JPWO2005097041A1 - Nucleated molded product and its manufacturing method - Google Patents

Abstract

  In a method for producing a dry-molded product using a double-punch pestle, a dry-molded product containing a large amount of microcapsule-like granules with the expected release characteristics and uniformity of content in the inner core is supplied and filled in the core portion. The object is to manufacture the process only once, the first is to make the surface of the microcapsule-like granules modified with an adhesive component, and the second is the microcapsules. A mixture of capsule-like granules and granules of the same size and higher in moldability than the microcapsule-like granules is used. Thirdly, a double punch having a central punch and a double punch having a tip diverged into two or more. The fourth is to use a double structure pestle, and the fourth is to form a cup-shaped molding by compression molding the outer layer molding material supplied and filled in the die with the upper center pestle protruding. This is a method of supplying microcapsule-like granules into this molded product. The invention also relates to the molded articles so produced.

Description

  TECHNICAL FIELD The present invention relates to a dry-molded article containing an outer layer and microcapsule-like granules inside, and a method for producing the same.

  In the field of pharmaceuticals, in order to reduce the therapeutic effect and side effects, there are cases where multiple unit type control for controlling the release of the drug from the preparation is performed by microcapsules or various coated granules. The multiple unit type formulation has less fluctuation in the absorption of the active substance in the body as compared with the single unit type formulation, and is a very useful administration method. This multiple unit type preparation is mainly taken by patients as capsules or granules, and it is desirable that the dosage form be tablets rather than capsules or granules because of ease of administration. However, in tableting of multiple unit type granules, since microcapsules and various coated granules have high moldability and high brittleness, damage to microcapsules and the like due to tableting pressure may lead to failure to obtain expected release characteristics, and Since granules and powders are mixed at the time of tableting, it is often difficult to make tablets, because the particle size segregation makes it impossible to ensure uniformity of content due to the difference in particle size between the two.

  To solve these problems, a method of blending other excipients as a buffer for microcapsules (Japanese Patent Laid-Open No. 61-212115), a protective layer by granulation or coating on the upper layer of the microcapsule controlled release film. To prevent contact between granules (Japanese Patent Laid-Open No. 2000-16932), multiple granules containing low-melting oils and fats and an elementary granule containing a main drug and an amorphous granule consisting of a controlled release film and a multiple unit type tablet consisting of a powder part (JP-A-7-316042), the granules are matrix granules of a water-insoluble polymer and an active ingredient, or a multiple unit type sustained-release tablet consisting of granules obtained by coating the matrix granules with a release-controlling membrane and a powder part. A method (Japanese Patent Laid-Open No. 2000-1429) has been proposed.

  However, since controlled-release microcapsules do not have moldability, mixing with powder is indispensable, and the amount added is large to obtain appropriate tablet moldability. Further, in the mixing process with the powder, segregation of the granule part and the powder part is likely to occur, the uniformity of the content cannot be sufficiently ensured, and it is necessary to add a large amount of the powder to the amount of the granules contained. There is a problem that the tablet becomes large and it is difficult to take a large amount of granules into the tablet while maintaining the small shape.

  On the other hand, as a method of not mixing with powder, a method (WO01/98067) has been proposed in which microcapsule-like granules are contained in the core of a dry-coated tablet, and a component having excellent moldability is sandwiched between them. .. This method has a punch in both the upper and lower directions of the die, and the upper and lower punches each have a double structure of a central punch and an outer punch surrounding the outer periphery of the central punch, and the central punch and the outer punch are An outer layer that supplies a molding material for the outer layer to a space above the lower central punch surrounded by the lower outer punch by using a compression molding means that is slidable and capable of performing compression operation, for example, a rotary compression molding machine. Feeding step 1, a core feeding step 1 surrounded by a lower outer punch and supplying microcapsule-like granules to the space on the outer layer molding material fed in the previous step, an outer layer surrounded by a lower outer punch and fed up to the previous step Outer layer supply step 2 for supplying the outer layer molding material to the space above the microcapsule-like granules and the outer layer molding material surrounded by the lower outer punch and supplied to the space above the microcapsule-like granules Nucleus supplying step 2 for supplying microcapsule-like granules, outer layer molding step for compression-molding outer layer molding material and microcapsule-like granules supplied up to the previous step, and further outer layer core molded in the previous step in the mortar A microcapsule-like granule comprising an outer layer supplying step 3 for supplying a molding material for an outer layer onto and around the molded article, and an overall molding step for compression-molding the outer core molding and the molding material for the outer layer. A method for producing a molded product having a core containing With this method, the release characteristics and the uniformity of the content can be solved, but if the core portion is supplied only once for the microcapsule-like granules, there will be a problem of moldability and a problem of transition to the next step. , It becomes impossible to contain a sufficient amount of microcapsule-like granules. Therefore, since the core portion is laminated with three layers of the microcapsule-like granules and the molding material for the outer layer, at least three supply/filling systems of the microcapsule-like granules and the molding material for the outer layer in the lamination portion of the core are required, and the device is required. It becomes a big problem that it becomes complicated and large. Furthermore, according to the method, even with a three-layer structure of microcapsule-like granules and a molding material for the outer layer, compaction of the granules in the microcapsule-like granule layer is unavoidable, so it is difficult to prevent damage to the granules. there were.

JP-A-61-221115 JP-A-7-316042 Japanese Patent Laid-Open No. 2000-1429 JP-A-2000-16932 WO01/98067

  In the tableting of microcapsule-like granules, we ensure that the expected release characteristics and the uniformity of the content are ensured and that a large amount of granules are incorporated into the tablet, so that the microcapsule is used as the core of the dry-coated tablet described above. Attention was paid to the method of encapsulating such granules. In the method for producing a microcapsule-like granule-containing cored molded product using this double-structured punch, the strength of the final molded product mainly depends on the outer layer part, so that the inner core part must have the same strength as the final molded product. Instead, it is sufficient to secure the strength that allows the process to be transferred to the next step. Therefore, it is not necessary to add more additives than necessary, which is suitable for increasing the content of microcapsule-like granules. In order to solve the problems of complication and increase in size of the apparatus for carrying out the present method, it is preferable that the supply process of the core portion is performed only once. Therefore, in the present invention, in the method for producing a dry-molded product using the double-structured punch, the dry-molded product having a large amount of microcapsule-like granules having the expected release characteristics and uniformity of content in the inner core. It is an object of the present invention to manufacture a product only once in the process of supplying and filling the core part.

  The following three methods were devised from the viewpoint of improving either or both of the strength of the core portion containing the microcapsule-like granules and the breakage of the granules. That is, it has a punch in both the upper and lower directions of the die, and the upper and lower punches have a double structure of a central punch having one or two or more branched tip ends and an outer punch surrounding the outer periphery of the central punch. An outer layer feeding step 1 in which each of the outer pestles is slidable and a compression molding means capable of performing a compression operation is used to supply a molding material for the outer layer to a space above the lower center pestle surrounded by the lower outer pestle. , A nucleus supply step of supplying the molding material for nuclei to the space above the molding material for outer layers supplied in the previous step surrounded by the lower outer punch, compressing the molding material for outer layers and the molding material for nuclei supplied up to the previous step Outer layer core molding step of molding, and further, outer layer supply step 2 of supplying an outer layer molding material to the space around and around the outer layer core molded article molded in the previous step in the die, the outer layer core molded article and outer layer molding In a method for producing a molded article having a core, which comprises an overall molding step of compression molding a material, the first is a micromolded material for a core, the surface of which is modified with an adhesive component. It is a method of preparing a mixture of capsule-like granules or microcapsule-like granules and microcapsule-like granules whose surface is modified with an adhesive component. The second is a method in which the molding material for nuclei is a mixture of microcapsule-like granules and granules of the same size and higher in moldability than the microcapsule-like granules. The third is a double-structured pestle, which is a double-layered pestle consisting of a central pestle with a tip diverging into two or more and an outer pestle surrounding the outer periphery of the central pestle. Granules, or a mixture of microcapsule-like granules and granules having the same size and moldability as those of the microcapsule-like granules. A solution from another point of view is to form a cup-shaped outer layer molded article by compression molding from the outer layer molding material supplied and filled in the die with the upper center pestle protruding, and place it in the cup. In this method, the core molding material to be supplied is microcapsule-like granules, or a mixture of microcapsule-like granules and granules having the same size and higher moldability than the microcapsule-like granules. In this way, it was possible to supply and fill a large amount of microcapsule-like granules in the inner core portion only in one supply and filling step.

  The present invention also relates to a molded product manufactured in this way. That is, the molded article of the present invention has 1) an inner core and an outer layer on the outer side thereof, and the surface is adhesive with the microcapsule-like granules or the microcapsule-like granules whose surface is modified with an adhesive component. Molded product characterized by comprising a mixture of microcapsule-like granules modified with components, 2) From a mixture of a microcapsule-like granule having an inner core of the same size and a moldability higher than that of the microcapsule-like granule 3) A molded product characterized by comprising: 3) a microcapsule-like granule obtained by modifying the surface of the above-mentioned molded product with a component having an adhesive property, or a surface having an adhesive property with the microcapsule-like granule. Molded product, which is a mixture with microcapsule-like granules modified with components, 4) Molded product has a plurality of inner cores arranged in the horizontal direction with respect to the pressing surface and an outer layer on the outer side, and the inner core is a microcapsule. Shaped granules, or a molded product characterized by comprising a mixture of granules of the same size and having a higher moldability than the microcapsule-like granules, or Is a molded product which is a microcapsule-like granule modified with a certain component, or a mixture of the microcapsule-like granule with a surface modified with an adhesive component.

  Summarizing the effects of the present invention, the present invention ensures the expected release characteristics and content uniformity in the method for producing a dry-molded article described in WO01/98067 using a double-structured punch. It is possible to manufacture a dry-molded article having a large amount of microcapsule-like granules in the inner core by only one step of supplying and filling the core. Therefore, in the rotary compression molding machine which implements this method, the mechanism can be greatly simplified.

  As an effect in each embodiment, in the embodiment using the microcapsule-like granules whose surface is modified with an adhesive component, the effect of preventing breakage of the granules in the final product is high. Further, in an embodiment in which microcapsule-like granules and granules having the same size and higher moldability as the microcapsule-like granules are used, it is not necessary to modify the granules, and therefore the microcapsules whose granule characteristics are likely to change due to the modification. It is suitable when such granules are used. Further, in the embodiment for creating a cup-shaped outer layer molded product, there is an advantage that a large amount of unmodified microcapsule-like granules can be added.

FIG. 3 is a front sectional view showing the operating mechanism of the upper and lower punches by unfolding the turntable of the rotary compression molding machine described in WO01/98067, and also in one embodiment of the rotary compression molding machine for carrying out the method of the present invention. It is a similar figure. Oblique lines as cross sections are omitted. It is an explanation drawing of a tip of a punch showing a first example of a method for producing a microcapsule-like granule-containing nuclear-molded article according to the present invention (shaded lines as cross sections are omitted). It is an explanation drawing of a tip of a punch showing a second example of the method for producing a microcapsule-like granule-containing nuclear-molded article according to the present invention (shaded lines as cross sections are omitted). It is an explanation drawing of the tip of a punch showing a third example of the method for producing a microcapsule-like granule-containing dry-molded article according to the present invention (oblique lines as cross sections are omitted). It is a tip operation|movement explanatory drawing which shows the 4th example of the manufacturing method of the microcapsule-like granule containing nuclear-molded article which concerns on this invention (the diagonal line as a cross section is abbreviate|omitted). It is a schematic plan view showing the rotary disk of the rotary compression molding machine described in WO01/98067, and also a schematic plan view showing the rotary disk of the rotary compression molding machine for carrying out the method of the present invention. Is.

Explanation of symbols

1: mortar
2A, 12A: Upper center pestle
2B, 12B: Kamigae
3A, 13A: Lower center pestle
3B, 13B: Shimogae punch
4A, 14A: Tip surface of upper center pestle
4B, 14B: The tip surface of the upper outer punch
5A, 15A: Tip surface of lower center pestle
5B, 15B: Tip surface of lower outer punch
6A, 16A, 26A, 36A: First outer layer supply space
6B, 16B, 26B, 36B: Nuclear supply space
6C, 16C, 26C, 36C: Second outer layer supply space
7A, 7B, 17A, 17B, 27A, 27B, 37A, 37B: Residual powder/removal unit
8: scraper
NP: Nuclear
OP1: First outer layer
OP2: Second outer layer
101: Molding material supply and filling section for the first outer layer
102: Nuclear molding material supply and filling section
103: Molding material supply and filling section for second outer layer

  In the present specification, microcapsules, such as microcapsules and coated granules, which are poor in moldability, have high brittleness, and further lose their properties, characteristics, or functions due to the destruction of particles, are collectively referred to as microcapsule-like granules. It is defined as. That is, microcapsule-like granules include microcapsules, seamless capsules, mini-soft capsules, microspheres in a broad sense such as microspheres, and various coated granules such as polymer-coated granules, wax-coated granules and sugar-coated granules. Furthermore, it also includes granules, such as enzyme-containing granules, which may be inactivated by high-pressure tableting and in which granular particles can be established as one functional unit. The various coated granules are granules having a coating coating on the granular particles, granules having cores in the granular particles, granules having a coating coating on the granules having cores in the granular particles, and the like, sustained release, It is a coated granule for the purpose of enteric solubility, easy solubility, heat resistance, light resistance, or stability and bitterness improvement.

  Many of the microcapsule-like granules used in this field usually have a size of 3 mm or less, preferably 2 mm or less, more preferably 1 mm or less. The lower limit is not particularly limited as long as it is a granule diameter that can be established as a functional unit, but is preferably 0.05 mm diameter or more.

  In order to explain in detail the method for producing a molded product having a core containing the microcapsule-like granules according to the present invention, a method for producing a dry-molded product which is the basis of the present invention, that is, WO01/98067 is described in advance. The outline of the method will be described. This method has a punch in both the upper and lower directions of the die, and the upper and lower punches each have a double structure of a central punch and an outer punch surrounding the outer periphery of the central punch, and the central punch and the outer punch are Both of them are slidable, and the compression molding means capable of compression operation is used to supply each of the molding material for the nucleus and the molding material for the outer layer and the compression of the molding material for the nucleus and/or the molding material for the outer layer. A method for producing a nuclear-molded article, which includes a molding step and a compression molding step for the entire molded article containing a core.

  Specifically, one is an outer layer supply step 1 in which the outer layer molding material is supplied to the space above the lower center pestle surrounded by the lower outer pestle, and the outer layer molding is surrounded by the lower outer pestle and supplied in the previous step. Nucleus supply process that supplies the molding material for nuclei to the space above the material, outer layer molding process that compresses and molds the molding material for the outer layer and the molding material for the nuclei that have been supplied up to the previous process, and molding in the previous process in the mortar Of the outer layer core molding product and the outer layer supply step 2 for supplying the molding material for the outer layer to the space around the outer layer core molding product, and the manufacturing of the core-molded product including the entire molding process for compression molding the outer layer core molding product and the outer layer molding material. Is the way.

  In addition, in these manufacturing methods, it is preferable to perform the outer layer molding step of compression-molding the outer layer molding material immediately after the outer layer supply step 1. Further, depending on the shape of the punch tip, it may be necessary or preferable to further carry out the step of removing the residual powder particles remaining on the lower outer punch and/or the molded product.

  The present invention utilizes the method for producing the above-described molded product with a core. Unless otherwise specified, the center pestle of the double-structured punch used in the method for producing a dry-molded article of the present invention is not limited to one shape in which the tip does not diverge, and the tip diverges into two or more. It also includes the case of a central punch. The term "central pestle having two or more tip ends" as used herein means a pestle shape diverging from the central pestle body portion and having two or more central mortar tips. However, although not preferred, a plurality of central punches may be provided from the body portion, and a punch having two or more central punch tip portions without branching may be used. Needless to say, as long as the outer pestle has a structure that completely surrounds one central pestle or the tip of the central pestle having two or more branches, the outer pestle may have only one structure. The above does not matter.

  First, the first molding material is a microcapsule-like granule whose surface is modified with an adhesive component or a microcapsule-like granule and a microcapsule-like granule whose surface is modified with an adhesive component. An embodiment of a mixture of granules will be described. Here, the molding material for nuclei is prepared by modifying the surface of a non-moldable microcapsule-like granule with an adhesive component, to obtain microcapsule-like granules alone or microcapsule modified with an adhesive component. The mixture with capsule-like granules ensures the strength that the core part can move to the next process and the moldability of the entire molded product. It becomes possible to enclose a large amount of microcapsule-like granules. At the same time, it is expected that direct contact between microcapsule-like granules alone due to compaction or uniform pressure transmission due to the attached component can be expected to reduce damage to granules and directly modify the surface of microcapsule-like granules. Therefore, it is not necessary to mix other granules, and it becomes possible to enclose a larger amount of microcapsule-like granules and prevent uneven content.

  The ratio between the microcapsule-like granules and the microcapsule-like granules whose surface is modified with an adhesive component (hereinafter referred to as modified microcapsule-like granules) can be set in any manner. It may be mixed so as to be about 1:100 to 1:1, but is preferably about 1:50 to 1:2, and more preferably about 1:20 to 1:5. It is preferable that the amount of the adhesive component that modifies the microcapsule-like granules is small, and it is preferable that the microcapsules are dispersed in a thin layer or in a thin layer. This is because by making the sizes of the microcapsule-like granules and the modified microcapsule-like granules as large as possible, it is possible to prevent the nonuniformity of the content due to the particle size segregation of the mixture thereof.

  Incidentally, the adhesiveness described in the present specification means the adhesiveness capable of causing intergranular bonding to the extent that there is no hindrance to the transition between the steps in the manufacturing process in the dry-molded article and the manufacturing method thereof described in WO01/98067. Means In addition, it is preferable that the final molded product after compression promotes the bonding between the granules and improves the moldability of the molded product itself. The term "adhesive component" as used in the present specification is an expression that also includes a component having a buffer function with respect to compression pressure. It should be noted that the component exhibiting adhesiveness is a generic term, and the component exhibiting adhesiveness may be a single component or a combination of a plurality of components.

  The method of modifying the surface of the non-moldable microcapsule-like granules with the adhesive component is, for example, by adsorbing the adhesive component to the microcapsule-like granules by melt coating, spray coating or mixing, It is possible to prepare microcapsule-like granules that are modified with an adhesive component. The ratio of modifying the surface of the microcapsule-like granules with the adhesive component is not particularly limited, and the mass ratio of the microcapsule-like granules to the adhesive component is 100:1 to 1:1. The surface may be modified to some extent, but is preferably about 50:1 to 2:1, more preferably about 20:1 to 5:1.

  Examples of the adhesive component that modifies the surface of the microcapsule-like granules include sugars, sugar alcohols, celluloses, water-soluble polymers, calcium phosphate and/or titanium oxide. Specifically, sugars such as glucose, xylose, lactose, sucrose, maltose and pullulan, sorbitol, xylitol, mannitol, maltitol, sugar alcohols such as erythritol and lactitol, crystalline cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl. Examples thereof include celluloses such as methyl cellulose, gum arabic, pregelatinized starch, water-soluble polymers such as polyvinyl alcohol and polyvinylpyrrolidone. As the adhesive component, a component having a buffer function against the compression pressure is preferable. Examples of the component having such a buffer function include crystalline cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose, and among them, crystalline cellulose is preferable.

  Next, the second molding material for nuclei is a mixture of microcapsule-like granules and granules of the same size and higher in moldability than the microcapsule-like granules (hereinafter referred to as "high-sized granules of the same size"). The method will be described. As the microcapsule-like granules, not only usual microcapsule-like granules but also modified microcapsule-like granules or a mixture of microcapsule-like granules and modified microcapsule-like granules can be used. Here, by using a mixture of microcapsule-like granules and highly-sized granules of the same size as the molding material for nuclei, it is possible to secure the strength that allows the core part to move to the next step and to ensure the moldability of the entire molded product. However, it becomes possible to enclose a large amount of microcapsule-like granules in the inner core portion by a single supply/filling step of the inner core portion. The reason why the granules of the same size are used is to prevent the particle size segregation by unifying the granule size of the molding material for nuclei and prevent the non-uniformity of the content due to the particle size segregation. The modified granules are as described above.

  The mixing ratio of the microcapsule-like granules and the high-sized granules of the same size is not particularly limited, but in order to secure the content of the microcapsule-like granules and the strength capable of moving to the next step, 20:1 to It may be mixed so as to have a ratio of about 1:1, but it is preferably about 20:1 to 2:1, more preferably about 20:1 to 5:1. The method for producing the high-sized granules of the same size is not particularly limited, but, for example, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method and the like are common.

  Examples of components of the high-sized granule having the same size include sugars, sugar alcohols, celluloses and/or calcium phosphate. Specifically, sugars such as glucose, xylose, lactose, sucrose, maltose and pullulan, sorbitol, xylitol, mannitol, maltitol, sugar alcohols such as erythritol and lactitol, crystalline cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl. Cellulose such as methyl cellulose may be mentioned.

  Thirdly, an embodiment will be described in which, as the double structure punch, a punch having a double structure of a central punch having a tip portion branched into two or more and an outer punch surrounding the outer periphery of the central punch is used. Here, by forming a core-shaped molded product having a plurality of inner cores arranged in the horizontal direction with respect to the pressurizing surface of the molded product and an outer layer on the outer side thereof, the inner core is supplied and filled only once, It is possible to enclose a large amount of microcapsule-like granules in a part. Here, as the molding material for nuclei, it is possible to use microcapsule-like granules or a mixture of microcapsule-like granules and highly-molded granules of the same size. As the microcapsule-like granules, not only usual microcapsule-like granules but also modified granules or a mixture of microcapsule-like granules and modified granules can be used. In this method, by arranging a plurality of inner cores in the horizontal direction with respect to the pressing surface of the molded product, the amount of the inner core is dispersed, and by sandwiching the outer layer that imparts moldability between them, the moldability of the entire molded product is improved. It becomes possible to secure. After the outer layer core molding step, when the second outer layer molding material is supplied, the second outer layer molding material may be supplied while the lower outer punch is lowered to facilitate the transition to the next step.

  Next, as a solution from another viewpoint, a fourth method will be described, which is a method utilizing another embodiment of WO01/98067. First, another embodiment of WO01/98067 is that the outer layer supplying step 1 in which the molding material for the outer layer is supplied to the space surrounded by the lower punch and the inner wall of the die, and the upper center punch is projected in the previous step. An outer layer molding step of compression-molding the outer layer molding material to form a cup-shaped molded article, a nucleus supply step of supplying the nucleus molding material to the space in the cup-shaped outer layer molded article formed in the previous step, and , An outer layer supply step 2 for supplying an outer layer molding material to the space on the outer layer core molded article or molding material that has been supplied or supplied/molded by the previous step in the die, the outer layer core molded article or molding material and outer layer molding A method for producing a molded article having a core, which comprises an overall molding step of compression molding a material.

  The fourth method is a method of forming a cup-shaped molded product from the molding material for the outer layer, which has been supplied and filled in the die as described above, and then supplies the microcapsule-like granules into the cup. That is, in another embodiment of WO01/98067, microcapsule-like granules or a mixture of microcapsule-like granules and highly-sized granules of the same size is used as the molding material for nuclei. Here, as the microcapsule-like granules, not only ordinary microcapsule-like granules but also modified granules or a mixture of microcapsule-like granules and modified granules can be used. In this embodiment, since the side surface portion of the molded product is molded before the supply of the molding material for nuclei, the strength of the side surface of the dry-molded molded product is higher than that of other manufacturing methods. In other words, even when microcapsule-like granules that do not have moldability and whose volume does not change significantly even when pressure is used as the molding material for nuclei, the strength of the entire nucleated molded product can be ensured and only once in the inner core part. In the feeding and filling step of, a large amount of microcapsule-like granules can be enclosed in the inner core part.

  A first example of the method for producing a microcapsule-like granule-containing dry-molded article according to the present invention will be described below in detail mainly with reference to FIG. This first example corresponds to the first method and the second method, and the microcapsule-like granules as described above can be used as the molding material for the nucleus. Here, as a preferred embodiment, the outer layer molding step is carried out, and the temporary compression operation is used as the compression operation.

  First, with the lower center pestle 3A lowered (Fig. 2A), the molding material for the first outer layer OP1 is supplied to the first outer layer space 6A on the lower center pestle 5A surrounded by the lower outer pestle 3B (Fig. 2B), if necessary, the lower center pestle 3A is raised to discharge the surplus molding material for the first outer layer to the outside of the die, and then the upper center pestle 2A and the lower center pestle 3A are moved toward each other to be temporarily compressed. (FIG. 2C), the first outer layer is temporarily molded. (Outer layer molding process)

  Next, the temporary molded product of the first outer layer OP1 is held by the lower center punch 3A and the lower outer punch 3B, the lower center punch 3A is lowered as necessary, and the first outer layer OP1 surrounded by the lower outer punch 3B is provided. The nuclear NP molding material is supplied to the nuclear space 6B on the temporary molded product (Fig. 2E, F). After that, if necessary, the lower center pestle 3A is raised to discharge the surplus molding material for the nucleus out of the die, and then the upper center pestle 2A and the lower center pestle 3A are moved and temporarily compressed toward each other (Fig. 2G), the first outer layer temporary molded product and the core are temporarily molded. (Outer layer core molding process)

  Furthermore, lower the lower punch (both lower center punch 3A and lower outer punch 3B or lower outer punch 3B) while lowering the first outer layer and the temporary molded product of the core by the lower central punch 3A and the lower outer punch 3B. (FIG. 2I), the molding material for the second outer layer OP2 is supplied to the space 6C for the second outer layer in and around the temporary molding of the first outer layer and the core in the die 1 (FIGS. 2J and K). The core temporary molded product held on the first outer layer temporary molded product is completely contained by the outer layer molding material and the outer layer temporary molded product (Fig. 2K), and the surplus second outer layer is formed as necessary. The molding material for OP2 is discharged to the outside of the die 1 (Fig. 2L). Incidentally, here, the lower outer pestle 3B may be sufficiently lowered first, and the temporary molding product of the first outer layer and the nucleus may be apparently pushed up, and then the molding material for the second outer layer OP2 may be supplied. . After that, the upper pestle (upper center pestle 2A and upper outer pestle 2B) and the lower pestle (lower center pestle 3A and lower outer pestle 3B) move toward each other, and consist of the first outer layer, the core, and the second outer layer. If necessary, the entire molded product is subjected to preliminary compression (temporary compression) and finally main compression is performed (FIG. 2M). (Overall molding step) Incidentally, FIG. 2N is a step of taking out a completed molded product.

  Next, FIG. 3 illustrates a second example of the method for producing a microcapsule-like granule-containing nuclear-molded article according to the present invention. This second example corresponds to the third method, and the microcapsule-like granules described above can be used as the molding material for the nucleus. Here, there are a plurality of nuclei.

  In this second example, a punch having a double structure of a central punch having the tip ends of the upper and lower punches branched into two or more and an outer punch surrounding the outer periphery of the central punch is used, and the second example is carried out in accordance with the first example. . Here, while pushing up the temporary molded product of the first outer layer and the nucleus into the die 1, while supplying the molding material for the second outer layer OP2 to the space 16C for the second outer layer on and around the temporary molded product of the first outer layer and the nucleus. (FIG. 3J), the temporary molding of the first outer layer and the core is pushed up and the molding material for the second outer layer is simultaneously supplied to prevent the temporary molding of the core from collapsing into the space for the second outer layer. It is possible (Fig. 3K).

  Next, a third example of the method for producing a microcapsule-like granule-containing dry-molded article according to the present invention is shown in FIG. This third example corresponds to the fourth method, and the microcapsule-like granules as described above can be used as the molding material for the nucleus. Here again, the method using temporary compression is used as the compression operation on the way. In this method, it is possible to omit the temporary compression operation of the molding material for nuclear NP.

  First, with the lower pestle (lower center pestle 3A and lower outer pestle 3B) lowered (Fig. 4A), fill the molding material for the first outer layer OP1 into the space 26A for the first outer layer on the lower pestle in the die. Then, if necessary, the lower center pestle 3A or the lower center pestle 3A and the lower outer pestle 3B are raised to a predetermined position (FIG. 4B), and the excess molding material for the first outer layer OP1 overflowing outside the die 1 is discharged. To do. After that, the upper pestle (the upper center pestle 2A and the upper outer pestle 2B) and the lower pestle (the lower central pestle 3A and the lower outer pestle 3B) that move the upper central pestle 2A to the lower central pestle 3A side move toward each other. By temporarily compressing, the cup-shaped first outer layer OP1 is temporarily molded (FIG. 4C).

  Next, the nucleus NP molding material is supplied to the nucleus space 26B in the cup-shaped first outer layer OP1 temporary molding (FIG. 4E), and excess nuclear NP molding material is discharged as necessary. Then, the upper center pestle is moved in the lower pestle direction to temporarily compress the molding material for the nuclear NP, and the nuclear NP or the nuclear NP and the first outer layer OP1 are temporarily molded (FIG. 4F).

  Furthermore, while holding the first outer layer OP1 and the nuclear NP temporary molded product on the lower punch in the die, lower the lower punch as necessary to remove the first outer layer OP1 and the nuclear NP temporary molded product in the die. The second outer layer OP2 molding material is supplied into the second outer layer space 26C (FIGS. 4G and H), and the lower punch is raised to a predetermined position as necessary to remove the surplus second outer layer OP2 molding material. Discharge to the outside of mortar 1. After that, the upper punch and the lower punch are moved toward each other, and the entire molded article composed of the first outer layer, the core and the second outer layer is subjected to preliminary compression (temporary compression) if necessary, and finally the Perform compression (FIG. 4I). FIG. 4J shows a step of taking out the completed molded product.

  Next, a fourth example of the method for producing a microcapsule-like granule-containing multi-nucleated and molded article according to the present invention is shown in FIG. In the fourth example, the third method and the fourth method are combined, and the microcapsule-like granules and the like as described above can be used as the molding material for the nucleus. The present manufacturing method is carried out according to the third example, using a punch having a double structure of a central punch having the tip ends of the upper and lower punches branched into two or more and an outer punch surrounding the outer periphery of the central punch.

  Basically, the method for producing a dry-molded article containing the microcapsule-like granules according to the present invention can be simply carried out by using the punch and the hydraulic press. That is, according to the process sequence of the present invention, the upper and lower punches or center punches, the outer punches are manually and/or automatically moved to predetermined positions, and the target molding material (molding material for outer layer, molding material for nucleus) is filled. After that, it can be easily carried out by pressing with a hydraulic press machine so as to be sandwiched from above and below and performing a series of steps according to the step sequence of the present invention. In addition, a rotary powder compression molding machine is preferably used as the compression molding means used for carrying out the present production method. Such a rotary compression molding machine is described in detail in WO01/98067, and a front sectional view showing the operating mechanism of the upper and lower punches by expanding the rotary disk is shown in FIG.

  Although the method for producing a dry-molded article containing microcapsule-like granules has been described above, the present invention also relates to the thus-produced article. The molded product of the present invention is a nuclear-molded product characterized by having an inner core containing microcapsule-like granules and an outer layer which is a compression coating layer on the outer side thereof. Here, the microcapsule-like granules are contained in the form of a large number of aggregates. The molded article of the present invention includes the following three embodiments.

  The first is a microcapsule-like granule (modified microcapsule-like granule) or a microcapsule-like granule having the outer layer on the outer side of the inner core, the inner core of which is modified with an adhesive component on the surface, and the modified micro-particle A molded product characterized by comprising a mixture of capsule-like granules.

  Secondly, it has an inner core and an outer layer on the outer side, and the inner core is composed of a mixture of microcapsule-like granules and granules of the same size and higher moldability than the microcapsule-like granules (high-sized granules of the same size). It is a molded product characterized by. Here, as the microcapsule-like granules, not only usual microcapsule-like granules but also modified microcapsule-like granules or a mixture thereof can be used.

  The third is a microcapsule-like granule having a plurality of inner cores arranged in the horizontal direction with respect to the pressing surface of the molded product and an outer layer on the outer side, and the inner core has the same size as the microcapsule-like granules. It is a molded product characterized by comprising a mixture with. Here, as in the second case, the microcapsule-like granules may be not only ordinary microcapsule-like granules but also modified microcapsule-like granules or a mixture thereof. In the microcapsule-like granule-containing multi-nucleated and nucleated molded product of this aspect, it is possible to divide the molded product after the division so as to include each inner core. In this case, a dividing line is provided on the surface of the outer layer, which enables accurate division. In addition, the feature of this split molded product is that the inner core is not exposed on the split surface. Therefore, the molded product after the division can maintain the same strength as that before the division, and since the microcapsule-like granules are not exposed, the quality can be maintained in appearance.

  The size and shape of the microcapsule-like granule-containing dry-molded article of the present invention are not particularly limited as long as the punch can be produced. The size and shape of the inner core are also the same, and various inner core shapes can be used depending on the shape of the tip of the central punch.

  In the present invention, the active ingredient of the microcapsule-like granules of the inner core is generally microencapsulated or various coated granules for the purpose of reducing therapeutic effects and side effects, masking bitterness, improving stability, etc. is there. For example, enteric coating or sustained release of ibudilast, tamsulosin hydrochloride, nicardipine hydrochloride, varnidipine hydrochloride, roxatidine acetate hydrochloride, theophylline, nifedipine, emedastine fumarate, pranlukast or lansoprazole can be mentioned.

  Hereinafter, the method for producing a dry-molded molded product containing microcapsule-like granules of the present invention and a dry-molded molded product as a product thereof will be described in detail with reference to Examples. The technical scope of the present invention is not limited to these embodiments.

Test Example Production Example 1 which is a product of the present invention in which the inner core is a mixture of microcapsules and granules having the same size and higher moldability as the microcapsules, the inner core is modified on the surface of the microcapsules with an adhesive component. Comparative Production Example 1 in which the inner core is sandwiched between microcapsules and an excipient in a layered form to form a dry-coated tablet, and the inner core is a microcapsule For Comparative Production Example 2 in the form of tablets, the moldability of tablets and the presence or absence of breakage of microcapsules were evaluated. The presence or absence of microcapsule destruction was evaluated by the following method. That is, whether or not the microcapsules are destroyed is determined by molding a tablet containing the vitamin E-containing microcapsules, and immediately after the molding, vitamin E (tocopherol) exudes and whether or not the tablet surface is colored. It was carried out by visual observation.

[Production Example 1]
It has a double structure with an inner diameter of 6.0 mmφ and an outer diameter of 8.0 mmφ, and a small amount of magnesium stearate (manufactured by Taihei Kagaku Sangyo Co., Ltd.) is applied to the surface of each of the upper and lower punches of the flat type that can be pressed. Lactose/crystalline cellulose granulated product 30mg (MEGGLE: Cellactose 80) is supplied to the space above the lower central pestle surrounded by the lower outer pestle while the central pestle is lowered, and the upper central pestle and the lower central pestle are The pieces were moved in a direction toward each other, and temporarily compressed manually until the surface became flat. Next, with the lower center pestle lowered, surrounded by the lower outer pestle, the microcapsules 60 mg (Vitamin E/C beads manufactured by Riken Vitamin Co.) were placed in the space above the lactose/crystalline cellulose temporary molded product. A mixture of 40 mg of lactose/crystalline cellulose granulated product of size (MEGGLE: Cellactose 80) is supplied, and the upper center pestle and the lower center pestle are moved toward each other, which enables a smooth transition in the next step. Temporary molding was performed to the extent that the moldability of Finally, with the lower pestle lowered, 70 mg of the remaining lactose/crystalline cellulose granulated product (MEGGLE: Cellactose) in the space inside and around the temporary molded product molded up to the previous step in the die. 80) to make the lactose/crystalline cellulose and microcapsule temporary molded product completely included in the lactose/crystalline cellulose granulated product, and move the upper and lower punches toward each other, and Was tableted using a hydraulic hand press (manufactured by Inoue Seieidou: 3 tons-high pressure jack) at a compression pressure of 7.9 kg/mm ² per tablet unit area (about 400 kg per punch). In addition, it was confirmed that vitamin E did not seep out on the tablet surface and the microcapsules were not broken.

[Production Example 2]
It has a double structure with an inner diameter of 6.0 mmφ and an outer diameter of 8.0 mmφ, and a small amount of magnesium stearate (same as above) is applied to the surface of each of the upper and lower punches with a flat edge that can be pressed, and the lower center punch is lowered. In that state, lactose/crystalline cellulose granulated product 30 mg (same as above) is supplied to the space above the lower central pestle surrounded by the lower outer pestle, and the upper central pestle and the lower central pestle move toward each other, and the surface It was temporarily compressed manually until it became flat. Next, with the lower center pestle lowered, surrounded by the lower outer pestle, the surface of the microcapsules 60 mg (same as above) in the space above the lactose/crystalline cellulose temporary molded product was lactose/crystalline cellulose 40 mg (same as above). Then, 100 mg of the product coated with 1. was supplied, the upper center pestle and the lower center pestle were moved in directions toward each other, and temporary molding was carried out to the extent that moldability capable of smooth transition was maintained in the next step. Finally, with the lower pestle lowered, supply the remaining lactose/crystalline cellulose granulated product 70 mg (same as above) to the space inside and around the temporary molded product molded up to the previous step in the die. The lactose/crystalline cellulose and the microcapsule temporary molded product are completely included in the lactose/crystalline cellulose granulated product, and the upper and lower punches are moved toward each other, and this time the hydraulic hand press Tablets were compressed using a machine (same as above) at a compression pressure of 7.9 kg/mm ² per tablet unit area (about 400 kg per punch). In addition, it was confirmed that vitamin E did not seep out on the tablet surface and the microcapsules were not broken.

[Comparative Production Example 1] Microcapsule-containing molded product described in WO01/98067 having a double structure with an inner diameter of 6.0 mmφ and an outer diameter of 8.0 mmφ, each of the upper and lower punches having a pressable flat-shaped edge angle, Apply a small amount of magnesium stearate (same as above), supply the lactose/crystalline cellulose granulated product 30mg (same as above) to the space above the lower center pestle surrounded by the lower outer pestle while lowering the lower center pestle, The upper center pestle and the lower center pestle were moved in directions toward each other, and were temporarily compressed manually so that the surface became flat. Next, with the lower center pestle lowered, microcapsules 30 mg (same as above) were supplied to the space above the lactose/crystalline cellulose temporary molded product surrounded by the lower outer pestle, and the upper center pestle and the lower center pestle were fed. The pieces were moved in a direction toward each other, and temporarily compressed manually until the surface became flat. Furthermore, lactose/crystalline cellulose granulated product 40 mg (same as above) is supplied to the space on the temporary molded product which is surrounded by the lower outer punch and molded by the previous step and which is composed of lactose/crystalline cellulose and microcapsules. And the lower center pestle were moved toward each other, and were temporarily compressed manually so that the surface became flat. Furthermore, 30 mg of the remaining microcapsules are supplied to the space on the temporary molded product which is surrounded by the lower outer punch and is manufactured up to the previous step, and the upper center punch and the lower center punch are moved toward each other in the next step. In the above, temporary molding was performed to such an extent that the moldability that enables smooth transition can be maintained. Finally, with the lower pestle lowered, supply the remaining lactose/crystalline cellulose granulated product 70 mg (same as above) to the space inside and around the temporary molded product molded up to the previous step in the die. The lactose/crystalline cellulose and the microcapsule temporary molded product are completely included in the lactose/crystalline cellulose granulated product, and the upper and lower punches are moved toward each other, and this time the hydraulic hand press Tablets were compressed using a machine (same as above) at a compression pressure of 7.9 kg/mm ² per tablet unit area (about 400 kg per punch). In addition, it was confirmed that vitamin E did not seep out on the tablet surface and the microcapsules were not broken.

[Comparative Production Example 2]
It has a double structure with an inner diameter of 6.0 mmφ and an outer diameter of 8.0 mmφ, and a small amount of magnesium stearate (same as above) is applied to the surface of each of the upper and lower punches of the flat edge that can be pressed, and the lower center punch is lowered. In that state, lactose/crystalline cellulose granulated product 55 mg (same as above) is supplied to the space surrounded by the lower outer punch on the lower central punch, and the upper central punch and the lower central punch move toward each other, It was temporarily compressed manually until it became flat. Next, with the lower center pestle lowered, microcapsules 60 mg (same as above) were supplied to the space above the lactose/crystalline cellulose temporary molded product surrounded by the lower outer pestle, and the upper center pestle and the lower center pestle were fed. Temporary molding was carried out so that the molds moved in a direction toward each other and the moldability capable of smooth transition was maintained in the next step. Next, with the lower pestle lowered, 85 mg of the remaining lactose/crystalline cellulose granulated product (same as above) was supplied to the space inside and around the temporary molded product molded up to the previous step in the die. The lactose/crystalline cellulose and the microcapsule temporary molded product are completely included in the lactose/crystalline cellulose granulated product, and the upper and lower punches are moved toward each other, and this time the hydraulic hand press Tablets were compressed using a machine (same as above) at a compression pressure of 7.9 kg/mm ² per tablet unit area (about 400 kg per punch). The tablet had large cracks on the side surface (circumferential surface) of the tablet when it was taken out, and when it was taken out of the tablet or after it was taken out by hand, it collapsed into layers. In addition, a small amount of microcapsules were present on a part of the side surface of the tablet.

As a result of producing the above-described four types of microcapsule-containing nuclear-molded articles, Production Example 1, Production Example 2, Comparative Production Example 1, and Comparative Production Example 2 contained the same amount of microcapsules having extremely poor moldability, and Despite the same amount of the excipient component and the same compression pressure at the time of tableting, Comparative Production Example 2 collapsed into a layer immediately after the production and was practically a molded product. I couldn't. In addition, as in Comparative Production Example 1, Production Example 1 and Production Example 2 were tablets in which the tablet side surface did not disintegrate in layers and microcapsules did not surface on the tablet side surface. As described above, it was found that it is possible to manufacture a microcapsule-containing nuclear-molded article equivalent to that of Comparative Production Example 1 by using the production method of the present invention.

Claims (19)

  The die has punches in both upper and lower directions, and the upper and lower punches have a double structure of a central punch and an outer punch surrounding the outer periphery of the central punch, and the central punch and the outer punch are slidable, respectively. , An outer layer feeding step 1 in which a molding material for outer layer is supplied to a space above the lower central punch surrounded by the lower outer punch using a compression molding means capable of compression operation, and a front step surrounded by the lower outer punch In the space on the molding material for the outer layer, a microcapsule-like granule whose surface is modified with an adhesive component or a mixture of the microcapsule-like granule and a microcapsule-like granule whose surface is modified with an adhesive component are used. Nucleus supply step to supply, outer layer molding material supplied up to the previous step and outer layer core molding step of compression molding the microcapsule-like granules whose surface is modified with an adhesive component, and further the previous step in the die An outer layer supplying step 2 for supplying an outer layer molding material onto and around the outer layer core molded article molded by 1., and an overall molding step for compression molding the outer layer core molded article and the outer layer molding material. A method for producing a molded article having a core containing microcapsule-like granules.   The microcapsule-like granule whose surface is modified with an adhesive component is prepared by adsorbing the adhesive component to the microcapsule-like granule by melt coating, spray coating or mixing. 1. A method for producing a molded product having a core containing the microcapsule-like granules.   The microcapsule according to claim 1 or 2, wherein the adhesive component that modifies the surface of the microcapsule-like granule is saccharide, sugar alcohol, cellulose, water-soluble polymer, calcium phosphate or/and titanium oxide. Of producing a molded article having a core containing granules.   The die has punches in both upper and lower directions, and the upper and lower punches have a double structure of a central punch and an outer punch surrounding the outer periphery of the central punch, and the central punch and the outer punch are slidable, respectively. , An outer layer feeding step 1 in which a molding material for outer layer is supplied to a space above the lower central punch surrounded by the lower outer punch using a compression molding means capable of compression operation, and a front step surrounded by the lower outer punch A nucleus supplying step of supplying a mixture of microcapsule-like granules and granules having the same size and higher moldability as the microcapsule-like granules into the space above the outer layer molding material, the outer layer molding material supplied up to the preceding step, and Outer layer core molding step of compressing and molding the granule mixture, and further, outer layer supply step 2 of supplying the outer layer molding material onto the outer layer core molded article molded in the previous step in the die and the space around it, the outer layer core molding A process for producing a molded product having a core containing microcapsule-like granules, which comprises an overall molding process of compression-molding the product and a molding material for the outer layer.   The microcapsule-like granules are microcapsule-like granules whose surface is modified with an adhesive component, or a mixture of microcapsule-like granules and microcapsule-like granules whose surface is modified with an adhesive component. A method for producing a molded article having a core containing the microcapsule-like granules according to claim 4.   The components of the microcapsule-like granules and/or the granules having the same size as the microcapsule-like granules whose surface is modified with an adhesive component and having higher moldability are saccharides, sugar alcohols, and celluloses. The method for producing a molded article having a core containing the microcapsule-like granules according to claim 4, which is or/and calcium phosphate.   The die has a punch in both the upper and lower directions, and the upper and lower punches have a double structure of a central punch having a tip portion branched into two or more and an outer punch surrounding the outer periphery of the central punch, and each of the central punch and the outer punch. However, the outer layer feeding step 1 for feeding the outer layer molding material into the space above the lower central punch surrounded by the lower outer punch using the compression molding means that is slidable and capable of compression Nucleus supply that supplies microcapsule-like granules or a mixture of microcapsule-like granules and granules of the same size and higher moldability than the microcapsule-like granules enclosed in the space above the molding material for the outer layer Process, outer layer molding material supplied up to the previous step and outer capsule molding step of compressing and molding microcapsule-like granules or a mixture of granules, and further on and around the outer layer molded article molded in the previous step in the mortar A core containing microcapsule-like granules, which comprises an outer layer supplying step 2 for supplying an outer layer molding material to the space, and an overall molding step for compression molding the outer layer core molded article and the outer layer molding material. Molded product manufacturing method.   The microcapsule-like granules are microcapsule-like granules whose surface is modified with an adhesive component, or a mixture of microcapsule-like granules and microcapsule-like granules whose surface is modified with an adhesive component. A method for producing a molded article having a core containing the microcapsule-like granules according to claim 7.   The die has punches in both upper and lower directions, and the upper and lower punches have a double structure of a central punch and an outer punch surrounding the outer periphery of the central punch, and the central punch and the outer punch are slidable, respectively. , An outer layer supplying step 1 for supplying a molding material for an outer layer to a space surrounded by a lower punch and an inner wall of a die using a compression molding means capable of a compression operation, and a step for supplying the outer central punch with the upper center punch projected. The outer layer molding step of forming the cup-shaped molded article by compression molding the outer layer molding material, the microcapsule-like granules or the same size as the space in the cup-shaped outer layer molded article formed in the previous step Nucleus supply step of supplying a mixture with granules having a higher property than the microcapsule-like granules, and further, an outer layer core molded article or a molding material for the outer layer that has been supplied or molded by the preceding step in the die A molded article having a core containing microcapsule-like granules, which comprises an outer layer supply step 2 for supplying a material, and an overall molding step of compression molding the outer layer core molded article or the molding material and the outer layer molding material. Production method.   The microcapsule-like granules are microcapsule-like granules whose surface is modified with an adhesive component, or a mixture of microcapsule-like granules and microcapsule-like granules whose surface is modified with an adhesive component. A method for producing a molded article having a core containing the microcapsule-like granules according to claim 9.   A microcapsule-like granule having an inner core and an outer layer on the outer side, the inner core having a surface modified with an adhesive component or a microcapsule-like granule and a microcapsule having the surface modified with an adhesive component A molded product characterized by comprising a mixture of granules.   The adhesive component for modifying the surface of the microcapsule-like granules is saccharide, sugar alcohol, cellulose, water-soluble polymer, calcium phosphate or/and titanium oxide, according to claim 11. Molded product.   A molded article having an inner core and an outer layer on the outer side thereof, wherein the inner core comprises a mixture of microcapsule-like granules and granules having the same size and higher moldability than the microcapsule-like granules.   The molded product according to claim 13, wherein the microcapsule-like granules of the inner core include microcapsule-like granules whose surface is modified with an adhesive component.   14. The granules having the same size as the microcapsule-like granules and higher moldability than the microcapsule-like granules, wherein the highly moldable component is saccharide, sugar alcohol, cellulose or/and calcium phosphate. Molded product described in.   Molded product having a plurality of inner cores arranged in the horizontal direction with respect to the pressing surface and an outer layer on the outer side thereof, and the inner core is a microcapsule-like granule, or a granule having the same size but having a higher moldability than the microcapsule-like granules A molded product characterized by comprising a mixture with.   The molded article according to claim 16, wherein the microcapsule-like granules of the inner core include microcapsule-like granules whose surface is modified with an adhesive component.   The molded product according to claim 16, wherein the molded product has a dividing line on the surface of the outer layer, and each of the molded products after the division can be divided so as to include an inner core.   The active ingredient of the microcapsule-like granules of the inner core is characterized in that ibudilast, tamsulosin hydrochloride, nicardipine hydrochloride, varnidipine hydrochloride, roxatidine acetate hydrochloride, theophylline, nifedipine, emedastine fumarate, pranlukast or lansoprazole. Item 17. A molded product according to item 11, 13 or 16.