JP2005232260A - Porous composite particle of cellulose inorganic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a porous composite particle of a cellulose inorganic compound as an excipient that is highly optimized to have moldability, fluidity and disintegration in the production of a molding containing various active ingredients , in particular in the production of a medicine molding having excellent moldability, fluidity and disintegration, where the medicine molding is apt to have poor moldability, fluidity and disintegration, with which a molding having excellent mixing uniformity with active ingredients, slight weight dispersion, excellent content uniformity, sufficient hardness, slight tableting failure, low friability and excellent disintegration is actualized by a simple process. <P>SOLUTION: This porous composite particle of the cellulose inorganic compound is an aggregate of a cellulose dispersed particle having ≥2.0 L/D of 10-200 μm fraction in a water dispersion state and a water-insoluble inorganic compound particle and has ≥0.260 cm<SP>3</SP>/g intergranular pore volume. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a cellulose inorganic compound porous composite particle excellent in moldability, disintegration property, and fluidity and suitable for pharmaceutical use, and a molded body composition containing the composite particle and one or more active ingredients.

Conventionally, in the fields of medicine, food, and other chemical industries, it has been widely practiced to prepare a molded body containing an active ingredient by using cellulose powder as an excipient.
At this time, as the cellulose powder to be used, crystalline cellulose, powdered cellulose, and cellulose inorganic compound porous composite particles are known. Examples of crystalline cellulose include the following.

Patent Document 1 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 2, 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.
Patent Document 3 describes a 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.
In Patent Document 4, as a cellulose powder having good moldability and disintegrability, an average degree of polymerization of 100 to 375 obtained by hydrolyzing 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.

In Patent Document 5, as a 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 6, as a 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.
The cellulose powder described in these publications is an aggregate formed of cellulose alone, and is not a composite particle obtained by combining cellulose and an inorganic compound. It is completely different in terms of particle structure.

Examples of the crystalline cellulose inorganic compound composite particles include the following.
In Patent Document 7, as a low-cost pharmaceutical excipient, there are fine particles obtained by co-treatment of hydrolyzed undried microcrystalline cellulose particles and calcium carbonate having a particle size of less than 30 μm. 75:25 to 35:65, having a fraction of 250 μm or more, an average particle size of 20 to 150 μm, and a bulk density of 0.35 to 0.45 g / cm ³ (apparent specific volume, 2.22 (Corresponding to ˜2.86 cm ³ / g) cellulose calcium carbonate composite particles. The purpose of this publication is to provide a low-cost excipient by combining microcrystalline cellulose and calcium carbonate, and by combining cellulose and an inorganic compound as in the present invention, particles The purpose is fundamentally different from that of obtaining particles having a high inner pore volume and excellent moldability, disintegration, and fluidity.

In Patent Document 8, as a pharmaceutical excipient with improved compressibility, it is composed of microcrystalline cellulose co-processed and fine particle agglomerate of about 0.1 to 20% by weight of silicon dioxide. Excipient compositions derived from silicon dioxide in which the silicon dioxide is associated with each other and the silicon dioxide portion of the agglomerate has an average primary particle size of about 1 nm to about 100 μm are described. The excipient particles do not have intentionally formed intraparticle pores, and are completely different from the cellulose inorganic compound composite of the present invention in terms of particle structure. This publication aims to improve the filling property at the time of compression, and improves the compression moldability at a blending amount that does not cover the surface of crystalline cellulose. Therefore, the idea is fundamentally different from that of increasing the pore volume in the particles and increasing the plastic deformability of the particles themselves by compounding with an inorganic compound as in the present invention. Moreover, since the pore volume in a particle | grain is less than 0.260 cm < ³ > / g and it does not have the pore formed intentionally, water did not osmose | permeate into a particle | grain and disintegration was inadequate.

Thus, conventionally, in the cellulose inorganic compound composite particles, with respect to the composite particles of cellulose and inorganic compounds, the pore volume in the particles is increased and the plastic deformability of the particles themselves is improved, thereby improving the compression moldability. Was not known. In the composite of cellulose and an inorganic compound, the present invention is a porous material in which moldability, fluidity, and disintegration are highly optimized by increasing the pore volume in the particles and increasing the plastic deformability of the particles themselves. The composite particles are obtained, and the effect can be obtained even in a formulation containing a high content of a low moldability drug.
Japanese Patent Publication No.40-26274 Japanese Patent Publication No.53-127553 JP-A-2-84401 JP-A-6-316535 Japanese Patent Laid-Open No. 11-152233 WO02 / 02643 pamphlet USP 4744987 Publication Japanese National Patent Publication No. 10-500426

  The present invention shows excellent moldability, fluidity, and disintegration in the production of molded articles containing various active ingredients as excipients, and particularly in the production of pharmaceutical molded articles having poor moldability, disintegration, and fluidity. Simple process for molding with excellent mixing uniformity with active ingredients, low weight variation, excellent content uniformity, sufficient hardness, low tableting trouble, low friability, and excellent disintegration An object of the present invention is to provide porous composite particles of cellulose inorganic compound that are highly optimized in terms of moldability, fluidity, and disintegration, which can be realized by the above.

In order to solve the above problems, the present inventors control the particle structure by combining cellulose particles having a specific particle shape and inorganic compound particles, and increase the pore volume in the particles. The present invention has been made by finding that the moldability is greatly improved in the apparent specific volume range having good disintegration.
That is, the present invention is as follows.
(1) An aggregate of cellulose dispersed particles having an L / D of 2.0 or more of a 10 to 100 μm fraction in a water-dispersed state and water-insoluble inorganic compound particles, and the pore volume in the particles is 0.00. Cellulose inorganic compound porous composite particles characterized by being 260 cm ³ / g or more.
(2) A molded body composition comprising one or more active ingredients and the cellulose inorganic compound porous composite particles described in (1).

  Since the cellulose inorganic compound porous composite particles of the present invention are extremely excellent in moldability, fluidity, and disintegration, the cellulose inorganic compound porous composite particles of the present invention are imparted in the production of molded articles containing various active ingredients. When used as a dosage form, it has excellent mixing uniformity with the active ingredient, less weight variation, excellent content uniformity of the active ingredient, sufficient hardness, less tableting trouble, low friability, It is possible to simply provide a molded article having excellent disintegration properties.

The present invention will be specifically described below with a focus on particularly preferred embodiments.
The cellulose inorganic compound porous composite particles of the present invention need to be composed of cellulose-dispersed particles having an average particle diameter of 10 to 100 μm in an aqueous dispersion state and having a main component L / D of 2.0 or more. Here, L / D is the ratio of the major axis to the minor axis for each cellulose particle. A large L / D means that the particle is elongated, and about 20 μm above and below the average diameter obtained from all the cellulose-dispersed particles. Means the average L / D of the main components fractionated in the range (if the average particle size is 20 μm or less, the lower limit of the main component is not set). Here, the larger the L / D of the cellulose-dispersed particles, the larger the pore volume in the particles, which contributes to an increase in the pore volume. However, when the L / D of the cellulose-dispersed particles is less than 2.0, the resulting inorganic compound This is not preferable because a large intraparticle pore volume cannot be given to the composite and the compression moldability deteriorates. L / D is particularly preferably 2.5 or more, and more preferably 2.8 μm or more. The upper limit of L / D is not particularly limited, but it is 6.0 at most when considered from the average particle diameter of the obtained cellulose inorganic compound porous composite particles.

In the cellulose inorganic compound porous composite particles of the present invention, the pore volume in the particles needs to be 0.260 cm ³ / g or more. The intra-particle pore volume contributes to the compression moldability and disintegration property of the particles. When the pore volume in the particles is large, the particles are easily crushed during compression, so that the plastic deformability is improved and the hardness of the molded body is increased. Moreover, since the penetration | invasion of the water into a particle | grain is accelerated | stimulated when the pore volume in a particle | grain is large, disintegration improves. The larger the pores in the particles, the better. The upper limit is not limited, but considering the limit of the volume applied to the particles, it is at most 3.0 cm ³ / g.

  The particle structure of the cellulose inorganic compound porous composite particle of the present invention needs to be an aggregate structure of cellulose dispersed particles and a water-insoluble inorganic compound. The aggregate structure here refers to, for example, drying a dispersion in which cellulose dispersion particles and inorganic compound particles are dispersed in a medium, or vigorously stirring the cellulose dispersion particles and inorganic compound wet or dry (so-called composite Means an aggregate structure that is physically bonded rather than a chemical bond, and was obtained by SEM (magnification 1500 to 8000 times), and the particle surface was observed. At this time, it is necessary to observe a secondary aggregation structure in which cellulose particles and inorganic compound particles are primary particles. When this structure is not used, for example, in the case of a physical mixture of cellulose-dispersed particles and a water-insoluble inorganic compound, the secondary aggregate structure is not taken, and only primary particles of cellulose and inorganic compounds exist individually. As in the present invention, a composite having excellent fluidity cannot be obtained. Further, when the L / D of the cellulose is less than 2.0, since the pore volume in the particles is small, even if a composite having good fluidity is obtained, the compression moldability is impaired. If the above requirements are not satisfied, it is not preferable because a product excellent in moldability, disintegration, and fluidity cannot be obtained as in the present invention.

  The inorganic compound in the cellulose inorganic compound porous composite particle of the present invention is not particularly limited as long as it is insoluble in water. For example, hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, magnesium alumina hydroxide, third Those used in pharmaceutical products such as calcium phosphate, talc, magnesium aluminate metasilicate, calcium hydrogen phosphate granule, etc. are preferred. Excipients and fluidized in “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) What is classified as an agent is mentioned. These may be used alone or in combination of two or more.

  The cellulose inorganic compound porous composite particles of the present invention preferably contain 0.1% by weight or more and 70% by weight or less of a water-insoluble inorganic compound. Here, since the inorganic compound suppresses contact between celluloses and does not excessively form intraparticle hydrogen bonds, it can impart a large pore volume in the particles. The content of the inorganic compound is preferably 0.1% by weight or more from the viewpoint of sufficiently providing the pore volume in the particles, and 70% by weight or less from the viewpoint of sufficiently exerting the compression moldability. The particle diameter of the water-insoluble inorganic compound used in the cellulose inorganic compound porous composite particle of the present invention is preferably 0.001 to 50 μm. The cellulose inorganic compound porous composite particle of the present invention is to make the composite particle porous by suppressing an excessive hydrogen bond between the cellulose dispersed particles by allowing an inorganic compound to exist between the cellulose dispersed particles. In view of providing sufficient pore volume in the composite particles, the particle diameter of the inorganic compound is preferably 0.001 μm or more, and in terms of aggregate formation, it is preferably 50 μm or less. Especially preferably, it is 0.001-25 micrometers, More preferably, it is 0.001-10 micrometers.

The average particle size of the cellulose inorganic compound porous composite particles of the present invention is preferably 30 to 250 μm. From the viewpoint of fluidity, the average particle diameter is preferably 30 μm or more, and the average particle diameter is preferably 250 μm or less from the viewpoint of suppressing separation and sizing.
The angle of repose of the cellulose inorganic compound porous composite particles of the present invention is preferably 45 ° or less in terms of fluidity. Especially preferably, it is 41 degrees or less. The angle of repose is preferably as small as possible, and the lower limit is not particularly limited, but it is at most 25 ° in view of separation and knitting with the active ingredient during high-speed continuous compression.
The apparent specific volume of the cellulose inorganic compound porous composite particles of the present invention is preferably 2.0 to 6.0 cm ³ / g. From the viewpoint of compression moldability, an apparent specific volume of 2.0 cm ³ / g or more is preferable, and from the viewpoint of filling property, an apparent specific volume of 6.0 cm ³ / g or less is preferable.

The production method of the cellulose inorganic compound porous composite particles of the present invention will be described below.
The cellulose inorganic compound porous composite particles of the present invention are obtained by drying a dispersion in which cellulose dispersion particles having an L / D of 10 to 100 μm of 2.0 or more in an aqueous dispersion state and inorganic compound particles are dispersed in a medium. can get.
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.

  As a method for obtaining cellulose dispersed particles having an L / D of 10 to 100 μm of 2.0 or more in an aqueous dispersion state, there are the following methods, for example: i) Cellulose fibers that have not undergone hydrolysis or have undergone hydrolysis Or a method of adjusting L / D by applying strong shearing, grinding, crushing, and crushing to particles, ii) subjecting cellulose fibers or particles not subjected to hydrolysis or subjected to hydrolysis to high pressure treatment such as explosion treatment, A method in which cellulose particles are divided in a major axis direction to form particles having a high L / D, and if necessary, a shearing force is applied to adjust L / D; iii) a cellulose fiber that has not undergone hydrolysis or has undergone hydrolysis; or A method of adjusting L / D by separating a low L / D component from cellulose dispersed particles having an L / D of 2.0 or less, and iv) a component having an L / D of 2.0 or more, and L / D is 2.0 or less May be any method such as a method of adjusting the L / D by mixing the components, the use of these methods alone or in combination over two. These shearing, grinding, and pulverizing methods may be performed wet, dry, or a combination thereof.

  As a method such as shearing, grinding, pulverization, crushing, and explosion, there is no limitation as long as it is a known method. For example, a one-way rotary type such as a portable mixer, a three-dimensional mixer, a side mixer, a multi-axis rotary type, Uses reciprocating reversal, up-and-down moving, rotating + up-and-down moving, pipe-type shearing methods using stirring blades, jet-type stirring shearing methods such as line mixers, high-shear homogenizer, high-pressure homogenizer, ultrasonic homogenizer, etc. For example, a shearing method of a shaft rotation extrusion type such as a kneader may be used. 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, and they may be used alone or in combination of two or more.

As a method for separating the high L / D component and the low L / D component, classification using a sieve, cyclone, centrifugal separation using a centrifuge, combil, flash mill, etc. are adjusted to obtain a desired L Any method such as a separation method that divides the / D component may be used alone or in combination of two or more.
While the L / D is verified by measuring the shape of the cellulose particles in the dispersion, the degree of polymerization of the raw material cellulose by hydrolysis and the conditions of the hydrolysis and / or dispersion process of cellulose, in particular of these solutions By adjusting the stirring force, the desired range can be controlled. In general, when the acid, alkali concentration and reaction temperature of the hydrolyzed solution are increased, the cellulose polymerization degree tends to decrease, the average cellulose dispersed particle size in the dispersion tends to decrease, and even if the stirring power of the solution is increased. The average particle size of the cellulose dispersed particles tends to be small.

The water-insoluble inorganic compound may be present in the dispersion liquid containing the medium before drying, and the addition method and order thereof are not particularly limited. For example, i) The cellulose particles and the inorganic compound are mixed. Either a method of adding a substance to a medium to form a dispersion, ii) a method of adding an inorganic compound to the cellulose dispersion to make a dispersion, or iii) a method of adding cellulose to the inorganic compound dispersion to make a dispersion can be used. May be.
The method for adding each component is not particularly limited as long as it is a commonly used method, but it is a small suction transport device, pneumatic transport device, bucket conveyor, pressure transport device, vacuum conveyor, vibratory quantitative feeder, spray, funnel Or the like may be added continuously or in a batch.

  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. Also, shaker-type container shaker mixers, portable mixers, three-dimensional mixers, side mixers, etc., one-way rotary type, multi-axis rotary type, reciprocating reversal type, vertical movement type, rotation + vertical movement type, pipeline type, etc. A dispersion method using a stirring blade, a jet-type stirring dispersion method such as a line mixer, a high shear homogenizer, a high-pressure homogenizer, a processing method using an ultrasonic homogenizer, etc., for example, an axial rotation extrusion shear method such as a kneader, It may be used alone or in combination of two or more.

The cellulose-dispersed particles and inorganic compound obtained by the above operation are preferably made into a dispersion having a concentration of 5 to 50% by weight before drying. 5% by weight or more is preferable in terms of self-fluidity and 50% by weight or less in terms of compression moldability. More preferably, it is 5 to 40% by weight, and further preferably 5 to 30% by weight.
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.

The aggregate structure of the composite particles obtained by the drying is achieved by simultaneously drying the inorganic compound particles in the dispersion containing the specific L / D cellulose particles. During drying, it is considered that the cellulose and the inorganic compound are homogeneously associated with each other and are densely aggregated due to capillary condensation when the medium is dried. This agglomerated structure cannot be obtained by adding an inorganic compound or cellulose to a cellulose alone or a dried inorganic compound alone.
Moreover, the pore volume in the particle | grains of the obtained composite particle is determined by L / D of the cellulose particle in a dispersion liquid. The greater the L / D, the greater the effect of suppressing excessive particle aggregation due to capillary condensation during drying, and therefore a larger pore volume can be formed in the particles.

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 preferable 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 the order of addition is not particularly limited.

Next, a composite method without drying will be described.
In the case of not drying, it may be combined by mixing cellulose particles with and without hydrolysis and an inorganic compound and subjecting them to physical treatment such as compression / shearing. You may heat.
As a compression method, the compressed particle may be pulverized by a compressor such as a pressure roller or a press machine, and the particle size may be adjusted. By applying a centrifugal force with a stirring blade rotating type or rotating plate type stirring machine, It may be combined, or it may be pressed during high-speed stirring (compression may be applied to form a composite.

The molded body composition referred to in the present invention only needs to contain one or more active ingredients and the cellulose inorganic compound porous composite particles of the present invention, and the amount thereof is not particularly limited. The active ingredient is 0.001 to 99%, and the cellulose inorganic compound porous composite particle of the present invention is 1 to 99%. Furthermore, it can be processed by a known method such as mixing, stirring, granulation, sizing, and tableting. The active ingredient is preferably 0.001% or more in terms of securing an effective amount for treatment, and 99% or less in terms of practical hardness, friability and disintegration.
The composition of the present invention comprises an active ingredient, a cellulose inorganic compound porous composite particle, and an excipient, a disintegrant, a binder, a fluidizing agent, a lubricant, a corrigent, a fragrance, and a colorant as necessary. It is also free to include sweeteners.

The active ingredient of the present invention refers to pharmaceutical medicinal ingredients, agricultural chemical ingredients, fertilizer ingredients, feed ingredients, food ingredients, cosmetic ingredients, pigments, fragrances, metals, ceramics, catalysts, surfactants, powder, crystalline, It may be in any form such as oil, liquid or semi-solid, and may be coated for the purpose of elution control and bitterness reduction. 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.

  Examples of oily and liquid active ingredients used in the present invention include teprenone, indomethacin farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipitol, 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 room 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 hot water, small blue dragon hot water, Mumon winter hot water, half 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.

  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, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean unsaponifiable matter, soybean lecithin, skim milk powder, talc, carbonic acid Ammonium, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low-substituted hydroxypropylcellulose, dextran, dextrin, natural aluminum silicate Corn starch, tragacanth powder, silicon dioxide, new calgen 204, calcium lactate, lactose, perfiller 101, white shellac, white petrolatum, crushed, sucrose, sucrose / starch spherical granules, powdered green leaf extract, naked malt leaf blue Juice dry powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, phytic acid, glucose, glucose hydrate, partial alphalation Starch, pullulan, propylene glycol, powdered maltose starch syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyethylene Oxyethylene hydrogenated castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate, polyvinyl acetal diethylaminoacetate, polyvinyl pyrrolidone, polyethylene Glycol (molecular weight 1500-6000), maltitol, maltose, D-mannitol, water candy, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granulated product, magnesium metasilicate aluminate, methylcellulose, cottonseed powder Cottonseed oil, mole, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, medicinal charcoal, peanut oil, sulfuric acid Luminium, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid, calcium hydrogen phosphate, calcium hydrogen phosphate, calcium hydrogen phosphate granulated product, sodium hydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid Included in the “Pharmaceutical Additives Encyclopedia” (published by Yakuji Nippo Co., Ltd.) such as calcium dihydrogen and sodium dihydrogen phosphate are listed as excipients. The above can also be used together.

  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.

Hereinafter, a method for producing a tablet composition comprising as a main component one or more active ingredients and the cellulose inorganic compound porous composite particles of the present invention will be described. However, it is an example, and the effect of the present invention is the following method. It is not limited.
The active ingredient here may be in any form of solid, liquid or semi-solid, and the active ingredient may be used alone or may be used by dissolving, suspending or emulsifying the active ingredient in a medium. Good. As a method, after mixing an active ingredient and the cellulose inorganic compound porous composite particle of the present invention, a compression molding method can be taken. At this time, in addition to the active ingredient, other additives may be blended as necessary. Examples of other additives include the excipients, disintegrants, binders, fluidizing agents described above, You may mix | blend 1 or more types chosen from the component of a lubricant agent, a corrigent, a fragrance | flavor, a coloring agent, a sweetening agent, and a solubilizing agent.

  The order of addition is not particularly limited, and i) a method in which the active ingredient, the cellulose inorganic compound porous composite particle of the present invention and other additives as needed are mixed together and compression-molded, and ii) the active ingredient and fluidization Any of the compression molding methods may be used after additives such as an agent and / or a lubricant are pretreated and mixed, and the cellulose inorganic compound porous composite particles of the present invention are mixed with other additives as necessary. A lubricant may be added to the mixed powder for compression molding obtained in i, ii) and further mixed, and then compression molded.

  In particular, when using an active ingredient hardly soluble in water, the following production method can be employed. Examples of the production method include: i) pulverizing an active ingredient or using it as it is, mixing the cellulose inorganic compound porous composite particles of the present invention with other components as necessary, and compression molding, ii) activity The components are dissolved or dispersed in water and / or an organic solvent and / or a solubilizing agent, and then mixed with the cellulose inorganic compound porous composite particles of the present invention and other additives as required, and water is added as necessary. And / or any method of distilling off the organic solvent and compression molding. The crystalline form of the active ingredient before compression molding may be the same as or different from the state before the preparation, but is preferably the same in terms of stability. When using a water-insoluble active ingredient, it is particularly effective to use a water-soluble polymer and a surfactant in combination as a solubilizing agent and disperse them in a medium. The other additives referred to here are additives other than the cellulose inorganic compound porous composite particles of the present invention. For example, the excipients, disintegrants, binders, fluidizing agents, lubricants, taste masking agents shown above. It is an additive such as an agent, a fragrance, a coloring agent, a sweetening agent, a solubilizing agent. These additives may be used alone or in combination of two or more. In particular, in the case of the method ii), there is an effect of improving the elution of the active ingredient because the process involves once dissolving or dispersing the slightly soluble and insoluble active ingredient in water. In particular, 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. Unless it is excellent in compression moldability and fluidity like the cellulose inorganic compound porous composite particles of the present invention, it cannot be tableted. 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.

  The method for adding each component is not particularly limited as long as it is a commonly used method, but it is a small suction transport device, pneumatic transport device, bucket conveyor, pressure transport device, vacuum conveyor, vibratory quantitative feeder, spray, funnel Or the like may be added continuously or in a batch. 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. .
The dissolution or dispersion method is not particularly limited as long as it is a commonly used dissolution and dispersion method, but it is a one-way rotation type such as a portable mixer, a three-dimensional mixer, a side mixer, a multi-axis rotation type, a reciprocating inversion type, and a vertical movement type. , Rotation + up / down moving type, stirring type mixing method using pipe type, jet type stirring mixing method such as line mixer, gas blowing type stirring mixing method, high shear homogenizer, high pressure homogenizer, ultrasonic homogenizer, etc. A mixing method using a shaker or a container shaking mixing method using a shaker may be used.

The organic solvent used in the above production method is not particularly limited as long as it is used in pharmaceuticals. For example, alcohols such as methanol and ethanol, ketones such as acetone, etc. Those classified as solvents in “Pharmaceutical Encyclopedia” (published by Yakuji Nippo Co., Ltd.) can be mentioned. They can be used alone or in combination of two or more.
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 tablet referred to in the present invention includes a cellulose inorganic compound porous composite particle of the present invention, one or more active ingredients, and other additives as required, and can be obtained by compression molding. Refers to the body. The tablet composition containing the cellulose inorganic compound porous composite particles of the present invention can be obtained with practical hardness by a simple method such as a direct tableting method without complicated steps. Depending on the dry granule compression method, wet granule compression method, latter method, multi-nuclear tablet with pre-compressed tablet as the core, multi-layer tablet manufacturing method that compresses multiple pre-compressed moldings and compresses again, etc. The manufacturing method may be used.

  Cellulose inorganic compound porous composite particles of the present invention are excellent in various physical properties required as compression moldability, fluidity, and disintegrant excipients, so that tablet hardness is particularly difficult to occur, cracking of the tablet surface, cracking, internal 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. Moreover, since the cellulose inorganic compound porous composite particles of the present invention are excellent in compression moldability and disintegration properties, tablets showing a practical degree of wear 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. The cellulose inorganic compound porous composite particles of the present invention are excellent in the splitting property of the particles themselves, and when used in a scored tablet or the like, the tablets can be easily divided uniformly. Furthermore, the cellulose inorganic compound porous composite particles of the present invention have a developed porous structure, and the cellulose inorganic compound porous composite particles themselves are excellent in the retention of fine particle drugs, suspension drugs, and solution components, Tablets using it are also excellent in retention of solid, suspension, 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 inorganic compound porous composite particles of the present invention have a developed porous structure, and the composite particles themselves are excellent in drug retention. Therefore, the particles in which the drug is supported in the pores are directly used as fine particles. Alternatively, they may be granulated and 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.

Cellulose inorganic compound porous composite particles of the present invention have a developed pore structure and have moderate water retention and oil retention, so that they can be used as core particles for layering and coating in addition to excipients, In that case, there exists an effect which suppresses aggregation between particle | grains in a layering and a coating process. 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. However, the embodiment of the present invention is not limited to the description of these examples. In addition, the measuring method of each physical property in an Example and a comparative example is as follows.
(1) Average particle diameter (μm) of cellulose dispersed particles and water-insoluble inorganic compound particles
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.
When a colloidal (0.1 μm or less) inorganic compound is used, the average particle size could not be specified by this measurement method because the particle size was too small.

(2) Average L / D of main components of cellulose dispersed particles
Using a JIS standard sieve (Z8801-1987), a wet fraction of about 20 μm above and below the average particle diameter measured in (1) (the lower limit of the fraction was not set when the average particle diameter was 20 μm or less) was used. The obtained dispersion was spread on a glass plate and dried to obtain a sample. Take a magnified image of the sample with a microscope (trade name, VH-7000, manufactured by KEYENCE) at 200 times, and use the image analysis device (trade name, Image Hyper, manufactured by Interquest Co., Ltd.) to obtain particles. The ratio of the long side to the short side (long side / short side) of the rectangle having the smallest area among the rectangles adjacent to is defined as L / D of the particle. The average value of at least 100 particles was used as the average L / D of the particles.

(3) 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.
(4) Intraparticle pore volume (cm ³ / g)
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. From the pore distribution obtained by measurement at an initial pressure of 20 kPa, a pore diameter of 0.1 to 10 μm was calculated as an intraparticle pore volume.

(5) 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.
(6) Compression molding of cellulose sample alone 0.5 g of each cellulose powder is weighed and placed in a mortar (manufactured by Kikusui Seisakusho, using material SUS2, 3), and a circular flat bowl having a diameter of 1.1 cm (manufactured by Kikusui Seisakusho, material SUS2). , 3) until the pressure becomes 10 MPa (product name, PCM-1A manufactured by Aiko Engineering, compression speed is 1 cm / min) and held at the target pressure for 10 seconds, then the cylindrical molded body is taken out It was.

(7) Tablet hardness (N)
Using a Schleingel hardness meter (Freund Sangyo Co., Ltd., trade name, 6D type), apply a load in the diameter direction of the cylindrical molded body or tablet, break it, and measure the load at that time. It was expressed as an average value of 10 samples.
(8) Collapse time (seconds)
A disintegration test was conducted in accordance with the 14th revised Japanese Pharmacopoeia, general test method, and disintegration test method for tablets. About a cylindrical molded object or a tablet, it calculated | required as disintegration time in 37 degreeC and a pure water with the disintegration tester (Toyama Sangyo Co., Ltd. make, brand name, NT-40HS type, no disk). The average value of 6 samples was expressed.

[Example 1]
2 kg of shredded commercially available pulp (wood-derived natural cellulose-dissolved pulp) and 30% of 0.4% hydrochloric acid aqueous solution in a low-speed stirrer (trade name, 30LGL reactor manufactured by Ikebukuro Sakai Kogyo Co., Ltd.) While stirring, the mixture was hydrolyzed at 116 ° C. for 1 hour to obtain an acid-insoluble residue (the average particle size of cellulose dispersed particles was 51 μm, and L / D was 3.4). Silicon dioxide (product of Tokuyama, trade name, fine seal, average particle size 5 μm) as an acid-insoluble residue and water-insoluble inorganic compound obtained in a 90 L polybucket with a quantity ratio of 50/50 (based on solid content) Introduced, pure water was added so that the total solid content concentration was 20% by weight, and neutralized with ammonia water while stirring with a 3-1 motor (pH after neutralization was 7.5 to 8.0). This was spray-dried (dispersion supply rate 6 kg / hr, inlet temperature 180 to 220 ° C., outlet temperature 50 to 70 ° C.) to obtain cellulose inorganic compound porous composite particles A. Table 1 shows properties of the cellulose inorganic compound porous composite particle A.

[Example 2]
Cellulose acid insoluble residue obtained in Example 1 (average particle size of cellulose dispersed particles was 51 μm, L / D was 3.4) and silicon dioxide (made by Tokuyama, trade name, fine seal, An average particle diameter of 5 μm) is introduced into a 90 L plastic bucket at a quantity ratio of 30/70 (solid content base), and pure water is added so that the total solid content concentration becomes 20% by weight, while stirring with a 3-1 motor, The mixture was neutralized with aqueous ammonia (pH after neutralization was 7.5 to 8.0), and spray-dried in the same manner as in Example 1 to obtain cellulose inorganic compound porous composite particles B. Various physical properties of the cellulose inorganic compound porous composite particles B are shown in Table 1.

[Example 3]
Cellulose acid insoluble residue obtained in Example 1 (average particle size of cellulose dispersed particles was 51 μm, L / D was 3.4) and silicon dioxide (manufactured by Aerosil Japan, trade name, Aerosil 200, The average particle size of 0.1 μm or less) is introduced into a 90 L plastic bucket at a volume ratio of 99/1 (solid content basis), pure water is added so that the total solid content concentration is 15% by weight, and the mixture is stirred with a 3-1 motor. While neutralizing with aqueous ammonia (pH after neutralization was 7.5 to 8.0), this was spray-dried in the same manner as in Example 1 to obtain cellulose inorganic compound porous composite particles C. Obtained. Various physical properties of the cellulose inorganic compound porous composite particles C are shown in Table 1.

[Example 4]
Cellulose acid insoluble residue obtained in Example 1 (average particle size of cellulose dispersed particles was 51 μm, L / D was 3.4) and talc (manufactured by Wako Pure Chemical Industries, average particle size of 5 μm) Prepared in a quantitative ratio of 98/2 (based on solid content) into a 90 L plastic bucket, and pure water is added so that the total solid content concentration becomes 15% by weight. The mixture was neutralized with aqueous ammonia (pH after neutralization was 7.5 to 8.0) and spray-dried in the same manner as in Example 1 to obtain cellulose inorganic compound porous composite particles D. Various physical properties of the cellulose inorganic compound porous composite particles D are shown in Table 1.

[Example 5]
Cellulose acid insoluble residue obtained in Example 1 (average particle size of cellulose dispersed particles was 51 μm, L / D was 3.4) and sodium aluminate silicate (Wako Pure Chemical Industries, average (Prepared so that the particle diameter is 10 μm) is introduced into a 90 L plastic bucket at a volume ratio of 50/50 (based on solid content), and pure water is added so that the total solid content concentration is 20% by weight. While stirring, the solution was neutralized with aqueous ammonia (pH after neutralization was 7.5 to 8.0), and spray-dried in the same manner as in Example 1 to obtain cellulose inorganic compound porous composite particles E. Got. Table 1 shows properties of the cellulose inorganic compound porous composite particle E.

[Example 6]
2 kg of shredded commercial pulp (natural cellulose-dissolved pulp derived from wood) and 30 L of 0.2% hydrochloric acid aqueous solution are added to a low-speed stirrer (Ikebukuro Sakai Kogyo Co., Ltd., trade name, 30LGL reactor) While stirring, the mixture was hydrolyzed at 116 ° C. for 1 hour to obtain an acid-insoluble residue (the average particle size of the cellulose dispersed particles was 72 μm, L / D was 4.0) and talc (sum) Mitsuru Pure Chemical Co., Ltd. (prepared so that the average particle size is 5 μm) is introduced into a 90 L plastic bucket at a quantitative ratio of 98/2 (solid content base), and pure water is added so that the total solid content concentration is 10% by weight. While 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 in the same manner as in Example 1 to obtain a cellulose inorganic compound. Porous composite particles F were obtained. Various physical properties of the cellulose inorganic compound porous composite particles F are shown in Table 1.

[Comparative Example 1]
2 kg of shredded commercial pulp (natural cellulose-dissolved pulp derived from wood) and 30 L of 0.65% hydrochloric acid aqueous solution are added to a low-speed stirrer (Ikebukuro Sakai Kogyo Co., Ltd., trade name, 30LGL reactor) While stirring, the mixture was hydrolyzed at 122 ° C. for 1 hour to obtain an acid-insoluble residue (the average particle size of the cellulose dispersed particles was 35 μm, L / D was 1.9) and silicon dioxide ( Nippon Aerosil Co., Ltd., trade name, Aerosil 200, average particle size 0.1 μm or less) is introduced into a 90-liter plastic bucket at a volume ratio of 98/2 (solid content basis), and pure so that the total solid content concentration is 20% 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 in the same manner as in Example 1. Cellulose inorganic compound porous composite To give a child G. Table 1 shows properties of the cellulose inorganic compound composite particle G.

  Since the cellulose inorganic compound porous composite particles of the present invention are extremely excellent in moldability, fluidity and disintegration, the cellulose inorganic compound porous composite particles of the present invention are mainly used in the production of molded articles containing various active ingredients. When used as an excipient in the pharmaceutical field, it has excellent mixing uniformity with the active ingredient, less weight variation, excellent content uniformity of the active ingredient, sufficient hardness, and less tableting trouble, A molded product having low friability and excellent disintegration can be provided by a simple method.

Repose angle and hardness of cellulose inorganic compound porous composite particles A to F in Examples 1 to 6 and cellulose inorganic compound composite particles G in Comparative Examples 1 to 3 (both weigh 0.5 g of sample at a compression pressure of 10 MPa. It is a graph which shows the relationship of the hardness of the cylindrical molded object made into the cylindrical molded object of (phi) 1.1cm. It can be seen that the examples have large intra-particle pores and high moldability, and overall the balance between fluidity and moldability is superior to the comparative examples. In particular, Examples 3, 4, and 6 show an angle of repose equivalent to that of Comparative Example 1, and show a hardness higher than that of the Comparative Example. Hardness and disintegration time of cellulose inorganic compound porous composite particles A to F in Examples 1 to 6 and cellulose inorganic compound composite particles G in Comparative Examples 1 to 3 (both weigh 0.5 g of sample at a compression pressure of 10 MPa. It is a graph which shows the relationship of the hardness of a cylindrical molded object made into the cylindrical molded object of (phi) 1.1cm, and disintegration time. It can be seen that the examples have large intraparticle pores and good disintegration, and overall, the balance between moldability and disintegration is superior to the comparative examples. In particular, Examples 1, 3, 4, and 5 show the same hardness as that of Comparative Example 1 and show a disintegration that exceeds the Comparative Example.

Claims (2)

An aggregate of cellulose dispersed particles having an L / D ratio of 2.0 or more of a 10 to 100 μm fraction in a water-dispersed state and water-insoluble inorganic compound particles, and the pore volume in the particles is 0.260 cm ³ / Cellulose inorganic compound porous composite particles characterized by being g or more.   A molding composition comprising one or more active ingredients and the cellulose inorganic compound porous composite particles according to claim 1.

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