JP2001335469A - Method for producing solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a solid preparation enabling quick dissolution of a scarcely water-soluble physiologically active component and having a proper hardness without using complicate procedures. SOLUTION: The method for the production of a solid preparation comprises the mixing of a scarcely water-soluble physiologically active component (A) with a nonionic surfactant and/or anionic surfactant (B), the support of the mixture on a water-swelling polymeric compound and the granulation of the product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a solid preparation having an improved dissolution property of a poorly water-soluble physiologically active ingredient, and more particularly to a solid preparation, particularly a tablet, which is effective for improving the bioavailability of pharmaceuticals. The present invention relates to a method for producing the composition.

2. Description of the Related Art If the solubility of a physiologically active ingredient in water is poor, acceptance into a living body is delayed, and this is a major problem in a preparation containing a drug expected to be immediately effective. It is well known that even in the case of formulation, a difference in absorption occurs even when the same physiologically active substance is used due to a difference in the production method. In addition, from the viewpoint of bioavailability, it is an issue from a pharmaceutical standpoint how to prepare a physiologically active substance in such a manner that it can be dissolved and absorbed in a living body quickly. In this sense, the dissolution property is used as a substitute property when a physiologically active substance is absorbed. As a solid preparation for oral use, after improving the mechanical suitability by previously mixing or appropriately granulating a physiologically active ingredient and an excipient, a binder, a disintegrant, a disintegration aid, an excipient, It has been common practice to add additives such as lubricants and to carry out a treatment for appropriate formulation to obtain a desired formulation. However, when trying to improve the dissolution performance by simply adding such additives, the appropriate hardness as a solid oral preparation is not maintained, so that abrasion or powdering occurs during the process of filling in an appropriate package. And serious drawbacks, such as the inability to reliably administer medication.

In addition, from the standpoint of the user, tablets need to be reduced in the amount of various additives from the viewpoint of ensuring portability and ingestibility, and from the standpoint of the manufacturer, they must be disintegrated. There is a demand for a configuration that can be manufactured in a simplified process that can stably maintain the properties. In response to these requests, a method using a polymorph of a physiologically active ingredient (Japanese Patent Laid-Open No. 2-4)
5416) and a method of converting a physiologically active ingredient into an acid addition salt (JP-A-2-129124). However, for these applications in pharmaceuticals, their pharmacological activities and properties are changed, which hinders appropriate appropriate treatment. May occur. There is also a method of molding a mixture which is mixed and pulverized with a water-soluble polymer (Japanese Patent Laid-Open No. 2-268117). However, this method involves adjusting the fluidity, scattering and classification of the powder when performing tablet molding in the case of pulverization. Will be an issue. Also, the method of blending a component containing oxygen (JP-A-4-8288) is concerned about the stability of the physiologically active component. Also, a method of blending a co-crystal of β-lactose and a sugar alcohol (Japanese Unexamined Patent Publication No. 5-1706)
69), and a method of dispersing microcrystalline cellulose in hydroxypropylmethylcellulose and then spray-drying the mixture (Japanese Patent Laid-Open No. Hei 6-239964), in which mass production requires complicated facilities in terms of cost.

[0003]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and has excellent elution of a water-insoluble physiologically active component without a complicated step, and has an appropriate hardness. An object of the present invention is to provide a method for producing a solid preparation and a solid preparation composition.

According to the present invention, a water-swellable polymer compound is mixed with a water-insoluble physiologically active ingredient and a nonionic surfactant and / or an anionic surfactant. The present inventors have found that a solid preparation having more excellent dissolution properties and good hardness can be obtained, and have completed the present invention. Therefore, the present invention provides a method of mixing a poorly water-soluble physiologically active component (A) with a nonionic surfactant and / or an anionic surfactant (B), and then supporting the mixture on a water-swellable polymer compound (C). And then granulating the solid preparation.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. (A) In the present specification, “a slightly water-soluble physiologically active ingredient” is “slightly soluble” as defined in the Japanese Pharmacopoeia.
"Soluble", "Extremely insoluble", "Almost insoluble". Specifically, tocopherol acetate, tocopherol, retinol, retinol acetate, retinol palmitate, vitamin A oil, liver oil, ergocasiferol, dihydrotaxosterol, alpha casidol, thiamine prosultiamine nitrate, fursultiamine, octtiamine, Thiamine disulfide, bisbenthamine bisbutiamine, benfotiamine, sicotiamine, riboflavin, riboflavin butyrate, pyridoxal phosphate, pyridoxal calcium phosphate, nicotinic acid, folic acid, cyanocobalamin, hydroxocobalamin acetate, balamine, biotin, tocopherol calcium succinate, Vitamins such as phytonadione, menatetrenone, cholecalciferol, etc .; aspirin, aspirin aluminum, etensamide, sazapyri , Salicylamide, ibuprofen, ketoprofen, naproxen, etc .; antipyretic and analgesic agents; butoctamide semisuccinate, allylisopropyl, acetylurea and other hypnotic sedatives; ephedra, nantenjitsu, spruce, onji, kanzo, kikyo, shazenshi, shazensou, senega, vimo, Fennel, bakaku, spinach, gejutsu, chamomile, cauliflower, gentian, gooh, beast gall (including yutan), shajin, shokyo, sujutsu, butterflies, cockscomb, juniper, ground dragon, chikussin carrot, carrot, valerian, buttonpi, An oil-refining component of crude drugs such as salmon can be mentioned.

[0005] Of these, tocopherol acetate, vitamin A oil, cholecalciferol, retinol palmitate, riboflavin, etenzamid, ibuprofen, naproxen, ketoprofen, butoctamide semisuccinate, allylisopropyl, and acetylurea are preferred. In the case of a fibrous physiologically active component containing a highly viscous liquid component such as a crude drug, it is preferable to use one that has been subjected to a trituration treatment. In the case of a synthetic bioactive ingredient, it recrystallizes after synthesis,
This can be ground and used. Further, more preferably, in order to make the disintegration more stable, it is more preferable to form and use porous particles by spray drying or the like. (A) in the solid preparation produced according to the present invention
The content of the component is preferably 0.5 to 70% by mass, more preferably 1 to 50% by mass. In the present specification, a simple expression “%” means “% by mass”.

(B) The pharmaceutically acceptable nonionic surfactant used in the present invention includes sucrose fatty acid ester, monostearic acid glyceride, polysorbate 40 and the like.
(Polyoxyethylene sorbitan monopalmitate),
Polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 80 (polyoxyethylene sorbitan monooleate), sorbitan monopalmitate, polyoxyethylene hydrogenated castor oil and the like are used. Of these, polysorbate 80, polyoxyethylene hydrogenated castor oil, and polysorbate 60 are preferred.
The nonionic surfactant used in the present invention preferably has an HLB according to the Griffin formula of 6 or more, particularly preferably 10 or more and 15 or less. It is preferable to use a nonionic surfactant having an HLB of 6 or more, since the release of the supported bioactive component is facilitated. Examples of the pharmaceutically acceptable anionic surfactant used in the present invention include sodium lauryl sulfate. In the above, a nonionic surfactant is preferably used.
The content of the component (B) in the solid preparation produced by the present invention is preferably 0.1 to 10% by mass, more preferably 1 to 7% by mass. When a nonionic surfactant and an anionic surfactant are used in combination, the mass ratio of both is 1 /
It is preferably from 9 to 9/1, more preferably from 3/7 to 7/3. Further, the ratio of the component (A) to the component (B) is preferably 5/95 to 95/5, more preferably 10/90 to 90/10, and particularly preferably 10/90 to 70 / by mass ratio. Preferably it is 30.

(C) Examples of the water-swellable polymer compound used in the present invention include cross-linked polyvinylpyrrolidone, carmellose calcium, hydroxypropyl starch, and low-substituted hydroxypropylcellulose (substitution degree of 5.0 to 16.
0%), corn starch, crystalline cellulose, partially pregelatinized starch, carmellose, croscarmellose, or a salt thereof, or a mixture of two or more thereof. Among them, crosslinked polyvinylpyrrolidone, crystalline cellulose, carmellose and croscarmellose sodium are preferred. Preferably not less than 5000 cm ² / g specific surface area, 5000cm ² / g~50000c
m ² / g, more preferably from 8000 cm ² / g to
It is particularly preferred that it is 30,000 cm ² / g. It is preferable that the specific surface area is within this range because scattering during dispersion is small. Further, it is preferable that the component (C) is water-swellable, so that a physiologically active component is eluted by moderate expansion in a living body. The content of the component (C) in the solid preparation produced according to the present invention is preferably 25 to 95% by mass,
More preferably, it is 40 to 97% by mass.

The water-swellable polymer compound (C) used in the present invention is porous and can carry a physiologically active component, but the larger the surface area, the better. In this case, it is conceivable that the amount of the released physiologically active component is reduced by the loading. The release can therefore not be impaired by using a suitable surfactant. That is, the taken solid preparation releases the physiologically active component by the water-swellable polymer absorbing water and swelling. However, when only a poorly water-soluble physiologically active component is supported, water is not absorbed by the support and swelling does not occur.
Therefore, by mixing and supporting a surfactant with a physiologically active component, water absorption and swelling can be promoted, and the physiologically active component can be released.

In the present invention, the shape and particle size of the physiologically active component are not particularly limited, but preferably the ratio of the average particle size of the physiologically active component to the water-swellable polymer compound is 1: 2.
It is preferably in the range of 2: 1. In addition, in order to carry efficiently, the particle diameter of the physiologically active ingredient is 1 to 50.
It is preferable to use a thickness of about μm,
It is preferably used at a thickness of from 20 to 20 μm, more preferably from 1 to 10 μm. It is preferable that the particle diameter of the physiologically active component is within this range, since the scattering property is low, and the problems such as uniform content during granulation, selective adsorption by static electricity, and reagglomeration are small. In addition, the desired disintegration performance is obtained,
It is preferable because the content becomes uniform. In particular, in the case of fibrous physiologically active components, the reduction of the disintegration time is liable to change. preferable. The diameter of the supported particles formed by adding a surfactant to the physiologically active component and the water-swellable polymer used in the present invention is not particularly limited.
It is preferably about 50 to 80, more preferably 50 to 80.
It is preferable that the thickness be in the range of 0 μm, more preferably 100 to 500 μm.

When granulating or compressing, the composition of the present invention may contain, if necessary, additives usually used, such as a lubricant,
Binder, coating agent, excipient, disintegrant, disintegration aid,
A dye or the like can be freely used alone or in combination of plural kinds. Specific examples of the optional additive include the following components. In addition, these additives
It can be appropriately added as long as the effects of the present invention are not hindered. Lubricants include gum arabic, cocoa butter, carnauba wax, hydrous silicon dioxide, dried aluminum hydroxide gel, glycerin, magnesium silicate, liquid paraffin, stearyl alcohol, stearic acid, lactose, sucrose, fumaric acid, beeswax, and the like. Can be Examples of the binder include gum arabic, hydroxypropylcellulose (degree of substitution: 53.4 to 77.5%), methylcellulose, gelatin, partially pregelatinized starch, and the like. Coating agents include glycerin, liquid paraffin, silicone resin, stearic acid, gelatin, sorbitol, corn oil, lactose, polyvinyl alcohol, macrogol,
Examples include methacrylic acid copolymer, calcium hydrogen phosphate, sodium hydrogen phosphate and the like.

As excipients, gum arabic, ethyl cellulose, kaolin, cocoa butter, fructose, xylitol,
Examples thereof include citric acid or a salt thereof, stearic acid or a salt thereof, dextran, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, calcium hydrogen phosphate, and sodium hydrogen phosphate. Disintegrators include cellulose or derivatives thereof, starch and derivatives thereof, and the like. Examples of the disintegration aid include cellulose or a derivative thereof, stearic acid, sodium hydrogen carbonate, and hydroxypropyl cellulose (substitution degree 53.4 to 53.4).
77.5%). In addition, flavoring agents such as l-menthol, sweeteners for aspartame sugar, sugar alcohols such as erythritol, and disintegration aids such as ascorbic acid or salts thereof can be used.

(Production method) The solid preparation of the present invention is produced as follows. A water-insoluble physiologically active component (A) is added to a liquid nonionic surfactant and / or anionic surfactant (B), and the mixture is stirred and uniformly dispersed. The anionic surfactant can be used preferably in the form of a 1.0 to 20% aqueous solution. Further, the component (A) and the component (B) may be mixed by dropping the component (B) while stirring the component (A). May be. Next, this dispersion is added to a water-swellable polymer compound (preferably having a specific surface area of 5,000 cm ² / g or more) and stirred and granulated to obtain particles carrying a physiologically active component. When two or more components (C) are used,
The components (A) and (B) may be mixed in advance before being combined, or may be added sequentially. The water-swellable polymer compound of the component (C) can improve the dissolution property of the component (A) by supporting the component (A) and the component (B) in the voids. Thereafter, other optional components are added as needed to further granulate. Finally, it is preferable to carry out pulverization and sieving for the purpose of adjusting the particle size. The granulating apparatus for supporting the physiologically active component and the surfactant on the water-swellable polymer compound is provided by an agitation type granulator for the biologically active component that is liquid at the operating temperature. For those in which the physiologically active ingredient is in a solid state, a mechanism in which these particles are crushed by compression and shearing, or a mechanism in which the particles are subjected to a compression treatment using a roll can be suitably used. Examples of commercially available devices include, for example, a high-speed mixer for the treatment of a liquid physiologically active ingredient during the previous production, and a Spartan Luizer (Fuji Paudal) or a dry roll compaction for the latter treatment of a solid physiologically active ingredient. Granulator (Turbo Kogyo). The solid preparation produced according to the present invention may be a preparation for internal use such as an uncoated tablet, a chewable tablet, an effervescent tablet; a preparation for oral cavity such as a troche tablet, a buccal tablet, and a sublingual tablet.
When a granular preparation is used, 100μ
It is preferably about m to 1000 μm. In the case of a tablet type, the particle size of the particles carrying the physiologically active substance is preferably 50 to 800 μm, particularly preferably 100 to 5 μm.
A particle size of 00 μm, other optional components are mixed as needed with a mixer, and a tableting pressure of 0.5 to 2 t is used with a tableting machine.
In the case where the tablet is circular and has a diameter of 6 mm or less, it is preferably 0.5 to 1 t and a diameter of 6 to 10 mm.
In the case of 0.7-1.2t and diameter 10mm or more,
It is more preferable to perform tableting at 0.7 t or more. When the tablet is a deformed tablet, it is preferable that the tablet be compressed at a pressure or lower.

[0013]

EFFECTS OF THE INVENTION The solid preparation produced according to the present invention has a remarkably improved dissolution property of the physiologically active ingredient, has little change over time, and has an appropriate hardness.

EXAMPLES The present invention will be described below in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. Experimental Example 1 A tablet having the following composition was prepared by the following method. [Composition] mg / tablet Tocopherol acetate 2 Vitamin A oil 2 Polyoxyethylene hydrogenated castor oil (HLB 12.5) 4.5 Crosslinked polyvinylpyrrolidone 75.5 Crystalline cellulose 45 Carmellose 15.4 l-menthol 2.0 Magnesium stearate 1.6 Total 148.0

Each of 80 g of tocopherol acetate, 80 g of vitamin A oil and 180 g of polyoxyethylene hydrogenated castor oil (water content: 0.11%) was taken at 300 rpm using a propeller type stirrer (2000G HEIDON).
The mixture was stirred for 0 minutes to obtain a uniform liquid. Next, 1510 g of the crosslinked polyvinylpyrrolidone was placed in a stirring mixer (FS-10J; manufactured by Fukae Kogyo KK), and 170 g of the above liquid was uniformly dispersed and supported. 800 g of this powder was placed in a V-type mixer (V-5; Tokuju Seisakusho), and 450 g of crystalline cellulose, 154 g of carmellose and 20 g of l-menthol that had been ground in advance with a mortar and passed through a 75 μm sieve were added and mixed for 15 minutes did.
Next, 16 g of magnesium stearate was added and mixed for 5 minutes, and 1 t using a rotary tableting machine (L-41; Hata Iron Works).
To obtain a tablet (Example 1) having an average mass of 148 mg and a diameter of 7 mm.

Using the same components as in Example 1, 755 g of crosslinked polyvinylpyrrolidone, 450 g of crystalline cellulose,
154 g of carmellose was placed in a V-type mixer (V-5; Tokuju Seisakusho) and mixed for 15 minutes. 100 g of the mixed powder was taken, tocopherol acetate 20 g, vitamin A oil 20 g.
And polyoxyethylene hydrogenated castor oil (water content of 0.1%).
11%, HLB12.5) 45g each with a crusher (R
-8; Nippon Riken Co., Ltd.), gently dispersed at 300 revolutions per minute, returned to a V-type mixer, mixed for 15 minutes, and further passed through a 75 μm sieve, 20 g of l-menthol.
Was added and mixed for 15 minutes. Next, 16 g of magnesium stearate was added and mixed for 5 minutes.
41; Hata Ironworks Co., Ltd.), and tablets were produced at 1 t to give tablets having a mean mass of 148 mg and a diameter of 7 mm (Example 2) in the same manner as in Example 1.

As a preparation not containing polyoxyethylene hydrogenated castor oil, a crosslinked polyvinylpyrrolidone 755 is used.
g, crystalline cellulose 450 g, and carmellose 154 g were mixed in a V-type mixer (V-5; Tokuju Seisakusho) for 15 minutes, 100 g of the mixed powder was taken, and 20 g of tocopherol acetate and 20 g of vitamin A oil were crushed by a grinder. (R
-8; Nippon Riken Co., Ltd.), gently dispersed at 300 revolutions per minute, returned to a V-type mixer, mixed for 15 minutes, and further passed through a 75 μm sieve, 20 g of l-menthol.
Was added and mixed for 15 minutes. Next, 16 g of magnesium stearate was added and mixed for 5 minutes, and tableted with a rotary tableting machine (L-41; Hata Iron Works) at 1 t. As in Example 1, the average mass was 143.5 mg and the diameter was 7 mm. (Comparative Example 3) was obtained. The hardness and dissolution state of the tablets obtained in Examples 1 and 2 and Comparative Example 1 were compared. The exam is
Evaluation was made based on the average value of 10 tablets. The hardness was measured with a Monsanto hardness meter (TH203-CP; manufactured by Toyama Sangyo Co., Ltd.). In the disintegration test, water was used as a test solution according to the method described in the Japanese Pharmacopoeia. The dissolution test was performed using the equipment described in the Japanese Pharmacopoeia, using the paddle method (rotation speed 10
(0 rotations / minute), and 500 ml of water was used as the eluate. As the eluate, 2 ml of a sample was collected at a predetermined time after the sample was introduced, and the same amount of water was supplied at the same time. The measurement was performed by a high performance liquid chromatography method.

[0017]

[Table 1] Table 1

Examples 1 and 2 were superior to Comparative Example 1 in disintegration time and dissolution rate. Further, in Example 1 in which a physiologically active component and a nonionic surfactant were mixed, and then the particles supported on a water-swellable polymer compound were used, the disintegration time and the dissolution rate were lower than those in the case where they were produced by a commonly used method. Excellent and good hardness was obtained. Experimental Example 2 A tablet having the following composition was prepared by the following method.

3000 g of ethenzamide was pulverized with a pulverizer (Atomizer; manufactured by Fuji Paudal Co.) and passed through a sieve to obtain particles having a particle size of 75 μm or less. This powder 1000
g in a stirring mixer (FS-10J; manufactured by Fukae Industries Co., Ltd.), and while stirring, polysorbate 80 (water content 0.15%,
100 g of HLB 15) was added dropwise. To this, 760 g of croscarmellose was added and further stirred to make it uniform. 930 g of this powder composition was added to a ribbon mixer (R-5 type;
30 g of carmellose and 140 g of crystalline cellulose were added and mixed for 15 minutes. Further, 10 g of magnesium stearate was added and mixed for 5 minutes. This powder was tableted using a rotary tableting machine (12UHK; Kikusui Seisakusho) at 1.2 ton diameter, 11 mm in diameter and 555 mg in average weight.
(Example 3) were obtained.

Pulverize with a pulverizer (Atomizer; manufactured by Fuji Paudal Co.), pass through a sieve, take 500 g of ethenzamide having a particle size of 75 μm or less into a ribbon mixer (R-5 type, Tokuju Seisakusho), and drop 50 g of polysorbate 80. did. To this, 380 g of croscarmellose was added, then 30 g of carmellose and 140 g of crystalline cellulose were added and mixed for 15 minutes. In addition, magnesium stearate 10
g was added and mixed for 5 minutes. This powder was tableted with a rotary tableting machine (12UHK; Kikusui Seisakusho) at 1.2 t to obtain a tablet (Example 4) having a diameter of 11 mm and an average mass of 555 mg.

The mixture is pulverized by a pulverizer (Atomizer; manufactured by Fuji Paudal Co., Ltd.) and passed through a sieve to give 1000 g of etensamide powder having a particle diameter of 75 μm or less to a stirring mixer (FS-10).
J; manufactured by Fukae Industry Co., Ltd.). To this, 760 g of croscarmellose was added and further stirred to make it uniform.
930 g of this powder composition was added to a ribbon mixer (R-5).
(Type: Tokuju Seisakusho), 30 g of carmellose and 140 g of crystalline cellulose were added and mixed for 15 minutes. Further, 10 g of magnesium stearate was added and mixed for 5 minutes. This powder was tableted with a rotary tableting machine (12UHK; Kikusui Seisakusho) at 1.2 tons, diameter 11 mm, average mass 5
30 mg tablets (Comparative Example 2) were obtained. Example 3 obtained
The hardness and dissolution state of the tablets of Comparative Examples 4 and 4 and Comparative Example 2 were compared. The test was evaluated by the average value of 10 tablets.
The hardness was measured with a Monsanto hardness meter (TH203-CP; manufactured by Toyama Sangyo Co., Ltd.). In the disintegration test, water was used as a test solution according to the method described in the Japanese Pharmacopoeia. The dissolution test was performed using the equipment described in the Japanese Pharmacopoeia, using the paddle method (rotational speed: 100 rpm).
ml of water was used. As the eluate, 2 ml of a sample was collected at a predetermined time after the sample was introduced, and the same amount of water was supplied at the same time. The measurement was performed by a high performance liquid chromatography method.

[0022]

[Table 2]

Experimental Example 3 A tablet having the following composition was prepared by the following method. [Composition] mg / tablet Cholecalciferol 0.2 Retinol palmitate 2 Polyoxyethylene hydrogenated castor oil (HLB12.5) 4 Crosslinked polyvinylpyrrolidone 75 Crystalline cellulose 30 Lactose 45 Carmellose 15.5 Erythritol 20 Hydroxypropyl cellulose (degree of substitution 7.5%) 3 Fragrance 1 Magnesium stearate 1.5 Total 188.0

8 g of cholecalciferol, 80 g of retinol palmitate, and 160 g of polyoxyethylene hydrogenated castor oil (water content: 0.8%) were each taken for 300 revolutions using a propeller-type stirrer (2000G HEIDON).
The mixture was stirred at a rate of 20 minutes per minute for a uniform liquid. Next, 1500 g of the crosslinked polyvinylpyrrolidone was mixed with a stirring mixer (FS-10J;
(Fukae Industry Co., Ltd.), and 124 g of the above liquid was uniformly dispersed and supported. 812 g of this powder was mixed with a V-type mixer (V-5
Type: Tokuju Seisakusho), lactose 450 g, crystalline cellulose 300 g, carmellose 155 g and erythritol 200 g hydroxypropyl cellulose 30 g, flavor 1
0 g was added and mixed for 15 minutes. Next, 15 g of magnesium stearate was added and mixed for 5 minutes, and the mixture was tableted with a rotary tableting machine (L-41; Hata Iron Works) at 1 t and had an average mass of 1%.
88 mg of a tablet having a diameter of 9 mm (Example 5) were obtained.

In the same manner as in Example 5, 750 g of crosslinked polyvinylpyrrolidone, 450 g of lactose, and 30 parts of crystalline cellulose 30 were used.
0 g, carmellose 155 g, erythritol 200 g
30 g of hydroxypropylcellulose was mixed with a V-type mixer (V-
100 g of the mixed powder, 2 g of cholecalciferol, 20 g of retinol palmitate and hydrogenated castor oil of polyoxyethylene (water content 0.8%, HLB 12.5) 40
g was gently dispersed at 300 revolutions per minute using a pulverizer (R-8; Nippon Rikagaku Kikai), returned to a V-type mixer and mixed for 15 minutes.
Mix for 5 minutes. Next, 16g of magnesium stearate
Was added to the mixture, and the mixture was mixed. The mixture was tabletted using a rotary tableting machine (L-41; Hata Iron Works) at 1 t, and the average mass was 18 as in Example 5.
8 mg tablets having a diameter of 9 mm (Example 6) were obtained.

As a preparation containing no polyoxyethylene hydrogenated castor oil, 750 g of a crosslinked polyvinylpyrrolidone, 450 g of lactose, 300 g of crystalline cellulose, 155 g of carmellose, erythritol 20 were prepared in the same manner as in Example 5.
0 g and 30 g of hydroxypropylcellulose were taken in a V-type mixer (V-5; Tokuju Seisakusho) and mixed for 15 minutes. 100 g of the mixed powder was taken and cholecalciferol 2
g and 20 g of retinol palmitate were gently dispersed at 300 revolutions per minute using a crusher (R-8; Nippon Rikagaku Kikai), and the mixture was returned to a V-type mixer and mixed for 15 minutes. Was added and mixed for 15 minutes. Next, 15 g of magnesium stearate was added and mixed for 5 minutes. The mixture was tableted using a rotary tableting machine (L-41; Hata Iron Works) at 1 t, and the average mass was 184 mg and the diameter was 9 as in Example 1.
mm tablets (Comparative Example 3) were obtained. Examples 5 and 6 obtained
And about the tablet of Comparative Example 3, the hardness and the dissolution state were compared. The test was evaluated by the average value of 10 tablets. The hardness was measured with a Monsanto hardness meter (TH203-CP; manufactured by Toyama Sangyo Co., Ltd.). In the disintegration test, water was used as a test solution according to the method described in the Japanese Pharmacopoeia. For the dissolution test, use the equipment described in the Japanese Pharmacopoeia,
Paddle method (100 rpm), 500 ml for eluate
Of water was used. The eluate is sample 2
ml were taken and at the same time replenished with the same amount of water. The measurement was performed by a high performance liquid chromatography method.

[0027]

[Table 3] Table 3

Experimental Example 4 A tablet having the following composition was prepared by the following method.

100 g of riboflavin was pulverized with a pulverizer (TJ60; manufactured by Turbo Kogyo Co., Ltd.) to obtain a powder having a particle diameter of 20 μm or less. To 75 g of this powder, 375 g of polysorbate 80 (water content: 0.12%) was added and 375 g of the powder was added at 300 rpm using a propeller-type stirrer (2000G HEIDON).
Stir for a minute to make a uniform dispersion. Separately, 2250 g of croscarmellose sodium was placed in a stirring mixer (FS-10J; manufactured by Fukae Industry Co., Ltd.), and the above dispersion was added dropwise while stirring at 150 revolutions per minute. 180 g of this composition is placed in a V-type mixer (V-5; Tokuju Seisakusho), and then ascorbic acid 4
0 g, sodium ascorbate 15 g, carmellose 25 g, mannitol 80 g, polyvinylpyrrolidone 2
0 g, 25 g of corn starch and 2 g of aspartame were added and mixed for 20 minutes. Further, 5 g of magnesium stearate was added and mixed for 5 minutes. This powder was tableted at 1.1 t using a rotary tableting machine (12UHK; Kikusui Seisakusho), diameter 10 mm, average weight 392 mg
(Example 7) was obtained.

A V-type mixer (V-5; Tokuju Seisakusho) is pulverized with a pulverizer (TJ60; manufactured by Turbo Kogyo) to have a particle size of 20 μm.
m, riboflavin 5 g, ascorbic acid 40 g, sodium ascorbate 15 g, carmellose 25 g,
80 g of mannitol, 20 g of polyvinylpyrrolidone, 25 g of corn starch and 2 g of aspartame were each added and mixed for 20 minutes. This mixed powder 100
25 g of polysorbate 80 was added dropwise to the crusher (R-
8; Nippon Riken Co., Ltd.) and dispersed gently at 300 revolutions per minute, and returned to the V-type mixer. Further, 5 g of magnesium stearate was added and mixed for 5 minutes. Using a rotary tableting machine (12UHK; Kikusui Seisakusho), this powder is 1.1t
To obtain a tablet (Example 8) having a diameter of 10 mm and an average mass of 392 mg.

A V-type mixer (V-5; Tokuju Seisakusho) is pulverized with a pulverizer (TJ60; manufactured by Turbo Kogyo Co., Ltd.) to a particle size of 20 μm.
m of riboflavin 50 g or less with croscarmellose 15
00g and a stirring mixer (FS-10J; Fukae Kogyo Co., Ltd.)
With stirring. 155 g of this powder and ascorbic acid 4
0 g, sodium ascorbate 15 g, carmellose 25 g, mannitol 80 g, polyvinylpyrrolidone 2
0 g, corn starch 25 g and aspartame 2 g were put into a V-type mixer (V-5; Tokuju Seisakusho) and mixed.
Mix for 0 minutes. In addition, 5g of magnesium stearate
Was added and mixed for 5 minutes. This powder was tabletted at 1.1 t using a rotary tableting machine (12UHK; Kikusui Seisakusho),
A tablet having 0 mm and an average mass of 367 mg (Comparative Example 4) was obtained.

The hardness and dissolution state of the tablets obtained in Examples 7 and 8 and Comparative Example 4 were compared. The exam is
Evaluation was made based on the average value of 10 tablets. The hardness was measured with a Monsanto hardness meter (TH203-CP; manufactured by Toyama Sangyo Co., Ltd.). In the disintegration test, water was used as a test solution according to the method described in the Japanese Pharmacopoeia. The dissolution test was carried out using a device described in the Japanese Pharmacopoeia, using a paddle method (100 rpm), and using 500 ml of water as the eluate. As the eluate, 2 ml of a sample was collected at a predetermined time after the sample was introduced, and the same amount of water was supplied at the same time. The measurement was performed by a high performance liquid chromatography method.

[Table 4] Table 4

Claims (6)

[Claims] 1. A water-swellable polymer compound (C) comprising a mixture of a poorly water-soluble physiologically active component (A) and a nonionic surfactant and / or an anionic surfactant (B). And then granulating the solid preparation. 2. The method according to claim 1, wherein (B) is a nonionic surfactant having an HLB of 6 or more according to the Griffin formula. 3. (A) / (B) is 5/95 to 95/5
(Mass ratio). The method for producing a solid preparation according to claim 1 or 2, wherein 4. The water-swellable polymer compound (C) has a specific surface area of 5000 cm ² / g or more.
3. The method for producing a solid preparation according to item 3. 5. The tableting pressure of the granular preparation according to claim 1 is 0.5.
A method for producing a tablet-type solid preparation, characterized in that tableting is performed at ２2t. 6. A solid pharmaceutical composition comprising (A) a water-insoluble physiologically active ingredient; (B) a nonionic surfactant; and (C) a water-swellable polymer compound.