JP2018083923A - Cellulose dispersion, method for producing cellulose dispersion, molded body composition, molded body, and method for producing molded body composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a molded product composition having excellent compression moldability and fluidity even if the contained active ingredient is poor in compression moldability. A particle having an average degree of polymerization of 100 to 350 and having a particle size distribution measured by a laser diffraction particle size distributor in the range of 0.5 to 12 μm and 0.3 to 25 μm in an integrated volume of 50%. A cellulose dispersion liquid containing cellulose particles having a volume ratio of 90% or more; a cellulose having an average degree of polymerization of 100 to 350 and an active ingredient, and the cellulose is a true sphere. The particles have a degree of 0.6 to 1.0, and the particle size distribution measured by the laser diffraction type particle size distribution meter when dispersed in water by ultrasonic treatment has an integrated volume of 50% and a particle size of 5 to 20 μm. A molded body composition, characterized in that the volume ratio of particles in the range of 2 to 50 μm is 90% or more, and the half-value width is 5 to 30 μm. [Selection diagram] None

Description

  The present invention relates to a molded body composition containing cellulose particles used in pharmaceutical, food and industrial applications. More specifically, in pharmaceutical / health food applications, a molded article that greatly improves the compression moldability of an active ingredient having poor compression moldability, prevents blocking of an active ingredient having high adhesion and cohesiveness, and imparts high fluidity. Relates to the composition.

  Active ingredients for use in pharmaceuticals and health foods are generally poor in compression moldability, and in general, excipients with high compression moldability are blended in addition to active ingredients to form tablets. As an excipient having high compression moldability, there is cellulose powder. Some active ingredients require a high dose for expression of the effect, and there are also those whose content per tablet exceeds 1 g. When obtaining tablets of active ingredients that require high doses, it is preferable to reduce additives such as excipients as much as possible and to make them as small as possible from the standpoint of preventing cracks and improving dosing due to enlargement. . In response to such problems, a highly moldable cellulose powder is used in pharmaceutical and health food applications.

  Patent Documents 1 to 4 are known as highly moldable cellulose powders. Patent Document 5 describes that a hydrolyzed cellulose slurry is used to provide improved compressibility of a granule composition containing a pharmaceutical ingredient when spray-dried.

  Further, in the recent pharmaceutical field, improvement of drug efficacy and reduction of side effects have been performed at the molecular level, and the active ingredient tends to be hardly soluble. Such an active ingredient increases the water solubility by forming a solid dispersion with a polymer such as hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose (HPC), crospovidone, etc. Is done. In order to prevent a decrease in solubility due to recrystallization of the active ingredient, the amount of polymer required for solid dispersion tends to increase, and the dose of the active ingredient required for a single administration increases more and more, and the tablet tends to increase in size. It is in.

Japanese Patent No. 4737754 Japanese Patent No. 5110757 Japanese Patent No. 5240822 Japanese Patent No. 4969104 Japanese Patent No. 4183279

  In molding a solid preparation containing a large amount of an active ingredient with extremely poor compression moldability, in order to impart sufficient hardness to the obtained solid preparation and to reduce the friability, it is possible to improve the moldability. A form is required. However, in the conventional highly formable cellulose powder and hydrolyzed cellulose slurry, a large amount of excipient is required to prepare a solid preparation with practical mechanical strength. Has a problem that it is large, easily worn, and difficult to take. From the viewpoint of easy drinking and compliance, it is ideal to make the tablet as small as possible, but no excipient has been known that can greatly improve the compression moldability of the active ingredient with the addition of a very small amount.

  In addition, when preparing a solid dispersion of an active ingredient and a polymer, there is a problem that the fluidity of the solid dispersion is poor when prepared by a spray-dry method, and moldability or disintegration when prepared by a hot-melt method. There is a problem that the nature is bad. For this reason, when making an active ingredient which needs solid dispersion into a large tablet, it is difficult to achieve moldability, fluidity, and disintegration, and the solution of these problems is desired.

  In view of the above-described problems, the present invention provides a molded article composition excellent in compression moldability and fluidity, and a method for producing the same, even if the active ingredient contained is poor in compression moldability, and the molded article composition. It aims at providing the molded object which shape | molded the cellulose dispersion liquid for manufacturing A, its manufacturing method, and the said molded object composition.

  As a result of intensive studies in view of the above problems, the present inventors have made the compression properties excellent in active ingredients with poor compression moldability by making the powder physical properties of cellulose fine particles used as excipients into a specific range. The present inventors have found that moldability can be imparted and completed the present invention. That is, the present invention is as follows.

[1] The average degree of polymerization is 100 to 350, and the particle size distribution measured by a laser diffraction particle size distribution meter is such that particles having an integrated volume 50% particle size in the range of 0.5 to 12 μm and 0.3 to 25 μm. Cellulose dispersion liquid characterized by containing the cellulose particle whose volume ratio is 90% or more.
[2] The cellulose dispersion according to [1], wherein the solid content concentration is 10% by mass or less.
[3] A step of hydrolyzing a natural cellulosic material to obtain a cellulose aqueous dispersion;
Centrifuge the cellulose aqueous dispersion, and recover the supernatant as a cellulose dispersion containing cellulose particles having an average degree of polymerization of 100 to 350;
Have
The particle size distribution measured by a laser diffraction particle size distribution meter of the cellulose particles is such that the volume ratio of particles having an integrated volume 50% particle diameter in the range of 0.5 to 12 μm and 0.3 to 25 μm is 90% or more. A method for producing a cellulose dispersion characterized by the above.
[4] contains cellulose having an average degree of polymerization of 100 to 350 and an active ingredient,
The cellulose is a particle having a sphericity of 0.6 to 1.0, and a particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment is 50% cumulative volume particle. A molded body composition characterized by having a volume ratio of particles of 90% or more and a full width at half maximum of 5 to 30 μm in a diameter range of 5 to 20 μm and 2 to 50 μm.
[5] The molded body composition according to [4], wherein the cellulose content is 0.5 to 20% by mass with respect to the entire composition.
[6] The molded product composition according to [4] or [5], wherein the hardness of a cylindrical molded product having a diameter of 1.13 cm obtained by compressing a weight of 0.5 g with a pressure of 10 kN is 50 N or more.
[7] The molded composition according to any one of [4] to [6], wherein the active ingredient is sparingly water-soluble.
[8] The molded composition according to any one of [4] to [7], wherein the active ingredient is supported on the cellulose particles.
[9] The molded article composition according to any one of [4] to [8], wherein the active ingredient is a pharmaceutical medicinal ingredient.
[10] A molded product comprising the molded product composition according to any one of [4] to [9].
[11] The molded article according to [10], wherein the content of the active ingredient is 80% by mass or more based on the entire molded article.
[12] A step of hydrolyzing a natural cellulosic material to obtain a cellulose aqueous dispersion;
Centrifuging the cellulose aqueous dispersion and recovering the supernatant as a cellulose dispersion;
A step of preparing a mixed liquid containing the cellulose dispersion and an active ingredient;
Drying the mixed liquid to obtain a molded body composition containing cellulose having an average polymerization degree of 100 to 350 and the active ingredient;
Have
The cellulose in the molded body composition is particles having a sphericity of 0.6 to 1.0, and the particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment. The volume ratio of particles having an integrated volume 50% particle diameter of 5 to 20 μm and a particle size in the range of 2 to 50 μm is 90% or more, and the half-value width is 5 to 30 μm. .
[13] The cellulose dispersion has an average degree of polymerization of 100 to 350, and a particle size distribution measured by a laser diffraction particle size distribution meter has an integrated volume 50% particle size of 0.5 to 12 μm and 0.3 to 25 μm. [12] The method for producing a molded product composition according to [12] above, comprising cellulose particles having a volume ratio of particles in the range of 90% or more.
[14] The method for producing a molded body composition according to [12] or [13], wherein the cellulose dispersion has a solid content concentration of 10% by mass or less.

  By using the cellulose dispersion according to the present invention, even if the active ingredient contained is poor in compression moldability, it has excellent compression moldability and can produce tablets with excellent hardness. A composition can be provided.

In Example 1, it is a particle size distribution of the cellulose dispersion liquid of the supernatant which centrifuged the cellulose dispersion liquid at 3000 rpm x10 minutes, 5000 rpm x10 minutes, or 8000 rpmx10 minutes. In Example 6, it is an electron micrograph (acceleration voltage 5 kV, magnification 4000 times) of the powder of metformin hydrochloride containing 5 mass% of cellulose particles derived from the cellulose dispersion A. 2 is a photograph of metformin hydrochloride powder prepared in Example 6. 6 is a photograph of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion A prepared in Example 6. FIG. Metformin hydrochloride powder (UPS / MtH) containing 5% by mass of cellulose particles derived from cellulose dispersion A produced in Example 6 and 5% by mass of cellulose particles derived from cellulose dispersion A produced in Example 12 Ascorbic acid powder (UPS / VC), glucosamine hydrochloride powder (UPS / GM-C) containing 5% by mass of cellulose particles derived from cellulose dispersion A produced in Example 17, cellulose G of Comparative Example 2 2 is a particle size distribution of a dispersion obtained by redispersing (SCP-100) and cellulose H (CP-051X) of Comparative Example 3 in water.

[Cellulose dispersion]
The cellulose dispersion according to the present invention has an average degree of polymerization of 100 to 350, a particle size distribution measured by a laser diffraction particle size distribution meter, an integrated volume of 50%, a particle size of 0.5 to 12 μm and 0.3 to 25 μm. Cellulose particles having a volume ratio of particles in the range of 90% or more are contained. The cellulose particles contained in the cellulose dispersion according to the present invention (hereinafter sometimes referred to as “the cellulose fine particles of the present invention”) are very fine particles having a relatively uniform size. High formability. For this reason, the cellulose fine particles of the present invention are useful as an excipient for molding a solid molded body. The cellulose dispersion according to the present invention is a dispersion in which the fine cellulose particles of the present invention are dispersed in a dispersion medium. The solid content concentration of the cellulose dispersion according to the present invention is preferably 10% by mass or less, and more preferably 5% by mass or less.

  The cellulose fine particles of the present invention can greatly improve the compression moldability of the active ingredient even when used in a relatively small amount. For this reason, the said cellulose fine particle is suitable as an excipient | filler used when shape | molding an active ingredient with especially poor compression moldability. By using the cellulose fine particles as an excipient, a solid preparation having practically sufficient hardness can be obtained without excessively increasing the size.

  Moreover, in order to reduce weight variation when continuously molding at high speed, an excipient with high fluidity is required. The fine cellulose particles of the present invention are effective in preventing blocking of active ingredients having high adhesion and aggregation properties, and also have the effect of greatly improving the fluidity of the active ingredients. Due to this characteristic, the cellulose fine particles of the present invention can be suitably applied as additives such as powders. Moreover, the cellulose fine particles of the present invention can be blended in a capsule for improving the filling property. Note that “blocking” refers to a phenomenon in which powders adhere to each other and harden (become damped).

  The cellulose fine particles of the present invention have an average degree of polymerization of 100 to 350, preferably 150 to 300, and more preferably 180 to 250. In order to impart excellent moldability and fluidity to the molded body composition described later, the average degree of polymerization of cellulose constituting the cellulose fine particles of the present invention needs to be 100 or more and 350 or less.

<Measurement of particle size>
In the present invention and the present specification, the particle size of cellulose particles is measured by a laser diffraction particle size distribution meter. In order to obtain a more accurate particle size distribution, the particle size distribution is preferably measured in a state where the particles are sufficiently dispersed by ultrasonic treatment in advance. Specifically, for example, the particle size distribution of the cellulose dispersion according to the present invention is a laser diffraction particle size distribution meter (manufactured by Horiba, LA-910; The refractive index is 1.20). The sonication time is sufficient if the cellulose particles are sufficiently dispersed, and is appropriately set in consideration of the model and strength of the sonication device to be used.

  The fine cellulose particles of the present invention have a particle size distribution measured by a laser diffraction particle size distribution meter (manufactured by Horiba, LA-910, refractive index 1.20, sonication for 1 minute). The spherical equivalent diameter of the particles when the cumulative volume is 50% with respect to the volume of the particles is 0.5 to 12 μm, and the volume ratio of the particles in the range of 0.3 to 25 μm is 90% or more. In the following description, the “integrated volume 50% particle diameter measured by a laser diffraction particle size distribution meter” may be referred to as “average particle diameter”.

  The smaller the average particle size and the uniform size of the fine cellulose particles, the more preferable in terms of moldability and fluidity. The average particle size of the cellulose fine particles of the present invention is preferably 0.5 to 7 μm, and more preferably 0.5 to 5 μm. Moreover, as a particle size distribution measured by the laser diffraction particle size distribution meter of the cellulose fine particles of the present invention, the volume ratio of particles in the range of 0.5 to 25 μm is preferably 90% or more, 0.5 to The volume ratio of particles in the range of 7 μm is more preferably 90% or more, and the volume ratio of particles in the range of 0.5 to 4 μm is more preferably 90% or more. In particular, the cellulose dispersion containing the cellulose fine particles is dried when the volume ratio of the particles having the average particle diameter of the cellulose fine particles in the range of 0.5 to 5 μm and 0.3 to 25 μm is 90% or more. Thus, the cellulose particles according to the present invention described later (particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment has an integrated volume of 50%, a particle size of 5 to 20 μm, 2 There is a high possibility that cellulose particles having a volume ratio of particles in the range of 50 μm of 90% or more and a half width of 5 to 30 μm are obtained.

<Dispersion medium>
By dispersing the cellulose fine particles of the present invention in a suitable medium, the cellulose dispersion according to the present invention can be obtained. The dispersion medium is not particularly limited as long as it is industrially used. For example, water and / or an organic solvent can be used. Examples of organic solvents include alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol, 2-methylbutyl alcohol, and benzyl alcohol; hydrocarbons such as pentane, hexane, heptane, and cyclohexane; ketones such as acetone and ethyl methyl ketone. And the like. In particular, organic solvents are preferably used for pharmaceuticals and include those classified as solvents in “Pharmaceutical Additives Encyclopedia 2007” (published by Yakuji Nippo Co., Ltd.). Water and the organic solvent may be used alone or in combination of two or more. Alternatively, the dispersion medium may be once dispersed with one kind of dispersion medium, and then the dispersion medium may be removed and dispersed in a different dispersion medium.

<Cellulose raw material>
The cellulose fine particles of the present invention can be prepared by refining a cellulose raw material so that the average degree of polymerization and the particle size distribution are in the above ranges. The cellulose raw material for preparing the cellulose fine particles of the present invention is preferably a natural cellulosic material (a fibrous material derived from a natural product containing cellulose). The natural cellulosic material may be plant or animal and may be derived from microorganisms. Examples of natural cellulosic materials include fiber materials derived from natural products containing cellulose such as wood, bamboo, wheat straw, rice straw, cotton, ramie, squirts, bagasse, kenaf, beet, and bacterial cellulose. Examples of commonly available natural cellulosic materials include natural cellulosic materials (powdered cellulose) that are in powder form, such as cellulose floc and crystalline cellulose.

  Known crystal forms of cellulose include type I, type II, type III, and type IV. Among them, type I and type II are widely used, and types III and IV are obtained on a laboratory scale. However, it is not widely used on an industrial scale. As the cellulose raw material of the cellulose fine particles of the present invention, the mobility of the structure is relatively high, the plastic deformability at the time of compression is sufficient, and it is easy to impart sufficient hardness to the molded body. It preferably has a crystal structure.

  As a cellulose raw material of the cellulose fine particles of the present invention, one kind of natural cellulosic substance may be used, or two or more kinds of natural cellulosic substances may be used in combination. The cellulose raw material is preferably used in the form of a refined pulp, but the method for purifying the pulp is not particularly limited, and any pulp such as dissolved pulp, kraft pulp, NBKP pulp may be used.

<Average degree of polymerization of cellulose>
The average degree of polymerization of cellulose can be measured according to the reduced specific viscosity method using a copper ethylenediamine solution described in the confirmation test (3) of “15th revised Japanese Pharmacopoeia Manual (published by Yodogawa Shoten)”.

<Hydrolysis of cellulose>
Examples of a method for controlling the average degree of polymerization of cellulose include hydrolysis treatment. By the hydrolysis treatment, the depolymerization of the amorphous cellulose inside the cellulose fiber proceeds, and the average degree of polymerization decreases. At the same time, the hydrolysis process removes impurities such as hemicellulose and lignin in addition to the above-described amorphous cellulose, so that the inside of the fiber becomes porous. Thereby, in the molded article composition described later, the active ingredient is easily carried on the cellulose particles.

  The method for hydrolysis is not particularly limited, and examples thereof include acid hydrolysis, alkaline oxidation decomposition, hydrothermal decomposition, steam explosion, and microwave decomposition. These methods may be used alone or in combination of two or more. In the acid hydrolysis method, for example, α-cellulose obtained as a pulp from a fibrous plant is used as a cellulose raw material, and this is dispersed in an aqueous medium, and an appropriate amount of proton acid, carboxylic acid, Lewis acid, heteropoly acid, etc. In addition, the average degree of polymerization can be easily controlled by heating while stirring. The reaction conditions such as temperature, pressure, and time at this time vary depending on the cellulose species, cellulose concentration, acid species, and acid concentration, but are appropriately adjusted so as to achieve the desired average degree of polymerization. For example, the conditions of using 2 mass% or less mineral acid aqueous solution and processing a cellulose for 10 minutes or more under 100 degreeC or more and pressurization are mentioned. Under these conditions, a catalyst component such as an acid penetrates into the inside of the cellulose fiber, the hydrolysis is accelerated, the amount of the catalyst component to be used is reduced, and subsequent purification is facilitated. In addition, the dispersion liquid of the cellulose raw material at the time of hydrolysis may contain a small amount of an organic solvent in a range not impairing the effects of the present invention, in addition to water.

<Refining cellulose>
The cellulose fine particles of the present invention can be prepared by refining cellulose having an average degree of polymerization adjusted within a predetermined range. For example, the cellulose fine particles of the present invention can be obtained by once drying the cellulose hydrolyzate and then crushing or grinding the obtained dry powder. The pulverization process or the grinding process can be performed by a conventional method using a known pulverizer such as a cutter mill, a hammer mill, a pin mill, or a jet mill. Moreover, the cellulose fine particle of this invention can also be obtained by removing a big particle from a cellulose hydrolyzate.

  From the viewpoint of good yield, the cellulose fine particles of the present invention are produced by hydrolyzing a natural cellulosic material to obtain a cellulose aqueous dispersion, and by centrifuging the cellulose aqueous dispersion, the supernatant is subjected to an average polymerization. And a step of recovering as a cellulose dispersion containing cellulose particles having a degree of 100 to 350. Centrifugation can be performed by a conventional method using a general centrifuge. Acid concentration and reaction temperature during hydrolysis, reaction time, scale (volume) and rotation speed (G) during centrifugation, centrifugation treatment time, amount of supernatant recovered after centrifugation (before centrifugation) By appropriately adjusting the ratio to the capacity, etc., cellulose particles having a particle size measured by a laser diffraction particle size distribution meter of more than 25 μm can be selectively precipitated, and 90% or more of the contained particles The supernatant liquid having a size of 25 μm or less and an average particle diameter of 0.5 to 12 μm can be recovered.

  The pH of the cellulose dispersion according to the present invention is preferably near neutral (5-8.5), and the IC (electrical conductivity) is preferably 200 μS / cm or less. When the IC is 200 μS / cm or less, the dispersibility of the particles in water is improved, and the disintegration property of the molded body obtained by molding the molded body composition prepared using the cellulose dispersion is also improved. The IC of the cellulose dispersion according to the present invention is more preferably 150 μS / cm or less, and further preferably 100 μS / cm or less.

  The cellulose dispersion according to the present invention may be used in the production of a molded product composition in the state of the dispersion, or may be dried to obtain a dry powder of the cellulose fine particles of the present invention. There is no particular limitation on the method for drying the cellulose dispersion. Examples of the drying method include freeze drying, spray drying, drum drying, shelf drying, airflow drying, vacuum drying, and a drying method of drying together with an organic solvent.

[Molded body composition]
The molded body composition according to the present invention contains a cellulose having an average degree of polymerization of 100 to 350 and an active ingredient, and is a composition used for forming a molded body. Cellulose contained in the molded body composition is particles having a specific sphericity and a particle size distribution. Specifically, the cellulose is a particle having a sphericity of 0.6 to 1.0, and the particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment, The volume ratio of the particles having an average particle diameter of 5 to 20 μm and 2 to 50 μm is 90% or more, and the half width is 5 to 30 μm. The molded body composition according to the present invention has high sphericity, an average particle diameter within a specific range, and contains cellulose particles having a relatively uniform size as an excipient. Even if it is a component, excellent compression moldability is imparted and a tablet can be produced.

  In the molded body composition according to the present invention, the active ingredient may be present as particles independent of the cellulose particles, but is preferably supported on the cellulose particles. By supporting it on cellulose particles, the solubility of the active ingredient in water can be improved, and in addition to preventing blocking of the obtained molded product composition, the effect of improving compression moldability is further improved. It can be obtained sufficiently.

<Active ingredient>
The active ingredients contained in the molded body composition according to the present invention are not particularly limited, and include medicinal medicinal ingredients, health food ingredients, food ingredients, agricultural chemical ingredients, fertilizer ingredients, feed ingredients, cosmetic ingredients, catalyst ingredients, etc. Is mentioned. The shape of the active ingredient in the molded body composition is not particularly limited, and may be any shape such as powder, crystal, oil, and solution. Further, it may be coated for elution control and bitterness reduction.

  For example, as medicinal medicinal ingredients, in addition to herbal medicines and herbal medicines, antipyretic analgesics, antihypnotics, hypnotic sedatives, antihypnotics, antipruritics, pediatric analgesics, stomachic medicines, antacids, digestives, cardiotonics, arrhythmic drugs Antihypertensive, Vasodilator, Diuretic, Antiulcer, Intestinal, Osteoporosis, Antitussive expectorant, Antiasthma, Antibacterial agent, Frequent urination, Nutrition tonic, Vitamin Stuff. The medicinal components may be used alone or in combination of two or more.

  Examples of the medicinal active ingredient used in the present invention include, for example, aspirin, aspirin aluminum, acetaminophen, etenzamide, sazapyrine, salicylamide, lactylphenetidine, isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, tripro hydrochloride hydrochloride Lysine, tripelenamine hydrochloride, tonsilamine hydrochloride, phenetazine hydrochloride, methodirazin hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, mebhydrolinate napadisylate, promethazine methylene disalicynoxalemate, maleic acid Chlorpheniramine maleate, d-chlorpheniramine maleate, Difterolate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate (carbetapentane citrate), tipepidine citrate, dibutate sodium, dextromethorphan hydrobromide, dextromethorphan / phenolphthalic acid, hibenzic acid Tipepidine, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin, sodium benzoate caffeine, caffeine, anhydrous caffeine In, vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof and salts thereof, vitamin C and derivatives thereof and salts thereof, Speridine 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, magnesium oxide, 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 co-precipitation product Coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, magnesium aluminate metasilicate, hydrochloric acid Ranitidine, cimetidine, famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine, promethazine hydrochloride, meclizine hydrochloride, dimenhydrinate, diphenhydramine tanninate, Diphenylpyraline acid, diphenhydramine fumarate, promethazine methylene disalicylate, spocollamine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropine bromide, methyl anisotropine bromide, methylspocholamine bromide, odor Methyl-1-hyostiamine, methylbenactidium bromide, belladonna extract, iodide Sopropamide, 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.Maoh, Nantenjitsu, Spruce, Onji, Licorice, Kyoka, Shazenshi, Shazenso, Senega, Baimo, Fennel, Oubak, Ouren, Gajutsu, Kamitsule, Keihi, Gentian, Gooh, Beast (including Yutan), Shajin, Syougyo, Sojutsu, Clove, Chimpi, Sandalwood, Earth , Chikutsu carrot, carrot, valerian, button pi, salamander and extracts thereof, insulin, vasopressin, interferon, urokinase, seratiothiopeptidase, somatostatin, etc. “Japanese Pharmacopoeia”, “Extraordinary group”, “USP” , "NF", and medicinal medicinal ingredients described in "EP", and the like. One selected from the above may be used alone, or two or more may be used in combination.

  As the medicinal medicinal ingredient used in the present invention, it is preferable to use a poorly water-soluble active ingredient. The poorly water-soluble active ingredient is, for example, a pharmaceutical active ingredient, and refers to that in the 14th revised Japanese Pharmacopeia, the amount of water required to dissolve 1 g of solute is 30 mL or more. Even when the active ingredient is sparingly soluble in water, solubility in water can be improved by supporting the active ingredient on cellulose particles.

  For example, acetaminophen, ibuprofen, benzoic acid, ethenamide, caffeine, camphor, quinine, calcium gluconate, dimethylcaprol, sulfamine, theophylline, theopromine, riboflavin, mephenesin, phenobarbital, aminophylline, thioacetazone, quercetin, rutin, Antipyretic analgesics such as salicylic acid, theophylline sodium salt, pyrapital, quinine hydrochloride, irgapilin, dichitoxin, griseofulvin, phenacetin, nervous system drugs, sedative hypnotics, muscle relaxants, blood pressure sclerosing agents, antihistamines, acetyl spiramycin, ampicillin, erythromycin , Antibiotics such as xatamycin, chloramphenicol, triacetyloleandomycin, nystatin, colistin sulfate, methyl test Steroid hormones such as sterone, methylandrosterol diol, progesterone, estradiol benzoate, ethinilestradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, brednisolone, dienestrol, hexastrol, diethylstil Non-steroidal yolk hormones such as bestosterol, diethylstilbestrol dibrohyone, chlorotrianicene, other fat-soluble vitamins, teprenone, indomethacin / farnesyl, menatetrenone, phytonadione, vitamin A oil, phenipentol, vitamin D Vitamins such as vitamin E, DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), liver oil, etc. Unsaturated fatty acids, coenzymes Q, oil-soluble flavorings such as orange oil, lemon oil, peppermint oil, ground dragon perch, cinnamon, peonies, buttonpi, valerian, salamander, ginger, chimpi, mao, nantenjitsu, saruhi , Onji, Kyo, Shazenshi, Shazenso, sarcophagus, Seneca, Baimo, Fennel, Oubak, Auren, Gajutsu, Chamomile, Gentian, Gouo, Beast, Shajin, Gyoza, Suzutsu, Coji, Chinhi, Bikkujutsu, Chikusetinjin, Chinese medicine or herbal medicine extracts such as carrot, kakkon-yu, katsushi-yu, kososan, purple katsura-yu, koshiro-yu, kosei-ryu, mumon-fuyu-yu, half-summer Kobaku-yu, mao-yu, oyster meat extract, Propolis and propolis extract can be mentioned, and one kind selected from the above may be used alone, or two kinds You may use the above together. In addition to said poorly water-soluble active ingredient, the molded article composition according to the present invention may further contain other active ingredients.

  Active ingredients for which solid dispersions have been investigated recently include antiemetics such as Nabilone, antifungals such as Itraconazole and Posaconazole, immunosuppressive drugs such as tacrolimus, and etravirin (Etravirine), ritonavir (Ritonavir), antiviral drugs such as Telaprevir, Everolimus, Vemurafenib and other antitumor drugs, cystic fibrosis drugs such as Ivacaftor, and fenofibrate There are antihyperlipidemic agents such as (Fenofibrate) and antihypertensive agents such as nifedipine, but the molded composition according to the present invention comprising these as active ingredients has high moldability, and these active ingredients are The containing tablet can be miniaturized.

  In addition, as active ingredients having poor compression moldability, for example, ascorbic acid, active ingredients that easily cause tableting troubles such as capping and sticking, antipyretic analgesics such as acetaminophen, diabetes drugs such as metformin hydrochloride, glucosamine hydrochloride There are health food ingredients such as salt, and antiviral drugs such as anti-HIV drugs. As a result of the marked improvement in compression moldability from the molded composition according to the present invention containing these as active ingredients, relatively small tablets having practically sufficient hardness can be produced.

  As the active ingredient used in the present invention, an active ingredient having high adhesion aggregation property is also preferable. By supporting the cellulose particles of the present invention, blocking is prevented, and as a result, the fluidity of the active ingredient is greatly improved. Examples of the active ingredient having high adhesion and aggregation properties include metformin hydrochloride.

<Cellulose particles>
Cellulose particles contained in the molded body composition according to the present invention (hereinafter sometimes referred to as “cellulose particles of the present invention”) are particles mainly composed of cellulose having an average degree of polymerization of 100 to 350. It is. It is preferable that at least some of the particles contained in the molded body composition carry an active ingredient. The molded body composition according to the present invention can improve the compression moldability more remarkably by supporting the active ingredient on cellulose particles having a specific size.

  The particle size distribution of the cellulose particles of the present invention is the same as that of the cellulose fine particles contained in the cellulose dispersion according to the present invention, in a state where the particles are sufficiently dispersed by ultrasonic treatment in an appropriate dispersion medium. It can be measured with a distribution meter. As the dispersion medium for dispersing the cellulose particles of the present invention, the same media as those mentioned as the medium for dispersing the cellulose fine particles of the present invention can be used.

  The cellulose particles of the present invention have an average particle size of 5 to 20 μm in a particle size distribution measured by a laser diffraction particle size distribution meter (manufactured by Horiba, LA-910, refractive index 1.20, ultrasonic treatment for 1 hour). The smaller the average particle diameter of the cellulose particles, the more preferable in terms of formability and fluidity. For this reason, the upper limit of the average particle diameter of the cellulose particles of the present invention is preferably about 25 μm, more preferably 20 μm or less, and further preferably 15 μm or less.

  The cellulose particles of the present invention are particles existing in a range of 2 μm or more and 50 μm or less in a particle size distribution measured by a laser diffraction particle size distribution analyzer (manufactured by Horiba, LA-910, refractive index 1.20, ultrasonic treatment 1 hour). It is necessary that the integrated value of the volume is 90% or more of the whole. Due to the small proportion of coarse particles exceeding 50 μm and ultrafine particles less than 2 μm, excellent moldability and fluidity can be obtained. The volume ratio of the particles in the range of 2 to 50 μm is preferably 95% or more, and most preferably 100%.

  The cellulose particles of the present invention have a half-value width of 5 to 30 μm in a particle size distribution measured by a laser diffraction particle size distribution analyzer (manufactured by Horiba, LA-910, refractive index 1.20, ultrasonic treatment for 1 hour). The cellulose particles contained in the molded body composition are more preferable in terms of moldability and fluidity as the size is uniform. For this reason, it is preferable that the half value width of the particle size distribution of the cellulose particle of this invention exists in the range of 5-20 micrometers.

  The cellulose particles of the present invention have a sphericity of 0.6 to 1.0 when observed with an electron microscope (manufactured by JASCO Corporation, JSM-5510LV, acceleration voltage 5 kV, magnification 4000 times). When the sphericity is 0.6 or more, the dispersibility of the cellulose particles and the active ingredient supported thereon is improved, and the moldability and fluidity can be improved. The sphericity of the cellulose particles of the present invention is preferably as close to 1.0, and more specifically, preferably 0.7 to 1.0, and more preferably 0.75 to 1.0. .

The cellulose particles of the present invention are more preferable in terms of moldability as the specific surface area is larger. The cellulose particles of the present invention preferably have a specific surface area of 1 m ² / g or more, more preferably 1.3 m ² / g or more, and further preferably 2.0 m ² / g or more. . The upper limit of the specific surface area is not particularly limited, and is about 20 m ² / g at most. Cellulose particles that have been subjected to grinding or the like have a specific surface area that is too narrow. If the specific surface area is too small, moldability may be difficult to be exhibited.

  Although content of the cellulose particle which the molded object composition which concerns on this invention contains is not specifically limited, It is preferable that they are 0.5 mass% or more and 20 mass% or less. Within this range, sufficient moldability and excellent fluidity tend to be compatible. Considering the advantage of the present invention that the moldability and flowability are compatible with a small amount of excipient, the content of the cellulose particles contained in the molded composition according to the present invention is more preferably 10% by mass or less, 5 mass% or less is more preferable.

  Although content of the active ingredient which the molded object composition concerning this invention contains is not specifically limited, It is preferable that they are 80 mass% or more and 99.5 mass% or less. A molded body of an active ingredient that requires a high dose when forming a molded body such as a tablet using the molded body composition by sufficiently increasing the proportion of the active ingredient in the entire molded body composition. It is possible to reduce the size of the remarkably efficiently.

  The molded body composition according to the present invention is, for example, a step of preparing a mixed liquid containing the cellulose dispersion according to the present invention and an active ingredient, and the prepared mixed liquid is dried, and the average degree of polymerization is 100 to 350. And a step of obtaining a molded body composition containing cellulose and the active ingredient. By simultaneously drying the cellulose dispersion and the active ingredient according to the present invention, it is possible to prepare cellulose particles having a specific size and at least partially supporting the active ingredient.

  When preparing the liquid mixture containing the cellulose dispersion and the active ingredient according to the present invention, the order and method of mixing are not particularly limited, and known methods can be employed. As the mixing medium for preparing the mixed liquid, the same dispersion medium as described above can be used. The dispersion medium of the cellulose dispersion may be used as a mixing medium, or may be replaced with another medium. As an example, a cellulose dispersion liquid dispersed in water is filtered, and washing with an organic solvent is repeated to prepare a dispersion liquid in which cellulose is dispersed in the organic solvent. May be dissolved. In addition, the active ingredient may be dissolved in an organic solvent compatible with water in advance, and the organic solvent solution of the active ingredient may be mixed with the cellulose dispersion according to the present invention dispersed in water. The water solubility of the active ingredient can be greatly improved by dissolving it once in an organic solvent and then supporting it on the cellulose particles of the present invention. Since the active ingredient is amorphous in the solid dispersion, there is a concern of recrystallization during storage, whereas the method using the cellulose particles of the present invention has the advantage that there is less concern.

  The molded body composition according to the present invention can be obtained by drying the mixed liquid containing the cellulose dispersion according to the present invention and the active ingredient obtained in the above-described steps. The drying of the liquid mixture is not limited as long as it is a known method. For example, any of freeze drying, spray drying, drum drying, shelf drying, airflow drying, and vacuum drying may be used, one kind may be used alone, or two or more kinds may be used in combination. From an economical viewpoint, spray drying is preferred.

  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., one type may be used alone, or two or more types may be used. May be used in combination. There are two types of nozzle (nozzle method) or disk (rotary atomizer method) in the spray dryer: pressurized two-fluid nozzle, two-fluid nozzle, twin jet nozzle, disk-type nozzle, and low cap nozzle. A pressurized two-fluid nozzle and a two-fluid nozzle are preferred. A spray dryer is generally called a spray dryer, and is a drying device that instantly dries a cellulose dispersion to form particles (Okawara Kako, Matsubo, GEA Process Engineering, Powdering Japan, Nippon Chemical Machinery, Fujisaki Electric) Can be used).

  When spray-drying the mixture containing the cellulose dispersion and the active ingredient according to the present invention, a trace amount of water-soluble polymer or surfactant may be added for the purpose of reducing the surface tension of the dispersion. For the purpose of accelerating the vaporization rate, a foaming agent or a gas may be added to the dispersion.

  In addition, it is not necessary to completely remove the solvent in the drying step, and it is also possible to use a wet powder tableting method after intentionally forming a wet powder.

[Molded body]
The molded product according to the present invention refers to a molded product containing the molded product composition according to the present invention and processed by appropriately selecting a known method such as mixing, stirring, granulation, tableting, sizing, and drying. . Examples of molded articles include solid preparations such as tablets, powders, fine granules, granules, extracts, pills, capsules, troches, and poultices when used for pharmaceuticals. Not only pharmaceuticals, but also foods such as confectionery, health foods, texture improvers, dietary fiber reinforcements, solid foundations, bath preparations, animal drugs, diagnostic agents, agricultural chemicals, fertilizers, ceramic catalysts, etc. It is contained in the molded object which concerns on invention.

  In the molded product according to the present invention, the content of the cellulose particles of the present invention is not particularly limited, but is preferably 0.5% by mass or more and 20% by mass or less based on the weight of the molded product. Within this range, sufficient moldability and excellent fluidity tend to be compatible. Considering the advantage of the present invention that the moldability and fluidity are compatible with a small amount of excipient, the content of the cellulose particles of the present invention relative to the entire molded body is preferably 10% by mass or less, and preferably 5% by mass or less. More preferred.

  The molded body according to the present invention preferably has a hardness of 50N or more, preferably 60N or more when it is a cylindrical molded body having a diameter of 1.13 cm obtained by compressing a weight of 0.5 g with a striking pressure of 10 kN. More preferably, it is more preferably 70N or more. Further, the molded body according to the present invention preferably has a friability of 1% or less, more preferably 0.5% or less, and further preferably 0.3% or less.

  In addition to cellulose and the active ingredient, the molded product according to the present invention includes a disintegrant, a binder, a fluidizing agent, a lubricant, a flavoring agent, a flavoring agent, a coloring agent, a sweetening agent, and a surfactant as necessary. It is also free to contain other additives such as.

  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 Starches, starches such as partially pregelatinized starch, crospovidone and the like can be mentioned. Crospovidone can also be used as a base for solid dispersions.

  Binders include sugars such as sucrose, glucose, lactose, fructose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, gelatin, pullulan, carrageenan, locust bean gum, agar, konjac mannan, xanthan gum, tamarind Water-soluble polysaccharides such as gum, pectin, sodium alginate, gum arabic, crystalline cellulose, powdered cellulose, celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, starches such as pregelatinized starch and starch paste, polyvinylpyrrolidone, Synthetic polymers such as carboxyvinyl polymer and polyvinyl alcohol, calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, aluminate silicate Inorganic acids such as Neshiumu like. Hydroxypropylcellulose, hydroxypropylmethylcellulose and the like can also be used as the base of the solid dispersion.

Examples of the fluidizing agent include hydrous silicon dioxide and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc and the like.
Examples of the corrigent include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol and the like.

Examples of the fragrances include oranges, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, mint oil, and green tea powder.
Examples of the colorant include food colors such as food red No. 3, food yellow No. 5, and food blue No. 1, copper chlorophyllin sodium, titanium oxide, riboflavin and the like.

Examples of sweeteners include aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and amacha powder.
Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and the like.

  The method for producing a molded body from the molded body composition according to the present invention can be roughly classified into two methods, ie, a compression molding method and a molding method using a mold.

  The compression molding method is a method for preparing a molded body by compression molding the molded body composition according to the present invention. When the molded body is a tablet, compression molding is a general method and is preferable. Examples of the compression molding method include known methods such as a direct tableting method, a granule compression method, a terminal powder method, and a wet powder tableting method.

  In sugar-coated tablets, wetting is used for the purpose of a sugar-coating reinforcement, an extrudability improving agent in extrusion granulation, crushing granulation, fluidized bed granulation, high-speed agitation granulation, rolling fluidization granulation, etc. It can also be used in granulation, and it is possible to prepare granules and granules for tableting. A dry granulation method may be used for preparing the granules for tableting. Furthermore, it is also possible to tablet by a method (late method) in which the molded composition according to the present invention is added to the granules for tableting obtained by a known method in this way and compression molded.

  The molding method using a mold is a method of molding by pouring the molded body composition according to the present invention into a mold as it is or dispersed in an appropriate mixing medium and drying it as it is. Any mold can be used as long as it can be shaped, and a known method can be adopted. As the mixed medium, the same dispersion medium as described above can be used.

  The invention is illustrated by the following examples. However, these do not limit the scope of the present invention. In addition, the measuring method of each physical property in an Example and a comparative example is as follows.

(1) Average degree of polymerization (-)
The value measured by the copper ethylenediamine solution viscosity method described in the 15th revised Japanese Pharmacopoeia, confirmation test (3) for crystalline cellulose was taken as the average degree of polymerization of cellulose.

(2) Average particle size (μm) and particle size distribution (μm) when dispersed in water
Cellulose fine particles, cellulose particles, or a molded product containing cellulose particles is put in 50 mg of water and subjected to ultrasonic treatment for 1 hour to sufficiently disperse the cellulose particles. Then, a laser diffraction particle size distribution meter (manufactured by Horiba, LA-910). , Refractive index 1.20, sonication for 1 minute or 1 hour), the particle diameter was equivalent to 50% as the integrated volume. In the particle size distribution, the minimum observed particle size was the lower limit, and the maximum particle size was the upper limit.

(3) Sphericality of cellulose particles (-)
Cellulose particles are dried as necessary, placed on a sample table with a carbon tape, and platinum palladium is vacuum-deposited (the film thickness of the deposited film is 20 nm or less), and an electron microscope (manufactured by JASCO, JSM- 5510 LV, acceleration voltage 6 kV, magnification 4000 times). About each particle | grain, the value which divided the minimum diameter by the maximum diameter was calculated | required, and it computed as a number average value. The larger the number, the better, and the average value of at least 100 or more.

(4) Cumulative volume of cellulose dispersion 50% particle size, particle size distribution (μm)
The 50% cumulative volume particle size of the cellulose dispersion is 50% as the cumulative volume when measured with a laser diffraction particle size distribution meter (manufactured by Horiba, LA-910, refractive index 1.20, ultrasonic treatment for 1 minute). The corresponding particle size was taken. In the particle size distribution, the minimum observed particle size was the lower limit, and the maximum particle size was the upper limit.

(5) Hardness (N)
Using a Schleingel hardness tester (Freund Sangyo Co., Ltd., 6D type) on the cylindrical molded body or tablet, a load is applied in the diameter direction of the cylindrical molded body or tablet, and the load when broken is determined as hardness. As measured. The hardness of each sample was shown by the number average value of five samples.

(6) Tablet friability (%)
Measure the weight (Wa) of 20 tablets, put it in a tablet friability tester (PTFR-A, manufactured by PHARMA TEST), rotate at 25 rpm for 4 minutes, remove fine powder adhering to the tablets, and again The weight was measured (Wb) and calculated from the following formula.

  Friction = 100 × (Wa−Wb) / Wa

  In order to obtain a tablet that can withstand practical use, when the tablet weight is 0.5 g or less, the friability is 0.5% or less, and when the tablet weight is 0.5 g or more, the friability is 1.0%. Must be:

[Example 1]
2 kg of commercially available SP pulp was shredded, placed in 30 L of a 0.14N (0.49%) hydrochloric acid aqueous solution, and hydrolyzed under the conditions of 121 ° C. and 1 hour. The obtained acid-insoluble residue was filtered using a Nutsche, and the filter residue was further washed with 70 L of pure water four times, neutralized with ammonia water, placed in a 90 L plastic bucket, and stirred with a three-one motor. A 17% cellulose dispersion was obtained (pH; 6.4, IC; 64 μS / cm).
This was centrifuged (3000 rpm × 10 minutes, 5000 rpm × 10 minutes, or 8000 rpm × 10 minutes) to obtain an aqueous cellulose dispersion. The particle size distribution of the supernatant cellulose dispersion centrifuged at each rotational speed is shown in FIG. The supernatant cellulose dispersion (solid content: 1.78% by mass) centrifuged at 8000 rpm × 10 minutes was designated as Cellulose Dispersion A, and the physical properties thereof were examined. The physical properties of the cellulose dispersion A are shown in Table 1.

[Example 2]
2 kg of commercially available KP pulp and 30 L of 4N hydrochloric acid aqueous solution were put into a low speed type stirrer (Ikebukuro Sakai Kogyo Co., Ltd., 50 L GL reactor) and hydrolyzed under conditions of 40 ° C. and 48 hours while stirring at 50 rpm. An insoluble residue was obtained. The obtained acid-insoluble residue is thoroughly washed with pure water, filtered, introduced into a 90 L plastic bucket, pure water is added so that the total solid content concentration becomes 15% by mass, and the mixture is stirred with a 3-1 motor. While neutralizing with aqueous ammonia. The pH after neutralization was 7.5 to 8.0. The obtained cellulose dispersion was centrifuged (5000 rpm × 10 minutes) to obtain a cellulose dispersion B having a solid content of 1.20% by mass. The physical property values of the cellulose dispersion B are shown in Table 1.

[Example 3]
2 kg of commercially available KP pulp and 30 L of 5N hydrochloric acid aqueous solution were put into a low-speed stirrer (Ikebukuro Sakai Kogyo Co., Ltd., 50 L GL reactor) and hydrolyzed under conditions of 40 ° C. and 20 hours while stirring at 30 rpm. An insoluble residue was obtained. The obtained acid-insoluble residue is thoroughly washed with pure water, filtered, introduced into a 90 L plastic bucket, pure water is added so that the total solid concentration is 18% by mass, and the mixture is stirred with a 3-1 motor. While neutralizing with aqueous ammonia. The pH after neutralization was 7.5 to 8.0. The obtained cellulose dispersion was centrifuged (3000 rpm × 10 minutes) to obtain a cellulose dispersion C having a solid content of 2.0% by mass. Table 1 shows the physical property values of the cellulose dispersion C.

[Example 4]
Commercially available KP pulp was shredded, placed in a 0.7% aqueous hydrochloric acid solution, and hydrolyzed under conditions of 125 ° C. and 150 minutes. The acid-insoluble residue obtained after the hydrolysis was neutralized, washed and filtered to obtain a wet cake. After sufficiently grinding in a kneader, pure water was added and stirred with a 3-1 motor to obtain a cellulose dispersion. The obtained cellulose dispersion was centrifuged (3000 rpm × 10 minutes) to obtain a cellulose dispersion D having a solid content of 4.0% by mass. The physical property values of the cellulose dispersion D are shown in Table 1.

[Example 5]
Commercially available crystalline cellulose “Theolas UF-702” (manufactured by Asahi Kasei Co., Ltd.) was subjected to wet milling (TK homomixer, 8000 rpm, 10 minutes, dispersion concentration 14.8%) twice, and a cellulose dispersion obtained Was centrifuged (5000 rpm × 10 minutes) to obtain a cellulose dispersion E having a solid content of 3.7% by mass. Table 1 shows the physical property values of the cellulose dispersion E.

[Comparative Example 1]
2 kg of commercially available KP pulp and 30 L of 4N hydrochloric acid aqueous solution were put into a low-speed type stirrer (Ikebukuro Sakai Kogyo Co., Ltd., 50 L GL reactor, blade diameter of about 30 cm), with stirring at 5 rpm, at 40 ° C. for 24 hours. Hydrolysis yielded an acid-insoluble residue having an average degree of polymerization of 310. The obtained acid-insoluble residue was filtered using Nutsche so as to have a solid content of 40%, and the filter residue was further washed with pure water, neutralized with ammonia water, put into a 90 L plastic bucket, and purified water. And a one-motor (manufactured by HEIDON, type 1200G, 8 M / M, stirring blade diameter 5 cm) and stirring at a stirring speed of 5 rpm to obtain a cellulose dispersion having a solid content concentration of 10%. The obtained cellulose dispersion was centrifuged (5000 rpm × 10 minutes) to obtain a cellulose dispersion F having a solid content of 1.65% by mass. The physical property values of the cellulose dispersion F are shown in Table 1.

[Comparative Example 2]
Commercially available KP pulp was shredded, placed in a 10% aqueous hydrochloric acid solution, and hydrolyzed at 105 ° C. for 60 minutes. The acid-insoluble residue obtained after hydrolysis was filtered and washed to obtain a cake having a solid content of about 40%. This cake was subjected to a grinding treatment with a universal mixing stirrer for 1 hour. Water was added to this ground cake-like product, and a 13% by mass solids cellulose dispersion was obtained with a homomixer. The obtained cellulose dispersion is subjected to a crushing process of passing through the high-pressure crusher three times under the condition of 120 MPa, and then the particle diameter, pH and IC are adjusted, and the rotating disk is rotated using an approximately 8 cm rotating disk. Spray drying under conditions of about 5000 rpm, flow rate of about 6 L / hour, supply temperature of about 170 ° C. and exhaust temperature of about 85 ° C., removing coarse particles with a sieve having an opening of 150 μm, and sieving fine particles with a sieve having an opening of 63 μm. Then, cellulose particles G (corresponding to Example 6 of Japanese Patent No. 4062436) were obtained. The physical property values of the cellulose particles G are shown in Table 1.

[Comparative Example 3]
1.5 kg of crystalline cellulose (average polymerization degree 250) was charged into a high-speed stirring granulator, 900 g of distilled water was added, and kneaded for 30 minutes. 2.4 kg of wet granules obtained by kneading were charged into a rolling fluid type coating apparatus, and 340 g of distilled water was supplied at a rate of 7.8 g / min, while rolling at a supply temperature of 25 ° C. for 45 minutes. Thereafter, rolling was performed for another 30 minutes. Thereafter, the air supply temperature is raised to 100 ° C. and dried. After drying, the mixture is sieved with a 75 μm sieve and a 45 μm sieve. Obtained. The physical property values of the cellulose particles H are shown in Table 1.

[Example 6]
Metformin hydrochloride is dissolved in cellulose dispersion A and then spray-dried to obtain metformin hydrochloride powder (corresponding to the molding composition according to the present invention) containing 5% by mass of cellulose particles derived from cellulose dispersion A. (Composition: Metformin hydrochloride / cellulose particles A of the present invention = 95/5, mass%). Table 2 shows the results of measurement of the sphericity, specific surface area, and particle size distribution when dispersed in water, together with the degree of polymerization of cellulose. FIG. 2 shows an electron micrograph of the powder (acceleration voltage 5 kV, magnification 4000 times). Metformin hydrochloride solidified during storage (see FIG. 3), whereas metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion A has no fluidity during storage and is fluid. It was a certain powder (angle of repose 47 °) (see FIG. 4).

0.5 g of metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion A is put into a mortar (manufactured by Kikusui Seisakusho, using material SUK2, 3), and has a diameter of 1.13 cm (bottom area is 1 cm ² ). The tablet was manufactured by compressing with a flat plate (manufactured by Kikusui Seisakusho, using materials SUK2 and 3) at 10 kN and maintaining the stress for 10 seconds. The compressor used was PCM-1A manufactured by Aiko Engineering Co., Ltd., and the compression speed was about 10 cm / min. Table 3 shows the hardness values of the tablets. The hardness of tablets of metformin hydrochloride produced in the same manner was 45N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion A was greatly improved to 105N. It had been.

[Example 7]
A tablet of metformin hydrochloride containing 5% by mass of cellulose particles was produced in the same manner as in Example 6 except that the cellulose dispersion A was changed to the cellulose dispersion B. Table 2 shows the results of measurement of the sphericity, specific surface area, and particle size distribution when dispersed in water of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion B, together with the degree of polymerization of cellulose. Table 3 shows the hardness values of the tablets produced. Metformin hydrochloride solidified during storage, whereas metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion B has no solidification during storage and is a fluid powder (rest angle) 49 °). The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45 N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion B was greatly improved to 120 N. It had been.

[Example 8]
A tablet of metformin hydrochloride containing 5% by mass of cellulose particles was produced in the same manner as in Example 6 except that the cellulose dispersion A was changed to the cellulose dispersion C. Table 2 shows the sphericity of the metformin hydrochloride powder containing 5% by mass of cellulose particles derived from the cellulose dispersion C, the specific surface area, and the particle size distribution when dispersed in water together with the polymerization degree of cellulose. Table 3 shows the hardness values of the tablets produced. Metformin hydrochloride solidified during storage, whereas metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion C has no solidification during storage and is a fluid powder (angle of repose). 45 °). The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion C was greatly improved to 110N. It was.

[Example 9]
A tablet of metformin hydrochloride containing 5% by mass of cellulose particles was produced in the same manner as in Example 6 except that the cellulose dispersion A was changed to the cellulose dispersion D. Table 2 shows the results of measurement of the sphericity, specific surface area, and particle size distribution when dispersed in water of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion D, together with the degree of polymerization of cellulose. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of only metformin hydrochloride produced in the same manner was 45 N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion D was 53 N, which is an improvement effect. It was observed.

[Example 10]
Metformin hydrochloride tablets containing 5% by mass of cellulose particles were produced in the same manner as in Example 6 except that the cellulose dispersion A was changed to the cellulose dispersion E. Table 2 shows the results of measurement of the sphericity, specific surface area, and particle size distribution of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion E together with the degree of polymerization of cellulose. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45 N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion E was significantly improved to 115 N. It was.

[Comparative Example 4]
A tablet of metformin hydrochloride containing 5% by mass of cellulose particles was produced in the same manner as in Example 6 except that the cellulose dispersion A was changed to the cellulose dispersion F. Table 2 shows the results of measuring the sphericity, specific surface area, and particle size distribution when dispersed in water of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion F, together with the degree of polymerization of cellulose. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45 N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion F was 45 N with no improvement effect. It was.

[Comparative Example 5]
A mixed powder of cellulose particles G and metformin hydrochloride (composition: metformin hydrochloride / cellulose particles G = 95/5, mass%) was prepared. Tablets were produced in the same manner as in Example 6 from 0.5 g of the mixed powder. The sphericity of the cellulose particles G, the specific surface area, and the results of measuring the particle size distribution when dispersed in water are shown in Table 2 together with the degree of polymerization of cellulose, and the hardness values of the tablets produced are shown in Table 3. . The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45 N, whereas the tablet hardness of metformin hydrochloride containing 5% by mass of cellulose particles G was 25 N, and there was no improvement effect.

[Comparative Example 6]
Metformin hydrochloride tablets containing 5% by mass of cellulose particles were produced in the same manner as in Comparative Example 5 except that the cellulose particles G were changed to cellulose H. The results of measuring the sphericity, specific surface area, and particle size distribution of the cellulose particles H when dispersed in water are shown in Table 2 together with the degree of polymerization of cellulose, and the hardness values of the tablets produced are shown in Table 3. . The hardness of the tablet of metformin hydrochloride alone produced in the same manner was 45 N, whereas the hardness of metformin hydrochloride containing 5% by mass of cellulose particles H was 30 N, and there was no improvement effect.

[Example 11]
Metformin hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion A obtained in Example 6 was compressed by rotary tableting to prepare tablets (manufactured by Kikusui Seisakusho, LIBRA2, φ12 mm, 760 mg tablet, turntable rotation Several 30 rpm, impact pressure 12 kN). Table 3 shows the hardness values of the tablets produced. In the case of tablets of crystalline cellulose “Theolas” KG-1000 / Metformin hydrochloride = 5/95 (mass ratio), the tablet hardness was 40 N and the friability exceeded 1%, whereas the cellulose obtained in Example 6 The hardness of the metformin hydrochloride tablet containing 5% by mass of the cellulose particles derived from the dispersion A was as high as 250 N, and the friability was as good as 0.8%.

  To date, even when using KG-1000, the highest moldability of commercially available crystalline cellulose, formulation: metformin hydrochloride / KG-1000 / disintegrant / silicic anhydride / magnesium stearate = 80/17 / In 2 / 0.5 / 0.5 (mass ratio) rotary tableting (conditions are the same as above), since tablet hardness exceeds 70N and friability of 1%, direct compression containing metformin hydrochloride at 80% by mass or more. You cannot make a lock. On the other hand, it was confirmed that if the cellulose particles of the present invention were used, it was possible to form a spill containing 95% by mass of metformin.

[Example 12]
Ascorbic acid was dissolved in cellulose dispersion A and then spray-dried to obtain ascorbic acid powder (corresponding to the molding composition according to the present invention) containing 5% by mass of cellulose particles derived from cellulose dispersion A ( Composition: ascorbic acid / cellulose particles of the present invention = 95/5, mass%). The sphericity of the powder, the specific surface area, and the particle size distribution when dispersed in water are the same as those of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from the cellulose dispersion A obtained in Example 6. Met. Tablets were produced in the same manner as in Example 6 from 0.5 g of the powder. Table 3 shows the hardness values of the tablets produced. The hardness of the ascorbic acid-only tablet produced in the same manner was 0N, whereas the tablet hardness of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion A was greatly improved to 100N.

[Example 13]
An ascorbic acid tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion B was produced in the same manner as in Example 12 except that the cellulose dispersion A was changed to the cellulose dispersion B. Table 3 shows the hardness values of the tablets produced. The hardness of the ascorbic acid-only tablet produced in the same manner was 0N, whereas the tablet hardness of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion B was greatly improved to 110N. In addition, the sphericity of the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion B, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion B obtained in Example 7. It was the same level as that of metformin hydrochloride powder containing 5% by mass of cellulose particles derived therefrom.

[Example 14]
An ascorbic acid tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion C was produced in the same manner as in Example 12 except that the cellulose dispersion A was changed to the cellulose dispersion C. Table 3 shows the hardness values of the tablets produced. The hardness of the ascorbic acid-only tablet produced in the same manner was 0N, whereas the tablet hardness of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion C was greatly improved to 105N. In addition, the sphericity of the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion C, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion C obtained in Example 8. It was the same level as that of metformin hydrochloride powder containing 5% by mass of cellulose particles derived therefrom.

[Example 15]
An ascorbic acid tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion D was produced in the same manner as in Example 12 except that the cellulose dispersion A was changed to the cellulose dispersion D. Table 3 shows the hardness values of the tablets produced. The ascorbic acid-only tablet produced in the same manner had a hardness of 0 N, while the ascorbine containing 5% by mass of cellulose particles derived from the cellulose dispersion D had a tablet hardness of 54 N, showing an improvement effect. . In addition, the sphericity of the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion D, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion D obtained in Example 9. It was the same level as that of metformin hydrochloride powder containing 5% by mass of cellulose particles derived therefrom.

[Example 16]
An ascorbic acid tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion E was produced in the same manner as in Example 12 except that the cellulose dispersion A was changed to the cellulose dispersion E. Table 3 shows the hardness values of the tablets produced. The tablet hardness of ascorbic acid alone produced in the same manner was 0 N, while the tablet hardness of ascorbine containing 5% by mass of cellulose particles derived from the cellulose dispersion E was greatly improved to 102 N. In addition, the sphericity of the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion E, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion E obtained in Example 10. It was the same level as that of metformin hydrochloride powder containing 5% by mass of cellulose particles derived therefrom.

[Comparative Example 7]
An ascorbic acid tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion F was produced in the same manner as in Example 12 except that the cellulose dispersion A was changed to the cellulose dispersion F. Table 3 shows the hardness values of the tablets produced. The ascorbic acid-only tablet produced in the same manner had a hardness of 0 N, while the ascorbine containing 5 mass% of cellulose particles derived from the cellulose dispersion F had a tablet hardness of 30 N, and the improvement effect was small. In addition, the sphericity of the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion F, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion F obtained in Comparative Example 4. It was the same level as that of metformin hydrochloride powder containing 5% by mass of cellulose particles derived therefrom.

[Comparative Example 8]
A mixed powder of cellulose particles G and ascorbic acid (composition: ascorbic acid / cellulose particles G = 95/5, mass%) was prepared. The sphericity of the mixed powder, the specific surface area, and the particle size distribution when dispersed in water were comparable to the mixed powder obtained in Comparative Example 5. Tablets were produced in the same manner as in Example 6 from 0.5 g of the mixed powder. Table 3 shows the hardness values of the tablets produced. The hardness of the ascorbic acid-only tablet produced in the same manner was 0 N, whereas the tablet hardness of ascorbic acid containing 5% by mass of cellulose particles G was 0 N, and there was no improvement effect.

[Comparative Example 9]
An ascorbic acid tablet containing 5% by mass of cellulose particles was produced in the same manner as in Comparative Example 8 except that the cellulose particles G were changed to cellulose particles H. Table 3 shows the hardness values of the tablets produced. The ascorbic acid-only tablet produced in the same manner had a hardness of 0N, while the ascorbine containing 5% by mass of cellulose particles H had a tablet hardness of 4N, and the improvement effect was small. In addition, the sphericity of the mixed powder of cellulose particles H and ascorbic acid, the specific surface area, and the particle size distribution when dispersed in water were almost the same as the mixed powder obtained in Comparative Example 6.

[Example 17]
Glucosamine hydrochloride is dissolved in cellulose dispersion A and then spray-dried to obtain glucosamine hydrochloride powder (corresponding to the molded product composition according to the present invention) containing 5% by mass of cellulose particles derived from cellulose dispersion A. (Composition: glucosamine hydrochloride / cellulose particles of the present invention = 95/5, mass%). The sphericity of the powder, the specific surface area, and the particle size distribution when dispersed in water are the same as those of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from the cellulose dispersion A obtained in Example 6. Met. Tablets were produced in the same manner as in Example 6 from 0.5 g of the powder. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of glucosamine hydrochloride alone produced in the same manner was 0N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion A was greatly improved to 85N. It was.

[Example 18]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion B was produced in the same manner as in Example 17 except that the cellulose dispersion A was changed to the cellulose dispersion B. Table 3 shows the hardness values of the tablets produced. The hardness of the glucosamine hydrochloride tablet produced in the same manner was 0 N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion B was greatly improved to 100 N. It was. In addition, the sphericity of the powder of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion B, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 7. It was about the same as the powder of metformin hydrochloride containing 5% by mass of B-derived cellulose particles.

[Example 19]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion C was produced in the same manner as in Example 17 except that the cellulose dispersion A was changed to the cellulose dispersion C. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of glucosamine hydrochloride alone produced in the same manner was 0N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion C was greatly improved to 90N. It was. In addition, the sphericity of the powder of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion C, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 8. It was the same as the powder of metformin hydrochloride containing 5% by mass of C-derived cellulose particles.

[Example 20]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion D was produced in the same manner as in Example 17 except that the cellulose dispersion A was changed to the cellulose dispersion D. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of glucosamine hydrochloride alone produced in the same manner was 0N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion D was 55N, which had an improvement effect. It was seen. In addition, the sphericity of the powder of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion D, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 9. It was the same level as the powder of metformin hydrochloride containing 5% by mass of cellulose particles derived from D.

[Example 21]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion E was produced in the same manner as in Example 17 except that the cellulose dispersion A was changed to the cellulose dispersion E. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of glucosamine hydrochloride alone produced in the same manner was 0N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion E was greatly improved to 95N. It was. In addition, the sphericity of the powder of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from cellulose dispersion E, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 10. It was about the same as the powder of metformin hydrochloride containing 5% by mass of E-derived cellulose particles.

[Comparative Example 10]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion F was produced in the same manner as in Example 17 except that the cellulose dispersion A was changed to the cellulose dispersion F. Table 3 shows the hardness values of the tablets produced. The hardness of the glucosamine hydrochloride-only tablet produced in the same manner was 0N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion F was 30N, and the improvement effect was It was small. In addition, the sphericity of the powder of glucosamine hydrochloride containing 5% by mass of cellulose particles derived from the cellulose dispersion F, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Comparative Example 4. It was almost the same as the powder of metformin hydrochloride containing 5% by mass of cellulose particles derived from F.

[Comparative Example 11]
A mixed powder of cellulose particles G and glucosamine hydrochloride (composition; glucosamine hydrochloride / cellulose particles G = 95/5, mass%) was prepared. The sphericity of the mixed powder, the specific surface area, and the particle size distribution when dispersed in water were comparable to the mixed powder obtained in Comparative Example 5. Tablets were produced in the same manner as in Example 6 from 0.5 g of the mixed powder. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of glucosamine hydrochloride alone produced in the same manner was 0 N, whereas the tablet hardness of glucosamine hydrochloride containing 5% by mass of cellulose particles G was 0 N, and there was no improvement effect.

[Comparative Example 12]
A glucosamine hydrochloride tablet containing 5% by mass of cellulose particles H was produced in the same manner as in Comparative Example 11 except that the cellulose particles G were changed to cellulose particles H. Table 3 shows the hardness values of the tablets produced. The hardness of the glucosamine hydrochloride alone tablet produced in the same manner was 0 N, whereas the glucosamine hydrochloride containing 5% by mass of cellulose particles H had a tablet hardness of 3 N, and the improvement effect was small. The sphericity of the mixed powder of cellulose particles H and glucosamine hydrochloride, the specific surface area, and the particle size distribution when dispersed in water were almost the same as the mixed powder obtained in Comparative Example 6.

[Example 22]
Acetaminophen is dissolved in cellulose dispersion A and then spray-dried to obtain acetaminophen powder (corresponding to the molded product composition according to the present invention) containing 5% by mass of cellulose particles derived from cellulose dispersion A. (Composition: acetaminophen / cellulose particles of the present invention = 95/5, mass%). The sphericity of the powder, the specific surface area, and the particle size distribution when dispersed in water are the same as those of metformin hydrochloride powder containing 5% by mass of cellulose particles derived from the cellulose dispersion A obtained in Example 6. Met. Tablets were produced in the same manner as in Example 6 from 0.5 g of the powder. Table 3 shows the hardness values of the tablets produced. The hardness of the acetaminophen-only tablet produced in the same manner was 3N, whereas the hardness of the acetaminophen tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion A was greatly improved to 60N. The friability was good at 0.25%.

[Example 23]
Acetaminophen tablets containing 5% by mass of cellulose particles derived from cellulose dispersion B were produced in the same manner as in Example 22 except that cellulose dispersion A was changed to cellulose dispersion B. Table 3 shows the hardness values of the tablets produced. The hardness of the acetaminophen-only tablet produced in the same manner was 3N, whereas the hardness of the acetaminophen tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion B was greatly improved to 80N. The friability was 0.19%. In addition, the sphericity of the powder of acetaminophen containing 5% by mass of cellulose particles derived from the cellulose dispersion B, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 7. It was about the same as the powder of metformin hydrochloride containing 5% by mass of B-derived cellulose particles.

[Example 24]
Acetaminophen tablets containing 5% by mass of cellulose particles derived from the cellulose dispersion C were produced in the same manner as in Example 22 except that the cellulose dispersion A was changed to the cellulose dispersion C. Table 3 shows the hardness values of the tablets produced. The acetaminophen-only tablet produced in the same manner had a hardness of 3N, whereas the acetaminophen tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion C had a significantly improved hardness of 70N. The friability was 0.45%. In addition, the sphericity of the powder of acetaminophen containing 5% by mass of cellulose particles derived from the cellulose dispersion C, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 8. It was the same as the powder of metformin hydrochloride containing 5% by mass of C-derived cellulose particles.

[Example 25]
Acetaminophen tablets containing 5% by mass of cellulose particles derived from the cellulose dispersion D were produced in the same manner as in Example 22 except that the cellulose dispersion A was changed to the cellulose dispersion D. Table 3 shows the hardness values of the tablets produced. The acetaminophen-only tablet produced in the same manner had a hardness of 3N, whereas an acetaminophen tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion D had an improvement effect of 51N. As seen, the friability was 0.85%. In addition, the sphericity of the powder of acetaminophen containing 5% by mass of cellulose particles derived from the cellulose dispersion D, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 9. It was the same level as the powder of metformin hydrochloride containing 5% by mass of cellulose particles derived from D.

[Example 26]
Acetaminophen tablets containing 5% by mass of cellulose particles derived from the cellulose dispersion E were produced in the same manner as in Example 22 except that the cellulose dispersion A was changed to the cellulose dispersion E. Table 3 shows the hardness values of the tablets produced. The hardness of the acetaminophen-only tablet produced in the same manner was 3N, whereas the hardness of the acetaminophen tablet containing 5% by mass of cellulose particles derived from the cellulose dispersion E was greatly improved to 85N. The friability was 0.61%. In addition, the sphericity of the powder of acetaminophen containing 5% by mass of cellulose particles derived from the cellulose dispersion E, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Example 10. It was about the same as the powder of metformin hydrochloride containing 5% by mass of E-derived cellulose particles.

[Comparative Example 13]
Acetaminophen tablets containing 5% by mass of cellulose particles derived from the cellulose dispersion F were produced in the same manner as in Example 22 except that the cellulose dispersion A was changed to the cellulose dispersion F. Table 3 shows the hardness values of the tablets produced. The hardness of the tablet of only acetaminophen produced in the same manner was 3N, whereas the tablet hardness of acetaminophen containing 5% by mass of cellulose particles derived from the cellulose dispersion F was 10N, and the improvement effect was It was small. The sphericity of the acetaminophen powder containing 5% by mass of cellulose particles derived from the cellulose dispersion F, the specific surface area, and the particle size distribution when dispersed in water are the cellulose dispersion obtained in Comparative Example 4. It was almost the same as the powder of metformin hydrochloride containing 5% by mass of cellulose particles derived from F.

[Comparative Example 14]
A mixed powder of cellulose particles G and acetaminophen (composition: acetaminophen / cellulose particles G = 95/5, mass%) was prepared. The sphericity of the mixed powder, the specific surface area, and the particle size distribution when dispersed in water were comparable to the mixed powder obtained in Comparative Example 5. Tablets were produced in the same manner as in Example 6 from 0.5 g of the mixed powder. Table 3 shows the hardness values of the tablets produced. The tablet hardness of acetaminophen alone produced in the same manner was 3N, whereas the tablet hardness of acetaminophen containing 5% by mass of cellulose particles G was 0N, and there was no improvement effect.

[Comparative Example 15]
Acetaminophen tablets containing 5% by mass of cellulose particles H were produced in the same manner as in Comparative Example 14 except that the cellulose particles G were changed to cellulose particles H. Table 3 shows the hardness values of the tablets produced. The tablet hardness in the case of only acetaminophen produced in the same manner was 3N, whereas acetaminophen containing 5% by mass of cellulose particles H had a tablet hardness of 5N, and the improvement effect was small. In addition, the sphericity of the mixed powder of cellulose particles H and acetaminophen, the specific surface area, and the particle size distribution when dispersed in water were almost the same as the mixed powder obtained in Comparative Example 6.

[Example 27]
Fenofibrate dissolved in acetonitrile is put into cellulose dispersion A, dried in an explosion-proof spray-drying state in a completely dissolved state, and fenofibrate powder containing 50% by mass of cellulose particles derived from cellulose dispersion A (present) (Corresponding to a molded article composition according to the invention) was obtained (composition: fenofibrate / cellulose particles of the present invention = 50/50, mass%). When the dissolution test using the Japanese Pharmacopoeia 1 liquid was performed on the powder, the solubility of fenofibrate was greatly improved. Even after the powder was put in a glass bottle and stored at 40 ° C. and 75% RH for 6 months, the elution profile hardly changed. Since the cellulose particles derived from the cellulose dispersion A were very small and the crystal form of fenofibrate remained the same, it was considered that the elution profile did not change with time.

[Comparative Example 16]
Acetaminophen is dissolved in a slurry of hydrolyzed cellulose described in Patent Document 5 (2.5N hydrochloric acid, hydrolyzed in a boiling water bath for 15 minutes, then washed with water and purified), and then spray-dried. A powder of acetaminophen containing 5% by mass of hydrolyzed cellulose was obtained (composition: acetaminophen / hydrolyzed cellulose = 95/5,% by mass). Tablets were produced in the same manner as in Example 6 from 0.5 g of the powder. Table 3 shows the hardness values of the tablets produced. The physical properties of the hydrolyzed cellulose slurry used are shown in Table 1. The tablet hardness of only acetaminophen produced in the same manner was 3N, whereas the tablet hardness of the powder was 30N, and the improvement effect was small. The friability exceeded 1% and was not put to practical use. It was.

  Since the hydrolyzed cellulose slurry described in Patent Document 5 is not centrifuged, it contains 95% by mass or more of particles larger than the average particle size and particle size distribution of the cellulose dispersion according to the present invention. When these large particles are present, if the active ingredient exceeds 85% by mass in the molded product composition, sufficient hardness and friability may not be imparted to the obtained molded product. From the results of these examples and comparative examples, the fine cellulose particles of about 5% by mass in the hydrolyzed cellulose slurry are essential components that impart crystallinity of the crystalline cellulose, and the presence of other components is In particular, it has been surprisingly found that as the amount of the active ingredient is increased, the moldability and the effect of preventing blocking of the active ingredient are inhibited.

  FIG. 5 shows metformin hydrochloride powder (UPS / MtH) containing 5% by mass of cellulose particles derived from cellulose dispersion A produced in Example 6, and cellulose particles derived from cellulose dispersion A produced in Example 12. Ascorbic acid powder containing 5% by mass (UPS / VC), glucosamine hydrochloride powder containing 5% by mass of cellulose particles derived from cellulose dispersion A produced in Example 17 (UPS / GM-C), comparative example 2 shows the particle size distribution of a dispersion obtained by redispersing cellulose G (SCP-100) 2 and cellulose H (CP-051X) of Comparative Example 3 in water. As shown in FIG. 5, the particle size distribution of the molded product composition produced from the cellulose dispersion A is almost the same regardless of the active ingredient, and the half-value width of the particle size distribution is the cellulose particle derived from the cellulose dispersion A. The powder of metformin hydrochloride containing 5% by mass contains 14 μm, the powder of ascorbic acid containing 5% by mass of cellulose particles derived from the cellulose dispersion A is contained 17.3 μm, and the cellulose particles derived from the cellulose dispersion A contains 5% by mass. The powder of glucosamine hydrochloride was 15.1 μm. The particle size distributions of the dispersions obtained by redispersing the powders produced in Examples 6, 12, and 17 were almost the same because the active ingredients are dissolved when these powders are redispersed in water. This is because the particle size distribution of the cellulose particles themselves is obtained. For this reason, the particle size distribution of the dispersion obtained by redispersing the powder produced in Comparative Example 5 or the like in water is almost the same as the dispersion of the cellulose particles G in FIG. The particle size distribution of the dispersion redispersed in water is almost the same as that of the dispersion of cellulose particles H in FIG.

  The molded body composition according to the present invention imparts excellent compression moldability to an active ingredient having poor compression moldability, and can prevent blocking of an active ingredient having high adhesion and cohesiveness, thereby greatly improving fluidity. For this reason, the molded body composition according to the present invention can extremely effectively reduce the size of an active ingredient tablet that requires a high dose, and can contribute to improvements in ease of drinking and compliance. It can also contribute to solubilization of poorly soluble active ingredients.

Claims (14)

  The average degree of polymerization is 100 to 350, and the particle size distribution measured by a laser diffraction particle size distribution meter is such that the volume ratio of particles having an integrated volume 50% particle size in the range of 0.5 to 12 μm and 0.3 to 25 μm. A cellulose dispersion characterized by containing 90% or more cellulose particles.   The cellulose dispersion liquid of Claim 1 whose solid content concentration is 10 mass% or less. Hydrolyzing natural cellulosic material to obtain a cellulose aqueous dispersion;
Centrifuge the cellulose aqueous dispersion, and recover the supernatant as a cellulose dispersion containing cellulose particles having an average degree of polymerization of 100 to 350;
Have
The particle size distribution measured by a laser diffraction particle size distribution meter of the cellulose particles is such that the volume ratio of particles having an integrated volume 50% particle diameter in the range of 0.5 to 12 μm and 0.3 to 25 μm is 90% or more. A method for producing a cellulose dispersion characterized by the above. Containing cellulose having an average degree of polymerization of 100 to 350 and an active ingredient,
The cellulose is a particle having a sphericity of 0.6 to 1.0, and a particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment is 50% cumulative volume particle. A molded body composition characterized by having a volume ratio of particles of 90% or more and a full width at half maximum of 5 to 30 μm in a diameter range of 5 to 20 μm and 2 to 50 μm.   The molded body composition according to claim 4, wherein a content of the cellulose is 0.5 to 20% by mass with respect to the entire composition.   The molded body composition according to claim 4 or 5, wherein the hardness of a cylindrical molded body having a diameter of 1.13 cm obtained by compressing a weight of 0.5 g with a pressure of 10 kN is 50 N or more.   The molded object composition according to any one of claims 4 to 6, wherein the active ingredient is poorly water-soluble.   The molded object composition as described in any one of Claims 4-7 with which the said active ingredient is carry | supported by the particle | grains of the said cellulose.   The molded object composition as described in any one of Claims 4-8 whose said active ingredient is a pharmaceutical active ingredient.   A molded body comprising the molded body composition according to any one of claims 4 to 9.   The molded product according to claim 10, wherein the content of the active ingredient is 80% by mass or more based on the entire molded product. Hydrolyzing natural cellulosic material to obtain a cellulose aqueous dispersion;
Centrifuging the cellulose aqueous dispersion and recovering the supernatant as a cellulose dispersion;
A step of preparing a mixed liquid containing the cellulose dispersion and an active ingredient;
Drying the mixed liquid to obtain a molded body composition containing cellulose having an average polymerization degree of 100 to 350 and the active ingredient;
Have
The cellulose in the molded body composition is particles having a sphericity of 0.6 to 1.0, and the particle size distribution measured by a laser diffraction particle size distribution meter when dispersed in water by ultrasonic treatment. The volume ratio of particles having an integrated volume 50% particle diameter of 5 to 20 μm and a particle size in the range of 2 to 50 μm is 90% or more, and the half-value width is 5 to 30 μm. .   The cellulose dispersion has an average degree of polymerization of 100 to 350, and a particle size distribution measured by a laser diffraction particle size distribution meter is such that the cumulative volume 50% particle diameter is in the range of 0.5 to 12 μm and 0.3 to 25 μm. The manufacturing method of the molded object composition of Claim 12 containing the cellulose particle whose volume ratio of a certain particle is 90% or more.   The method for producing a molded body composition according to claim 12 or 13, wherein the cellulose dispersion has a solid content concentration of 10% by mass or less.