WO2006004069A1

WO2006004069A1 - Very small capsule and method for producing same

Info

Publication number: WO2006004069A1
Application number: PCT/JP2005/012261
Authority: WO
Inventors: Takao Ohnishi; Toshikazu Hirota
Original assignee: Ngk Insulators, Ltd.
Priority date: 2004-07-01
Filing date: 2005-06-27
Publication date: 2006-01-12
Also published as: JPWO2006004069A1

Abstract

Disclosed is a novel method for producing a very small capsule. This method comprises a step wherein a material for capsule wall containing a capsule wall (10) or a raw material thereof is supplied toward a surface (22) of a carrier (20) to which surface (22) at least the material for capsule wall is adherable, and a step wherein a material for core substance containing one or more core substances (4) or raw materials thereof is supplied toward a surface on which at least the material for core substance is adherable.

Description

Technical field

The present invention relates to a microcapsule and a method for producing the same. Background art

Small capsules of micrometer to nanometer size, including micro-force pusels, etc., are minute containers with solid and liquid inclusions (core substance) covered with wall material (capsule wall). Microcapsules are used in a wide range of fields such as pharmaceuticals, foods, printing, and liquid crystal for the purpose of protecting unstable substances, isolating reactive substances, and controlling diffusion of inclusions. This type of microcapsule manufacturing method includes interface polymerization, in situ polymerization, and liquid

Chemical methods such as medium-curing coating methods, phase separation methods, physicochemical methods such as submerged drying methods, and mechanical methods such as spray drying methods and air suspension methods are known. Vol. 7, No. 1, p. 2 8-p. 3 3). These are all dispersed in a medium in which the core substance is hardly restrained, and a capsule wall material is introduced into this system to form a thin-walled capsule wall surrounding the core substance with the surface of the core substance set as an evening spot. In common. Further, Japanese Patent Application Laid-Open No. 2 00-0 5 593 and Japanese Patent Application Laid-Open No. 2 0 0 1 2 3 2 1 7 8 disclose that in such a capsule manufacturing method, as means for dispersing or supplying a core substance. The use of an ink jet method using a piezoelectric element or the like is disclosed. Summary of the Invention

However, in the microcapsules obtained by these methods, the capsule wall covers the surface of the core material particles in a dispersion medium such as gas or liquid such as air. Will be. That is, the obtained microcapsule has an outer shape that follows the surface shape of the core substance, and the film thickness of the capsule wall is approximately constant. In addition, in the manufacturing method of microcapsules, various methods have been tried from the viewpoint of forming a uniform film on the core material and encapsulating the core material. A method for producing microcapsules of the formula has not yet been provided.

Accordingly, one object of the present invention is to provide a novel method for producing a microcapsule, and another object is to provide a method for producing a microcapsule capable of imparting a desired outer shape to the microcapsule. Furthermore, it is still another object to provide a method for producing a microforce psel having a novel inclusion form of a core substance. Another object of the present invention is to provide a microcapsule having a novel core substance encapsulation form, and another object to provide a microcapsule having a novel outer shape. Furthermore, another object of the present invention is to provide a microcapsule holding body including one or two or more microcapsules.

In order to solve the above-mentioned problems, the present inventors have focused on using a printing method such as a micro-droplet ejection system used in an inkjet printer, and further, a core material and a capsule wall The present inventors have found that a microcapsule having a three-dimensional shape can be constructed on a surface by adhering a liquid material as a material to a predetermined surface, thereby completing the present invention. That is, according to the present invention, the following means are provided.

According to one aspect of the present invention, a microcapsule comprising one or more core materials, and a capsule wall that holds the core material therein, the surface of the micromaterial from the surface of the core material. A microcapsule having anisotropy for a distance up to is provided. Further, according to one aspect of the present invention, the microcapsule includes one or more core substances, and a capsule wall that holds the core substance therein, and the surface of the microcapsules is small. There is also provided a microcapsule having a flat portion in part. In these forms, the capsule wall preferably includes the whole of the one or more core substances, and at least a part of the surface of the microcapsule has a flat portion. Both are preferable. It is also a preferred embodiment that the microcapsule has a plate-like portion. Furthermore, in these microcapsules, it is a preferable aspect to have a flat part, and it is also a preferable aspect to have a spherical part consisting of a part of the spherical body surface. Further, these microcapsules preferably have a circular or elliptical planar form. Moreover, a bank part can also be provided in the periphery of the said flat-shaped part.

Furthermore, in any of these microcapsules, it is preferable that the core substance is encapsulated in the capsule wall in a flat form. In addition, it is preferable that two or more core materials are provided, and the two or more core materials have two or more types of materials, and the capsule wall material has two or more types. Is also a preferred embodiment. In any one of these microcapsules, the capsule wall includes a first capsule wall that covers a part of the surface of the one or more core substances, and a surface of the one or more core substances. It is preferable that the second capsule wall covering the remaining portion is provided. Moreover, in any of these microcapsules, it is preferable that regions facing each other in the capsule wall have different surface areas. In this embodiment, it is a preferable embodiment that the surface area is different depending on the uneven shape and Z or surface roughness of the opposing regions in the capsule wall.

Furthermore, in any one of the above microcapsules, it is also a preferable aspect that a concave portion and a Z or convex portion are provided in one of the opposing regions of the capsule wall, and the opposing region of the capsule wall has a different thickness and It is also preferable to have Z or composition. Furthermore, it is a preferred embodiment that one of the opposing regions of the capsule wall is the core substance or its component release control region, and the other is the microcapsule arrival region control region.

Furthermore, in any one of these microcapsules, it is preferable that the maximum dimension is 2 mm or less and the ratio of the maximum dimension to the minimum dimension is 200,000 or less. In a preferred embodiment, the capsule wall contains independent pores. Furthermore, it is preferable that the core substance or its components have a concentration gradient. The ratio of the maximum dimension to the minimum dimension of the microcapsules (maximum dimension Z minimum dimension) is preferably 5 or more.

According to another embodiment of the present invention, there is provided a method for producing a microcapsule comprising one or more core materials and a capsule wall that holds the core material inside, the capsule wall or a raw material thereof. Supplying the capsule wall material containing at least the surface of the carrier having a surface to which the capsule wall material can adhere, and one or more of the core material or a core material containing the raw material Supplying the material to at least a surface to which the core material can adhere, and supplying these materials, wherein at least a part of the adhering material of the core material on the surface is the capsule wall material There is provided a method for producing a microcapsule, which is carried out so as to be encapsulated with a deposit. In this embodiment, it is preferable that the capsule wall material supplying step and the core substance material supplying step are steps of supplying the capsule wall material and the core substance material respectively to predetermined positions on the surface. It is an aspect.

Further, in any one of the above microcapsule manufacturing methods, the capsule wall material is supplied.

At least one of the steps and the supply step of the core material material is preferably performed by discharging droplets of the core material material and / or the capsule wall material by a microphone pump method. It is also a preferred aspect that at least one of the capsule wall material supply step and the core substance material supply step is performed by a screen printing method. Furthermore, it is also preferable that the capsule wall material supply step is performed by a screen printing method, and the core material material supply step is performed by discharging the core material material droplets by a micropump method.

Further, in any one of these microcapsule manufacturing methods, the inner layer on which the microcapsules are formed or the inner layer material including the raw material thereof is positioned on the inner layer side with respect to the capsule wall positioned on the outermost layer. It is a preferable aspect to supply to the deposit on the core material or the capsule wall deposit. Furthermore, the capsule The core material supply step is performed on the capsule wall material deposit formed by the wall material supply step, and the capsule wall material supply step is performed on the core material deposit. This is also a preferred embodiment. And in this aspect, prior to the supplying process of the core substance material or following the supplying process, the supplying process of the inner layer material that suppresses the diffusion or penetration of the core substance material into the capsule wall material may be performed. preferable.

In any one of the above-described microcapsule manufacturing methods, the carrier is preferably a flexible material, and the carrier is preferably a stretchable material. It is also a preferred embodiment that the carrier has at least a foamable material layer on its surface, and that the carrier also has a liquid repellent layer on at least its surface. Furthermore, it is a preferable aspect that the carrier has a selective permeability to a gas.

Furthermore, in any one of the above microcapsule manufacturing methods, it is preferable that the carrier has a substantially flat portion, and the carrier is supplied with the core material material and the capsule wall material. It is also a preferred embodiment to have a recess, and in this embodiment, the recess is formed by a flat plate-like first carrier and a through-hole provided in a second flat plate carrier that is superimposed on the first carrier. Preferably, in these embodiments, the through hole is preferably tapered.

In any one of the above-described methods for producing microcapsules, it is preferable that the method includes a step of separating the microcapsules formed on the carrier from the carrier. In this aspect, the separation step is preferably a step of deforming at least the surface of the carrier with respect to the microcapsules on the carrier. Moreover, it is preferable that the separation step is a step of deforming the carrier into an uneven shape by applying an external force from a surface opposite to the surface of the carrier. Furthermore, the separation step is preferably a step in which an external force is directly applied to the microcapsules on the carrier. According to another aspect of the present invention, there is provided a microcapsule holding body comprising: a carrier; a core material held by the carrier; and a plurality of microcapsules that hold the core material inside. Is done. In this embodiment, it is preferable that a part of the carrier constitutes a capsule wall of the microcapsule, and the carrier is soluble or disintegrable in any part of the living body. It is a preferred embodiment that it is a pharmaceutical carrier comprising Brief Description of Drawings

FIG. 1 is a diagram showing an example of a microcapsule according to the present invention,

FIG. 2 is a diagram showing another example of a microcapsule according to the present invention.

FIG. 3 is a view showing another example of a microcapsule according to the present invention,

FIG. 4 is a view showing another example of a microcapsule according to the present invention,

FIG. 5 is a diagram showing a laminated structure of microcapsules according to the present invention,

FIG. 6 is a diagram showing a laminated structure of microcapsules according to the present invention,

Fig. 7 is a diagram showing the two-dimensional form in the core capsule microcapsule,

Fig. 8 shows a model of the amount of dissolution per unit time of the core material in various microcapsules.

FIG. 9 is a diagram showing an example of a method for producing a microcapsule of the present invention,

FIG. 10 is a diagram showing an example of manufacturing a microcapsule using a carrier having a recess corresponding to the size of a microcapsule.

Fig. 11 is a diagram showing an example of dividing the carrier.

Figure 12 shows another example of dividing the carrier.

Fig. 13 shows an example of microcapsules arranged in a desired pattern on a carrier, Fig. 14 shows an example of a method for separating microcapsules,

Fig. 15 is a diagram showing another example of the separation method of microcapsules,

Fig. 16 shows another example of a method for separating microcapsules, Fig. 17 is a diagram showing another example of the separation method of microcapsules,

Figure 18 is a diagram showing another example of a method for separating microcapsules,

FIG. 19 is a diagram showing microcapsule holders (a) and (b) using a pharmaceutical carrier as a carrier. BEST MODE FOR CARRYING OUT THE INVENTION

The microcapsule according to the present invention comprises one or more core materials, and a capsule wall that holds the core material inside, and is anisotropic with respect to the distance from the surface of the core material to the surface of the microcapsules. It is characterized by having. This microcapsule has anisotropy in the distance from the core material to the surface of the microcapsule, in other words, the distance between the core substance and the outside. That is, the thickness of the capsule wall differs from site to site with respect to the core material. Such a core substance encapsulating form is a structure that could not be obtained by a conventional method of manufacturing microcapsules that forms a capsule wall following the surface shape of the core substance. For this reason, according to the present microcapsule, it becomes possible to control the release that could not be achieved with the microcapsule. For example, anisotropy can be imparted to the diffusion or release of the core material. For this reason, in one microcapsule, the diffusion timing or release timing of the core substance can be varied depending on the site. In addition, according to the present microcapsule, even in a minute size, it is possible to control the release in units of one capsule, so that it is possible to suppress variations in the release control amount, for example, the elution amount of the core substance with respect to time.

In addition, another microcapsule of the present invention comprises one or more core materials and a capsule wall that holds the core material inside, and a flat portion is provided on at least a part of the surface of the microcapsules. It is characterized by having. According to this microcapsule, unlike the conventional microcapsule, since the flat portion is provided, it is possible to secure a contact area with a site where the microcapsule is to be held, so that the microcapsule can be easily held at the site. Can be made. Therefore, for example, the core material can be held at a specific site until the core material is released, and the core material can be reliably released at a desired site. In addition, since the load can be distributed and received by the flat portion, the strength of the microcapsule can be easily secured. For this reason, breakage of the microcapsules and leakage of the core material can be effectively prevented.

Furthermore, the method for producing a microcapsule according to the present invention provides one or more core materials or a core material material containing the raw material to at least a carrier having a surface to which the core material material can adhere. Supplying the capsule wall or the capsule wall material containing the raw material thereof to at least the surface to which the capsule wall material can be attached. It is characterized in that at least a part of the core material adhering material is encapsulated by the capsule wall material adhering material on the surface to which the material can adhere. According to this manufacturing method, it is possible to construct a micro three-dimensional force pellet having a desired three-dimensional shape from the deposit of the core material material and the capsule wall material on the surface of the carrier. That is, in this manufacturing method, the core substance material and the capsule wall material are supplied and adhered to a predetermined surface, and the supply amount and supply site thereof can be easily adjusted. 3D shapes can be freely constructed. Therefore, the microcapsules of the above form can be easily constructed.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings for the microcapsules of the present invention, and the method for producing the microcapsules of the present invention will be described.

(Micro capsule)

As shown in FIGS. 1 to 7, the present microcapsule 2 includes a core material 4 and a capsule wall 10 that holds the core material 4 inside. Only one core material 4 may be provided, or a plurality of core materials 4 may be provided. In addition, when a plurality of core substances 4 are included, these core substances 4 may be made of two or more kinds of materials, which may be different or the same kind.

The core material 4 can be liquid, solid or gaseous. Preferably, it is liquid or solid. Such core material 4 is roughly enclosed by the capsule wall 10. It is sufficient that the core material 4 is filled with the whole or a part of the internal portion (space) formed by the capsule wall 10 and to be filled with the core material 4. If the form is roughly filled, it can contain a lot of core substance 4, and the elution rate of core substance 4 can be differentiated. Hereinafter, in the various forms exemplified, the form of the core material 4 is assumed to coincide with the space filled with the core substance 4. As will be described later, the presence state of the core material 4 in the microcapsule 2 varies depending on the supply amount and supply form of the core material and the capsule wall material, but as shown in FIGS. 1, 2, 4 and 5. Mononuclear or dispersed as shown in Figures 3 and 6

(Multinuclear) can be taken.

The shape (existing form) of the underlying core substance 4 also varies depending on the supply amount and supply form of the core substance material, etc., but as shown in some examples in FIGS. 1 to 6, it has a flat shape such as a spherical shape or a plate shape. Various forms such as a rod shape and an indefinite shape can be adopted.

The existence pattern of the core substance 4 in the microcapsule 2 is not limited to a simple mononuclear or simple multinuclear shape, and various patterns can be set. Figure 7 shows the two-dimensional form of core material 4. The two-dimensional form is the form from the surface with the largest surface area. For example, as shown in FIGS. 7 (a) and (b), a designed planar configuration can be provided. In FIG. 7 (a), the core material 4 is arranged in a ring shape, and two or more rings can be provided. The ring of the core material 4 does not necessarily have to be continuously present, and may be formed of discontinuous core material 4 dots. In FIG. 7 (b), the lines of the core material 4 are arranged in a cross shape. The line of the core material 4 may be a single wire, and may not be arranged in a cross shape but may be arranged in parallel. Further, the core material 4 line may be formed by discontinuous core material 4 dots. By adopting the existence form of the core substance 4 as described above, the above-described anisotropy in the present micro force process 2 can be obtained. In these examples, the planar form of the microcapsules 2 is all circular, but the same applies to the microcapsules 2 of other planar forms. In these various forms, the concentration of active substance in core substance 4 or core substance 4 Can also be inclined. By giving a concentration gradient, it becomes possible to control the release amount of the core substance 4 or the active ingredient. The form of the concentration gradient of the core substance 4 or active ingredient is not particularly limited, but it has a gradient composition in which the concentration is high on the center side of the microcapsule 2 and decreases from the center toward the outside. Or vice versa. Further, anisotropy can also be provided in the concentration gradient, and for example, a concentration gradient in which the concentration decreases from the central portion of the high concentration toward a part of the surface of the microcapsule 2 can be provided. The concentration gradient may be continuous or non-continuous. A method of forming a concentration gradient for the core substance 4 or its components will be described later.

As such a core substance 4, a substance or a composition is selected according to the use of the microcapsule 2. For example, an enzyme agent, a hormone agent, an antiallergic agent, an antibody drug, a cell medicine, an antibacterial agent, and an antiinflammatory agent. , Pain relieving agents, anti-cancer agents, anti-diabetic agents, anti-hypertensive agents, thrombus-lysing agents, etc., or compositions containing the same, oligonucleotides such as DNA and vector

Nucleotides, deodorants, insecticides, insecticides and agricultural chemicals or compositions containing these, other seasonings such as vitamins, proteins and sugars, food ingredients such as spices, or compositions containing the food ingredients, essential oils and fragrances Readily volatile components such as, or component compositions thereof, oils such as ribosomes and edible oils, magnetic materials or magnetic material compositions, liquid crystal materials or liquid crystal compositions, inorganic materials such as metals or ceramics, or compositions thereof Can be mentioned. When a magnetic material or a liquid crystal material is used as the core substance 4, these materials are encapsulated in a state of being dispersed in an appropriate liquid dispersion medium. Examples of magnetic materials include flaky iron, nickel, metal powders or alloys such as iron-nickel alloys, or those coated with an organic compound to improve dispersion stability, or by aluminum vapor deposition. A material having a higher reflectivity can be used.

In addition to the active ingredient, the core substance 4 contains active ingredients in the living body, oral cavity, nasal cavity, ear cavity, lacrimal gland, eye membrane, stomach, small intestine, large intestine, rectum, etc., blood vessels, urinary tract, vagina The womb An adhesive material having adhesiveness on the surface of the mucous membrane of any sunset part in any of various living bodies can also be contained. As the adhesive material, any material that easily adheres to the surface of the mucous membrane to which the microcapsules 2 are allowed to reach is sufficient, and a material that exhibits an appropriate viscosity is preferably used.

it can. For example, various acrylic acid-based copolymers such as strong ruboxy vinyl polymer, acrylic acid, octyl acrylate acrylate copolymer, gum arabic, polyvinyl alcohol, polyvinyl pyrrolidone, etc., or those obtained by adding a plasticizer to these. By including such an adhesive material as the core substance 4, the active ingredient is likely to adhere to the mucosal surface together with these adhesive materials when the microforce pusher 2 collapses or when the core substance 4 is released. As a result, the retention and absorption of the core substance 4 at the target site can be improved.

Such a core material 4 is held inside the capsule wall 10. Here, being held inside the capsule wall 10 is sufficient if it is partitioned from the outside by the capsule wall 10. Therefore, the capsule wall 10 may be dense enough to suppress the permeation of components from the outside or the inside thereof, or may be partially missing. For example, the entire core substance 4 may be covered with the capsule wall 10 and enclosed in the capsule wall 10, or the capsule wall 10 having a through hole or arranged oppositely may be provided. It is also possible to adopt a form in which the core substance 4 is held inside the capsule wall 10 where the wall is partially missing, such as a part that is not closed. If the core material 4 is sealed inside the capsule wall 10, the core material 4 is protected by the capsule wall 10, and when contacting between the capsules 2, the surface of the capsule 2 in contact with the core material 4 It will not adhere to. For this reason, it is effective when it is desired to elute the core substance by holding the individual microcapsules 2 more accurately at the gettering site such as the surface in the living body without aggregating the microcapsules 2 with each other. It should be noted that the core substance 4 is exposed at the missing portion of the capsule wall 10.

Such a capsule wall 10 is also made of a material suitable for the use of the present microcapsule 2. can do. Examples of the polymer material include polyolefins such as (meth) acrylate, polyethylene, and polypropylene, polyurethane, polystyrene, polyethylene terephthalate, polyether, polyether ether ketone, naphthalene, polyurea, polyamide, and copolymers thereof. Can also be used. Note that the core substance 4 or a part thereof may also be included in the capsule wall 10. The cab cell wall 10 can be composed of one or more materials. In addition, although the micro cab cell 2 may be composed of a single capsule wall 10, it can also be provided with a capsule wall 10 of two or more materials. The different types of capsule walls 10 may cover different surfaces, such as covering one side and the other side of the core material 4, or may form different layers around the core material 4. It may be covered.

When the microcapsule 2 is used for pharmaceutical applications such as pharmaceuticals, it is preferable that at least a part of the capsule wall 10 has selective solubility or disintegration at various targeting sites in the living body. As the composition having selective or preferable solubility in the oral cavity, stomach, intestine, etc., those known in the pharmaceutical field can be used. The capsule wall 10 can also have adhesion to the mucosa of the targeting site. As will be described later, when the microcapsules 10 are encapsulated, granulated, or held on a carrier, the outer skin or matrix can be provided with solubility or disintegration at the gettering site. At this time, if the microcapsule 2 has adhesiveness to the targeting site, the reachability of the core substance 4 to the evening site can be further increased. An adhesive material used for the core substance 4 can be used as a material that exhibits adhesiveness.

The capsule wall 10 can contain pores. The dissolution or disintegration rate of the capsule wall 10 can be controlled by containing pores. For example, in the case of containing independent pores such as bubbles, the core material 4 can be effectively isolated from the outside by the capsule wall 10, and dissolution and disintegration can be promoted. Also, continuous When it has pores, it can contribute to the sustained release of the core substance 4 in addition to promoting the dissolution and disintegration of the capsule wall 10 itself.

The microcapsule 2 can take various three-dimensional shapes without depending on the three-dimensional shape of the core substance 4. It is not excluded to adopt a three-dimensional shape that depends on the three-dimensional shape of the core material 4. In this microcapsule 2, the shape of the capsule wall 10 greatly contributes to the three-dimensional shape of the microcapsule 2. As will be described later, the three-dimensional shape of the micro force pusher 2 can be a desired shape depending on the supply form of the capsule wall material and the supply form. For example, various parts such as a spherical part, a flat part, a cone part, and a columnar part made of at least a part of a spherical body can be included in at least a part thereof. Furthermore, it is preferable to have a flat part on at least a part of the surface of the capsule wall 10, that is, the surface of the microcapsule 2, separately from these parts or in combination with these parts. As described above, by having such a flat portion, it is possible to secure a contact area with respect to a predetermined surface on which the microcapsule 2 is to be attached or held, and to easily hold the microcapsule 2 at the site. In addition, the load resistance of the microcapsule 2 can be improved by receiving a load at the flat portion. Therefore, a plate-like body shown in FIGS. 1 to 3, a hemispherical body shown in FIG. 4, a columnar body having a substantially semicircular cross section, and the like are preferable forms. In addition, when the microcapsule 2 has a flat portion such as a plate-like body, the solubility of the microcapsule 2 in a living body can be improved.

Furthermore, as shown in FIG. 2, the surface of the microcapsule 2 can be provided with irregularities such as a thick portion (semicircular cross section) and a thin portion (flat portion and flat portion). In this way, by combining the flat part with another thick film part, the caps in one micro capsule 2

The difference in thickness of the cell walls 10 can be increased, and the range of the sustained release time can be increased. The uneven shape on the surface of the microcapsule 2 may be finer. Further, the recess here includes a hole reaching the core material 4. Also, The planar form of the micro force pusher 2 can be various forms, but it is preferable to take a circular shape or an elliptical shape in consideration of damage or the like.

Further, in this way, it is preferable that the regions of the capsule wall 10 facing each other in the microcapsule 2 have different surface areas. In this way, the release form of the core substance 4 or the active ingredient and the adhesion to the target site can be made different on the surface of the opposing capsule wall 10. Here, the region of the capsule wall 10 in an opposing shape may be a region facing the core substance 4 and may not be parallel. Such a difference in surface area can be created not only by the difference in the form of protrusions and recesses on the surface of the microcapsule 2 described above, but also by the difference in surface roughness. Here, the shape of the unevenness is not particularly limited. For example, in the case of a convex portion, the ratio of the width to the height (height / width) is set to 0.0001 or more and 0.003 or less.

It is preferable. If the width is fixed, the height is reduced, and it is made smaller than 0.0001, it becomes difficult to create a difference in surface area. Also, if it is larger than 0.003, the convex part will be damaged. Furthermore, considering the manufacturing process, the diameter φ of the microcapsule 2 should be 0.1 to 0.2 mm, the convex width should be about 0.01 to 0.075 mm, and the height should be 5 m or less. Is preferred. A more preferable height is 0.5 / zm or less. Also, the difference in surface roughness can be measured by a generally used apparatus capable of measuring the surface roughness. The difference in surface roughness can be detected using any one of or a combination of centerline average roughness (Ra), maximum height (R max), ten-point average height (Rz), etc. . Here, the difference in the unevenness amount can be, for example, a surface roughness with Rmax of 1 / im or less. As an apparatus for measuring the surface roughness, for example, an optical interferometer such as a Fizeau interferometer using a laser as a light source can be used. In addition, the difference in the surface area in the facing region of the microcapsule 2 can be created by combining the above-described unevenness amount and surface roughness, or can be created by only one of them.

Microcapsule 2 is a preparation that can be administered to reach any part of the body. If

The one region facing the capsule wall 10 can be a release region for the core substance 4 and the other region can be a target site adhesion region. For example, in the form shown in FIG. 2, a bank is provided around the flat part at the center, so that a concave part is provided on the surface of one side of the region opposite to the capsule wall 10 of the microcapsule 2. That is, on the side of the microcapsule 2 having the concave portion, the surface area is increased due to the presence of the bank portion, but the portion that can contact the target site is limited to the top portion of the bank portion, so that adhesion to the target site is prevented. As a result of the restriction, the other surface (here, having a flat portion without a bank portion) selectively functions as an attachment region to the target site. Thus, when the adhesion region is on one side, the other side can be configured to function as the core material 4 or its component release region.

Further, the opposing capsule walls 10 can be configured to have different thicknesses, Zs, or compositions. By doing so, it is possible to impart different functions in each region, for example, the ability to adhere to the target site and the ability to release the ^three- core substance 4 or the like.

Such a microcapsule 2 is constituted by, for example, a laminated form of a core material 4 and a capsule wall 10. 5 and 6 show the laminated structure of the present microcapsule 2. FIG. In the example shown in FIG. 5, a disk-shaped core substance 4 is similarly laminated on a disk-shaped capsule wall 10a, and further a disk-shaped capsule 10b is laminated. This laminated structure is one structure for obtaining the outer shape of the microcapsule 2 illustrated in FIG. 1, and according to this structure, the capsule 10a covering a part of the surface of the core material 4; A capsule wall 1 O b covering the remainder of the surface of the core material 4. In the example shown in FIG. 6, disk-shaped capsule walls 10 a to l 0 c are stacked, and core materials 4 a and 4 b are interposed between the capsule walls. Unlike the capsule walls 10 a and 10 c, the capsule wall 10 b can be provided not only as a force pzel wall but as an inner layer having other functions. Further, by having such a laminated structure, the capsule walls 10 to be laminated are melted. By making the solution characteristics and strength characteristics different, the sustained release effect and strength can be made different between the front side and the back side. The typical form of the present microcapsule 2 has a flat circular shape or an elliptical outer shape, and a shape in which the flat core substance 4 is held inside the capsule wall 10 constituting such an outer shape. is there. As will be described later, this form is also a typical form obtained by a microcapsule manufacturing method using a printing system.

The maximum size of the microcapsule 2 is preferably 2 mm or less. Here, the maximum dimension means any one of the maximum thickness, length, width, and diameter of the capsule. Increasing the anisotropy of the encapsulation form of the core substance 4 and the solubility of the capsule wall 10 by flattening the maximum dimension to exceed 2 mm, etc., reduces the rigidity of the microcapsule 2 and causes deformation, etc. It becomes easy to occur and it becomes impossible to maintain a flat part or a flat part. As a result, the original usefulness of the present microcapsule 2 becomes difficult to obtain, for example, the adhesion to the surface of the living body tends to be lowered. If the maximum dimension is 2 mm or less, the microcapsule 2 can be efficiently manufactured by using a printing system described later. More preferably, it is 0.5 mm or less. In addition, the maximum size of the present microcapsule 2 is preferably 1 zm or more, and if it is less than 1 m, it tends to aggregate and becomes difficult to use as a microcapsule of the intended size. More preferably, it is 10 zim or more, and more preferably 50 m or more.

As described above, this microcapsule 2 has a cross-sectional or planar aspect ratio of 1 in its outer shape itself, such as a flat shape, a hemispherical shape, a rod shape, or a spindle shape, rather than a spherical shape or a cubic shape. It is possible to easily obtain a form greatly exceeding. For this reason, when the aspect ratio of the present microcapsule 2 is sufficiently large, for example, the smallest dimension (which is the smallest thickness, length, width, or diameter in the force capsule) is several! Even if the size is about ˜1 zm or less, if the maximum dimension is about 10 xm or more, the mutual contact area can be effectively reduced, and the aggregation of the microcapsules 2 can be prevented. Conventional microcapsules have cross-section or planar shape The outer shape of the contact ratio tends to be close to 1 and the volume of contact tends to be larger than that of the volume. However, according to the present microcapsule 2, aggregation can be suppressed by the outer shape itself. It is preferable that the aspect ratio (ratio between the maximum dimension and the minimum dimension) is 2 0 00 0 0 0 or less. Furthermore, considering the rigidity of the microcapsule 2, the aspect ratio is preferably 100 or less, and when the microcapsule 2 is manufactured, fine cracks are generated in the microforce pusher 2 when it is peeled off from the carrier 20 In view of suppressing the above, 2500 or less is more preferable. On the other hand, in order to suppress the occurrence of strain in the microcapsule 2 and prevent cracking, the thickness is preferably 10 im or less, and is preferable in consideration of the maximum dimension being 50 / m or more. The aspect ratio is 5 or more

In such a micro force pusher 2, the distance from the surface of the core material 4 to the surface of the microcapsule 2 varies depending on the part due to the presence form of the core material 4 and the force pusher wall 10 as described above. Anisotropy can be provided. The anisotropy of the distance in the micro force pusher 2 can be exemplified as follows. In the circular plate-like microcapsule 2 in FIG. 1, the distance L from the left and right ends of the core material 4 to the left and right end surfaces of the microcapsule 2 and the upper direction from the center of the upper portion of the core material 4 in the figure The distance S to the surface of the microcapsule 2 is different. Further, in the circular plate-like microcapsule 2 of FIG. 2, the left and right ends of the core material 4 are exposed on the surface of the microcapsule 2, and the distance SS becomes 0, but the upper left and right sides of the core material 4 The distance L in the directly upward direction from the near part is different from the distance S in the upward direction from the center of the upper part. Further, in the circular plate-like microcapsule 2 in FIG. 3, the core materials 4a and 4b are present in eccentric positions in the microcapsule 2, and are directly above the core materials 4a and 4b. The distances S 1 and S 2 in the direction are different from the distances L 1 and L 2 from the core materials 4 a and 4 b to the left and right sides, respectively.

In the substantially hemispherical micro-force cell 2 shown in Fig. 4, the upper left part of the core material 4 The distance S in the upward direction is different from the distance L in the upward direction from the upper center. Thus, in the microcapsule 2 having a spherical portion, the distance can be easily and continuously varied by making the core substance 4 exist in a flat form or in an eccentric portion. In the circular plate-shaped micro force pusher 2 shown in FIGS. 1 to 3, the distance can be varied by making the core substance 4 in a flat form or in a biased part. In addition, if the microcapsules 2 are provided with different shape portions as shown in FIG. 2, the distances can be further diversified. Further, in the microcapsule 2 of FIG. 4, the distances in the left-right direction from the left and right ends of the core material 4 are different from the distance S and the distance L, respectively.

The microcapsule 2 has anisotropy at such a distance, so that the sustained release timing or the sustained release rate of the core substance 4 can be controlled. An example of the sustained release effect due to the anisotropy of the distance in the microcapsule 2 is shown in FIG. Fig. 8 shows models for the amount of core material dissolved per unit time in various microcapsules. The dissolution curve a (—dotted line) for a microcapsule with a roughly uniform capsule wall on the outer surface of a conventional core material shows that the core material dissolves all at once after a certain period of time because the capsule wall is approximately uniform in thickness. It shows that On the other hand, the dissolution curve b (thick line) of the plate capsule (in the form of Fig. 1), which is an example of the present microcapsule 2, shows the maximum peak of dissolution at a later time than in the conventional example. The size of the hemispherical capsule (example shown in Fig. 4) of the hemispherical capsule Psel 2 is small, and the dissolution curve c (thin line) shows the maximum peak at a later time. The size is getting smaller. As described above, according to the present microcapsule 2, even a single microcapsule can provide a timed release effect of the core substance 4 and a sustained release effect. It should be noted that by combining various two-dimensional or three-dimensional forms of the core substance 4 already described, for example, the blood concentration of the active ingredient contained in the core substance 4 can be maintained longer in the effective treatment area, etc. More complicated timed release control

Release control is possible. Also, the capsule wall 10 has different characteristics depending on the part. Therefore, these controls are possible.

The microcapsules of the present invention can be used in various forms of preparations containing a plurality of microcapsules as pharmaceutical preparations. Such preparations include, but are not limited to, various oral preparations such as tablets, capsules, granules, pills, aerosols, syrups, troches, injections, eye drops, patches, suppositories, transdermal Examples include external preparations, subcutaneous implantable preparations, oral and nasal mucosa application preparations, and the like. It should be noted that a known formulation technology can be applied to various formulations such as tableting, encapsulation, and granulation.

(Method for producing microcapsules)

Next, a method for manufacturing a microcapsule suitable for manufacturing the present microcapsule will be described. Fig. 9 shows an example of the flow of this manufacturing method. This flow is suitable for manufacturing the micro cab cell 2 shown in FIG. This manufacturing method includes a step of supplying a core material 4 such as a liquid containing the core material 4 or its raw material to at least a carrier having a surface to which the core material can adhere, and a liquid containing the capsule wall or its raw material. Supplying a capsule wall material such as the above to the surface to which at least the capsule wall material can adhere.

(Process for supplying capsule wall material and core material)

The capsule wall can be made of the materials already mentioned. In this manufacturing method, a capsule wall material configured to finally obtain these materials is prepared and used. For example, when the capsule wall 10 is made of a polymer material, the polymer material or the material that becomes polymerized by reaction is suspended or dissolved in an appropriate solvent, and various additives are added as necessary. Thus, a capsule wall material is prepared. The capsule wall material is preferably prepared in a liquid or best shape. When it is liquid or pasty, it becomes easy to use a printing method to supply the capsule wall material. In addition, the liquid state includes solutions and suspensions. The capsule wall material may be in the form of powder in addition to liquid or paste.

In addition, by introducing appropriate bubbles into the capsule wall material, pores (especially independent pores are mainly used). Capsule wall 10 containing the body). For example, a capsule wall material containing pores can be obtained by introducing bubbles by stirring or the like during preparation of a capsule wall material or by using a chemical foaming agent. In such a force-pessel wall material, it is preferable to previously remove bubbles having a size that hinders supply from a supply means such as a micropump described later.

Also, prepare a core material containing the core material 4 already described. As the core material, only the core material 4 may be used, but various additives can be added to obtain an appropriate composition. It is also possible to prepare and use two or more types of core material materials having different concentrations of the core material 4 and different types of the core material 4. The core material is preferably in the form of a liquid or paste in the same manner as the capsule wall material. The core material may be in powder form.

Next, the carrier 20 for producing the microcapsule 2 will be described. In the present invention, the capsule wall material is supplied to at least the surface of the carrier 20 having the surface 22 to which the capsule wall material can adhere. The carrier 20 may be a solid, liquid, or gel, as long as it has a surface to which the capsule wall material can adhere. The solid or gel may be elastic or plastic. In addition, the liquid can hold a minute amount of the capsule wall material on its surface. In addition, by adjusting the temperature or salt concentration of the liquid as necessary, and adjusting the viscosity and specific gravity by using an organic solvent, etc., a surface suitable for the attachment or landing of the capsule wall material is constructed. it can. Further, the carrier 20 can attach and hold the force capsule wall material and can give the capsule wall 10 a shape following the surface 22. Therefore, get

By selecting the carrier 20 having the surface 22 according to the shape of the microcapsule 2 to be intended, a desired outer shape can be easily imparted to the microforce psell 2.

As the carrier 20, a pharmaceutical carrier (carrier) having solubility or disintegration at any site in the living body can be used. By using such a carrier 20, the microcapsule 2 is dissolved or disintegrated at the target site to release the microcapsule. Preparation (microcapsule holder) can be supplied. For example, when the microcapsule 2 is used as a preparation that acts on the oral mucosa, gums, teeth, etc., the carrier 20 can be easily dissolved or disintegrated by moisture such as saliva in the oral cavity. It is preferable to release the microcapsules 2 at. Similarly, in order to release the microcapsules 2 in the digestive tract and blood vessels such as the stomach or intestine, the carrier 20 can be made of a material and a structure that dissolves or disintegrates at each site. Further, as the carrier 20, the capsule wall 10 in the living body can be made of an adhesive material having adhesiveness to the mucous membrane of the setting part. By improving the adherence of the carrier 20 to the gastric mucosa and intestinal mucosa, a preparation (microcapsule holder) having improved reachability of the microforce pusher 2 to the evening gating site can be obtained. When such a soluble or adhesive material is used as the carrier 20, in these cases, the carrier 20 can be composed of the same material as that used for the capsule wall 10 already described. 0 functions as at least a part of the capsule wall 10. For example, in the example shown in FIG. 19 (a), the carrier 20 functions as a part of the capsule wall 10. When the carrier 20 is a part of the capsule wall 10, the remaining capsule wall 10 can be the same as or different from the constituent material of the carrier 20. In addition, by using a lumber carrier that facilitates swallowing or bitterness masking as the carrier 20, a large number of microforce pushells 2 or multiple types of microforce pushells 2 can be easily and collectively administered to the carrier 20. The so-called wafer-like or encapsulating material-like functions can be added (Fig. 19 (b)). The carrier 20 having an oblate-like function includes a gum, gel, or a pharmaceutical carrier that absorbs water to form a gel.

Examples of the material of the carrier 20 include various polymer materials such as polypyrrolidone, gelatin, polypinyl alcohol, sodium polyacrylate, carboxymethyl cellulose, starch, xanthan gum, caraja gum, sodium alginate, Methylcellulose, strong loxyvinyl polymer, agar, hydro In particular, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, hydroxymethylpropylcellulose terephthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and methacrylic acid copolymer are enteric polymer materials. Can be mentioned. Further, as the carrier 20, skin substitute materials formed from cultured skin, collagen, gelatin and the like, and various organ substitute materials such as artificial blood vessels can be used. When such a carrier 20 is used, by forming microcapsules by the micropump method described later, it is possible to suppress the obstacles to these alternative materials and to effectively hold the drug or the like. In addition, the required amount of drug can be accurately retained at the required site. Note that the micro force cell 2 formed in this way is used as a micro force cell holder together with the carrier 20.

Further, the surface 22 of the carrier 20 may have appropriate liquid repellency. The liquid repellency referred to here is at least liquid repellency to the capsule wall material. When the surface 22 has liquid repellency, the adhesion form of the capsule wall material adhered to the surface 22 can be controlled. When the capsule wall material adheres to a highly liquid-repellent surface, the form of adhesion is close to a sphere, and when the liquid repellency is low, it becomes a flat form of adhesion. Furthermore, the surface 22 has a liquid-repellent part and a non-liquid-repellent part (part having affinity for the capsule wall material), and a liquid-repellent part is provided around the non-liquid-repellent part.

Thus, it is possible to control the adhesion form of the force-pessel wall material.

The shape of the carrier 20 is not particularly limited, but is preferably a plate shape or a sheet shape in consideration of use of the printing system. It may have a curved surface to which the printing system can be applied. Also, as shown in FIG. 9, when the surface 22 of the carrier 2.0 is flat, a flat portion can be formed on the capsule wall 10. Further, as shown in FIG. 10, by having a concave portion corresponding to the size of the micro force pusher 2, a shape corresponding to the concave portion can be easily imparted to the microcapsule 2. By forming the hemispherical inner surface in the recess, the micro force pusher 2 having a spherical portion as shown in FIG. 4 can be easily obtained. The Furthermore, as shown in FIG. 11, the first carrier 20 a is a flat plate, the second carrier 20 b is a flat plate overlapping the first carrier 20 a, and the flat plate By forming a through hole corresponding to the microcapsule 2 in 20 b, the carrier 20 having the recess 24 on the surface 22 can be easily obtained. Further, as will be described later, the microcapsule 2 can be easily demolded by dividing the carrier 20 into the first carrier 20a and the second carrier 20b as described above. it can. In addition, as shown in FIG. 12, when the through hole of the second carrier 20b is formed in a taper shape, it can be removed more easily.

As will be described later, in consideration of separating the microcapsules 2 produced on the carrier 20 from the surface 22 thereof, the carrier 20 is preferably a plastic material. By deforming the surface 22 of the carrier 20, the microcapsules 2 can be easily separated from the surface 22. The carrier 20 may be a stretchable material at least in one direction on the surface 22. The microcapsules 2 can be separated by expanding and contracting the carrier 20 along the direction. The carrier 20 may have a foamable material layer 30 on its surface 22. After the microcapsules are manufactured, by heating the carrier 20 or the like, the foaming agent or the like inherent in the foamable material layer 30 is foamed, so that gas is ejected from the surface 22 or the shape of the surface 22 is changed. Microcapsules 2 can be separated. The carrier 20 is preferably provided with a liquid repellent layer at least on the surface 22. This is because the contact area of the micro-force psel 2 on the surface 22 can be reduced and the adhesion strength can be reduced. A material having selective permeability to gas can also be used as the carrier 20. That is, using a material that does not easily allow liquid to pass through and easily allows gas to pass through, and uses the gas-selective permeability of the material so that the gas passes from the surface other than the surface 22 of the carrier 20. By supplying gas to the carrier 20, the microcapsules 2 formed on the surface 22 of the carrier 20 can be easily separated. Examples of such a selective gas permeable material include the use of porous materials such as ceramics, metals, and polymer materials. Among these, by using a polymer material such as a polypropylene film, the microcapsules 2 can be easily separated by their flexibility. Also, polymer material By utilizing the high water repellency due to the low surface energy of the material, even if the porosity is relatively high, the penetration of the capsule wall material into the pores of the carrier 20 is suppressed and the low ventilation pressure is achieved. Therefore, the microcapsule 2 can be separated. The preferred pore size in such materials varies depending on the water repellency of the material itself, the characteristics of the capsule wall material (surface tension, viscosity, pH, etc.), and the amount of gas applied and pressure, but the average diameter is It is preferably 200 nm or less. The average diameter is more preferably 10 nm or less, and still more preferably 1 nm or less, in order to more reliably suppress the penetration of the capsule wall material and ensure the separation of the microcapsules.

Next, a method for supplying the capsule wall material and the core material to the carrier 20 will be described. As such a supply method, it is preferable to use a printing system. In the printing system, specifically, by using the recording material supply method in the printing system, in the core material supply process and the capsule wall supply process,

22 The core material and the capsule wall material can be respectively supplied to two predetermined positions. Therefore, a large number of microcapsules 2 can be easily manufactured, and microcapsules 2 having a desired shape can be manufactured. Furthermore, as shown in FIG. 13, a large number of microcapsules 2 can be arranged in a desired pattern on a carrier 20.

Specifically, the printing system used in this manufacturing method includes a micro-bump method used in ink jet recording and a stencil printing method represented by screen printing. According to the micropump method, microdroplets of the capsule wall material can be ejected onto the carrier 20 and landed on the surface 22 and adhered thereto. According to the micropump method, supply amount control and landing point control can be performed with high accuracy. Therefore, it is convenient for the supply of the capsule wall material, but it is particularly preferable to perform the core material supply process that requires highly accurate supply amount control and supply position control by the micropump method. In addition, it is suitable for the production of micro cab cells 2 that are relatively small (several / several tens of meters). Examples of the micropump method include a charge control method, an electromechanical conversion method, an electrothermal conversion method, and an electrostatic suction method. In the present manufacturing method, any of these can be used, but it is preferable to use a piezoelectric liquid discharge method that is an electromechanical conversion method in which a discharge pressure can be obtained without heating the liquid. . As a specific device, a pump section provided with one or more night body pressurizing chambers is connected to a nozzle section provided with a plurality of nozzle holes for ejecting liquid. In addition, a part of the wall of the liquid pressurizing chamber may be deformed by a piezoelectric ζ electrostrictive element so that the liquid supplied to the liquid pressurizing chamber is ejected from the nozzle hole. In addition, if the liquid inlets used for supplying the liquid to the pressurizing chamber via the liquid reservoir flow path are alternately arranged, it is possible to discharge with an accurate amount of minute droplets. In this manufacturing method, it is not always necessary to use an equivalent to that used in an ink jet recording apparatus.

Of the stencil printing methods, the screen printing method is preferably used. In the screen printing, the capsule wall material can be supplied in a desired pattern to the carrier 20 through a screen film patterned in a desired planar form. Moreover, according to screen printing, the microcapsule 2 larger than the inkjet method (several tens of m to 200 / m or less) can be easily manufactured. Screen printing is also suitable for supplying capsule wall materials that are more quantitative than core material materials.

The step of supplying the capsule wall material and the core material is performed so that at least a part of the deposit on the core material is encapsulated on the surface 22 with the deposit on the capsule wall material. In this way, at least a part of the microcapsules is manufactured. In this manufacturing method, as shown in FIG. 9, first, the capsule wall material is supplied to the surface 22 of the carrier 20, and the core material material is supplied to the adhered substance on the capsule wall material. . In this way, a desired shape can be imparted to the capsule wall 10 using the surface 22. In addition, by supplying the core material to the capsule wall material, the core material 4 is securely held inside the capsule wall 10 without depending on the type of carrier 20 or the liquidity of the core material. Possible Can be located. In addition, after supplying the capsule wall material to the surface 22, when supplying the core material, the capsule wall material can be cured to a necessary degree by appropriately leaving, drying, heating, and the like.

In order to form a concentration gradient for the core material 4 or its components, a core material with a different concentration for the core material 4 or component to be concentration-graded is supplied. For example, in order to produce a microcapsule 2 having a concentration gradient in which the concentration decreases from the central portion of the thickness toward the lower layer and the upper layer, after supplying the capsule wall material, some effective in the core material 4 Supplying a core material containing an ingredient at a first concentration, then supplying a core material containing the same active ingredient at a second wetness higher than the first concentration, and further supplying the same active ingredient By supplying the core substance material contained at the first concentration and supplying the capsule wall material, microcapsules with a concentration gradient can be formed. When laminating various core material materials, the lower core material material is sufficient.

When the next core material is supplied to the core material and the interface becomes clear depending on the type of core material, etc., it is dried to the extent that the lower core material will diffuse or mix into the next core material. A continuous concentration gradient can be formed by supplying the next core material in the state.

Next, the capsule wall material is supplied so as to cover the deposit on the core material. In this way, a holding structure is formed by the lower and upper force psell wall materials for the core material. When manufacturing microcapsules in this order, the supply of various materials is the largest for the capsule wall material on the lower side, then the material for the upper capsule wall, and the least amount of material for the core material. A micro force psel 2 that completely encapsulates the whole with the capsule wall 10 can be obtained. These quantitative ratios also apply to the relationship between the lower capsule wall, the upper capsule wall, and the core substance.

Note that if the supply amount of the core material and the supply amount of the capsule wall material supplied to the core material are large, or the core material and the capsule wall material are compatible, the core material is a powerful wall. The capsule wall will eventually end up when it is easy to penetrate or diffuse into the material or in the opposite direction Prior to supplying the material, a small amount of capsule wall material or the like can be supplied in advance to the deposits of the core material material to form an inner layer that suppresses such penetration and diffusion. Such an inner layer may be the same as the capsule wall material, but may be configured separately. The inner layer is not limited to such a purpose, and an inner layer material such as a liquid can be appropriately supplied so as to be interposed between the capsule wall 10 and the core substance 4.

In this way, the microcapsule 2 as illustrated in FIG. 5 can be obtained on the carrier 20. In this state, the microcapsule 2 remains attached to the carrier 20. If drying or heating is necessary to finally form the capsule wall 10 in the microcapsule 2 on the carrier 20, these steps may be performed in this state. The microcapsules 2 obtained in this way can be used in a state where a large number of microcapsules 2 are held on the carrier 20. That is, it can be used as a microcapsule holder that holds the microcapsules 2. In particular, when a pharmaceutical carrier having solubility or disintegration at a predetermined site in the living body is used as the carrier 20, the microcapsule carrier is a preparation that can be administered as it is. According to such a preparation, a preparation that is preliminarily provided with a form suitable for administration can be provided by omitting the operations such as capsule filling, granulation, and packing that are usually required for a microphone mouth capsule. For example, when the microcapsules 2 are arranged in a predetermined pattern and contain an active ingredient of a pharmaceutical as the core substance 4, the percutaneous external preparation, the subcutaneous implantable preparation, the oral cavity Or it can be used for preparations for nasal mucosa, suppositories, oral preparations, etc. These can also be provided with a dividing line as appropriate. In these applications, the microcapsule 2 can exhibit a time-release effect or a time-release effect.

The carrier 20 can also be used as a packaging carrier that temporarily holds the microcapsules 2. That is, the microcapsule holding body can be used as it is, or a packaging body can be formed by performing a packaging process with a transparent film so that it becomes a normal capsule packaging body as it is. In addition, when the carrier 20 is used as a microcapsule 2 holder, the carrier 20 made of a material suitable for the application is selected, and if necessary, a protective film or binder for the microcapsule 2, An adhesive layer for fixing the carrier 20 to a predetermined site, a protective layer for protecting the adhesive layer, and the like can be provided. In addition, it is preferable to use a material having a binding force to the carrier 20 as the capsule wall 10. Such a microcapsule holder may be formed by forming the capsule wall 10 on the carrier 20, supplying the core substance 4, and supplying the capsule wall 10, but the material and surface 2 of the carrier 20 If the shape of 2 is selected, the core material is supplied directly to the surface of the carrier 20 and

Even if the material for the back capsule wall is supplied and the core substance 4 is encapsulated by the surface of the carrier 20 and the capsule wall 10, it can function as a microcapsule holder. In this case, it can be said that the carrier 20 functions as a part of the capsule wall 10 (see FIG. 19 (a)).

In order to use the microcapsules 2 individually, a step of separating the microcapsules from the carrier 20 is performed. In order to separate the microcapsules 2, as described above, when a flexible material is used as the carrier 20, the microcapsules 2 can be separated by deforming at least the surface thereof. For example, as shown in FIG. 14, the carrier 20 holding the microcapsules 2 is sequentially sent by a belt conveyor or the like, and the carrier 20 is bent at the end of the conveyor, so that the minute at the end. Capsule 2 can be separated. In order to separate the microcapsules 2 more surely, as shown in FIG. 15, a blade 40 can be provided so that the microcapsules 2 are brought into contact with and pressed at the end portions. The blade 40 can be provided not only with the microcapsule 2 but also with a cutting edge that is easily inserted between the microcapsule 2 and the surface 22. The blade 40 can also be positioned so as to abut on the minute force pusher 2 on the carrier 20 that moves without being bent. In this way, the microcapsule 2 may be separated. In addition, an external force that separates the microcapsule 2 from the surface 22 can be applied using a gas shot such as air instead of the blade 40. Also, as shown in FIG. 16, by applying an external force from the surface 22 of the carrier 20 holding the microcapsule 2 and the opposite surface 26, the carrier 20 is deformed into an uneven shape. The microcapsules 2 can also be separated from the carrier 20. In FIG. 16, the opposite surface (back surface) of the carrier 20 is a large number of protrusions 52 on the side of 4 and suction holes 5 4 connected to a number of vacuum suction devices provided between the protrusions 52. The microcapsule separating device 50 having the above is disposed, the protrusion 52 is brought into contact with the back surface 26 of the carrier 20, and positioned so as to correspond to the position of the microforce pusher 2. A cavity capable of being vacuum-sucked is formed from the suction hole 54 on the back surface 26 between the adjacent microforce Psell 2 and the microcapsule 2 and the surface between the adjacent protrusions 5 4 of the separation device 20. Then, by operating the vacuum suction device and vacuum suction from the suction hole 54, the back surface 2 6 of the carrier 20 that has formed the cavity is adsorbed to the projection 54 side, and as a result, the micro force push The carrier 20 at the peripheral edge of the bottom of the cell 2 is peeled off from the bottom, and the tip of the protrusion 54 presses the center of the bottom of the microcapsule 2 upward from the back surface 26 of the carrier 20. Thereby, the micro force psell 2 can be easily separated from the carrier 20.

Also, as shown in FIG. 17, when an elastic material is used as the carrier 20, the microcapsule 2 can be separated by stretching the carrier 20 at least on the surface 22, as shown in FIG. As described above, when the carrier 20 has the foamable material layer 30 at least on the surface layer, the microforce pushell 2 can be separated by foaming by heating or the like. As shown in FIGS. 11 and 12, even when the carrier 20 is divided, the microforce cell 2 can be easily separated from the carrier 20.

When a selective gas permeable material is used as the carrier 20, by supplying a gas such as air to the carrier 20 so that the gas is discharged from the surface 22 of the carrier 20, The microcapsule 2 can be separated from the surface 22 2 by the pressure of the gas.

As described above, according to the present manufacturing method, the amount of the core material 4, the form, the film thickness of the capsule wall 10, and the shape are controlled by using the printing system, and the desired three-dimensional shape micro-cube. A cell can be constructed. In addition, it is a method capable of constructing an unwrapped form of the core material 4 that has not existed before. In addition, according to the present manufacturing method, all the various three-dimensional shapes of the microcapsules 2 and the inclusion form of the core substance 4 can be realized.

In the above description, the microcapsules are formed on the surface of the carrier 20.

By adjusting the supply pressure of the force-pell wall material, the core material, and the material of the carrier 20 using a micropump, the carrier 20 is supplied so that the capsule wall material and the core material are embedded in the carrier 20 Microcapsules 2 can also be formed at 20. Furthermore, the microcapsule 2 can be supplied to the carrier 20 to form a microforce pushell 2 holder. Alternatively, the microcapsule 2 can be formed by injecting only the core material material into the carrier 20 using the carrier 20 as the capsule wall.

In the above description, the carrier on which the microcapsules 2 are formed can be used as a microcapsule holder as it is. However, when a plastic material is used as the carrier 20 or plasticized with water or heat, the carrier is predetermined. In the case of using a material capable of giving the shape, the carrier 20 holding the microcapsules 2 can be plasticized under a predetermined condition to give an arbitrary shape. For example, in the case of a preparation that reaches a predetermined site in the living body by oral administration or a surgical or tube method, it can be formed into a form corresponding to the administration form or administration site. For example, each carrier region on which a certain amount of microforce pusher 2 is formed can be formed into a spherical shape, a rod-like body, a tablet-like shape, or the like presented for oral administration.

In the above description, a microcapsule having a capsule wall and the use of a printing system using a micropump or the like in the manufacturing method of the microcapsule have been described. The same applies to the production of microtablets. That is, by supplying the active ingredient and the binding material to the carrier by the micropump method, the already-explained outer shape and / or laminated shape and / or component distribution form of the microcapsule can be obtained. Can do. Active ingredients and binders can be supplied at the same time Can be supplied as separate shots. Therefore, the use of a printing system such as a micro pump provides a micro size preparation such as a micro capsule and a micro evening bullet and a manufacturing method thereof. Example 1

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not restrained by a following example.

(Production example 1 of microcapsules)

This example is an example of manufacturing a microcapsule having the structure shown in FIG. 5, and conforms to the manufacturing process shown in FIG. The capsule wall material was an anionic polymer based on methacrylic acid and methacrylic acid ester, and an aqueous solution with a polymer concentration of 1 Owt% was used as the force capsule wall material. In addition, water-soluble ink (solid content 10% by weight) was used as a core material and as a substitute for drugs. The carrier used was a polyethylene terephthalate (PET) sheet of resin. In this example, droplets of the capsule wall material and the core material were discharged by an inkjet method using a piezoelectric liquid discharge method. The unit used was the structure disclosed in Japanese Patent Publication No. 2003-75305. The drive waveform applied to the piezoelectric body was adjusted so that the discharge volume was about 200 pl per shot for each material.

First, 10 shots of capsule wall material (liquid volume 2000 pL) were discharged on a flat surface on the carrier, landed and air-dried to form a capsule wall (step 1). Next, a core material was formed on the capsule wall by discharging one shot of the core material (liquid amount 200 pL) and air-drying (step 2). Next, 1 shot (200 pL) of capsule wall material is discharged and air-dried to form a diffusion suppression layer, and then 4 shots of capsule wall material (liquid amount 800 p 1) are discharged and air-dried to obtain microcapsules. (Process 3). Four such microcapsules were prepared at the same time.

(Evaluation of microcapsules) Next, when measuring the diameter and film thickness of the parts (capsule wall and core material) produced in each process

In both cases, the diameter and film thickness of the microcapsules finally obtained were measured, and further, they were observed with a stereomicroscope to confirm the encapsulation. An optical interferometer was used for film thickness measurement, and an optical microscope was used for diameter measurement.

As a result, the capsule wall formed in step 1 has a diameter of about 0.2 mm and a film thickness of about 300 nm, and the core material formed in step 2 has a diameter of about 0.05 mm and a film thickness of about 20 nm. It was hot. The capsule wall formed in step 3 had a diameter of about 0.1 mm and a film thickness of about 100 nm. The finally obtained micro-force psell had a film thickness of about 400 nm and a diameter of about 0.2 mm. Furthermore, when the main pushell was confirmed with a stereomicroscope, it was confirmed that it was encapsulated.

For the microcapsules obtained, using a Fizeau interferometer, the surface roughness of the capsule wall (bottom surface) formed in contact with the carrier in step 1 and the force psal wall (top surface) formed in step 3 The Rmax on the bottom surface was 0.1 zm or less, and the Rmax on the top surface was 0.5 xm. From the above, it can be seen that microforce pusels with different surface roughness can be easily produced by producing microforce pusels on a carrier.

From the above, it is clear that microcapsules can be constructed on a carrier by using a printing system. Therefore, it can be seen that various forms of microcapsules can be obtained by using a system such as a microdroplet ejection system or a screen printing system. Example 2

(Production example of microcapsule 2)

In this example, a microcapsule having a concentration gradient for a certain component in the core material was produced. Use the same capsule wall material as in Example 1, and use it as a core material. Water-soluble inks having a solid content of 10% by weight and a solid content of 0.1% by weight were used. The water-soluble ink having a solid content of 0.1% by weight was added with a 1 wt% aqueous solution of the same polymer used in Example 1 and the capsule wall material. The carrier, capsule wall material, and core material material were discharged in the same manner as in the example, and the capsule wall material 10 liquid (liquid volume 2 00 pL) was discharged onto the flat surface of the carrier and landed. The capsule wall was constructed by air drying. Next, 7 shots of low-concentration core material on the capsule wall (liquid volume 140,000 pL) were discharged and air-dried, and then 1 shot of high-concentration core material material (liquid volume 200 pL) After discharging and air-drying, 7 shots of low-concentration core material were air-dried to form a core material. Next, the capsule wall material was discharged by 10 shots (2 0 00 p L) and air-dried to obtain a micro-force psule.

When the prepared microcapsules are observed visually and under a microscope, dark colored portions due to water-soluble ink are observed at the center of the microcapsules. The degree of coloring gradually toward the upper and lower layers of this colored portion. Was observed to be reduced. From the above, it can be seen that microcapsules having a concentration gradient can be obtained by stacking core material materials having different component concentrations. Example 3

(Example of capsule wall production)

In this example, a capsule wall having pores was produced. The material of the capsule wall is an anionic polymer based on methacrylic acid and methacrylic acid ester, and the excitation wavelength is 5500 nm and the detection wavelength is 5700 nm in an aqueous solution with a polymer concentration of 10 wt%. A solution to which a fluorescent agent was added was used as a capsule wall material. This capsule wall material is stirred with a micropipette to introduce bubbles, and then centrifuged to remove large bubbles. By using the same discharge method as in Example 1, a suitable amount is shot and air dried to produce only the capsule wall. did. When the capsule wall was observed with a fluorescence microscope, it was confirmed that bubbles (independent pores) of about several millimeters existed in the capsule wall. From the above, it has pores It can be seen that a force pushell wall can be produced.

The present invention relates to a Japanese patent application 2 0 0 4-1 9 5 9 1 9 filed on July 1, 2000 and a Japanese application filed on August 20, 2000 The national patent application 2 0 0 4-2 4 1 3 8 7 is the basis of the priority claim, and all of its contents are incorporated.

Claims

The scope of the claims

1. Microcapsules,

One or more core materials,

A force pushell wall that holds the core material therein;

With

A microcapsule having anisotropy with respect to a distance from the core material surface to the microcapsule surface.

2. The microcapsule according to claim 1, wherein the capsule wall encloses the one or more core substances.

3. The microcapsule according to claim 1 or 2, wherein at least a part of the surface of the microcapsule has a flat portion.

4. The microcapsule according to any one of claims 1 to 3, wherein the microcapsule has a flat portion.

5. The microcapsule according to any one of claims 1 to 4, wherein the microcapsule has a plate-like portion.

6. The microcapsule according to any one of claims 1 to 5, wherein a part of the microcapsule has a spherical portion made of a part of a spherical surface.

7. The micro force pushell according to any one of claims 1 to 6, wherein a planar form of the microcapsule is circular or elliptical.

8. The microcapsule according to any one of claims 1 to 7, wherein the core substance is encapsulated in the capsule wall in a flat form.

9. Microcapsules,

One or more core materials,

A force pushell wall that holds the core material therein;

With A micro force pusher having a flat portion on at least a part of the surface of the micro force pusher.

10. The microforce pushell according to any one of claims 1 to 9, wherein two or more core substances are provided, and the two or more core substances are made of two or more kinds.

11. The microcapsule according to any one of claims 1 to 10, wherein there are two or more kinds of materials for the capsule wall.

1 2. The force pusher wall includes a first force pusher wall that covers a part of the surface of the one or more core materials, and a second shell that covers the remainder of the surface of the one or more core materials. The microcapsule according to any one of claims 1 to 11, further comprising:

1 3. The maximum dimension of the microcapsule is 2 mm or less, and the ratio of the maximum dimension to the minimum dimension (maximum dimension Z minimum dimension) is in the range of 5 or more and 2 0 0 0 0 0 0 or less.

1 A microcapsule according to any one of 2 above.

1 4. The microcapsule according to any one of claims 1 to 13, wherein opposing regions in the capsule wall have different surface areas.

15. The microcapsule according to claim 14, wherein regions facing each other in the capsule wall have different surface areas depending on uneven shapes and differences in Z or surface roughness.

16. The microcapsule according to any one of claims 1 to 15, further comprising a concave portion and / or a convex portion in one of the opposing regions of the capsule wall.

17. The microforce pushell according to any one of claims 1 to 16, wherein the opposing regions of the capsule wall have different thicknesses and Z or compositions.

18. One of the opposing regions of the capsule wall is a release region of the core substance or a component thereof, and the other is a region to which the microcapsule is attached. The microcapsules described.

19. The microcapsule according to any one of claims 1 to 18, wherein the capsule wall contains independent pores.

20. The microcapsule according to any one of 1 to 19, which has a gradient with respect to the concentration of the core substance or its components.

2 1.1 A method for producing a microcapsule comprising one or more core materials and a capsule wall for holding the core materials inside,

Supplying the capsule wall material including the capsule wall or the raw material thereof at least toward the surface of the carrier having a surface to which the capsule wall material can adhere; and

Supplying one or two or more core substances or a core substance material including the raw material thereof at least on the surface to which the core substance material can be attached;

With the '

A method for producing a microcapsule, wherein the supplying step is carried out so that at least a part of the deposit on the core material is encapsulated with the deposit on the capsule wall material on the surface to which the core material can adhere.

2. The capsule wall material supply step and the core substance material supply step are steps of supplying the capsule wall material and the core substance material to predetermined positions on the surface, respectively. The manufacturing method of the microcapsule as described in 1 above.

2 3. At least one of the force-pell wall material supply step and the core material material supply step discharges the core material material and / or the capsule wall material droplets by a micropump method. The method for producing microcapsules according to claim 21 or 22.

2 4. The production of microcapsules according to any one of claims 21 to 23, wherein at least one of the supply step of the capsule wall material and the supply step of the core material material is performed by a screen printing method. Method.

25. The capsule wall material supply step is performed by a screen printing method, and the core material material supply step is performed by discharging the core material material droplets with a micropump method. The manufacturing method of the microcapsule in any one of.

26. Further, the inner layer material on which the microcapsules are formed or the inner layer material containing the raw material is attached to the core material material or the capsule wall so that the inner layer side is positioned with respect to the capsule wall positioned at the outermost layer. It supplies with respect to the deposit | attachment of material. The manufacturing method of the microcapsule in any one.

27. Carrying out the core material supply step on the capsule wall material deposit formed in the capsule wall material supply step, and supplying the capsule wall material to the core material deposit The method for producing microcapsules according to any one of claims 21 to 26, wherein the step is carried out.

28. The step of supplying an inner layer material that suppresses diffusion or penetration of the core material into the capsule wall material is performed prior to or subsequent to the supply step of the core material material. The manufacturing method of the microcapsule in any one of -27.

29. The method for producing a microcapsule according to any one of claims 21 to 28, wherein the carrier is a flexible material.

30. The method for producing a microcapsule according to any one of claims 21 to 28, wherein the carrier is a stretchable material.

31. The carrier has a foamable material layer at least on the surface thereof.

28. A method for producing a microcapsule according to any one of 8 above.

32. The method for producing a microforce psell according to any one of claims 21 to 28, wherein the carrier has a liquid repellent layer at least on a surface thereof.

3 3. The method of manufacturing a micro force psel according to any one of claims 21 to 32, wherein the carrier has a substantially flat portion.

3 4. The method for producing a microcapsule according to any one of claims 21 to 33, wherein the carrier has a recess to which the core material and the capsule wall material are supplied.

35. Manufacture of microcapsules according to claim 34, wherein the recess is formed by a flat plate-like first carrier and a through hole provided in a second flat plate-like carrier that is overlapped with the first carrier. Method.

36. The method for manufacturing a microcapsule according to claim 34, wherein the through hole is tapered.

3 7. Further, the step of separating the microcapsules formed on the carrier from the carrier The method for producing microcapsules according to any one of claims 21 to 36.

38. The method for producing microcapsules according to claim 37, wherein the separating step is a step of deforming at least the surface of the carrier with respect to the microcapsules on the carrier.

39. The method for producing a micro force psor according to claim 38, wherein the separation step is a step of deforming the carrier into an uneven shape by applying an external force from a surface opposite to the surface of the carrier. .

40. The method for producing microcapsules according to any one of claims 37 to 39, wherein the separating step is a step of directly applying an external force to the microcapsules on the carrier.

41. The method according to any one of claims 21 to 40, wherein the carrier has selective permeability to a gas.

4 2. With carrier

A microcapsule holding body, comprising: a core substance that is held by the carrier; and a plurality of microcapsules that hold the core substance inside.

4 3. The micro force psell holder according to claim 42, wherein a part of the carrier constitutes a capsule wall of the micro capsule.

4. The microcapsule holder according to claim 42 or 43, wherein the carrier is a pharmaceutical carrier having solubility or disintegration at any site in the living body.