid, stearic acid, bechenic acid, oleic acid, linoleic acid, conjugated linoleic acid, linolenic acid, docosahexaenoic acid, eikosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, tall oil , Natural fatty acids such as lanolin fatty acids, synthetic fatty acids such as isononanoic acid, caproic acid, 2-ethylbutanoic acid, isopentanoic acid, 2-methylpentanoic acid, 2-ethylhexanoic acid, isopentanoic acid, and fats and oils containing these fatty acids as fatty acid composition. Etc. can be contained.

As vitamins, vitamin A group: retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: fursultiamine, thiamine hydrochloride, thiamine sulfate (vitamin B1) ), Riboflavin (vitamin B2), pyridoxin (vitamin B6), cyanocobalamine, methylcobalamine (vitamin B12), folic acids, nicotinic acids, pantothenic acids, biotins, choline, inositols, vitamin C group: ascorbic acid or its derivatives, Vitamin D group: Ergocalciferol (Vitamin D2), Cholecalciferol (Vitamin D3), Dihydrotaxterol, Vitamin E group: Vitamin E or its derivatives, ubiquinones, Vitamin K group: Phytonadion (Vitamin K1), Menaquinone (Vitamin) K2), menatetrenone, menadion (vitamin K3), menadiol (vitamin K4), other essential fatty acids (vitamin F), carnitine, ferulic acid, γ-orizanol, ollotic acid, vitamin Ps (rutin, eriocitrin, hesperidin), It can contain vitamin U and the like. In addition, lutein can also be contained.

As the stimulant, it can contain peppermint tincture, peppermint oil, nonyl acid vanilamide, cantalis tincture, ginger tincture, ginger oil, peppermint oil, l-menthol, camphor, benzyl nicotinate and the like.

Benzophenone derivatives (2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, 2-hydroxy-4-methoxybenzophenone-5-sulfonate sodium, dihydroxydimethoxy) can be used as UV absorbers and blocking agents. Benzophenone, dihydroxydimethoxybenzophenone-sodium sulfonate, 2,4-dihydroxybenzophenone, tetrahydroxybenzophenone, etc.), paraaminobenzoic acid derivatives (paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, para Octyl dimethylaminobenzoate, etc.), methoxycinnamic acid derivatives (ethyl paramethoxycinnamic acid, isopropyl paramethoxycinnamic acid, octyl paramethoxycinnamic acid, 2-ethoxyethyl paramethoxycinnamic acid, sodium paramethoxycinnamate, potassium paramethoxycinnamic acid, diparamethoxy cinnamic acid mono -2-ethylhexarate glyceryl, etc.), salicylic acid derivatives (octyl salicylate, phenylsalicylate, homomentyl salicylate, dipropylene glycol salicylate, ethylene glycol salicylate, myristyl salicylate, methyl salicylate, etc.), anthranilic acid derivatives (methylanthranylate, etc.), urocanine Acid derivatives (urocannic acid, ethyl urocanate, etc.), coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furan derivatives, pyron derivatives, nucleic acid derivatives, allantin derivatives, Nicotinic acid derivative, Vitamin B6 derivative, Umberiferon, Esculin, benzyl cinnamic acid, Synoxate, Oxybenzophenone, Dioxybenzophenone, Octabenzophenone, Slysobenzophenone, Benzoresolsinol, Arbutin, Guiaazulene, Sikonin, Baikarin, Baikarain, Belverin, Neoheliopan, Escalol, It can contain zinc oxide, talc, kaolin and the like.

As whitening agents, paraaminobenzoic acid derivatives, sartylic acid derivatives, anthranyl acid derivatives, coumarin derivatives, amino acid compounds, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, camphor derivatives, furan derivatives, pyron derivatives, nucleic acids Derivatives, allantin derivatives, nicotinic acid derivatives, vitamin C or its derivatives (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), vitamin E or its derivatives, kodiic acid or its derivatives, oxybenzone, benzophenone, albutin, guaiazulene, ciconin , Baikarin, baikarain, velverin, placenta extract, ellagic acid, lucinol and the like can be contained.

As a tyrosinase activity inhibitor, vitamin C or a derivative thereof (vitamin C phosphate magnesium salt, vitamin C glucoside, etc.), hydroquinone or a derivative thereof (hydroquinone benzyl ether, etc.), yarrow acid or a derivative thereof, vitamin E or a derivative thereof, N. -Acetyltyrosine or its derivatives, glutathione, hydrogen peroxide, zinc peroxide, placenta extract, ellagic acid, arbutine, lucinol, silk extract, plant extracts (chamomile, mulberry, sardine, touki, waremokou, clara, yomogi, watermelon, Kihada, Dokudami, Matsuhodo, Hatomugi, Odorikosou, Hop, Sanzashi, Eucalyptus, Yarrow, Artea, Keihi, Mankeishi, Hamamelis, Karagwa or Yamagwa, Life-extending grass, Kikyo, Toshishi, Sequel, Dried, Mao, Senkyu, Dokkatsu Psycho, bow hu, hama bou hu, ginger, peony bark, shakuyaku, genno shoko, kudzu root, licorice, quintuplet, aloe, ginger, red flower, green tea, tea, assen medicine, blueberry, turlenge) and the like can be contained.

As the melanin pigment reduction or decomposition substance, phenylmercury hexachlorophene, mercury oxide, mercury chloride, hydrogen peroxide solution, zinc peroxide, hydroquinone or a derivative thereof can be contained.

Hydroquinone, lactic acid bacteria extract, placenta extract, Reishi extract, vitamin A, vitamin E, allantoin, spleen extract, thoracic gland extract, yeast extract, fermented milk extract, plant extract (Aloe, Ogon) as turnover promoting action and cell activator , Sugina, Gentiana, Gobo, Shikon, Carrot, Hamamelis, Hop, Yokuinin, Odori Kosou, Senburi, Touki, Tokinsenka, Amacha, Otogirisou, Cucumber, Tachijakousou, Mannenrou, Parsley) and the like.

Astringents can contain succinic acid, allantin, zinc chloride, zinc sulfate, zinc oxide, calamine, zinc paraphenol sulfonate, potassium aluminum sulfate, resorcin, ferric chloride, tannic acid (including catechin compounds), etc. is there.

As an active oxygen scavenger, SOD, catalase, glutathione peroxidase and the like can be contained.

As antioxidants, vitamin C or a salt thereof, stearic acid ester, vitamin E or a derivative thereof, nordihydroguaseletic acid, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), hydroxytyrosole, parahydroxyanisole, It can contain propyl gallate, sesamol, sesamolin, gosipole, propolis and the like.

As a lipid peroxide production inhibitor, β-carotene, plant extracts (cultured sesame cells, amacha, sesame seeds, hamamelis, cloves, melissa, emmeiso, white hippo, salvia, mannenrou, nantenmi, agetsu, ginkgo, green tea), etc. can be contained. Is.

Anti-inflammatory agents include ictamol, indomethacin, kaolin, salicylic acid, sodium salicylate, methyl salicylate, acetylsalicylic acid, diphenhydramine hydrochloride, d-camfur, dl-camfur, hydrocortisone, guaiazulene, camazulene, chlorpheniramine maleate, glycyrrhizinic acid or salts thereof. , Glycyrrhizic acid or a salt thereof, licorice extract, indomethacin extract, agetsu extract, propolis and the like can be contained.

As antibacterial / bactericidal / disinfectants, acrinol, sulfur, calcium gluconate, chlorhexidine gluconate, sulfamine, mercurocrom, lactoferrin or its hydrolyzate, alkyldiaminoethylglycine chloride solution, triclosan, sodium hypochlorite, chloramine T, salashi Powder, iodine compound, iodoform, sorbic acid or salt thereof, propionic acid or salt thereof, salicylic acid, dehydroacetic acid, parahydroxybenzoic acid esters, undecylenic acid, thiamine lauryl sulfate, thiamine lauryl sulfate, phenol, cresol, p- Chlorophenol, p-chloro-m-xylenol, p-chloro-m-cresol, timol, phenethyl alcohol, o-phenylphenol, Irgasan CH3565, halocarban, hexachlorophene, chlorohexidine, ethanol, methanol, isopropyl alcohol, benzyl alcohol, Ethylene glycol, propylene glycol, 2-phenoxyethanol, 1,2-pentanediol, zincpyridion, chlorobutanol, isopropylmethylphenol, nonionic surfactants (polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene) Octylphenyl ether, etc.), amphoteric surfactant, anionic surfactant (sodium lauryl sulfate, potassium lauroyl sarcosin, etc.), cationic surfactant (cetyltrimethylammonium bromide, benzalkonium chloride, benzethonium chloride, methylrosanilin chloride), formaldehyde , Hexamine, Brilliant Green, Malachite Green, Crystal Violet, German, Photosensitizer 101, Photosensitizer 201, Photosensitizer 401, N-long-chain acyl basic amino acid derivative and its acid addition salt, Zinc oxide, Hinokithiol, Kudin , Propolis and the like can be contained.

As a moisturizing agent, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin tricaprylcaprate, glycolic acid (α-hydroxylic acid), hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, water-soluble chitin or Derivatives or chitosan derivatives, pyrrolidone carboxylic acid or salts thereof, sodium lactate, urea, sorbitol, amino acids or derivatives thereof (valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, aspartic acid, glutamine, serine , Cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine, arginine, ornithine, histidine and their sulfates, phosphates, nitrates, citrates, or pyrrolidone carboxylic acids) It is possible.

As various organic acids, glycolic acid, citric acid, malic acid, tartaric acid, lactic acid, ferulic acid, phytic acid and the like can be contained.

As a hair preparation, selenium disulfide, alkylisoquinolinium bromide solution, zinc pyrithione, biphenamine, thiantol, castari tincture, ginger tincture, sugarcane tincture, quinine hydrochloride, strong ammonia water, potassium bromate, sodium bromate, thioglycol It can contain acids and the like.

Natural animal fragrances such as jaco, civet, castorium, and amberglis, anis essential oil, angelica essential oil, ylang ylang essential oil, iris essential oil, uikyo essential oil, orange essential oil, cananga essential oil, caraway essential oil, cardamon essential oil, guayakwood essential oil, cumin Essential oil, black letter essential oil, cay skin essential oil, cinnamon essential oil, geranium essential oil, copaiba balsam essential oil, Korean del essential oil, perilla essential oil, cedarwood essential oil, citronella essential oil, jasmine essential oil, gingergrass essential oil, cedar essential oil, spare mint essential oil, western hacker essential oil, large Aroma essential oil, tuberose essential oil, choji essential oil, orange flower essential oil, winter green essential oil, true balsam essential oil, butchery essential oil, rose essential oil, palmarosa essential oil, hiba essential oil, hiba essential oil, ebony essential oil, petitgrain essential oil, bay essential oil, bechiba essential oil, bergamot essential oil , Peruvian balsam essential oil, boad rose essential oil, sardine essential oil, mandarin essential oil, eucalyptus essential oil, lime essential oil, lavender essential oil, linaroe essential oil, lemongrass essential oil, lemon essential oil, rosemary (mannen wax) essential oil, Japanese hacker essential oil and other vegetable fragrances , Other synthetic fragrances such as coffee flavor and yogurt flavor can be contained.

Furthermore, it can contain nutritional supplements and health food ingredients. Specifically, fish oil, garlic, vitamin B1, so-called egg oil (a traditional health food material, a brown to black liquid obtained by heating egg yolks over low heat for a long time using an iron pan while stirring) And so on.

The film solution in the present invention can contain a film component usually used as a film for soft capsules, and may contain a solvent such as water if necessary. In the present invention, the film component is not particularly limited and may be a hydrophobic film component or a hydrophilic film component, but a hydrophilic film component is preferable. As the hydrophilic film component, modified gelatin such as gelatin and succinate gelatin, carrageenan, agar, sodium alginate, purulan, glucomannan, arabic rubber, farceleran, euchemia algae, gellan gum, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, One or a combination of two or more hydrophilic polymers such as polyvinyl alcohol and starch can be mentioned, and gelatin or modified gelatin can be preferably mentioned. In addition, the film components include plasticizers such as glycerin, sorbitol, propylene glycol and polyethylene glycol, light-shielding agents such as titanium dioxide, pH adjusters such as sodium phosphate, chelating agents such as trisodium citrate and sodium metaphosphate, and lactic acid. Gelation accelerators such as calcium and potassium chloride, surfactants such as polyglycerin fatty acid ester and lecithin, taste agents, fragrances, preservatives, colorants, solubilizers and the like may be added. In addition, various starches (including modified starch, modified starch, starch, and starch decomposition products) and various polysaccharides can be contained as a film-forming additive.

The gelatin used in the film solution in the present invention is produced by heating and extracting crude collagen obtained by treating, for example, the skin, bones, tendons of cows, pigs, chickens, fish, etc. with acid or alkali. Can be mentioned. Further, modified gelatin such as a hydrolyzate of gelatin, an enzymatic decomposition product, amberized gelatin, and phthalated gelatin can also be used. Any type of gelatin can be preferably used. The jelly strength of gelatin is preferably 100 to 300 g, more preferably 130 to 250 g. The jelly strength can be measured according to JISK-6503 (2001). When gelatin and water are used as the coating liquid, the content of gelatin is preferably 1.0 to 10.0% by mass, more preferably 2.0 to 8.0% by mass with respect to water.

In the aggregate of soft capsules of the present invention, in addition to gelatin, other gelling agents such as carrageenans, agar, and gellan gum may be used as the film component contained in the film solution. By adding carrageenans, the surface of the resulting microcapsules can be made smoother and the particle hardness can be increased. The carrageenans used in the coating liquid in the present invention are a kind of galactan having a sulfate group, and are known to be present in red algae. Carrageenans can be classified into three types, Iota carrageenan (ι carrageenan), Kappa carrageenan (κ carrageenan), and Lambda carrageenan (λ carrageenan), depending on their gelling properties and structure. The Japanese food additive regulations stipulate three types: "refined carrageenan," "processed yukema algae," and "yukema algae powder." (See List Commentary "(1999)), but these differ only in the degree of purification, and are essentially all included in the carrageenans used in the coating solution of the present invention. In the present invention, ι carrageenan and κ carrageenan are preferable from the viewpoint of gelling ability. The carrageenans may be pure products or may contain standardized substances. Here, examples of the standardized substance include one or more selected from the group consisting of sugars such as sucrose, glucose, maltose, and lactose, and dextrin. Sucrose and dextrin are preferable. As the dextrin, acid-decomposed dextrin and enzymatically decomposed dextrin are preferable. In addition, a blended raw material in which ι carrageenan and κ carrageenan are mixed in advance is also available. The content of carrageenan used together with gelatin in the coating liquid is preferably 0.1 to 1.0% by mass, more preferably 0.1 to 0.8% by mass with respect to water. Further, in the aggregate of the soft capsules of the present invention, a gelling agent such as carrageenan, agar, or gellan gum can be used instead of gelatin as the film component contained in the film solution, such as dextrin and starch decomposition products. A substance that does not inhibit gelation can also be used in combination as a thickener or filler. By using these gelling agents, problems such as adhesion can be improved.

The carrier liquid in the present invention is not particularly limited as long as it is immiscible with the coating liquid. For example, when the coating liquid contains a hydrophilic film component, various fats and oils, fatty acids, fatty acid esters of sugars, and aliphatic hydrocarbons are used. Hydrophobic liquids such as hydrogen, aromatic hydrocarbons, chain ethers, higher fatty acid esters, higher alcohols, and terpenes can be mentioned. Specifically, saflower oil, flaxseed oil, sesame oil, olive oil, mustard oil, sesame oil, corn oil, soybean oil, evening primrose oil, terpene oil, rapeseed oil, palm oil, palm kernel oil, jojoba oil, cottonseed oil, Various animal and vegetable oils such as palm oil, peanut oil, EPA, DHA, shark liver oil, cod liver oil, medium chain fatty acid triglyceride (MCT), diacylglycerol, etc. Mineral oils such as crystallin wax can be mentioned, and MCT can be preferably mentioned. When gelatin and water are used as the coating liquid, the coating liquid is usually prepared by setting the liquid temperature to 70 to 90 ° C., but the carrier liquid preferably has a liquid temperature of 0 ° C. to 25 ° C. (room temperature). The temperature of the content liquid is preferably about the same as that of the coating liquid. Further, when the formed droplets are dropped into the curing liquid and cooled to gel and solidify, the curing liquid is not particularly limited as long as it is immiscible with the coating liquid, and the above carrier liquid is exemplified. You can use things. If the same components are used for the carrier liquid and the curing liquid, cleaning becomes easy.

Since the soft capsule of the present invention having an average particle size of 900 μm or less has a very small particle size, it is possible to obtain a texture or a feeling of ingestion that is not uncomfortable even when added to foods or oral medicines. Therefore, it is possible to prevent volatilization and deterioration of the contents in the capsule until the time of eating or taking, and it is possible to obtain a food having no discomfort in the formulation at the time of eating or taking. The average particle size included in the range of 900 μm or less in the present invention is 900 μm or less, 800 μm or less, 700 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, 100 μm or less, 100 to 900 μm. , 100-800 μm, 100-700 μm, 100-600 μm, 100-500 μm, 100-400 μm, 100-300 μm, 100-200 μm, 400-900 μm, 400-800 μm, 400-700 μm, 400-600 μm, 450-900 μm, 450 Examples thereof include ~ 800 μm, 450 to 700 μm, 450 to 600 μm, 500 to 900 μm, 500 to 800 μm, 500 to 700 μm, 500 to 600 μm, 550 to 900 μm, 550 to 800 μm, 550 to 700 μm, 600 to 700 μm and the like. Since the soft capsule of the present invention has a small particle size, it can be uniformly mixed with powders, granulated products and high-viscosity products. Further, according to the present production method, since the particle size of the soft capsule aggregate can be adjusted, the soft capsule having the above average particle size can be produced, and the soft capsule of the present invention has the type of base material, powder, and particle size of the granulated product. It can be blended with various base materials without choosing. In particular, when gelatin is used as a film, it becomes a soft capsule having sufficient strength as a film and having appropriate solubility when eating or taking. Further, according to this manufacturing method, the shape of the coating surface of the soft capsules constituting the soft capsule aggregate can be adjusted, the soft capsule having a smooth coating surface can be manufactured, and the soft capsule having an uneven coating surface can be manufactured. it can. When carrageenans are added to the film in addition to gelatin, the surface of the soft capsule can be smoothed. However, according to this production method, a soft capsule having a smooth surface can be obtained without adding carrageenans. The soft capsule of the present invention is excellent in film uniformity and fluidity during use. Since the soft capsule of the present invention has excellent mixing uniformity with various base materials, it may be monodispersed in a base material used in pharmaceuticals, foods, cosmetics, pesticides, etc., or in a processed product obtained by further processing the mixed base material. It can exist in a state close to that. For example, when mixed with powder or granulated product, it can exist as a simple substance or a state close to a simple substance in the powder or granulated product. Further, in foods, by mixing the soft capsule of the present invention with a high-viscosity substance such as a raw material for gum or dough for noodles, the soft capsule of the present invention is dispersed in the high-viscosity substance in a simple substance state or a state close to a simple substance. It exists in a similar state in the solidified product. Further, the soft capsule of the present invention in which irregularities are formed on the film surface of the soft capsule does not easily come off from the locked product due to the anchor effect of the uneven portions when the lock is applied. As a method of forming irregularities on the surface of the soft capsule film, a method of arranging capsules having a soft capsule film before drying on a mesh such as a wire mesh or a cloth mesh (in this case, in a drying device with a mesh). It may be dried), a method of arranging it in a powder of cellulose, starch or the like and removing the powder after drying, a method of immersing it in ethanol, a method of mixing cellulose, starch or the like in a film, and the like. ..

The composition for oral administration of the present invention is characterized by containing the soft capsule assembly of the present invention. When used in pharmaceuticals or foods as a composition for oral administration, the soft capsule assembly of the present invention may be used alone or in combination with other ingredients in tablets, powders, granules, powders, granules, dry syrups, etc. It can be used in any solid, semi-solid, liquid, etc. form such as suspending agent, liquid agent, etc. When used as food, frozen food, ice cream, retort food, delicatessen, lunch, seasoning, spice , Beverages and the like can be used in any solid, semi-solid, liquid or other form. These compositions can also be said to be compositions for oral ingestion. In addition, the soft capsule assembly of the present invention can also be used for compositions for parenteral administration such as compositions for external use such as ointments, creams, and poultices, and compositions for other purposes. The tablet of the present invention is characterized by containing the soft capsule assembly of the present invention. The tablet in the present invention is obtained by molding the soft capsule aggregate of the present invention or a mixture of the soft capsule aggregate of the present invention and other components into a solid dosage form, and is a compression molding method such as tableting. It can be molded by such means. The tablet of the present invention is not particularly limited in shape, size, etc., and can be appropriately determined according to the purpose of use. Examples of the shape include a round shape, an elliptical shape, a triangular shape, and a square shape. Further, the tablets of the present invention include not only pharmaceutical tablets but also foods in the form of tablets. The drug is not particularly limited in terms of its use, efficacy, shape, etc., and examples thereof include internal tablets, oral tablets, external tablets, etc., and may be uncoated tablets or coated tablets. In addition, sugar-coated tablets, film-coated tablets, enteric-coated tablets, chewable tablets, long-acting tablets (sustained-release, long-acting), wax matrix, gradumet, repetab, spantab, rontab, spacetab, resinate, buccal tablets, sublingual tablets, Examples include troche tablets and adhesive tablets. The tablets of the present invention may contain any other pharmaceutical or edible component, if necessary, as a component other than the soft capsule assembly. Other ingredients include, for example, excipients, binders, disintegrants, moisturizers, adsorbents, lubricants, surfactants, absorption promoters, colorants, fillers, preservatives, stabilizers, emulsifiers. , Solubilizers, flavors, sweeteners, any useful ingredients and the like. Known components can be appropriately used as these components, and examples of the excipients include lactose hydrate, anhydrous lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltol, and maltose. , Sucrose, sucrose, glucose, starch (corn starch, potato starch, rice starch, wheat starch, etc.), hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, carboxymethyl starch sodium, dextrin, powdered reduced malt sugar water candy, etc. Examples of the binder include hydroxypropyl cellulose, hypromellose, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, sodium carmellose and the like, and examples of the binder include disintegrant. Examples include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, canten powder and the like. Examples of the moisturizing agent include water. Ethylene glycol-containing sheets and the like can be mentioned, examples of the adsorbent include silicic anhydride, starch and the like, and examples of the lubricant include light anhydrous silicic acid, magnesium stearate and calcium stearate. , Sodium stearyl fumarate, talc, hardened oil and the like. Examples of the surfactant include polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polysorbate, glycerin monostearate and lauryl sulfate. Examples of the absorption accelerator include sodium and the like, and examples thereof include a quaternary ammonium base and sodium lauryl sulfate. Examples of the colorant include iron yellow oxide, yellow iron sesquioxide and sesquioxide. Examples include iron, β-carotene, titanium oxide, edible pigments (eg, edible blue No. 1), copper chlorophyll, riboflavin, etc. Examples of fragrances include orange, vanilla, strawberry, yogurt, menthol, starch oil, etc. Examples thereof include kehi oil, touhi oil, starch oil, green tea, etc. Examples of sweeteners include aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, martitol, sclarose, and fructose. , Xylitol, starch syrup, amacha powder, etc. In addition, as pharmaceutical components, for example, antipyretic analgesic and anti-inflammatory drug, nourishing tonic health drug, psychotropic drug, antidepressant drug, anxiolytic drug, hypnotic sedative, antispasmodic drug, central nervous system agent, cerebral metabolism improving agent, cerebral circulation Improving agents, antiepileptic agents, sympathomimetics, gastrointestinal agents, antacids, anti-ulcer agents, antitussive sputum, antiemetics, respiratory promoters, vasodilators, allergic agents, antihistamines, dental and oral agents, cardiotonic agents , Arrhythmia, diuretics, hypotension, vasodilators, coronary vasodilators, peripheral vasodilators, blood coagulation inhibitors, hyperlipidemia agents, antacids, antibiotics, chemotherapeutic agents, diabetes Drugs, osteoporosis drugs, anti-rheumatic drugs, skeletal muscle relaxants, sedatives, hormones, alkaloid drugs, sulfa drugs, gout remedies, antineoplastic agents, etc. It may be contained, or may be contained in a portion other than the soft capsule in the tablet. The content of the soft capsule aggregate of the present invention in the composition for oral administration of the present invention is not particularly limited, but is preferably 0.1 to 50% by mass, more preferably 1 to 30% by mass, and further 1 to 10% by mass. preferable. The content of the soft capsule aggregate of the present invention in the tablet of the present invention is not particularly limited, but from the viewpoint of tablet moldability, 0.1 to 50% by mass is preferable, and 1 to 30% by mass is more preferable. 10% by mass is more preferable. Examples of combinations of capsule contents and tablets include: (1) Multivalent unsaturated substances such as ω3 fatty acids (EPA and DHA, which are abundant in blue fish, and α-linolenic acid, which is abundant in flaxseed oil, etc.) as capsule contents. (A type of fatty acid) and statin drugs (Mevastatin, Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Cerivastatin, Atorvastatin, pitavastatin) as tablet ingredients. (Pitavastatin), Rosuvastatin (Rosuvastatin). (2) Fat-soluble vitamins such as vitamin A, vitamin D, and vitamin E can be mentioned as capsule contents, and water-soluble vitamins such as vitamin B group and vitamin C can be mentioned as tablet components, and (3). ) Antibiotics (clarithromycin, erythromycin, cephalexin, cefloxacin, offloxacin), quinine hydrochloride, ibuprofen, noscapin, carbamatepine, doxorubicin, tachlorimus, famotidine, lansoprazole, etc. have a strong bitter taste, but are administered as powders for children. It is known as a difficult-to-take drug with a strong bitter taste because it often occurs. Examples thereof include powder preparations that are easy to swallow or dry syrups in which bitterness is masked by filling microcapsules with powdered flavoring agents such as white sugar and administering them. The above-mentioned components can be appropriately contained in compositions for oral administration other than the tablets of the present invention.

The method for producing the soft capsule assembly of the present invention will be further described with reference to FIG. FIG. 1 is a diagram showing an example of a nozzle portion used in the present manufacturing method. The content liquid nozzle 1 (inner nozzle) to which the content liquid is supplied and discharged and the coating liquid nozzle 2 (outer nozzle) to which the coating liquid is supplied and discharged are provided above the forming tube 4 through which the carrier liquid flows. In FIG. 1, the upper end 3 of the forming tube is composed of the forming tube 4 and the outer tube 5, and the portion surrounded by the end of the forming tube 4 is the carrier liquid discharging portion, and the carrier liquid is discharged. The flow rate (discharge rate) is the flow rate per unit time that flows into the forming pipe 4 from the upper end 3 of the forming pipe 4. The content liquid, the coating liquid, and the carrier liquid are sent by a pump to the content liquid nozzle 1, the coating liquid nozzle 2, and the upper end 3 of the forming tube, respectively. When the content liquid and the coating liquid are discharged from the respective nozzles into the carrier liquid, droplets in which the content liquid is encapsulated in the coating liquid are formed. By dropping the droplets on the carrier liquid flowing down into the forming tube, the coating liquid of the droplets is gelled and hardened to form a soft capsule. The soft capsules in the cured solution can be collected with a sieve or the like, washed, and then dried to obtain a dried soft capsule. The drying method is not particularly limited, and a known drying method can be used. For example, natural drying, static drying, blast drying, fluidized bed drying, centrifugal rolling granulation, tumbler drying, vacuum drying, freeze drying and the like can be used. Can be mentioned. The above manufacturing method is a method for manufacturing a capsule having a two-layer structure in which the core portion containing the content liquid is directly encapsulated with a coating layer formed from the coating liquid. However, the soft capsule assembly of the present invention has a two-layer structure. It is not limited to the above, and may have a three-layer structure or a multi-layer structure having more than that, and it is sufficient that unevenness is formed in the film layer which is the outermost layer of the soft capsule. For the soft capsule having a three-layer structure, for example, a triple nozzle in which an intermediate nozzle is provided between the inner nozzle and the outer nozzle in the double nozzle of FIG. 1 is used, and the content liquid is applied from the inner nozzle and the coating liquid is applied from the outer nozzle in the middle. It can be manufactured by discharging, for example, a protective liquid from a nozzle. In this case, the discharge rate of each liquid is 0.1 to 5 mL / min for the content liquid, 0.1 to 10 mL / min for the coating liquid, and 0 for the discharge speed of the liquid discharged from the intermediate nozzle. It may be 1 to 10 mL / min and the discharge rate of the carrier liquid may be 1500 to 30000 mL / min, and a soft capsule aggregate having an average particle size similar to that of a capsule having a two-layer structure can be obtained. Since the film made of gelatin or a mixture of agar and water-soluble polymer contains water, if the core contains a substance that is contraindicated with water, the film and core must be separated. Must be. By forming the capsule into a three-layer structure and providing, for example, a protective layer containing an oily substance between the film layer and the core, a soft capsule containing a substance having a contraindication relationship with water in the core can be produced. Further, as another aspect of the present invention, the particle size is not limited, and it is an aggregate of soft capsules in which the contents are encapsulated with a film, and irregularities are formed on the surface of the film, and the average circularity is average. Soft capsule aggregates having a degree of 0.95 or less, soft capsule aggregates having a surface roughness of 20 μm or more, soft capsule aggregates having an average length of 0.04 or more, and these soft capsule aggregates. Examples thereof include tablets containing these ingredients, compositions for oral administration other than tablets containing aggregates of these soft capsules, compositions for parenteral administration such as compositions for external use, and compositions for other purposes. Compositions other than tablets include powdered, granular, powdered, granular, dry syrups, suspensions, ointments, creams, poultices, liquids, and other solid, semi-solid, and liquid pharmaceuticals. When used as a composition in the form of, and when used as a food, in the form of solid, semi-solid, liquid, etc. of instant food, retort food, delicatessen, lunch, seasoning, spice, frozen food, ice cream, beverage, etc. The composition is listed. The method and preferred range for measuring the circularity, unevenness, and length / shortness are the same as those described above, and when the circularity, unevenness, or length is within the range, the particle size is irrelevant. The effect of improving the mixing property with other solid or semi-solid materials and the effect of preventing chipping during molding can be obtained.

[Example 1]
Using a concentric double nozzle as shown in FIG. 1, the content liquid having the composition shown in Table 1 flows from the inner nozzle, and the coating liquid having the composition shown in Table 2 flows from the outer nozzle into the MCT. The undried capsules obtained were immersed in an MCT solution (about 4 ° C.) for 5 days. The capsules in the MCT solution were collected, and the collected capsules were washed with ethanol and then allowed to stand at about 20 ° C. for 15 hours to dry. The film ratio was set to 40%. The discharge rate of the content liquid was 2.02 mL / min, the discharge rate of the coating liquid was 5.26 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. The inner diameter of the opening of the discharge port of the inner nozzle was 0.5 mm, the inner diameter of the opening of the discharge port of the outer nozzle was 1 mm, and the inner diameter of the opening at the upper end of the forming tube was 22 mm. The viscosity of the content liquid having the composition shown in Table 1 was 14.0 mPa · s / 21.8 ° C., and the viscosity of the coating liquid having the composition shown in Table 2 was 36.8 mPa · s / 65.6 ° C. The viscosity was measured using a viscometer measuring device VISCOMETER TVC-1 (Toki Sangyo Co., Ltd.).

[Reference example 1]
Using the same nozzles used in Example 1, the content liquid having the composition shown in Table 3 was discharged from the inner nozzle, and the coating liquid having the composition shown in Table 4 was discharged from the outer nozzle into the inside of the forming tube. The undried powder was dropped into the flowing MCT, and the obtained undried powder was immersed in the MCT solution (about 4 ° C.) for 5 days. The capsules in the MCT solution were collected, the collected capsules were washed with ethanol, and the washed capsules were dried for 22 hours using a tumbler drying device (manufactured by Fuji Capsule Co., Ltd.) (drying temperature: about 20 ° C.). .. The film ratio was set to 40%. The discharge rate of the content liquid was 2.02 mL / min, the discharge rate of the coating liquid was 4.2 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. When the viscosity was measured in the same manner as in Example 1, the viscosity of the content liquid having the composition shown in Table 3 was 20.9 mPa · s / 21.1 ° C., and the viscosity of the coating liquid having the composition shown in Table 4 was 36.9 mPa. -S / 65 ° C.

[Example 2]
Using the same nozzles used in Example 1, the content liquid having the composition shown in Table 5 flows from the inner nozzle, and the coating liquid having the composition shown in Table 6 flows from the outer nozzle into the inside of the forming tube. It was discharged into the MCT and dropped, and the obtained undried capsules were immersed in the MCT solution (about 4 ° C.) for 5 days. The capsules in the MCT solution were collected, the collected capsules were washed with ethanol, and the washed capsules were allowed to stand and dry for 15 hours (drying temperature: about 23 ° C.). The film ratio was set to 40%. The discharge rate of the content liquid was 2.02 mL / min, the discharge rate of the coating liquid was 5.26 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. When the viscosity was measured in the same manner as in Example 1, the viscosity of the content liquid having the composition shown in Table 5 was 20.9 mPa · s / 21.1 ° C., and the viscosity of the coating liquid having the composition shown in Table 6 was 35.2 mPa. -S / 65.0 ° C.

[Examples 3 to 7, Comparative Examples 1 to 2]
Using a concentric double nozzle as shown in FIG. 1, the content liquid having the composition shown in Table 7 flows from the inner nozzle, and the coating liquid having the composition shown in Table 8 flows from the outer nozzle into the forming tube. The undried capsules were discharged and dropped, and the obtained undried capsules were immersed in an MCT solution (about 4 ° C.) for 5 days. The capsules in the MCT solution were collected, and the collected capsules were immersed in ethanol (purity: 99.5%, 1 to 2 ° C.) and then dried for 15 hours using a tumbler drying device (manufactured by Fuji Capsule Co., Ltd.). (Drying temperature about 20 ° C). In Examples 3 to 7, the immersion time in ethanol was set to 2, 3, 5, 10, and 15 minutes, respectively. The film ratio was set to 40%. The discharge rate of the content liquid was 1.80 mL / min, the discharge rate of the coating liquid was 4.91 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. The inner diameter of the opening of the discharge port of the inner nozzle was 0.2 mm, the inner diameter of the opening of the discharge port of the outer nozzle was 0.6 mm, and the inner diameter of the opening at the upper end of the forming tube was 22 mm. The viscosity of the content liquid having the composition shown in Table 7 was 21.6 mPa · s / 19.2 ° C., and the viscosity of the coating liquid having the composition shown in Table 8 was 35.7 mPa · s / 68.9 ° C. The viscosity was measured using a viscometer measuring device VISCOMETER TVC-1 (Toki Sangyo Co., Ltd.). Under the same conditions as in Examples 3 to 7, the immersion time in ethanol was 0 and 1 minute, which were designated as Comparative Examples 1 and 2, respectively.

[Examples 8 to 11]
Using the same nozzles as in Examples 3 to 7, the content liquid having the composition shown in Table 9 is flowed from the inner nozzle to the coating liquid having the composition shown in Table 10 from the outer nozzle into the MCT flowing inside the forming tube. The undried capsules were discharged and dropped, and the obtained undried capsules were immersed in MCT solution (about 4 ° C.) for 5 days. The capsules in the MCT solution were collected, and the collected capsules were immersed in ethanol (purity: 99.5%, 1 to 2 ° C.) and then dried for 15 hours using a tumbler drying device (manufactured by Fuji Capsule Co., Ltd.). (Drying temperature about 20 ° C). In Examples 8 to 11, the immersion time in ethanol was 2.5, 5, 10 and 15 minutes, respectively. The film ratio was set to 40%. The discharge rate of the content liquid was 1.80 mL / min, the discharge rate of the coating liquid was 4.91 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. The inner diameter of the opening of the discharge port of the inner nozzle was 0.4 mm, the inner diameter of the opening of the discharge port of the outer nozzle was 0.8 mm, and the inner diameter of the opening at the upper end of the forming tube was 22 mm. The viscosity of the content liquid having the composition shown in Table 9 was 20.8 mPa · s / 21.0 ° C., and the viscosity of the coating liquid having the composition shown in Table 10 was 48.9 mPa · s / 61.6 ° C. The viscosity was measured using a viscometer measuring device VISCOMETER TVC-1 (Toki Sangyo Co., Ltd.).

[Reference Example 2] (Example of carrageenan capsule)
Using the same nozzles used in Example 1, the method for preparing the coating liquid was in accordance with the description in the international publication pamphlet WO2010 / 146845, and from the outer nozzle, "88.9 parts by mass of caraginan, 11.1 parts by mass of sodium alginate". , 21.2 parts by mass of glycerin, 1.4 parts by mass of dipotassium hydrogen phosphate, 0.6 parts by mass of citric acid, and an appropriate amount of purified water. It was discharged into the MCT flowing inside the forming tube, dropped, and immersed in the MCT solution (about 4 ° C.) for 1 day. The film ratio was set to 40%. The discharge rate of the content liquid was 2.02 mL / min, the discharge rate of the coating liquid was 5.26 mL / min, and the inflow speed of the carrier liquid into the forming tube was 20000 mL / min. The undried capsules thus obtained were dried by standing drying (about 20 ° C.) for 20 hours to obtain soft capsules. When the diameter was simply measured with a caliper, the average particle size of N = 10 was 670 μm.

[Evaluation of the obtained soft capsule]
(Measurement of particle size)
The soft capsules obtained in Examples 1 to 11, Reference Example 1 and Comparative Examples 1 and 2 were analyzed using a particle image analyzer (device name: Moforogi G3, Malvern) to determine the average particle size and particle size distribution. .. The average particle size and particle size distribution are the average and distribution of the “Circle Equivalent (CE) diameter” determined by the particle image analyzer. The average particle size, the minimum particle size, and the maximum particle size are shown in Tables 11 and 12, and the particle size distribution is shown in FIGS. 2 to 4. As shown in the measurement results, a soft capsule aggregate having an average particle size of 700 μm or less can be obtained in any of the examples, and in Reference Example 1, a soft capsule aggregate having an average particle size of 600 μm or less can be obtained by adjusting the conditions. I was able to. Further, the particle size distribution of the obtained soft capsule aggregates as shown in FIGS. 2 to 4 was very sharp, and the soft capsule aggregates having a narrow particle size distribution were obtained. As can be seen from Table 12, soft capsule aggregates having a particle size in the range of 200 to 900 μm, 300 to 900 μm, or 400 to 900 μm were obtained.

(Observation of particle shape)
The soft capsules obtained in Examples, Reference Examples and Comparative Examples were observed using a high-resolution 3DX ray microscope (nano3DX-J, Rigaku Co., Ltd.). 5 and 6 show the X-ray CT images observed in Reference Example 1 and Example 2. In addition, the soft capsules obtained in the examples were observed using a photochemical microscope (VHX-D510, KEYENCE CORPORATION). 7 and 8 show the microscope images observed in Example 1 and Reference Example 1. From these observation results, it can be seen that spherical soft capsules close to true spheres were obtained. Further, according to this production method, a soft capsule having a smooth film surface was obtained, and in Reference Example 1, a soft capsule having a very smooth surface was obtained. Further, by adjusting the drying conditions, it is possible to obtain soft capsules having irregularities on the surface as in Examples 1 to 11. Table 13 shows the unevenness, the average circularity, the average length and shortness, and the ratio of the film thickness to the particle size (film thickness / diameter (%)). For the degree of unevenness, 620 cross-sectional images were taken from the top to the bottom of the soft capsule particles placed on a flat surface using a high-resolution 3DX ray microscope (nano3DX-J, Rigaku Co., Ltd.), and the 310th image from the top. Measured using a cross section. 9 to 19 show cross-sectional images obtained by measuring the degree of unevenness. 9 is Comparative Example 1, FIG. 10 is Comparative Example 2, FIG. 11 is Example 3, FIG. 12 is Example 4, FIG. 13 is Example 5, FIG. 14 is Example 6, FIG. 15 Example 7, and FIG. 8 and 17 are images of Example 9, FIG. 18 is an image of Example 10, and FIG. 19 is an image of Example 11. The average circularity and the average length and shortness are "HS Circularity" and "Elongation", which are obtained by a particle image analyzer (device name: Moforogi G3, Malvern), respectively. The film thickness / diameter (%) was obtained from the cross-sectional image used for measuring the degree of unevenness.

(Observation of mixing)
1 g of each of the soft capsule aggregates obtained in Examples and Comparative Examples was weighed, lightly mixed with 9 g of silica (amorphous silicon dioxide: Clearsorb, Fuji Silysia Chemical) in a plastic bag, and then covered with a 15 mL lid. The mixture was charged into a test tube. The test tube into which the mixture was charged was shaken with a seesaw at 60 rpm for 10 minutes using a small shaker (manufactured by In vitro Shaker TAITEC), and then the mixture was visually confirmed. A photograph of the state after mixing is shown in FIG. The microcapsules obtained in Comparative Example 1, Comparative Example 2, Example 3, Example 4, and Example 5 were used in this order from the left. Since the microcapsules are colored red, in Examples 3 to 5, the red microcapsules are well mixed with the white silica and the microcapsules are nearly uniform in the silica as compared with Comparative Examples 1 and 2. It can be seen that they are dispersed.

(Observation of tableting property)
In one tablet (200 mg), these are mixed so that the soft capsule aggregate is 10 mg, the spray-dried mannitol for direct striking (Parteck200) is 188 mg as an excipient, and magnesium stearate is 2 mg as a lubricant. The tablets were tableted with a single-shot tableting machine (N-30E) using a flat mortar of 8 mmφ at a tableting pressure of 8 kN. Images of the tablet surface thus obtained observed by a scanning electron microscope (SEM) are shown in FIGS. 21 to 23. FIG. 21 is an image of a tablet (a) using the microcapsules obtained in Example 5 and a tablet (b) using the microcapsules obtained in Comparative Example 1, and FIG. 22 is an image obtained in Example 3. It is an image of the tablet (a) using the microcapsules and the tablet (b) using the microcapsules obtained in Comparative Example 1, and FIG. 23 is a further enlarged image of FIG. 21. As can be seen from FIGS. 21 to 23, in the tablets using the microcapsule aggregate of the present invention, no omission of the microcapsules was observed on the surface, whereas the microcapsules having no unevenness formed in the present invention were used. The tablets lacked surface microcapsules. This is because, as schematically shown in FIG. 24, in the case of microcapsules of the micron order as in the present invention, the area of contact between the matrix component of the tablet such as an excipient and the microcapsules is small, so that the unevenness is formed. This is because microcapsules that are close to spheres with a smooth surface are easily removed from the tablet surface.

Furthermore, by applying the enteric-coated seamless capsule manufacturing technique described in International Publication No. 2016/056229 to the present invention, enteric-coated microseamless capsules can be obtained. Enteric-soluble microseamless capsules can be incorporated into OD tablets (orally disintegrating tablets) to create a DDS (DRUG DELIVERY SYSTEM) formulation in which the tablet components are released in the mouth and the capsule contents disintegrate in the intestine. Can also be expected to be applied.

The microcapsule aggregate of the present invention can be suitably used for foods including pharmaceuticals, general foods, functional foods, health foods, beverages, cigarettes, cosmetics, pesticides and the like. General foods include, for example, edible foods such as retort foods, frozen foods, lunch boxes, delicatessen items, instant foods, seasonings, and spices, as well as chewing gum, candies, caramel, ice candies, ice cream, jelly, chocolate, and tablets. Including confectionery such as caramel (lock confectionery), cosmetics include shaving lotions, soaps, creams and toiletries such as foams, colons, deodorants, antiperspirants, etc. Includes bath oils, shampoos, hair treatment compositions, conditioners, tanning lotions, talcum powders, face creams, hand creams, eye drops and the like. For example, in the field of pharmaceuticals, any solid, semi-solid or liquid such as tablets, powders, granules, powders, granules, dry syrups, suspensions, ointments, creams, poultices, liquids, etc. It can be used for morphological compositions and suspension injections for subcutaneous and intramuscular injections, and in the field of foods, it is used to add flavor components, umami components, etc. to foods such as gums and noodles. Can be used as a filter for tobacco flavors. In addition, if it is used as an insecticide or rodenticide, it can be fed to small creatures, and it can also be used as a herbicide or soil conditioner that dissolves in the rain. According to this production method, soft capsules having a particle size of less than 1 mm on the order of microns, particularly minute soft capsule aggregates having an average particle size of 800 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or 100 μm or less can be produced. ..

1 Nozzle for content liquid 2 Nozzle for coating liquid 3 Upper end of forming pipe 4 Forming pipe 5 Outer pipe

Claims (9)

An aggregate of soft capsules whose contents are covered with a film.
The average particle size is 900 μm or less,
Unevenness is formed on the surface of the film,
An aggregate of soft capsules having an average circularity represented by the formula (1) of 0.95 or less.
Circularity = 4πS / L ² (1)
(In the formula (1), S represents the projected area of the projected image of the soft capsule particles, and L represents the peripheral length of the projected image.) An aggregate of soft capsules whose contents are covered with a film.
The average particle size is 900 μm or less,
Unevenness is formed on the surface of the film,
The degree of unevenness indicating the degree of the unevenness is determined by observing the cross section of the soft capsule, centering on the center of gravity, the radius of the circle tangent to the convex portion located at the position farthest from the center of gravity, and the center of gravity. When defined by the difference from the radius of the circle tangent to the recess closest to the center of gravity,
A soft capsule aggregate having a degree of unevenness of 20 μm or more. The soft capsule assembly according to claim 1 or 2, wherein the average of the lengths and shortnesses represented by the formula (2) is 0.04 or more.
Long / short diameter = 1-minor / major (2) The soft capsule assembly according to any one of claims 1 to 3, wherein the ratio of the film thickness to the particle size of the soft capsule is 0.08 to 0.15. The soft capsule assembly according to any one of claims 1 to 4, wherein the average particle size is 700 μm or less. The soft capsule assembly according to any one of claims 1 to 5, wherein the average particle size is 300 μm or more. A composition for oral administration, which comprises the soft capsule assembly according to any one of claims 1 to 6. The composition for oral administration according to claim 7, wherein the composition contains 0.1 to 50% by mass of a soft capsule aggregate. The composition for oral administration according to claim 7 or 8, wherein the composition is a tablet.

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