JP2005255616A - Solid pharmaceutical preparation composition comprising liquid or semi-solid active ingredient and porous cellulose aggregate particle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a solid pharmaceutical preparation composition preventing bleeding of a liquid ingredient and having good tableting and disintegrating properties in a solid pharmaceutical preparation comprising the liquid or semisolid active ingredient by using a porous cellulose aggregate having a large intraparticle pore volume. <P>SOLUTION: This solid pharmaceutical preparation composition is characterized as comprising an active ingredient which is liquid or semisolid at normal temperature and the porous cellulose aggregate. Furthermore, the porous cellulose aggregate has a secondary aggregate structure in which cellulose primary particles are aggregated and ≥0.265 cm<SP>3</SP>/g intraparticle pore volume, contains I type crystals, has >30 μm average particle diameter, 1.3-20 m<SP>2</SP>/g specific surface area and <44° angle of repose and disintegrates in water. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a solid pharmaceutical composition comprising cellulose having a specific particle structure and powder physical properties used in the chemical industry field, particularly pharmaceuticals and foods, and particularly in pharmaceuticals, a liquid / semi-solid active ingredient. It relates to prevention of oozing.

Conventionally, it has been widely performed to mix cellulose particles such as crystalline cellulose and powdered cellulose with an active ingredient in the fields of medicine, food, and other chemical industries. In particular, in pharmaceutical products, solid preparations containing one or more active ingredients and porous cellulose include the following.
In Patent Document 1, a third component such as a crystalline substance that is insoluble or hardly soluble in water and soluble in an organic solvent is mixed, granulated and dried using water or an aqueous solution of a water-soluble organic solvent. Then, the crystal form obtained by extracting and removing the third component with an organic solvent is type I, the pore diameter is 0.1 μm or more, the pores are 20% or more, and 350 There are described porous cellulose particles having a fraction of 90% by weight or more of mesh or more. Since the porous cellulose particles described in the literature form a dense and strong cellulose wall structure in which the cellulose primary particles are uniformly continuous so that the boundaries of the particles are unclear. The particle structure is completely different from that of the porous cellulose aggregate. Although the cellulose particles are excellent in fluidity, water does not easily penetrate into a dense and continuous cellulose wall, so that the cellulose particles do not disintegrate in water and sometimes impede the rapid release of active ingredients. In addition, the plastic deformability during compression of cellulose is poor, the moldability is inadequate, and since an organic solvent is used in the production process, not only the production cost increases, but the active ingredient may be deactivated. , It was insufficient for stable use as an excipient.

Patent Document 2 discloses that a particulate natural cellulose dispersed in an organic solvent is granulated and dried by a spray drying method, the crystal form is I type, the specific surface area is 20 m ² / g or more, and the diameter is Porous microcellulose particles having a porous structure with a pore volume of 0.01 μm or more having a pore volume of 0.3 cm ³ / g or more and an average particle diameter of at most 100 μm are described. It has the above-mentioned cellulose wall structure, and the particle structure is completely different from the porous cellulose aggregate of the present invention. Since the porous cellulose aggregate particles also use an organic solvent in the production process, not only the production cost is increased, but also the active ingredient may be deactivated, which is insufficient for stable use as an excipient. Met.

Patent Document 3 describes a cellulose powder having an average degree of polymerization of 150 to 375, an apparent specific volume of 1.84 to 8.92 cm ³ / g, and a particle size of 300 μm or less as a cellulose powder having good moldability and disintegration. ing.
In Patent Document 4, as a cellulose powder having good fluidity and disintegration, the average degree of polymerization is 60 to 375, the apparent specific volume is 1.6 to 3.1 cm ³ / g, and the apparent tapping specific volume is 1.4 cm ³ / A microcrystalline cellulose aggregate having an angle of repose of 35 to 42 ° and a component of 200 mesh or more of 2 to 80% by weight is described. The cellulose powders obtained by the examples described in these documents have a very small pore volume in the particles and are completely different from the pore structure intentionally formed as in the present invention. For this reason, these cellulose powders have a specific surface area as small as 0.6 to 1.2 m ² / g and low compression moldability. These patent documents disclose that the value of the apparent specific volume is adjusted to control the moldability, fluidity, and disintegration property of the cellulose particles, but the apparent specific volume is 2.0 to 2.9 cm ^3. In a small range of / g, the fluidity and disintegration are excellent, but the moldability is not satisfactory. On the other hand, when the apparent specific volume is slightly increased to 3.0 to 3.2 cm ³ / g, the moldability is Although excellent, there was a problem that fluidity and disintegration deteriorated.

Patent Document 5 describes β-1,4-glucan powder having an average particle size of 30 μm or less and a specific surface area of 1.3 m ² / g as cellulose powder having good moldability. The β-1,4-glucan powder described in this document does not have a secondary aggregation structure, and individual primary particles exist alone. Although this glucan powder has good moldability, it has a problem of poor fluidity due to poor disintegration and a small average particle diameter.

In Patent Document 6, as a cellulose powder having good moldability and disintegration, an average degree of polymerization of 100 to 375 obtained by hydrolysis of a cellulosic substance, an acetic acid retention rate of 280% or more, Kawakita formula (P · V ₀ / (V ₀ −V) = 1 / a · b + P / a) has an a value of 0.85 to 0.90, a b value of 0.05 to 0.10, and an apparent specific volume of 4.0 to 6 There is a description of cellulose powder having 0.0 cm ³ / g, substantially no particles of 355 μm or more, and an average particle size of 30 to 120 μm. The cellulose powder obtained by the method of the example described in this document is also intentionally formed as in the present invention because the pore volume is small according to the result of the pore distribution measurement using mercury porosimetry. It is completely different from the pore structure. Although there is a description that the cellulose powder is excellent in compression moldability and disintegration, when the angle of repose is measured for the example of the most well-balanced example disclosed specifically, the repose angle exceeds 55 ° and the fluidity is sufficient. A formulation that is not satisfactory and contains many active ingredients with poor fluidity has a problem that the coefficient of variation of the tablet weight increases and affects the uniformity of drug content. In addition, the cellulose powder of this document can give high hardness when molded under high pressure, but there is no intentionally formed intra-particle pores, and the water penetration into the interior of the particles is low. There was a problem of delay.

In Patent Document 7, as cellulose powder having good moldability, fluidity, and disintegration, the average degree of polymerization is 100 to 375, particles passing through a 75 μm sieve and remaining on the 38 μm sieve are 70% or more of the total weight, And the crystalline cellulose characterized by the average value of the major axis / minor axis ratio of the particles being 2.0 or more is described.
In Patent Document 8, as the cellulose powder having good moldability, disintegration and fluidity, the average L / D (major axis / minor axis ratio) of particles having an average degree of polymerization of 150 to 450 and 75 μm or less is 2.0 to 4. Cellulose powder having an average particle size of 20 to 250 μm, an apparent specific volume of 4.0 to 7.0 cm ³ / g, an angle of repose of 54 ° or less, and a specific surface area of 0.5 to ⁴ m ² / g Is described. Similarly to the above, the cellulose powder described in these documents was intentionally formed as in the present invention because the pore volume in the particles was small according to the results of the pore distribution measurement using mercury porosimetry. It is completely different from the pore structure. The cellulose powders described in these documents impart high hardness to the molded body by elongating the shape of the particles, but because of the elongated shape, the apparent specific volume is increased and the moldability is increased. The higher the value, the lower the fluidity. In the cellulose powders of the examples described in these documents, the angle of repose of the best fluidity is 44 °, for example, a formulation containing many active ingredients with poor fluidity, and high In the case of continuous molding at a speed, the coefficient of variation of the tablet weight becomes large and affects the uniformity of the drug content, so that it is not satisfactory in terms of fluidity. Furthermore, although the cellulose powder described in these documents can give high hardness when molded under high pressure, there are no intentionally formed intra-particle pores and water permeability into the interior of the particles Since it was low, there was a problem that the collapse was delayed.

Although these cellulose powders described in Patent Documents 5 to 8 have sufficient moldability in a large region having an apparent specific volume of 2.3 to 6.4 cm ³ / g or more, they have fluidity and disintegration. There was a problem of getting worse.
As described above, in the cellulose particles of the prior art, moldability, fluidity, and disintegration are mutually contradictory properties, and it has been desired to realize cellulose particles having all these physical properties in a balanced manner. . In addition, these cellulose particles do not have intentionally formed intraparticle pores, and the intraparticle pore volume is small, so that active components cannot be supported in the particles, and liquid components may ooze out during compression molding. There was a problem that tableting trouble occurred.

Conventionally, a composition containing an active ingredient that is oily, liquid, or semi-solid at room temperature has a problem with tableting because the liquid ingredient oozes out from the preparation when compression-molded as compared with the solid active ingredient. There are problems such as the occurrence of spots of liquid components on the surface of the resulting preparation, and the occurrence of poor fluidity in the case of a granular preparation. These problems not only significantly reduce the quality of the product, but also cause variations in active ingredient concentration and medicinal efficacy, so that improvement is a very important issue.
In Patent Documents 9 to 20, in the production of tablets, an active ingredient that is liquid or semisolid at room temperature is held on an adsorption carrier as it is, or the active ingredient is water, an organic solvent, an oil or fat, a water-soluble polymer, a surfactant. A method of compressing and molding the obtained dry powder or granule after holding a solution dissolved, emulsified and suspended in a drying step is described. However, in these documents, there is no description regarding the pore volume in the particles of the cellulose particles, and by holding the active ingredient that is liquid or semisolid at room temperature in the porous cellulose aggregate particles having a large pore volume in the particles. It has not been known at all to prevent the oozing out of liquid components of solid preparations such as powders, granules and tablets. In addition, in this method, many processes related to drying are essential, and the associated equipment cost and the energy cost used for drying are high.

Japanese Laid-Open Patent Publication No. 1-272643 JP-A-2-84401 Japanese Patent Publication No.40-26274 Japanese Patent Publication No.53-127553 JP-A 63-267331 JP-A-6-316535 Japanese Patent Laid-Open No. 11-152233 WO02 / 02643 pamphlet JP-A-56-7713 JP 60-25919 A Japanese Patent Application Laid-Open No. 61-207341 JP 11-193229 A JP 11-35487 A JP 2000-16934 A JP 2000-247869 A JP 2001-181195 A JP 2001-316248 A Special Table 2002-534455 JP 2003-161 A JP 2003-55219 A

  The present invention relates to a porous cellulose aggregate having a specific particle structure and specific powder properties (hereinafter also referred to as porous cellulose aggregate particles) in a solid preparation containing one or more liquid, semi-solid active ingredients. ) To prevent the liquid or semi-solid active ingredient from oozing out, and to provide a solid preparation composition with good disintegration.

In order to solve the above-mentioned problems, the present inventors blended a specific particle structure and porous cellulose aggregate particles having specific powder physical properties, thereby preventing liquid and semi-solid active ingredients from oozing out. It has been found that there is an epoch-making effect in imparting tabletability and disintegration, and the present invention has been made.
That is, the present invention is as follows.
One or more active ingredients that are liquid or semi-solid at normal temperature and a secondary aggregate structure in which cellulose primary particles are aggregated, and the intra-particle pore volume is 0.265 cm ³ / g or more, and type I Porous cellulose aggregate particles comprising primary cellulose particles containing a crystal form, having an average particle diameter of more than 30 μm, a specific surface area of 1.3 to ²⁰ m ² / g, an angle of repose of less than 44 °, and disintegrating in water A solid pharmaceutical composition with good disintegration, which prevents the liquid tablet component from oozing out.

  The porous cellulose aggregate particles used in the present invention have a specific particle structure and specific powder physical properties, and therefore provide a solid agent that prevents liquid and semi-solid active ingredients from oozing out. it can.

Hereinafter, the present invention will be specifically described focusing on its preferred form.
The porous cellulose aggregate particles used in the present invention must have a secondary aggregate structure in which primary particles are aggregated. This means a secondary aggregate structure in which the boundary of primary particles is clear when the surface and cross section of the particle are observed with a scanning electron microscope (SEM) at 250 times and 1500 times. The secondary aggregate structure in which the primary particles are aggregated is closely related to the disintegration property. If the particle structure is not this, the disintegration property is deteriorated, which is not preferable.
In addition, this secondary agglomeration structure is uniformly distributed regardless of the inside and the surface of the particle, and when mixed with the active ingredient, the active ingredient can be held in the gap between the primary cellulose particles, so that it is liquid. This is preferable because it prevents the component from oozing out.

As the porous cellulose aggregate particles used in the present invention, the pore volume in the particles must be 0.265 cm ³ / g or more. The larger the pore volume in the particle, the greater the effect that can be obtained. The upper limit is not particularly limited, but it is 3.0 cm ³ / g in consideration of the volume that can be imparted to the particle. Porous particles having a large intra-particle pore volume are preferable because they are excellent in plastic deformability and are easy to be crushed during compression. The porous cellulose agglomerates used in the present invention are those in which the pore volume in the agglomerated particles is intentionally increased in addition to those derived from the original cellulose. It has improved deformability. Therefore, high compression moldability is expressed regardless of the apparent specific volume of the particles. When the pore volume in the particle is less than 0.265 cm ³ / g, it has only the pores in the particle inherent to cellulose, or the pores in the particle due to spontaneous aggregation of cellulose without intentional formation. In order to improve the moldability, it is necessary to increase the apparent specific volume of the particles, resulting in poor fluidity of the particles. The porous cellulose aggregate used in the present invention can ensure good moldability with its relatively small apparent specific volume, and as a result, a product excellent in fluidity can be obtained.

If the pore volume in the particle is 0.265 cm ³ / g or more, the particle has a sufficient pore volume, so that the active ingredient once taken into the pores in the particle surface or the particle surface during the mixing process is removed. Since it is difficult to separate, a liquid component can be held in the pores in the particles, which is preferable because it is excellent in preventing bleeding. If the pore volume in the particle is less than 0.265 cm ³ / g, the above effect is difficult to obtain, which is not preferable.
The pore size distribution of the porous cellulose aggregate used in the present invention is measured, for example, by mercury porosimetry. In particular, it is preferable that a “clear peak” can be identified in the range of 0.1 to 10 μm. Further, the central pore diameter, which is the peak top of the pore distribution, is closely related to the permeability of water into the particles, and the central pore diameter is preferably 0.3 μm or more. When the median pore diameter is 0.3 μm or more, the water permeation rate increases and the disintegration property is further improved. The larger the median pore diameter, the better, but considering the distribution range, it is at most about 5 μm.

  The crystalline form of the porous cellulose aggregate used in the present invention must be type I. Known crystal forms of cellulose include type I, type II, type III, type IV, etc. Among them, type I is called “natural cellulose” and type II is called “regenerated cellulose”, and is widely used. Although type III, type IV are obtained on a laboratory scale, they are not widely used on an industrial scale. Natural cellulose has been used for food as vegetable fiber since ancient times, and is currently widely used as a dispersion stabilizer for liquid foods and as a pharmaceutical excipient. On the other hand, regenerated cellulose is obtained by removing a chemical solution such as carbon disulfide and sodium hydroxide and a solvent to regenerate and changing the crystal structure, and is partially used as a shape retainer for food. Regenerated cellulose with a crystal form of type II changes its crystal form from natural cellulose with a crystal form of type I, making the particles stiffer, reducing plastic deformability during compression, and providing sufficient hardness to the molded body Is not preferred because it cannot be imparted.

The average particle diameter of the porous cellulose aggregate used in the present invention must exceed 30 μm. Particularly preferably, it is more than 30 μm and 250 μm or less. When the average particle size is 30 μm or less, the cellulose particles are likely to aggregate with each other, and when mixed with the active ingredient, the active ingredient is difficult to uniformly disperse, and the active ingredient variation of the obtained molded product tends to increase. , The variation in the weight of the molded product during continuous production tends to increase. On the other hand, when the average particle diameter exceeds 250 μm, segregation and segregation are likely to occur when the prescription powder mixed with the active ingredient having poor fluidity is continuously compressed.
The specific surface area of the porous cellulose aggregate used in the present invention ^must be 1.3m ² / g~20m 2 / g. When the specific surface area is less than 1.3 m ² / g, the compression moldability becomes low, and high hardness and low friability cannot be imparted to the molded body. Furthermore, if the specific surface area is less than 1.3 m ² / g, the amount of active ingredient retained per unit weight is unfavorable. Further, if the specific surface area exceeds 20 m ² / g, when the active ingredient which is easily deactivated by cellulose is blended, the contact area between the cellulose and the active ingredient becomes excessively large. .

  The angle of repose of the porous cellulose aggregate used in the present invention must be less than 44 °. Usually, active ingredients are prepared in such a way that they diffuse in the gastric juice / intestinal fluid medium when taken and can rapidly improve the drug efficacy, and are often pulverized or originally finely divided. Since they are fine powders, they have poor fluidity, but when the repose angle of the cellulose powder is 44 ° or more, the fluidity of the mixed powder is not sufficient when a large amount of active ingredients with poor fluidity are blended. It is not preferable. In particular, variation in the weight of the molded article at the time of high-speed tableting of tens of thousands to hundreds of thousands of tablets / hour increases. The smaller the angle of repose, the better the fluidity, but it is preferably 25 to 42 °, particularly preferably 25 to 40 °. From the viewpoint of suppressing segregation and segregation with the active ingredient, the angle of repose is preferably 25 ° or more.

The apparent specific volume of the porous cellulose aggregate used in the present invention is preferably 2.0 to 6.0 cm ³ / g. Since the cellulose aggregate of the present invention has a porous structure, it has hardness, fluidity, and disintegration in a balanced manner over almost the entire area of the apparent specific volume compared to the conventional one. However, the apparent specific volume is preferably 2.0 cm ³ / g or more from the viewpoint of imparting high compression moldability, and 6.0 cm ³ / g or less from the viewpoint of imparting fluidity. More preferably, it is 2.5-5.0 cm < ³ > / g.
The production method of the porous cellulose aggregate particles used in the present invention is not particularly limited as long as the above physical properties are satisfied. For example, the porous cellulose aggregate particles can be obtained by the following method.

For example, the porous cellulose aggregate particles used in the present invention are dispersions containing a dispersion particle and a medium of two or more kinds of natural cellulose substances having different average particle diameters, and the average particle diameter of the cellulose dispersion particles is It can be obtained by drying a cellulose dispersion having a size of 1 to 110 μm.
The natural cellulosic material may be plant or animal. For example, fibers derived from natural products containing cellulose such as wood, bamboo, straw, rice straw, cotton, ramie, bagasse, kenaf, beet, squirt, and bacterial cellulose. It is preferable that it is a crystalline substance and has a cellulose I type crystal structure. As a raw material, one kind of natural cellulosic substances among the above may be used, or a mixture of two or more kinds may be used. Moreover, although it is preferable to use with the form of refined pulp, there is no restriction | limiting in particular in the refinement method of a pulp, You may use any pulp, such as a dissolving pulp, a kraft pulp, and NBKP pulp. Here, the natural cellulosic material may or may not hydrolyze raw materials such as pulp. In particular, when hydrolyzing, it may be acid hydrolysis, alkali oxidative decomposition, hydrothermal decomposition, steam explosion, etc., either method alone or in combination of two or more. Also good.

  In the above production method, the medium used when the solid content containing the cellulosic material is then dispersed in an appropriate medium is preferably water, but is not particularly limited as long as it is industrially used. Water and / or organic solvents may be used. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol, hydrocarbons such as pentane, hexane, heptane, and cyclohexane, acetone, and ethyl methyl ketone. Ketones are mentioned. In particular, the organic solvent is preferably used for pharmaceuticals, and examples thereof include those classified as solvents in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.). Water and organic solvents can be used alone or in combination of two or more, and once dispersed in one medium, the medium can be removed and dispersed in a different medium. Good.

  The porous cellulose aggregate particles used in the present invention can be obtained by drying a cellulose dispersion obtained by mixing two or more types of cellulose dispersion particles having different average particle diameters. Although there is no restriction | limiting in particular in the average particle diameter of each cellulose dispersion particle group, 1-110 micrometers is preferable. The present invention only needs to include two or more types of cellulose-dispersed particle groups having different average particle diameters in this average particle diameter range, and unless the average particle diameter is the same, which average particle diameter is You may mix | blend what it has. For example, when mixing two types of cellulose-dispersed particle groups having different average particle diameters, those having a large average particle diameter are 10 to 110 μm, and those having a small average particle diameter are 0.005 to 0.99 relative to the average particle diameter. The average particle size is preferably doubled. More preferably, the smaller one has an average particle size of 0.01 to 0.8 times the larger average particle size. Most preferably, the smaller one has an average particle size of 0.01 to 0.7 times the larger average particle size. Mixing two or more types of cellulose dispersed particle groups having different average particle sizes means that when the cellulose dispersion is dried, cellulose dispersed particles having a small average particle size enter between cellulose dispersed particle components having a large average particle size. This contributes to suppressing excessive aggregation between cellulose dispersed particle groups having a large average particle diameter. In order to suppress capillary condensation that occurs when the medium is vaporized, the structure of the cellulose-dispersed particles at the time of drying takes a secondary agglomeration structure in which each is a primary particle, and maintains a large pore volume in the particle.

The weight ratio of the cellulose particle group having a large average particle diameter and the cellulose particle group having a small average particle diameter may be usually in the range of 5 to 95 to 95 to 5, although it depends on the purpose. Preferably, it is 10 to 90 to 90 to 10, more preferably 20 to 80 to 80. By selecting an appropriate weight ratio, the value of the pore volume can be controlled.
At this time, it is preferable to use a cellulose particle group having a large average particle diameter in which the ratio of the average value of the major axis to the minor axis (L / D) is 2.0 or more. The larger the L / D, the greater the effect of suppressing excessive particle aggregation during drying, so that a large pore volume can be maintained in the particles.

  There is no particular limitation on the method for obtaining the dispersion from the above-mentioned two or more types of cellulose particle groups having different average particle diameters, but i) prepared separately from a plurality of cellulose particle groups having different average particle diameters. A method of mixing the obtained cellulose particle dispersion, ii) a method of treating a part of a group of cellulose particles and preparing and mixing those having different average particle diameters. iii) Cellulose particle groups having one average particle size may be fractionated and each treated, and those having different average particle sizes may be prepared and mixed. The production methods i to iii) can be used alone or in combination of two or more. The treatment method applied here may be wet or dry, and even if each obtained by wet is mixed before drying, each obtained by dry is mixed before drying Alternatively, those obtained by wet or dry methods may be combined. Although there is no restriction | limiting in particular, For example, you may grind | pulverize and grind | pulverize, you may use methods, such as classification using a sieve, cyclone, centrifugation using a centrifuge, and the method of combining them.

  As a grinding method, a stirring blade such as a one-way rotary type such as a portable mixer, a three-dimensional mixer, a side mixer, a multi-axis rotary type, a reciprocating inversion type, a vertical movement type, a rotation + vertical movement type, and a pipe type is used. Any milling method, jet-stirring grinding method such as a line mixer, grinding method using a high shear homogenizer, high-pressure homogenizer, ultrasonic homogenizer, etc., for example, an axial rotation extrusion type grinding method such as a kneader, etc. . As the pulverization method, a screen-type pulverization method such as a screen mill or a hammer mill, a blade-rotating shear screen-type pulverization method such as a flash mill, an air-flow-type pulverization method such as a jet mill, a ball-type pulverization method such as a ball mill or a vibration ball mill, a blade Any of the stirring type pulverization methods may be used.

The cellulose dispersed particles obtained by the above operation are preferably made into a dispersion having a concentration of 5 to 40% by weight before drying. The obtained porous cellulose aggregate particles are preferably 5% by weight or more in terms of self-fluidity and 40% by weight or more in terms of compression moldability. More preferably, it is 10-40 weight%, More preferably, it is 15-40 weight%.
Moreover, it is preferable that the average particle diameter of the cellulose dispersion particle which exists in the said 5 to 40 weight% concentration cellulose dispersion liquid is 1-110 micrometers. When the average particle size exceeds 110 μm, the cellulose particles after drying become excessively large, and depending on the type of active ingredient, separation and sizing may occur when mixed with them, while the average particle size is 1 μm or less. In some cases, the cellulose particles after drying become excessively small, and it may be difficult to maintain good fluidity. More preferably, it is 5-90 micrometers, More preferably, it is 10-80 micrometers. An average particle diameter here can be calculated | required by the method generally used of the volume particle size distribution measurement measured with a laser diffraction type particle size distribution meter (the product made from HORIBA, a brand name, LA-910 type), for example.

  The average particle size is controlled by measuring the average dispersed particle size in the dispersion, while adjusting the degree of polymerization by hydrolysis of the raw material cellulose by an existing method, and / or the conditions of the dispersion process, particularly the degree of polymerization of cellulose. The lower the particle diameter, the easier the average particle diameter to decrease due to dispersion, and it can be controlled within a desired range by adjusting the stirring power of the hydrolysis solution or dispersion solution. In general, when the hydrolysis conditions (acid, alkali concentration, reaction temperature) are increased and the stirring force is increased, the average particle size of the dispersed particles tends to decrease.

The drying method is not particularly limited, and for example, any of freeze drying, spray drying, drum drying, shelf drying, airflow drying, and vacuum drying may be used. You may use the above together. The spraying method for spray drying may be any spraying method such as a disk type, a pressurized nozzle, a pressurized two-fluid nozzle, a pressurized four-fluid nozzle, etc. May be used in combination.
When spray drying is performed, a foaming agent or a gas is added for the purpose of accelerating the vaporization rate of the medium even if a small amount of water-soluble polymer or surfactant is added for the purpose of reducing the surface tension of the dispersion. It may be added to the dispersion.

  Examples of water-soluble polymers include “Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, carboxo vinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, gum arabic, starch glue,“ pharmaceutical additive encyclopedia ” Water-soluble polymers described in (published by Yakuji Nippo Co., Ltd.) may be mentioned, and one kind may be used alone or two or more kinds may be used in combination.

  Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, Polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan sun monolaurate, polysorbate, sorbitan monooleate, monostearate glyceride, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, polyoxymonooleate "Pharmaceutical Additives Encyclopedia" such as ethylene sorbitan, sorbitan monopalmitate, sodium lauryl sulfate ) Issued) those classified as a surfactant can be mentioned, even using it alone, it is free to combination of two or more.

  As foaming agents, pharmaceutical encyclopedias such as tartaric acid, sodium hydrogen carbonate, potato starch, anhydrous citric acid, medicated soap, sodium lauryl sulfate, lauric acid diethanolamide, laumacrogol (published by Yakuji Nippo Co., Ltd.) Can be used alone or in combination of two or more. In addition to pharmaceutical additives, use bicarbonates that generate gas by thermal decomposition such as sodium bicarbonate and ammonium bicarbonate, and carbonates that generate gas by reacting with acids such as sodium carbonate and ammonium carbonate. May be. However, when using the above carbonates, it is necessary to use them together with an acid. Examples of the acid include organic acids such as citric acid, acetic acid, ascorbic acid, and adipic acid, protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and acidic substances such as Lewis acids such as boron fluoride. Although what is used as is preferable, it has the same effect other than that. Instead of the foaming agent, the dispersion may be impregnated with a gas such as nitrogen, carbon dioxide, liquefied petroleum gas, or dimethyl ether. These water-soluble polymers, surfactants, and substances that generate gas may be added before drying, and there is no particular limitation on the timing of the addition.

The solid pharmaceutical composition of the present invention needs to contain one or more active ingredients and porous cellulose aggregate particles. The amount of the porous cellulose aggregate is preferably 1 to 99% by weight, and the active ingredient is preferably 0.001 to 99% by weight. If the active ingredient is less than 0.001%, it is difficult to ensure a therapeutically effective amount, and if it exceeds 99%, the cellulose aggregate of the present invention is less than 1%, so that the effects of the present invention are hardly obtained. .
The solid preparation composition here is generally used as a solid preparation such as powder, granule, tableting powder, tableting granule, tablet, capsule and the like, and each is a coating agent. The coated one is also included. In addition, the effect of the present invention is not affected by the shape and weight thereof, and the method for producing the solid preparation composition is not particularly limited as long as it is a general method for producing a solid preparation.

Although the manufacturing method of the solid formulation composition of this invention is described below, it is an example and is not limited to the following.
The active ingredient as used in the present invention refers to pharmaceutical medicinal ingredients, agricultural chemical ingredients, fertilizer ingredients, feed ingredients, food ingredients, cosmetic ingredients, pigments, fragrances, metals, ceramics, catalysts, or surfactants, powders, crystals It may be in any form such as a solid, oily, liquid, or semi-solid form, or it may be coated for the purpose of controlling elution or reducing bitterness. The active ingredients may be used alone or in combination.
For example, anti-pyretic analgesics, antihypnotics, drowsiness preventives, antipruritics, pediatric analgesics, stomachic drugs, antacids, digestives, cardiotonic drugs, arrhythmic drugs, antihypertensives, vasodilators , Diuretics, anti-ulcer drugs, intestinal drugs, osteoporosis treatments, antitussive expectorants, anti-asthma drugs, antibacterial agents, frequent urination drugs, nourishing tonics, vitamins, etc. . The medicinal component can be used alone or in combination of two or more.

The liquid and semi-solid active ingredient referred to in the present invention refers to those which are liquid and semi-solid at normal temperature and normal pressure. Here, even if it is solid at normal temperature and normal pressure, it may be dissolved or dispersed in a medium, or the solution or dispersion held in a carrier may be semi-solid.
Examples of oily and liquid active ingredients used in the present invention include, for example, teprenone, indomethacin farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D, vitamin E and other vitamins, DHA (docosahexaenoic acid) , “Japanese Pharmacopoeia”, “Extraordinary Group”, such as EPA (eicosapentaenoic acid), higher unsaturated fatty acids such as liver oil, coenzyme Q, orange oil, lemon oil, peppermint oil, etc. Medicinal medicinal ingredients described in “USP”, “NF”, “EP” and the like. Vitamin E has various homologues and derivatives, but is not particularly limited as long as it is liquid at normal temperature. For example, dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, d-α-tocopherol acetate and the like can be mentioned. Even if one kind selected from the above is used alone, two or more kinds can be used. Can also be used together.

Semi-solid active ingredients include, for example, earth dragons, licorice, cinnamon, peonies, buttonpi, valerian, salamander, ginger, chimpi, mao, nantenjitsu, ohhi, onji, kyoukyo, shazenshi, shazenso, sarcophagus, seneca, baimo , Fennel, autac, auren, gadget, chamomile, gentian, goo, beast gall, shajin, ginger, sojutsu, clove, chinhi, sandalwood, chiketsu carrot, carrot, kakkonto, katsushiyu, kososan, purple katsura Mention herbal or herbal extracts such as hot water, small purple koto hot water, small blue dragon hot water, Mumon winter hot water, semi-summer Koboku hot water, Mao hot water, oyster meat extract, propolis and propolis extract, coenzyme Q, etc. It is possible to use one kind selected from the above alone or to use two or more kinds in combination.
In addition to the active ingredient and the porous cellulose aggregate of the present invention, the solid preparation composition of the present invention includes other physiologically active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants as necessary. It is also free to include agents, flavoring agents, flavoring agents, coloring agents, and sweetening agents.

  Other physiologically active ingredients used in the present invention include, for example, aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, hydrochloric acid Difeterol, triprolidine hydrochloride, tripelenamine hydrochloride, tonsilamine hydrochloride, phenetazine hydrochloride, methodirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline tecolate, mebhydromethylene napadisylate Disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorfe d-maleate Lamin, dipheterol phosphate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate (carbetapentane citrate), tipepidine citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorphan / phenol phthalate Phosphoric acid, tipipedin hibenzate, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacol sulfonate, guaifenesin, sodium caffeine benzoate, Caffeine, anhydrous caffeine, vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof, and salts thereof, vitamin C and derivatives thereof and the like Salts, hesperidin and its derivatives and their salts, vitamin B6 and its derivatives and their salts, nicotinamide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, oxidation Magnesium, dihydroxyaluminum / aminoacetate (aluminum glycinate), aluminum hydroxide gel (as dry aluminum hydroxide gel), dry aluminum hydroxide gel, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / sodium bicarbonate Coprecipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, Coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, Magnesium carbonate, Magnesium aluminate metasilicate Uranium, ranitidine hydrochloride, cimetidine, famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol hydrochloride, diphenylpyraline, diphenhydramine hydrochloride, promethazine hydrochloride, meclizine hydrochloride, dimenhydranthinate ditanhydrinate ditannin Acid phenetadine, diphenylpyraline teocrate, diphenhydramine fumarate, promethazine methylene disalicylate, spocollamine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methyl atropine, methyl anisotropine bromide, bromide Methylspocollamine, methyl-1-hyostiamine bromide, methylbenactidium bromide, veradon Extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate, aminophylline, diprophylline, theophylline, sodium bicarbonate, fursultiamine, isosorbide nitrate, Ephedrine, cephalexin, ampicillin, sulfixazole, sucralfate, allylisopropylacetylurea, bromvalerylurea, etc. , Chamomile, keihi, gentian, goo, beast gall (including yutan), shajin, ginger, sojutsu, clove, chimpi “Japanese Pharmacopoeia” and “Extraordinary Group” such as sand pea, ground dragon, chixetsu carrot, carrot, valerian, button pi, salamander and their extracts, insulin, vasopressin, interferon, urokinase, seratiothiopeptidase, somatostatin, etc. , “USP”, “NF”, “EP”, and the like, and the medicinal medicinal ingredients can be mentioned, and one kind selected from the above can be used alone or two or more kinds can be used in combination. .

  Excipients include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, inositol, ethylcellulose, ethylene Vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice grains, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry magnesium sulfate, agar, Agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay granules, croscarmellose nato Um, crospovidone, magnesium aluminate silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose / carmellose sodium, crystalline cellulose (grain) Synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ flour, rice, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, white beeswax, zinc oxide, titanium oxide, Magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, baked gypsum, sucrose fatty acid ester, hydroxylation Alumina magnesium, aluminum hydroxide / gel, aluminum hydroxide / sodium bicarbonate coprecipitate, magnesium hydroxide, sucurawan, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, purified gelatin, purified shellac, purified Sucrose, refined sucrose spherical granules, cetostearyl alcohol, polyoxyethylene cetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean unsaponifiable matter, soybean lecithin, skim milk powder, talc, ammonium carbonate, Calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn Powder, tragacanth powder, silicon dioxide, calcium lactate, lactose, lactose G, perfiller 101, white shellac, white petrolatum, crushed, sucrose, white sugar / starch spherical granules, powdered green leaf extract, naked malt green juice dried powder, honey , Paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powder reduction Maltose starch syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polio Cypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polyoxyethylene sorbitan monooleate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, polyethylene glycol, maltitol, maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granulated product, magnesium metasilicate aluminate, methyl cellulose, cottonseed powder, cottonseed oil, owl, aluminum monostearate, monostearic acid Glycerin, sorbitan monostearate, medicinal charcoal, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin Din, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc. Are classified as excipients in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.). They can be used alone or in combination of two or more.

  Disintegrants include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, celluloses such as low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato Listed as disintegrants in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as starches, starches such as partially pregelatinized starch, synthetic polymers such as crospovidone and crospovidone copolymers Can do. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.

  As binders, sugars such as sucrose, glucose, lactose, fructose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, gelatin, pullulan, carrageenan, locust bean gum, agar, gluconannan, xanthan gum, tamarind Water-soluble polysaccharides such as gum, pectin, sodium alginate, gum arabic, etc., celluloses such as crystalline cellulose, powdered cellulose, hydroxypropylcellulose, methylcellulose, starches such as pregelatinized starch, starch paste, polyvinylpyrrolidone, carboxyvinyl polymer, Synthetic polymers such as polyvinyl alcohol, inorganic compounds such as calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, magnesium aluminate silicate etc. "May include those classified as a binder (Yakujinipposha Corporation published). Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.

Examples of the fluidizing agent include those classified as fluidizing agents in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as silicon compounds such as hydrous silicon dioxide and light anhydrous silicic acid. . Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.
Examples of lubricants include those classified as lubricants in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, and talc. be able to. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.
As a corrigent, "Pharmaceutical Additives Encyclopedia" such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. (published by Yakuji Nippo Co., Ltd.) ) Can be listed as a corrigent. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.

Perfumes include orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, mint oil, and other “pharmaceutical additives” (published by Yakuji Nippo Co., Ltd.). The thing classified as a flavoring agent and a fragrance | flavor can be mentioned. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.
Coloring agents include food colorings such as Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, etc., “Pharmaceutical Additives Encyclopedia” such as copper chlorofin sodium, titanium oxide and riboflavin (published by Yakuji Nippo Co., Ltd.) And those classified as colorants. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.
As sweeteners, those classified as sweeteners in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as aspartame, saccharin, dipotassium gilicyrrhizinate, stevia, maltose, maltitol, chickenpox, and amacha powder Can be mentioned. Even if it uses individually by 1 type chosen from the above, it is also free to use 2 or more types together.
Examples of the composition include tablets, powders, fine granules, granules, extracts, solid preparations of pills and the like when used for pharmaceuticals. The present invention includes not only pharmaceuticals but also foods such as confectionery, health foods, texture improvers, dietary fiber reinforcing agents, solid foundations, bath preparations, animal drugs, diagnostic agents, agricultural chemicals, fertilizers, ceramic catalysts, etc. include.

In the following, a method for producing a tablet composition comprising at least one active ingredient and porous cellulose aggregate particles as main components is described, but this is an example, and the effect of the present invention is limited to the following method. is not.
As used herein, the active ingredient may be used alone or may be used by dissolving, suspending or emulsifying the active ingredient in a medium.

  The order of addition of the active ingredient and the porous cellulose aggregate particles is not particularly limited. I) The active ingredient is pulverized or used as it is, and mixed with the porous cellulose aggregate particles and other ingredients as necessary. The other additive referred to herein is an additive other than the porous cellulose aggregate particles used in the present invention. For example, the above-mentioned excipients, disintegrants, binders, fluidizers, lubricants It refers to additives such as agents, flavoring agents, fragrances, coloring agents, sweetening agents, solubilizing agents and the like. These additives may be used alone or in combination of two or more. ii) The active ingredient is pulverized or used as it is, and the resulting active ingredient is pretreated and mixed with an additive such as a fluidizing agent, and then mixed with porous cellulose aggregate particles and other ingredients as necessary. Iii) after adding the active ingredient with water and / or an organic solvent and, if necessary, a solubilizing agent, dissolving or dispersing the active ingredient, and if necessary, the porous cellulose aggregate particles used in the present invention and / or Any method of adsorbing to other additives, mixing the porous cellulose aggregate particles and other additives as required, and distilling off water and / or the organic solvent as necessary may be used. Here, when an active ingredient that forms crystals at room temperature is used, the crystal form of the active ingredient after the solid preparation composition may be the same as or different from the pre-formulation state, but the stability It is preferable that it is the same at this point.

In particular, in the case of the method iii), since the process of once dissolving or dispersing the slightly soluble and insoluble active ingredient in water is performed, there is also an effect of improving the elution of the active ingredient.
Further, when a liquid dispersion such as polyethylene glycol is used in combination as a dispersion of a pharmaceutical active ingredient, even if the original active ingredient is a crystalline powder, the dispersion in which it is dispersed becomes liquid or semi-solid. Therefore, tableting is difficult unless it is excellent in compression moldability and fluidity like the porous cellulose aggregate used in the present invention. In addition, when polyethylene glycol or the like is used as a dispersion of a pharmaceutical active ingredient, it is said that when the active ingredient is absorbed into the body, it has a structure covered with polyethylene glycol in the blood and is metabolized in the liver. It is also expected to have an effect of sustaining the medicinal effects of the active ingredients that are easily applied.

  There are no particular restrictions on the method of dissolving or dispersing the active ingredient in the medium as long as it is a commonly used dissolution and dispersion method, but one-way rotary type, multi-axis rotary type, reciprocal inversion such as portable mixer, three-dimensional mixer, side mixer, etc. , Vertical movement, rotation + vertical movement, pipe-type stirring and mixing methods, line-type and other jet-type stirring and mixing methods, gas blowing type stirring and mixing methods, high shear homogenizers, high-pressure homogenizers Alternatively, a mixing method using an ultrasonic homogenizer or the like, a container shaking mixing method using a shaker, or the like may be used.

  Although it will not restrict | limit especially if it is used for a pharmaceutical as a solvent used in said manufacturing method, For example, you may use water and / or an organic solvent. Examples of the organic solvent include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol, hydrocarbons such as pentane, hexane, heptane, and cyclohexane, acetone, and ethyl methyl ketone. Ketones are mentioned. In particular, the organic solvent is preferably used for pharmaceuticals, and examples thereof include those classified as solvents in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.). Water and organic solvents can be used alone or in combination of two or more, and once dispersed in one medium, the medium can be removed and dispersed in a different medium. Good.

Examples of the water-soluble polymer as a solubilizer include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, ethylcellulose, gum arabic, and starch paste. Water-soluble polymers described in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) can be mentioned. They can be used alone or in combination of two or more.
Examples of fats and oils as solubilizers include stearic acid monoglyceride, stearic acid triglyceride, stearic acid sucrose ester, paraffins such as liquid paraffin, hardened oils such as carnauba wax and hardened castor oil, castor oil, stearic acid , Oils and fats described in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as stearyl alcohol, polyethylene glycol, etc. are listed. They can be used alone or in combination of two or more. It is.

  Surfactants as solubilizers include, for example, phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxy Ethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan sun monolaurate, polysorbate, sorbitan monooleate, glyceride monostearate, monooxyethylene sorbitan monopalmitate, monooxyethylene sorbitan monostearate, Pharmaceutical additives such as polyoxyethylene sorbitan monooleate, sorbitan monopalmitate, sodium lauryl sulfate, etc. "(Yakujinipposha Corporation published) those classified as a surfactant can be mentioned, even using it alone, it is free to combination of two or more.

The method for adding one or more kinds of active ingredients to the porous cellulose aggregate used in the present invention and other additives is not particularly limited as long as it is a commonly used method. These may be added continuously using a bucket conveyor, a pressure-feed type transport device, a vacuum conveyor, a vibratory quantitative feeder, a spray, a funnel or the like, or may be charged all at once.
When the active ingredient is a solution, suspension or emulsion, the dispersion of the active ingredient concentration in the final product is reduced by adopting a method of spraying them on porous cellulose aggregates or other additives. preferable. As a spraying method, a method of spraying an active ingredient solution / dispersion using a pressure nozzle, a two-fluid nozzle, a four-fluid nozzle, a rotating disk, an ultrasonic nozzle, etc., a method of dropping an active ingredient solution / dispersion from a tubular nozzle Either of these may be used. When adding the active ingredient solution / dispersion liquid, it may be layered or coated such that the active ingredient is laminated on the surface of the porous cellulose aggregate particles, or may be supported inside the porous cellulose aggregate particles. Alternatively, porous cellulose aggregate particles or a mixture of porous cellulose and other additives may be granulated in a matrix using the active ingredient solution / dispersion as a binding liquid. The effect is the same whether the layering or coating is wet or dry.

Since the porous cellulose aggregate used in the present invention is excellent in liquid component retention, when it is used as a core particle, aggregation of particles with layering and coating can be suppressed.
In addition, when the active ingredient is a solution, suspension, or emulsion, the active ingredient solution, such as dipping using porous cellulose aggregate particles or a mixture of porous cellulose aggregate particles and other additives as a carrier, A method can be used in which the active ingredient is retained by dipping in a suspension or emulsion. Although depending on conditions such as active ingredient species and concentration, the liquid dipping method such as dipping is practically uniform in the active ingredient, and is superior in that the process is simpler than the above spraying.

Further, when the active ingredient is a solution, suspension, or emulsion, the active ingredient solution, suspension, or mixture of porous cellulose aggregate particles or porous cellulose aggregate particles and other additives is used as a carrier. After being immersed in the emulsion, the dispersion may be spray-dried to form a composite.
The porous cellulose aggregate particles before and after the addition of the active ingredient solution / dispersion liquid, or the mixture of the porous cellulose aggregate particles and other additives were aggregated even when each unit particle was individually dispersed. You may take the form of the granulated material.
The method for adding one or more active ingredients, porous cellulose aggregate particles, and other additives is not particularly limited as long as it is a commonly used method, but a small suction transport device, a pneumatic transport device, a bucket conveyor, They may be added continuously using a pressure-feed type transport device, a vacuum conveyor, a vibratory quantitative feeder, a spray, a funnel or the like, or may be added all at once.

  As granulation methods in the case of undergoing granulation in the production process, there are dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. As the wet granulation method, specifically, the fluidized bed granulation method, the stirring granulation method, the extrusion granulation method, the crushing granulation method, and the rolling granulation method are effective. In the fluidized bed granulation method, In a fluidized bed granulator, the fluidized powder is granulated by spraying the binding liquid. In the stirring granulation method, powder is mixed, kneaded, and granulated simultaneously in a sealed structure by rotating a stirring blade in a mixing tank while adding a binding liquid. In the extrusion granulation method, granulation is performed by forcibly extruding the wet mass kneaded by the addition of the binding liquid from a screen of an appropriate size by a screw type or basket type method. In the crushing granulation method, the wet lump kneaded by the addition of the binding liquid is sheared and crushed with a rotary blade of a granulator, and granulated by ejecting it from the outer peripheral screen by its centrifugal force. In the rolling granulation method, rolling is performed by the centrifugal force of a rotating rotor, and granulation is performed by growing spherical granules having a uniform particle size in a snowman manner with a binding liquid sprayed from a spray gun. .

The granulated product can be dried by hot air heating type (shelf drying, vacuum drying, fluidized bed drying), conduction heat transfer type (flat pan type, shelf box type, drum type), or freeze drying. Can also be used. In the hot air heating type, the material is brought into direct contact with hot air, and at the same time, evaporated water is removed. In the conduction heat transfer type, the material is indirectly heated through the heat transfer wall. In lyophilization, the material is frozen at −10 to 40 ° C. and then sublimated by heating under high vacuum (1.3 × 10 ^{−5 to} 2.6 × 10 ⁻⁴ MPa). To remove.

For example, i) a mixture of an active ingredient and porous cellulose aggregate particles, or a mixture of one or more active ingredients and porous cellulose aggregate particles and, if necessary, other additives as usual Compression molding with. (Direct tableting method) or ii) After mixing the active ingredient, porous cellulose aggregate particles, and other additives as necessary, granulate to form granules, and compression molding by ordinary methods Good. (Wet / Dry Granule Compression Method) Furthermore, iii) Active ingredient, porous cellulose aggregate particles, and other additives as necessary are mixed, granulated to give granules, and further, porous cellulose aggregate particles If necessary, other additives may be mixed and compression molded by a usual method. (Wet / dry granule after-compression method)
The method for adding one or more active ingredients, porous cellulose aggregates, other additives, or granules is not particularly limited as long as it is a commonly used method, but is a small suction transport device, pneumatic transport device, bucket It may be added continuously using a conveyor, a pressure-feed type transport device, a vacuum conveyor, a vibration type quantitative feeder, a spray, a funnel or the like, or may be added all at once.

The mixing method is not particularly limited as long as it is a normal method, but a container rotary mixer such as a V type, W type, double cone type, container tack type mixer, or a high speed stirring type, a universal stirring type. Further, a stirring type mixer such as a ribbon type, a pug type or a Nauter type mixer, a high-speed flow type mixer, a drum type mixer or a fluidized bed type mixer may be used. A shaker mixer such as a shaker can also be used.
The compression molding method of the composition is not particularly limited as long as it is a commonly performed method, but a method of compression molding into a desired shape using a mortar and a pestle, after having been previously compression molded into a sheet shape, into a desired shape A method of cleaving may be used. As the compression molding machine, for example, a roller press such as a hydrostatic press, a briquetting roller press, a smooth roller press, a compressor such as a single punch tablet press, or a rotary tablet press can be used. .

  Next, a method of using a composition containing one or more active ingredients and porous cellulose aggregate particles will be described. The solid, liquid, semi-solid active ingredient and porous cellulose aggregate particle composition obtained by the method described so far can be used as a solid preparation in the form of a powder or granule. Further, a coating agent may be coated and used as a coating powder or a granular solid preparation. The obtained powdered or granular composition with or without the coating may be filled into capsules and used, or may be compressed and used as a tablet-type solid preparation. Further, capsules or tablets may be coated and used.

  Examples of the coating agent used for coating are, for example, ethyl acrylate / methyl methacrylate copolymer dispersion, acetylglycerin fatty acid ester, aminoalkyl methacrylate copolymer, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, octyl Decyl triglyceride, olive oil, kaolin, cacao butter, kaso, castor wax, caramel, carnauba wax, carboxyvinyl polymer, carboxymethyl ethyl cellulose, carboxymethyl starch sodium, carmellose calcium, carmellose sodium, hydrous silicon dioxide, dry aluminum hydroxide gel , Dried milky white rack, dried methacrylic acid copolymer, ume powder, fish scale powder, gold leaf, silver leaf, triethyl citrate, glyce Glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid, light anhydrous silicic acid-containing hydroxypropylcellulose, light liquid paraffin, whale wax, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic wax, high glucose starch syrup, hard Wax, succinylated gelatin, wheat flour, wheat starch, rice starch, cellulose acetate, vinyl acetate resin, cellulose acetate phthalate, honey beeswax, titanium oxide, magnesium oxide, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, dimethylpolysiloxane, Dimethylpolysiloxane / silicon dioxide mixture, silicon oxide mixture, baked gypsum, sucrose fatty acid ester, zinc oxide powder, aluminum hydroxide gel, hydrogenated rosin glycerin ester, stearyl alcohol , Stearic acid, aluminum stearate, calcium stearate, polyoxyl stearate, magnesium stearate, purified gelatin, purified shellac, purified white sugar, zein, sorbitan sesquioleate, cetanol, gypsum, gelatin, shellac, sorbitan fatty acid ester, D- Sorbitol, D-sorbitol solution, tricalcium phosphate, talc, calcium carbonate, magnesium carbonate, simple syrup, medium gold foil, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, terpene resin, starch (soluble), corn syrup, corn oil, Triacetin, calcium lactate, white shellac, white sugar, honey, hard fat, paraffin, pearl powder, potato starch, hydroxypropyl cellulose, hydroxy Propylcellulose, hydroxypropylcellulose acetate succinate, hydroxypropylcellulose / titanium oxide / polyethylene glycol mixture, hydroxypropylmethylcellulose phthalate, piperonyl butoxide, castor oil, diethyl phthalate, dibutyl phthalate, britphthalyl butyl glycolate, glucose, partial alpha Starch, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydroxypropyl cellulose mixture, pullulan, propylene glycolose, powdered sugar, bentonite, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) Glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, poly Xylethylene sorbitan monostearate, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol (partially saponified product), polyethylene glycol, terminal hydroxyl group-substituted methylpolysiloxane silicone resin copolymer, D-mannitol, starch syrup, beeswax, myristyl alcohol, anhydrous silicic acid water Japanese, phthalic anhydride, anhydrous calcium hydrogen phosphate, methacrylic acid copolymer, magnesium aluminate metasilicate, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, owl, glyceryl monostearate, monostearic acid Sorbitan, sorbitan monolaurate, montanic acid ester wax, medicinal charcoal, lauromacrogol, calcium sulfate, fluid coumarone resin, fluid paraffin , Dl-malic acid, calcium monohydrogen phosphate, calcium hydrogen phosphate, sodium hydrogen phosphate, calcium dihydrogen phosphate, rosin, etc., described in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) A coating agent is mentioned, It is also free to use it alone, or to use 2 or more types together.

  The tablet referred to in the present invention includes a porous cellulose aggregate used in the present invention, one or more active ingredients, and other additives as necessary, and can be obtained by compression molding. Say. The tablet composition containing the porous cellulose aggregate can be obtained with practical hardness by a simple method such as a direct tableting method without going through complicated steps. Use any of the manufacturing methods such as compression method, wet granule compression method, later powder method, multi-core tablet with pre-compressed tablet as inner core, multi-layer tablet manufacturing method that compresses multiple compressed bodies and compresses again May be.

  The porous cellulose aggregate used in the present invention is excellent in various physical properties required as an excipient for compression moldability, self-flowability, and disintegration. Tablets that are prone to tableting problems such as peeling and cracking from tablets, and tablets containing a large amount of drugs, such as tablets containing a mixture of extract powders such as popular medicines and Kampo medicines, small tablets, and constriction of the edges are applied evenly. It is effective for non-circular deformed tablets having difficult portions, drugs such as enzymes and proteins that are easily inactivated by compression and friction with excipients, and tablets containing coated granules. In addition, since the porous cellulose aggregate used in the present invention is excellent in compression moldability and disintegration, a tablet showing a practical friability at a relatively low compression pressure can be obtained. Therefore, since a space | gap (water conduit) can be maintained in a tablet, it is effective also in an orally disintegrating tablet which disintegrates rapidly in an oral cavity. In addition, for multi-layered tablets and dry-coated tablets that are compression-molded with several components in one step or other steps, in addition to the above-mentioned hardness imparting and suppression of general tableting problems, delamination and cracking are suppressed. There is also an effect. Since the cellulose aggregate of the present invention has a secondary aggregate structure in which primary particles are aggregated, it is excellent in the splitting property of the particles themselves, and when used in a scored tablet or the like, the tablet can be easily divided uniformly. Furthermore, porous cellulose aggregates have a developed porous structure, and the cellulose particles themselves have excellent retention of fine-particle drugs, suspension drugs, and solution-like components, so tablets using them are also solid and suspended. Excellent retention of liquid and solution components. Therefore, layering of suspension and solution components on tablets, coating tablets, and layering of sugar-coated tablets, etc. in which components such as sugar and calcium carbonate are laminated on the tablet surface in a suspended state, coating layers, sugar coating layers It is also effective to use for prevention of peeling and reinforcement.

  The cellulose aggregate used in the present invention has a developed porous structure, and the particles themselves have excellent drug retention. Therefore, even if the particles in which the drug is supported in the pores are used as they are, they are granulated. They may be used as granules or they may be compression molded. Those fine granules, granules and tablets may be further coated thereon. The loading method is not particularly limited as long as it is a known method, but i) a method in which it is mixed with a fine particle drug and loaded in the pores, ii) a powdered drug is mixed with high shearing, and is forcedly finely divided. A method of supporting in the pores, iii) a method of once mixing with the drug in the form of a solution or dispersion and supporting in the pores, then drying and supporting if necessary, iv) mixing with a sublimable drug and heating And / or a method of sublimating and adsorbing in the pores by reducing the pressure, or v) a method of mixing with a drug before or during heating and supporting a molten product in the pores, Even if it uses, 2 or more types may be used together.

The cellulose aggregate used in the present invention has a developed pore structure and has moderate water retention and oil retention, so it can be used as core particles for layering and coating in addition to excipients. Has an effect of suppressing aggregation between particles in the layering and coating processes. The effects of layering and coating are the same whether they are dry or wet.
Besides being compressed and molded as described above and used as a tablet, the tablet composition of the present invention is excellent in retention of solid and liquid components, and thus improves fluidity, blocking resistance, and aggregation resistance. You may use as a granule or a powder for the purpose. As a method for producing granules and powders, the same effect can be obtained by using any of dry granulation, wet granulation, heat granulation, spray drying, and microencapsulation.

The present invention will be described based on examples.
(1) Average particle diameter of cellulose dispersed particles (μm)
The sample dispersed with water was expressed as a 50% cumulative volume particle measured with a laser diffraction particle size distribution meter (manufactured by Horiba, trade name, LA-910), without ultrasonic treatment and with a refractive index of 1.20. . However, this measured value does not necessarily correlate because the measurement principle and the particle size distribution of the dry particles obtained by the following low tap method are completely different. Usually, the cellulose dispersed particles are in the form of an elongated fiber, and the average particle diameter measured by laser diffraction is regarded as a sphere having a diameter of 80% of the major diameter of the fibrous particle, It is measured by volume frequency with respect to the diameter. On the other hand, the average particle size obtained by the low tap method is to shake the obtained powder on a sieve, fractionate, and measure the weight frequency with respect to the particle size. Here, the particle fraction is: Depending on the minor axis of the fiber. Therefore, in general, the laser diffraction type that depends on the major axis of the fiber has a larger value than the low tap type that depends on the minor axis of the fiber.

(2) Observation of particle surface and pores by SEM Each cellulose sample was placed on a sample table with a carbon tape attached, and platinum palladium was vacuum-deposited (the film thickness of the deposited film was 20 nm or less at this time). Co., Ltd., trade name, JSM-5510LV, and when observed at an acceleration voltage of 6 kV, magnification of 250, and 1500 times, the primary particles are continuously aggregated, and the boundaries of the primary particles are clear and can be confirmed. A sample having a secondary aggregated particle structure in which primary particles having a central pore diameter of 0.1 μm or more were aggregated was marked with ◯, and a sample with other structures was marked with ×.

(3) Intraparticle pore volume (cm ³ / g), median pore diameter (μm)
The pore distribution was determined by mercury porosimetry using a trade name, Autopore 9520 type, manufactured by Shimadzu Corporation. Each sample powder used for the measurement was dried under reduced pressure at room temperature for 15 hours. By measuring the initial pressure at 20 kPa, from the obtained pore distribution, a “clear peak portion” within the pore diameter range of 0.1 to 10 μm was calculated as the intraparticle pore volume. Further, from the obtained pore distribution, the peak top of the “clear peak” seen in the pore diameter of 0.1 to 10 μm was taken as the central pore diameter, and the value was read.

(4) Crystal form X-ray diffraction was performed using an X-ray diffractometer, and the X-ray pattern was used for determination.
(5) Average particle diameter of dry particles (μm)
The average particle size of the powder sample is obtained by sieving 10 g of the sample for 10 minutes using a low-tap sieve shaker (trade name, sieve shaker A type, manufactured by Hira Kogakusho), JIS standard sieve (Z8801-1987). The particle size distribution was measured and expressed as a 50% cumulative weight particle size.
(6) Specific surface area (m ² / g)
Measurement was performed by the BET method using a product name, TriSTAR manufactured by Micromeritics Co., Ltd., using nitrogen as an adsorption gas. About 1 g of each sample powder was charged into a cell and measured. Each sample powder used for measurement was dried under reduced pressure at 110 ° C. for 3 hours.
(7) Apparent specific volume (cm ³ / g)
Using a 100 cm ³ graduated cylinder, coarsely fill a powder sample over 2-3 minutes using a quantitative feeder, etc., and level the top of the powder layer with a soft brush like a brush. This is the value obtained by reading the volume and dividing this by the weight of the powder sample. The weight of the powder was appropriately set so that the volume became 70 to 100 cm ³ .

(8) Angle of repose (°)
Using a Sugihara-style repose angle measuring device (slit size depth 10x width 50x height 140mm, protractor installed at a position of 50mm width), using a quantitative feeder, the movement when dropping cellulose powder into the slit at 3g / min Self-fluidity was measured.
(9) Disintegration of cellulose particles in water 0.1 g of each cellulose sample was introduced into a glass test tube, 10 g of pure water was added, and after ultrasonic treatment for 1 minute, a microscope was used with or without ultrasonic treatment. (The product made by KEYENCE, a brand name, VH-7000) was observed, and the presence or absence of particle | grain collapse was observed. Those in which disintegration was observed were marked with ◯, and those not observed were marked with x.

[Example 1]
2 kg of chopped commercial pulp (wood-derived natural cellulose-dissolved pulp) and 30 L of 4N hydrochloric acid aqueous solution are placed in a low-speed stirrer (Ikebukuro Sakai Kogyo Co., Ltd., trade name, 30LGL reactor) and stirred. Then, hydrolysis was performed at 40 ° C. for 48 hours to obtain an acid-insoluble residue. The obtained acid-insoluble residue was sufficiently washed with pure water and then filtered to obtain wet floc (the average particle size of cellulose-dispersed particles of this acid-insoluble residue was 55 μm). 50% by weight of the obtained wet floc was further thoroughly washed with pure water, neutralized, filtered again, and air-dried to obtain a flock-shaped dried product. After crushing this flock-like dried product with a home-use mixer, it is further pulverized using an airflow pulverizer (trade name, single-track jet mill STJ-200 type, manufactured by Seishin Enterprise Co., Ltd.) The cellulose particle diameter was 5 μm) to obtain a pulverized product. The obtained pulverized product and the wet acid-insoluble residue in a composition of 50 parts by weight and 50 parts by weight (dry base) were introduced into a 90-liter plastic bucket and purified so that the total solid content was 25% by weight. While adding water and stirring with a 3-1 motor, the solution was neutralized with aqueous ammonia (pH after neutralization was 7.5 to 8.0) and spray-dried (dispersion supply rate 6 kg / hr, Cellulose particles A were obtained at an inlet temperature of 180 to 220 ° C. and an outlet temperature of 50 to 70 ° C. Various physical properties of the cellulose particles A are shown in Table 1.

  Cellulose particles A5 g are charged into 20 g of a solution-like active ingredient obtained by diluting ibuprofen-polyethylene glycol solution (quantity ratio 1: 5) 10 times with ethanol (manufactured by Wako Pure Chemicals, special grade), and 5 minutes with a magnetic stirrer in a beaker. Mixed. The obtained mixed solution was vacuum dried using an evaporator to obtain a powder. 0.2 g of the obtained powder is weighed and placed in a mortar (manufactured by Kikusui Seisakusho, using material SUS2, 3), and pressure is applied with a circular flat bowl having a diameter of 0.8 cm (manufactured by Kikusui Seisakusho, using material SUS2, 3). Was compressed to 100 MPa (manufactured by Aiko Engineering, trade name, PCM-1A used, compression speed was 1 cm / min), held at the target pressure for 10 seconds, and then the cylindrical molded body was taken out. When the surface of the compression-molded molded body was observed, the liquid component did not ooze out. When a sieve with a mesh size of 1000 μm is placed in a beaker with 100 mL of pure water and stirred with a stirrer so as to cover the stirrer, and this sieve molding is put on the sieve and left for 1 minute. The state of was observed. The results are shown in Table 1.

[Comparative Example 1]
50% by weight of cellulose is commercially available crystalline cellulose “Avicel” PH-101 (registered trademark) and pharmacopeia acetaminophen (manufactured by Merck Whey) finely pulverized with a bantam mill (made by Hosokawa Iron Works Co., Ltd., use screen diameter 2 mm). A composition of 50% by weight of acetaminophen is introduced, and 500 g of a powder meter is introduced into a high-speed stirring granulator (trade name, NSK250 type, manufactured by Gohashi Seisakusho), and the rotation speed of the stirring blade is rotated at 500 rpm for 1 minute. Then, the mixture was further mixed for 2 minutes while adding 245 to 255 g of 50 wt% aqueous ethanol solution as a binding solution to obtain a spherical granulated product. The obtained granulated product was dried at 50 ° C. for 12 hours, and then a fraction of 12 mesh or more was cut as coarse particles, and then acetaminophen was extracted with acetone for 20 hours using a Soxhlet extractor. This was again dried at 50 ° C. for 12 hours, and sieved with a sieve having an opening of 177 μm to obtain cellulose particles B (corresponding to Example 2 of JP-A-1-272463) as the amount passing through the sieve. Various physical properties of the obtained cellulose particles B are shown in Table 1.
In the same manner as in Example 1, a liquid component-containing molded body was produced, the liquid component was soaked, and a disintegration test was performed. The results are shown in Table 1.

[Comparative Example 2]
A commercially available dissolving pulp was cut and hydrolyzed in a 7% hydrochloric acid aqueous solution at 105 ° C. for 20 minutes, and the resulting acid-insoluble residue was neutralized, washed, filtered, and dehydrated wet cake (water content 50% by weight) Is dispersed in isopropyl alcohol, filtered, dehydrated and redispersed twice, and further using Manton Gorin homogenizer (trade name, 15M type, manufactured by Nippon Seiki Seisakusho Co., Ltd.) three times at a processing pressure of 400 kg / cm ^2. Dispersion treatment was performed, the solid content concentration was 9.8 wt%, the water content was 2.5 wt%, and the isopropyl alcohol was 87.7 wt%, and this was spray dried using a nitrogen circulating spray dryer. The obtained sample was cut using a JIS standard sieve to cut a coarse fraction of 250 μm or more to obtain cellulose particles C (corresponding to Example 2 of JP-A-2-84401). Various physical properties of the obtained cellulose particles C are shown in Table 1.
In the same manner as in Example 1, a liquid component-containing molded body was produced, the liquid component was soaked, and a disintegration test was performed. The results are shown in Table 1.

[Comparative Example 3]
A commercially available crystalline cellulose “Avicel” PH-101 (registered trademark, manufactured by Asahi Kasei Chemicals Corporation) was used to prepare a mixed powder in the same manner as in Example 1 to produce a compression molded body. Various powder physical properties of “Avicel” PH-101 (registered trademark) are shown in Table 1. In the same manner as in Example 1, a liquid component-containing molded body was produced, the liquid component was soaked, and a disintegration test was performed. The results are shown in Table 1.

[Comparative Example 4]
A commercially available crystalline cellulose “Avicel” PH-301 (registered trademark, manufactured by Asahi Kasei Chemicals Corporation) was used to prepare a mixed powder in the same manner as in Example 1 to produce a compression molded body. Various powder physical properties of “Avicel” PH-301 (registered trademark) are shown in Table 1. In the same manner as in Example 1, a liquid component-containing molded body was produced, the liquid component was soaked, and a disintegration test was performed. The results are shown in Table 1.

[Comparative Example 5]
A commercially available crystalline cellulose “Theolas” KG-802 (registered trademark, manufactured by Asahi Kasei Chemicals Corporation) was used to prepare a mixed powder in the same manner as in Example 1 to produce a compression molded body. Table 1 shows the various powder physical properties of “Theolas” KG-802 (registered trademark). In the same manner as in Example 1, a liquid component-containing molded body was produced, the liquid component was soaked, and a disintegration test was performed. The results are shown in Table 1.

  The composition of the present invention can be suitably used as a solid preparation in the entire chemical industry, particularly in the fields of medicine and food.

Claims (1)

One or more active ingredients that are liquid or semi-solid at normal temperature and a secondary aggregate structure in which cellulose primary particles are aggregated, and the intra-particle pore volume is 0.265 cm ³ / g or more, and type I Characterized by containing a porous cellulose aggregate containing a crystal form, having an average particle diameter of more than 30 μm, a specific surface area of 1.3 to ²⁰ m ² / g, an angle of repose of less than 44 °, and disintegrating in water. A solid pharmaceutical composition.