JP2000034224A - Sustained-release tablet, additive composition thereof and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an additive composition for producing a sustained-release tablet having excellent fluidity at the time of tableting and capable of accurately controlling the dissolution rate of a medicinal component. SOLUTION: The composition contains 50 to 100% by weight of a hydrophilic matrix base and 0 to 50% by weight of an inert filler, and has a loose apparent density of 0.35 g / ml or more and a repose angle of 40 ° or less. Additive composition for sustained-release tablets comprising granules The composition, sustained-release tablets containing the composition and the active ingredient, and methods for producing them.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an additive composition for producing a sustained-release tablet having excellent fluidity at the time of tableting and capable of accurately controlling the dissolution rate of a medicinal component, a method for producing the same and a method for producing the same. The present invention relates to a sustained-release tablet containing an agent composition and a method for producing the tablet.

[0002]

2. Description of the Related Art Sustained-release preparations have been developed for the purpose of improving compliance with a reduction in the number of administrations and reducing the fluctuation range of blood concentration to prevent side effects and to expect a stable therapeutic effect. In recent years, various preparations have been put on the market.

[0003] Among them, sustained-release tablets using a hydrophilic matrix base are simple in structure and production process, and are advantageous in practical use. Conventionally, the production method includes a direct powder compression method in which a hydrophilic matrix base and a drug powder are mixed, a lubricant is added to the mixture, and tableting is performed, and the hydrophilic matrix base and the drug are mixed using a binder. There is a wet granule compression method in which powder is wet-granulated, and the resulting granules are tableted with other additives or lubricants. The sustained-release tablet obtained by such a method forms a continuous gel layer on the tablet surface upon contact with water and delays the infiltration of water into the tablet, so that it can maintain its shape without disintegration for a long time. The dissolution of the drug is controlled by the rate of water intrusion, and exhibits a sustained release effect.

The following are known as sustained-release tablets using a hydrophilic matrix base produced by a direct powder compression method. (1) Japanese Patent Publication No. 4-5208 discloses an average molecular weight of 5
20,000 or more, that is, the viscosity of a 2% aqueous solution at 20 ° C. is about 800 cP or more, the methoxyl group content is 16 to 24% by weight, and the hydroxypropoxyl group is 4 to
It describes that hydroxypropyl methylcellulose (HPMC), which is 32% by weight, is used up to 25% of the tablet weight. (2) JP-B-5-9413 discloses that the average molecular weight is 2
3,000 or less, that is, using 2% aqueous solution of HPMC having a viscosity of about 50 cP or less at 20 ° C. and 9 to 12% by weight of hydroxypropoxyl group is described. (3) Japanese Patent Publication No. 7-51516 discloses that a 2% aqueous solution at 20 ° C. has a viscosity of 15 cP or more, a methoxyl group content of 28 to 32% by weight, and a hydroxypropoxyl group of 7 to 12% by weight. And H prepared to pass 95% by weight or more through a sieve having a particle size of 100 mesh.
One using PMC is described.

(4) JP-A-6-172161 discloses that the viscosity of a 2% aqueous solution at 20 ° C. is 14,000 c.
HPMC having a methoxyl group content of 19 to 24% by weight, a hydroxypropoxyl group of 4 to 12% by weight and a particle size of 95% by weight or more passing through a sieve of 100 mesh. The ones used are described. (5) Japanese Patent No. 2686215 discloses that a 2% aqueous solution at 20 ° C. has a viscosity of 1,000 cP or more, a methoxyl group content of 19 to 30% by weight, and a hydroxypropoxyl group of 4 to 12% by weight. And the particle size is 1000
A description is given of a case using HPMC prepared so as to be able to pass 95% by weight or more of a mesh sieve and to have a loose apparent density of 0.35 g / ml or less.

As examples of sustained-release tablets using a hydrophilic matrix base produced by a wet granule compression method, the following are known, for example. (6) Japanese Patent Publication No. 4-164025 discloses that a 2% aqueous solution at 20 ° C. has a viscosity of 80 cP or more and methyl cellulose is mixed with a main drug and excipients, and then kneaded by adding water or a water-containing organic solvent. The use of the obtained granules is described. (7) JP-A-5-255125 discloses a partial wet granulation method in which a drug granule obtained by wet granulating a drug using a binder is mixed with HPMC or a water-soluble component, and tableting is performed. The preparation of a sustained release tablet from which a drug is released according to the following relation is described.

Further, as an additive composition which is excellent in fluidity and can be directly hit by using a wet granule compression method, for example, the following are known. (8) Japanese Patent Publication No. Hei 6-25073 discloses that 20-60% by weight of a hydrophilic material comprising a heteropolysaccharide and a polysaccharide material capable of crosslinking the heteropolysaccharide, and an inert pharmaceutical filler 4
The use of granules comprising from 0 to 80% by weight is described. (9) JP-A No. 4-31522 discloses that HPMC is suspended in hot water having a melting temperature or higher, and tannic acid, acrylate-methyl methacrylate-dimethylaminoethyl methacrylate copolymer or methacrylic acid-acrylate copolymer is used. A composition using a composition obtained by spray-drying after addition is described. (10) Japanese Patent Application Laid-Open No. Hei 6-239964 discloses a composition using a composition obtained by spray-drying an aqueous HPMC solution in which microcrystalline cellulose is dispersed.

[0008]

However, the HPM widely used in the production of sustained-release tablets as described above is used.
It is known that powders of a hydrophilic matrix base (such as cellulose ethers) represented by C have poor fluidity at the time of tableting, and the physical properties are more remarkable as the viscosity is higher (high molecular weight type). . (1)-using direct powder compression method
In the method described in the publication (5), the dissolution rate of the medicinal component is accurately controlled because the total weight of the tablet becomes non-uniform or the miscibility with the drug or other excipients deteriorates. Things get harder. Depending on the prescription, there is a possibility that the production itself with a rotary tableting machine cannot be performed. In the case of the direct powder compression method, most of the improvement efforts for sustained release tablets are directed to the sustained release aspect, and the tableting aspect is not sufficiently mentioned. When a low-viscosity type is used as the hydrophilic matrix base, the fluidity is slightly improved, but the gel strength during hydration is small, so the tablet form collapses before the gel layer is sufficiently formed. However, even if a gel layer is formed, the disintegration time is so short that a sustained release effect cannot be obtained. As a result, it is necessary to increase the amount of the sustained-release base component to be added, which causes a problem that the diameter of the whole tablet becomes large and it becomes difficult to take the tablet.

On the other hand, in the case of the production method by the wet granulation compression method, in the method (7) described in JP-A-5-255125, only the production of granules mainly containing a drug is carried out, and the fluidity and the mixing property are poor. Although it may be effective for a drug having difficulty in compression molding, it has no relation to the physical properties of HPMC, and therefore has the same drawbacks as in the direct powder compression method described above. On the other hand, the method (6) described in JP-A No. 4-164025 uses granules obtained by mixing a drug or an excipient with methylcellulose and adding water or a water-containing organic solvent and kneading the mixture. Therefore, the properties of methylcellulose seem to be improved. However, it is preferable to mix and form tablets in an untreated state because there are concerns about decomposition of water-unstable drugs. It is hard to say that it is appropriate to perform granulation together with the above.

[0010] Therefore, an additive composition having excellent fluidity, which can provide a sustained-release tablet simply by mixing it with a drug powder, is desired, but the method described in JP-B-6-25073 (8) In (2), since the additive composition contains natural gums such as tragacanth and acacia, the quality may vary between lots. The methods described in JP-A-4-31322 (9) and JP-A-6-239964 (10) both perform spray drying, and the methods for preparing the additive composition include cost and productivity. Is not preferred in terms of The physical properties of the obtained composition are also described in JP-A-6-23.
No. 9764, the apparent density is low (0.20 g / ml) despite the low HPMC content (20%) in the composition, and it is filled when performing tableting with a rotary tableting machine or the like. The amount can be limited.

An object of the present invention is to provide an additive composition having excellent fluidity at the time of tableting, which is useful for producing a sustained-release tablet in which the dissolution rate of a medicinal ingredient is accurately controlled, and a method for producing the same. To provide. In particular, the present invention has a high gel strength at the time of hydration and is excellent in terms of sustained release such as a small amount of addition to tablets, but is poor in fluidity and mixing properties in terms of tableting. Despite the high viscosity type hydrophilic matrix base material such as HPMC as the main component, which is one of the factors that hinder the spread due to the need for advanced technology to granulate, An object of the present invention is to provide an additive composition for sustained-release preparation comprising excellent fine particles and a method for producing the same. Another object of the present invention is to provide a sustained-release tablet containing the above-mentioned additive composition comprising fine granules excellent in fluidity and mixing properties, and a method for producing the same.

[0012]

The additive composition for producing the sustained-release tablet of the present invention, which has been made to achieve the above object, comprises a hydrophilic matrix base or a hydrophilic matrix base. And an inert pharmaceutical filler are wet-granulated using a solvent or a binder, and mainly include the following inventions.

(1) Hydrophilic matrix base material 50 to 10
0% by weight and 0 to 50% by weight of an inert drug filler, characterized by comprising fine particles having a loose apparent density of 0.35 g / ml or more and an angle of repose of 40 ° or less. An additive composition for tablets. (2) The sustained release tablet according to (1), wherein the hydrophilic matrix base contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. Additive composition. (3) The inert pharmaceutical filler contains at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. Item or the additive composition for sustained-release tablets according to item (2).

(4) A hydrophilic matrix characterized by wet granulating a hydrophilic matrix base or a composition of the hydrophilic matrix base and the inert pharmaceutical filler using a solvent or a binder. Base 50-100% by weight
And an inert pharmaceutical filler having a loose apparent density of 0.35 g / ml or more and an angle of repose of 40% by weight.
方法 A method for producing an additive composition for sustained-release tablets comprising the following fine granules. (5) To the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler, kneading is performed by adding an organic solvent containing water at a ratio below which the hydrophilic matrix base starts dissolving. The method for producing an additive composition for sustained-release tablets according to item (4), wherein the kneaded product is sized with a crusher.

(6) To the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler, an organic solvent containing water at a ratio below which the hydrophilic matrix base starts dissolving is added. The method for producing an additive composition for sustained-release tablets according to item (4), wherein stirring granulation is carried out by stirring. (7) wet granulating the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler with hot water or a water-containing organic solvent having a temperature equal to or higher than the melting temperature of the hydrophilic matrix base. The method for producing the additive composition for sustained release tablet according to item (4), which is characterized by the above-mentioned.

(8) An inert pharmaceutical filler consisting of crystalline cellulose or powdered cellulose infiltrated with water,
The method for producing an additive composition for sustained-release tablets according to item (4), wherein the hydrophilic matrix base is dispersed and wet-granulated. (9) The method according to (4), wherein the hydrophilic matrix base is sprayed on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose soaked in with water to perform centrifugal tumbling granulation. 5. The method for producing the additive composition for sustained release tablets according to the above.

(10) The inert pharmaceutical filler is lactose,
Any one of the above items (4) to (7), comprising at least one selected from sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. A method for producing the additive composition for sustained-release tablets according to the above. (11) The hydrophilic matrix base comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose, wherein (4) to (10). A method for producing the additive composition for sustained-release tablets according to claim 1.

(12) hydrophilic matrix base 50-1
An additive composition for a sustained-release tablet, comprising fine particles having a loose apparent density of 0.35 g / ml or more and a repose angle of 40 ° or less, comprising: A sustained-release tablet comprising a main ingredient. (13) The additive composition for sustained-release tablets contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose as a hydrophilic matrix base,
(12) The sustained-release tablet according to the item (12).

(14) The additive composition for sustained-release tablets is characterized by inactivating at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. The sustained-release tablet according to the item (12) or (13), which is contained as a pharmaceutical filler. (15) The additive composition for a sustained release tablet is obtained by wet granulating the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler using a solvent or a binder. The sustained-release tablet according to any one of the above items (12) to (14), which is manufactured by the following method.

(16) The additive composition for sustained release tablets is prepared by dissolving the hydrophilic matrix base in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. Kneading by adding an organic solvent containing water at a starting ratio or less, characterized by being manufactured by sizing the kneaded product with a crusher,
The sustained-release tablet according to any one of items (12) to (14). (17) The ratio at which the additive composition for sustained release tablets starts dissolving the hydrophilic matrix base in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert drug filler. The sustained-release property according to any one of items (12) to (14), wherein the product is produced by adding the following organic solvent containing water and performing stirring granulation. tablet.

(18) The additive composition for sustained-release tablets is prepared by mixing the hydrophilic matrix base or the mixture of the hydrophilic matrix base and the inert drug filler with the dissolution temperature of the hydrophilic matrix base. The sustained-release tablet according to any one of the above items (12) to (14), which is produced by wet granulation with the above-mentioned hot water or a water-containing organic solvent. (19) The additive composition for sustained release tablets is wet-granulated by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been impregnated with water. The sustained-release tablet according to any one of the above items (12) to (14), which is manufactured by the above method. (20) The above-mentioned additive composition for sustained-release tablets is produced by a method in which a hydrophilic matrix base is sprayed on crystalline cellulose or powdered cellulose which has been infiltrated with water to perform centrifugal tumbling granulation. (1)
The sustained-release tablet according to any one of items 2) to (14).

(21) hydrophilic matrix base 50-1
An additive composition for sustained-release tablets comprising fine particles having a loose apparent density of 0.35 g / ml or more and a repose angle of 40 ° or less, the composition comprising 100% by weight of an inert pharmaceutical filler and 0 to 50% by weight of an inert pharmaceutical filler. A method for producing a sustained-release tablet, characterized by adding the main drug as it is and compressing it, or adding fine particles obtained by adding other additives to the main drug and granulating, and tableting. (22) The additive composition for sustained-release tablets contains, in the composition, at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose.
The method for producing a sustained-release tablet according to item (21), comprising a hydrophilic matrix base comprising a seed.

(23) The additive composition for sustained-release tablets contains lactose, sucrose, fructose, dextrin,
(21) or (22), wherein the composition comprises an inert pharmaceutical filler comprising at least one selected from cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. Method for producing a dispersible tablet. (24) The additive composition for sustained release tablets is obtained by wet granulating the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler using a solvent or a binder. The method for producing a sustained-release tablet according to any one of the above items (21) to (23), characterized by being manufactured by the above method.

(25) The additive composition for sustained release tablets is prepared by dissolving the hydrophilic matrix base in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. (2) kneading by adding an organic solvent containing water at a ratio not more than the starting ratio, kneading the mixture, and sizing the kneaded product with a crusher.
The method for producing a sustained-release tablet according to any one of items 1) to 23). (26) The additive composition for sustained release tablets, wherein the ratio at which the hydrophilic matrix base starts dissolving in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. The sustained-release property according to any one of the above items (21) to (23), which is produced by adding the following organic solvent containing water and performing stirring granulation. Tablet manufacturing method.

(27) The additive composition for sustained-release tablets is prepared by mixing the hydrophilic matrix base or the mixture of the hydrophilic matrix base and the inert pharmaceutical filler with the dissolution temperature of the hydrophilic matrix base. The sustained-release tablet according to any one of (21) to (23), which is manufactured by wet granulation with the above hot water or a water-containing organic solvent. Production method. (28) The additive composition for sustained release tablets is wet-granulated by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been infiltrated with water. The method for producing a sustained-release tablet according to any one of the above items (21) to (23), characterized by being manufactured by the above method.

(29) The above-mentioned additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose soaked with water and centrifuging. (21) characterized by being manufactured by rolling granulation.
Item 20. The method for producing a sustained-release tablet according to any one of items 23 to 23. (30) The additive composition for sustained-release tablets comprises lactose, sucrose, fructose, dextrin,
Cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol, characterized by being manufactured using an inert pharmaceutical filler consisting of at least one selected from the group consisting of:
(24) The method for producing a sustained-release tablet according to any one of the above items (27) to (27).

(31) The additive composition for sustained-release tablets according to the present invention, wherein the hydrophilic matrix base comprises at least one hydrophilic compound selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. The method for producing a sustained-release tablet according to any one of the above items (24) to (30), which is produced using a matrix base.

The term “loose apparent density” as used herein refers to a value determined by the following measuring method. Using a Casa specific gravity measuring instrument (manufactured by Kuramochi Kagaku Kikai Seisakusho Co., Ltd.) manufactured based on the Japanese Industrial Standards, Vinyl Chloride Resin Test Method (JIS K6721), put a predetermined amount of sample into a funnel with a damper, and immediately The damper is pulled out and the sample
Drop naturally continuously into a 00 ml receiver. After the sample raised from the receiver is ground with a glass rod, the weight of the receiver containing the sample is measured to calculate the density. The “angle of repose” indicates a value obtained by an injection method. That is, a predetermined amount of a sample is dropped on a measurement table by vibration using an electromagnetic vibration type repose angle measuring device (manufactured by Tsutsui Rikakiki Co., Ltd.), and is continued until the sample starts to spill from around the table. The deposit is formed and the angle of inclination is read with a protractor.

[0029]

BEST MODE FOR CARRYING OUT THE INVENTION As the hydrophilic matrix base used in the additive composition, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, sodium carboxymethylcellulose and a mixture of two or more thereof are used. And those containing one selected from the group consisting of: In the case of HPMC, there is HPMC 2208 of the Japanese Pharmacopoeia (13th revision), for example, one marketed by Shin-Etsu Chemical Co., Ltd. under the trade name Metrolze. Among them, 2
90SH-4000, 90SH which are high viscosity types in which the viscosity of a 2% aqueous solution at 0 ° C. is 4,000 cP or more.
-15000, 90SH-30000, 90SH-10
For example, those having a particularly poor mixing property with a drug or fluidity during tableting, such as 0000, can be used. Similarly, HPC
In the case of, those having a viscosity of 1,000 cP or more (HP
In the case of CH, manufactured by Nippon Soda Co., Ltd.), and methylcellulose, those having a viscosity of 1,500 cP or more (SM-15)
00, SM-4000, SM-8000, manufactured by Shin-Etsu Chemical Co., Ltd.) and the like.

Inert pharmaceutical fillers used in the additive composition include lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol, sorbitol, and mixtures of two or more thereof. Is mentioned.

The method for producing an additive composition for tablets of the present invention is intended to improve the disadvantageous physical properties of the above hydrophilic matrix base in terms of tableting. Alternatively, a solvent or a binder is added to a mixture of a hydrophilic matrix base and an inert drug filler, kneaded, and granulated.

As the solvent to be added at the time of granulation, an organic solvent containing water at a ratio equal to or lower than the ratio at which the hydrophilic matrix base starts dissolving is suitable. For example, 90S of HPMC2208
H-4000 begins to dissolve when the water ratio exceeds 30%. When 35% or more of the water-containing organic solvent is used,
Since HPMC immediately gels and becomes highly viscous,
It becomes difficult to spread the liquid over the entire powder layer, and only a non-uniform substance consisting of powdery cohesive soul and untreated powder is obtained. The ratio at which the hydrophilic matrix base starts dissolving means the following. That is, the hydrophilic matrix base is added in advance to the organic solvent in a sufficiently small amount of about 0.1%, stirred, and dispersed. To this is added a certain amount of water and the dispersion is continued. When the dispersion is stopped and the mixture is left for 30 minutes, in a region where the water content ratio is low, the hydrophilic matrix base precipitates and causes phase separation, but starts to form a homogeneous phase from a certain ratio or more. It indicates the water content ratio at this time. Any organic solvent may be used as long as it is compatible with water, and lower alcohols such as methanol, ethanol, and isopropanol, acetone, and the like can be used. Ethanol is preferred from the viewpoint of toxicity.

The method for producing the additive composition used for producing this sustained-release tablet is as follows: a hydrophilic matrix base or a mixture of a hydrophilic matrix base and an inert pharmaceutical filler is added to a water-containing organic solvent. Or a high-speed stirring granulation method, or a crushing granulation method in which the mixture is kneaded in a kneader, sized with a crusher (pulverizer), and then dried in a fluidized bed.
When the fluidized bed granulation method is used, since the binder adheres to only a part of the particle surface in the powder layer, tertiary particles are formed without compaction, and only bulky granules can be obtained. Can not. When using the composite fluidized bed granulation method, it is easy to spread the solvent to the entire powder bed,
It is possible to compact the particles somewhat. However, since the hydrophilic matrix base is often a fibrous particle, it is necessary to perform compaction by entanglement of the particles, and a granulated material that imparts desired fluidity and apparent density is required. In order to obtain, the stirring granulation method is preferable, and the crushing granulation method is most preferable.

When using an inert pharmaceutical filler rich in water absorption and plastic deformation (plasticity) such as crystalline cellulose or powdered cellulose (hereinafter, referred to as cellulose), exceptionally, it can be produced only with water. it can. A method in which cellulose is charged into a centrifugal tumbling granulator, and while rotating a rotating disk, water is sprayed to infiltrate the cellulose, a hydrophilic matrix base is sprayed, and water is further sprayed to perform granulation. It is. In this method, despite granulation of water only,
Because of the water absorption of cellulose, the hydrophilic matrix base does not cause gelation / aggregation, and the growth of the composite particles proceeds uniformly. If it is desired to obtain a more compact granule, water is added to the cellulose using a kneader and the mixture is kneaded, and then the hydrophilic matrix base is gradually sprayed on and kneaded until the mixture becomes homogeneous. After sizing the mixture with a crusher, the mixture is transferred to a centrifugal tumbling granulator and sprayed with water to perform granulation.

The content of the hydrophilic matrix base in the additive composition is preferably selected according to the dose of the active ingredient from the sustained release tablet produced using the additive composition. For a drug such as chlorpheniramine maleate or nifedipine having a single dose of several mg, a hydrophilic matrix base having a content of 50% by weight or more may be used. For those requiring a single dose of several hundred mg, such as acetaminophen or theophylline, use a composition having a hydrophilic matrix base content of 80% by weight or more to avoid an increase in tablet weight and tablet diameter. Preferably, it is used.

The particle size of the additive composition is usually one that can pass through a No. 18 sieve, preferably 3
Those which can pass through a No. 0 sieve, most preferably those which can pass through a No. 42 sieve. In the case where particles remaining in the sieve of No. 18 are used, the distribution in the tablet does not easily become dense even when the particles are compression-formed because the surface area of the particles is small.
Therefore, intrusion of water is caused in a state in which a continuous gel layer is hardly formed, and the tablet may be disintegrated at an early stage of dissolution, which is not preferable. Note that the particle size referred to here is a standard screen sieve specified in Japanese Industrial Standards / Test Sieve (JIS Z8801), and is based on the general rules for sieving test method (J
IS Z8815).

To the additive composition obtained by this method, the main ingredient is directly added and mixed, or fine granules obtained by adding another additive to the main ingredient and granulating are added and mixed, Further, after adding a lubricant and the like as needed, a sustained release tablet can be prepared by a tableting machine according to a conventional method. The additive composition described above has excellent mixing properties with the main drug and other excipients, and when mixed with a V-type mixer, the drug content becomes constant immediately after mixing, and the dispersion is small. Further, since the angle of repose is 40 ° or less, the fluidity is excellent, and the weight variation coefficient of the tablet is extremely small. Therefore, the contents of the hydrophilic matrix base and the base drug in the tablet can be accurately controlled, and the dissolution rate of the active ingredient can be more easily adjusted and set. Further, the loose apparent density is, for example, 0.35 g / ml or more in a composition comprising 100% by weight of a hydrophilic matrix base such as HPMC (90SH-4000), and 50% by weight of the hydrophilic matrix base and Since the composition comprising 50% by weight of the inert pharmaceutical filler is 0.45 g / ml or more, the tablet composition can be filled in a tableting machine to a desired tablet weight.

When adjusting the dissolution rate of the medicinal component, the content of the hydrophilic matrix base in the tablet varies depending on the type of the matrix base, the solubility of the medicinal component in water and digestive juices, and the desired sustained release performance. Usually, it is 5 to 90% by weight, preferably 20 to 60% by weight. If it is less than 5% by weight, it may not be possible to obtain a sufficient sustained release performance in some cases, and if it is more than 90% by weight, the dissolution rate of the active ingredient may be too low, which is not preferred.

The additive composition of the present invention increases the amount of swelling during hydration as compared with an untreated hydrophilic matrix base, so that the residence time in the digestive tract can be extended.
This is because, when the additive composition is manufactured, intermolecular hydrogen bonds (physical crosslinks) are formed in the particles of the hydrophilic matrix base swelled during the drying step, and the crystal structure is increased. This is because the swelling property becomes larger during hydration. As a result, the adhesion to the inner wall of the digestive tract is increased, and the residence time in the digestive tract can be increased. In addition, by imparting swelling properties, when the high viscosity type hydrophilic matrix base is used, the collapse of the gel layer is extremely delayed, and the elution occurs when the remaining amount of the medicinal component is reduced. The speed does not decrease.

[0040]

EXAMPLES Hereinafter, specific embodiments of the present invention will be described with reference to Examples and Comparative Examples, but the present invention is not limited by these descriptions.

Example 1 HPMC (manufactured by Shin-Etsu Chemical Co., Ltd., Metrose, 90S)
H-4000) and lactose (DMV, Pharm
(atose, 350M Lactose), 500 g, into an 8-liter kneader (manufactured by Fukae Kogyo Co., Ltd.), and 1.0 kg of a water / ethanol = 25/75 mixed solution.
The mixture was kneaded for 15 minutes. Crusher (made by Dalton Co., Ltd., Power Mill P-3) equipped with a 3 mm diameter screen for the kneaded material
, And dried with a fluid bed granulator (FLO-5, manufactured by Freund Corporation), and the dried granules were sieved and sieved using a No. 30 sieve. This operation is repeated three times.
2 kg of fine granules were obtained. Table 1 shows the angle of repose and the apparent density of looseness.

Comparative Example 1 100 g of HPMC (90SH-4000) and lactose 100
g in a fluidized-bed granulator (manufactured by Freund Corporation, FL-
(MINI type), and 200 g of a mixed solution of water / ethanol = 25/75 was sprayed at a rate of 30 mL / min (spray pressure: 0.1 MPa, intake temperature: 70-75 ° C., exhaust temperature: 30-35 ° C.). . After drying, the mixture was sieved and sieved using a No. 30 sieve to obtain 178 g of fine granules. Table 1 shows the angle of repose and the apparent density of looseness.

Comparative Example 2 250 g of HPMC (90SH-4000) and lactose 250
g in a composite fluidized bed granulator (manufactured by Freund Corporation)
SFC-MINI type), water / ethanol = 25
/ 75 of a mixed solution of 50/75 was sprayed at a rate of 80 ml / min (spray pressure: 0.2 MPa, rotor rotation speed: 30).
0 rpm, agitator rotation speed: 500 rpm, supply air temperature: 70-75 ° C, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved and sieved with a No. 30 sieve to obtain 339 g of fine granules. Table 1 shows the angle of repose and the apparent density of looseness.

[0044]

[Table 1]

Example 2 800 g of HPMC (90SH-4000) and lactose 200
g was charged into a kneader, and 1.2 kg of a mixed solution of water / ethanol = 20/80 was added and kneaded for 15 minutes. Thereafter, sizing, drying, and sieving were performed under the same operating conditions as in Example 1, and 75
2 g of fine granules were obtained. Table 2 shows the angle of repose and loose apparent density.
It was as follows.

Comparative Example 3 96 g of HPMC (90SH-4000) and 24 g of lactose were mixed with a fluidized-bed granulator (FL-MI, manufactured by Freund Corporation).
NI type), and 150 g of a mixed solution of water / ethanol = 20/80 was sprayed at a rate of 20 ml / min (spray pressure: 0.1 MPa, intake air temperature: 70-75 ° C., exhaust air temperature: 30-35 ° C.). . After drying, the mixture was sieved and sized with a No. 30 sieve to obtain 79 g of fine granules. Table 2 shows the angle of repose and the apparent density of looseness.

Comparative Example 4 240 g of HPMC (90SH-4000) and 60 g of lactose
Is mixed fluidized bed granulator (Freund Sangyo Co., Ltd., S
FC-MINI type), water / ethanol = 20 /
375 g of a mixed solution of No. 80 was sprayed at a rate of 54 ml / min (spray pressure: 0.2 MPa, rotor rotation speed: 300).
rpm, agitator rotation speed: 500 rpm, supply temperature: 70-75 ° C, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved and sized with a No. 30 sieve to obtain 173 g of fine granules. Table 2 shows the angle of repose and the apparent density of looseness.

[0048]

[Table 2]

Example 3 1.0 kg of HPMC (90SH-4000) was charged into a kneader, and a mixed solution of water / ethanol = 20/80 was used.
2 kg was added and kneaded for 15 minutes. Thereafter, sizing, drying and sieving were performed under the same operating conditions as in Example 1 to obtain 813 g of fine granules. Table 3 shows the angle of repose and the apparent apparent density.

Comparative Example 5 120 g of HPMC (90SH-4000) was charged into a fluidized bed granulator (FL-MINI type, manufactured by Freund Corporation) and 150 g of a mixed solution of water / ethanol = 20/80.
Was sprayed at a rate of 20 ml / min (spray pressure: 0.1
MPa, intake temperature: 70-75 ° C, exhaust temperature: 30-3
5 ° C). After drying, sieved and sized with a sieve No. 30, 81 g
Fine granules were obtained. Table 3 shows the angle of repose and the apparent apparent density.

Comparative Example 6 300 g of HPMC (90SH-4000) was mixed with a composite fluidized bed granulator (SFC-MIN manufactured by Freund Corporation).
375 g of a mixed solution of water / ethanol = 20/80 was sprayed at a rate of 54 ml / min (spray pressure: 0.2 MPa, rotor rotation speed: 300 rpm, agitator rotation speed: 500 rpm, supply air temperature: 70-7
5 ° C, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved with a No. 30 sieve to obtain 153 g of granules. Table 3 shows the angle of repose and the apparent apparent density.

Comparative Example 7 The angle of repose and the loose apparent density of untreated HPMC (90SH-4000) were measured. Table 3 shows the results.

[0053]

[Table 3]

Using various granulation methods, an additive composition was produced in which the content ratio of HPMC was changed. As shown in Tables 1 to 3, after kneading with a kneader, sizing was performed with a crusher. The crushing and granulation method performed was most suitable for obtaining a material having a large loose apparent density, a small angle of repose, and good fluidity.

Example 4 The additive composition obtained in Example 1 (HPMC / lactose (50 /
50)) To 800 g, 155 g of lactose for direct hitting (manufactured by Freund Corporation, Dilactoose-S) and 40 g of chlorpheniramine maleate (manufactured by Fukuju Pharmaceutical Co., Ltd.) were added, and a V-type mixer (Tokuju Co., Ltd.) (V-10, manufactured by Kosakusho). During the mixing, sampling was performed over time from three places in the mixer, and a spectrophotometer (Ub, manufactured by JASCO Corporation)
est-35), the amount of chlorpheniramine maleate was determined, and the mixability was evaluated from the ratio. The results are shown in FIG. Immediately after mixing, the drug content is constant and the dispersion is small, indicating that the additive composition of the present invention is excellent in mixing properties.

Comparative Example 8 Lactose for direct hitting (Dilactose, manufactured by Freund Corporation) was added to 400 g of untreated HPMC (90SH-4000).
S) 555 g and 40 g of chlorpheniramine maleate were charged into a V-type mixer, and the mixing properties were examined in the same manner as in Example 4. The results are shown in FIG. Even after 20 minutes, the drug content was not constant, and the dispersion was large.

Example 5 Magnesium stearate was added to the mixture prepared in Example 4 in an amount of 0.5%, and tableting was performed using a rotary tableting machine (HT-30, manufactured by Hata Ironworks Co., Ltd.). Was. The tablet weight of the obtained tablet was 200 mg, and the weight variation coefficient was 1.
The tablet hardness was as small as 6%, and the tablet hardness was as high as 9.7 kg / cm ² .

Comparative Example 9 A tableting experiment was conducted on the mixture prepared in Comparative Example 8 in the same manner as in Example 5, but it was found that the powder had poor fluidity and could not be sufficiently tableted.

Example 6 Single-shot tableting machine (FY-MCU-, manufactured by Fuji Pharmaceutical Co., Ltd.)
T-type) and the additive composition HPMC / lactose (50 mg) prepared in Example 1 and chlorpheniramine maleate (6 mg).
/ 50) HP containing 140 mg, added lactose for direct compression and magnesium stearate to a tablet weight of 200 mg, HP
500 tablets of 8 mm diameter containing 35% MC were produced. The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester (DT-610, manufactured by JASCO Corporation). According to the Japanese Pharmacokinetic Dissolution Test Method 2 (paddle method), 900 ml of purified water was used as a test solution, and a required amount of tablets was charged at a liquid temperature of 37 ° C. and a paddle rotation speed of 100 rpm. The results are shown in FIG.

Example 7 Using a single-shot tableting machine, chlorpheniramine maleate 6
8 mg of the additive composition HPMC / lactose (50/50) prepared in Example 1 and lactose for direct compression and magnesium stearate to make the tablet weight 200 mg, 8 mm diameter containing 40% of HPMC. 500 tablets
Tablets were manufactured. The drug elution pattern from the obtained tablets was examined under the same conditions as in Example 6. The results are shown in FIG.

Example 8 Using a single-shot tableting machine, chlorpheniramine maleate 6
8 mg of the additive composition HPMC / lactose (50/50) prepared in Example 1 and lactose for direct compression and magnesium stearate to obtain a tablet weight of 200 mg. 500 tablets
Tablets were manufactured. The drug elution pattern from the obtained tablets was examined under the same conditions as in Example 6. The results are shown in FIG. FIG.
As shown in the figure, the elution of the drug was delayed by increasing the amount of the additive composition. By using the product of the present invention, it is easy to accurately control the dissolution rate of the medicinal component.

Example 9 Using the tablets obtained in Example 7, the effect of the test solution on the dissolution pattern was examined. As the test solution, three types of purified water, the Japanese Pharmacopoeia Disintegration Test Method, the first solution (artificial gastric juice, pH 1.2) and the second solution (artificial intestinal fluid, pH 6.8) were used. The results are shown in FIG. As shown in FIG. 3, the sustained-release tablet using the product of the present invention can elute a medicinal component without being affected by liquidity.

Example 10 Using a single-shot tableting machine, containing 143 mg of acetaminophen fine granules (acetaminophen / lactose = 70/30) and 100 mg of a single granulated HPMC prepared in Example 3,
Lactose for direct compression and magnesium stearate were added to make the tablet weight 250 mg, 9 mm containing 40% of HPMC
500 tablets having a diameter were produced. Acetaminophen fine granules are separately available from a high-speed mixer (Fukae Kogyo Co., Ltd.)
FMD-25J type), and agitation granulation was performed using a No. 30 sieve. The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester. Purified water 9
Using 00ml, liquid temperature 37 ° C, paddle rotation speed 100rpm
m. FIG. 4 shows the results.

Example 11 Using a single tableting machine, containing 143 mg of theophylline fine granules (theophylline / lactose = 70/30) and 100 mg of the single granulated HPMC prepared in Example 3, lactose for direct compression was used. Add magnesium stearate and weigh the tablet 250mg
Of a 9 mm diameter tablet containing 40% HPMC
00 tablets were manufactured. Theophylline fine granules were separately granulated by stirring with a high-speed mixer and sieved and sized with a No. 30 sieve. The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester. Purified water 900m according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method)
1 and at a liquid temperature of 37 ° C. and a paddle rotation speed of 100 rpm. FIG. 5 shows the results.

Example 12 Using a single-shot tableting machine, 100 mg of nifedipine fine granules (nifedipine / carboxymethylethylcellulose (manufactured by Freund Corporation) / lactose = 10/20/70) and the additive prepared in Example 2 Composition HPMC / lactose (80 /
20) HP containing 87.5 mg, and adding lactose for direct compression and magnesium stearate to a tablet weight of 200 mg.
500 tablets of 8 mm diameter containing 35% MC were produced. Nifedipine fine granules were separately granulated by a composite fluidized bed granulator (SFC-MINI type, manufactured by Freund Corporation) and sieved with a No. 30 sieve. The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester. According to the Japanese Pharmacokinetic Dissolution Test Method 2 (paddle method), the Japanese Pharmacokinetic Disintegration Test Method Test Liquid 2nd Solution 90
0ml, liquid temperature 37 ° C, paddle rotation speed 100rpm
Then, the required amount of tablets was charged. FIG. 6 shows the results.

Example 13 Crystalline cellulose (Abicel, PH, manufactured by Asahi Kasei Corporation)
-101) Charge 1,000 g into a kneader and add 740 water.
g was added and kneaded for 15 minutes. The kneaded material was halved and HPMC (90SH-400) was fed using a screw feeder.
0) Kneading was continued while spraying 500 g at a rate of 50 g / min. After the spraying was completed, kneading was continued for another 15 minutes. A crusher equipped with a screen with a diameter of 3 mm for this kneaded material (Co., Ltd.)
After sizing with a power mill P-3 type, manufactured by Dalton, a centrifugal rolling granulator (CF-36, manufactured by Freund Corporation)
0), while rotating the rotating disk, water was added at 10 ml /
Sprayed at a speed of 270 g (rotor rotation speed: 200
~ 400, spray air pressure: 0.1MPa, spray air amount: 15 liter / min, slit air amount: 150 ~ 4
00 liters / minute). After drying, the dried granules were sieved and sized with a No. 42 sieve to obtain 778 g of fine granules. The angle of repose of these fine grains is 38 ° and the loose apparent density is 0.38 g /
ml.

[0067]

As described above, according to the present invention, as shown in, for example, FIGS. 4 to 6, even in various drugs having different solubility in water, the sustained-release tablet using the product of the present invention can The desired elution pattern of the active ingredient can be easily obtained.

[Brief description of the drawings]

FIG. 1 is a view showing uniform mixing properties of an additive composition of the present invention.

FIG. 2 is a view showing a drug elution pattern of the sustained-release tablet of the present invention.

FIG. 3 is a graph showing the effect of a test solution on the drug dissolution pattern of the sustained-release tablet of the present invention.

FIG. 4 is a view showing an elution pattern of acetaminophen in a sustained-release tablet of the present invention.

FIG. 5 is a view showing the elution pattern of theophylline in the sustained-release tablet of the present invention.

FIG. 6 is a view showing an elution pattern of nifedipine in the sustained-release tablet of the present invention.

Claims (31)

[Claims] 1. A fine particle comprising 50 to 100% by weight of a hydrophilic matrix base and 0 to 50% by weight of an inert pharmaceutical filler, having a loose apparent density of 0.35 g / ml or more and a repose angle of 40 ° or less. An additive composition for a sustained release tablet, comprising granules. 2. The sustained-release form according to claim 1, wherein the hydrophilic matrix base contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. An additive composition for tablets. 3. An inert pharmaceutical filler comprising at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. Item 3. The additive composition for sustained release tablets according to Item 1 or 2. 4. A composition comprising a hydrophilic matrix base or a hydrophilic matrix base and an inert pharmaceutical filler.
Characterized by wet granulation using a solvent or a binder, comprising 50 to 100% by weight of a hydrophilic matrix base and 0 to 50% by weight of an inert pharmaceutical filler, and having a loose apparent density of 0.35 g / ml. A method for producing an additive composition for sustained release tablets comprising fine granules having a repose angle of 40 ° or less as described above. 5. An organic solvent containing water at a ratio at which the hydrophilic matrix base starts dissolving is added to the hydrophilic matrix base or the composition containing the hydrophilic matrix base and the inert pharmaceutical filler. The method for producing an additive composition for sustained-release tablets according to claim 4, further comprising kneading and sizing the kneaded product with a crusher. 6. An organic solvent containing water at a ratio at which the hydrophilic matrix base starts dissolving is added to the hydrophilic matrix base or the composition containing the hydrophilic matrix base and the inert pharmaceutical filler. The method for producing an additive composition for sustained-release tablets according to claim 4, wherein stirring granulation is additionally performed. 7. A method of wet-forming the hydrophilic matrix base or the composition containing the hydrophilic matrix base and the inert pharmaceutical filler with hot water or a water-containing organic solvent at a temperature not lower than the melting temperature of the hydrophilic matrix base. Characterized by granulation,
A method for producing the additive composition for sustained release tablets according to claim 4. 8. The method according to claim 4, wherein the hydrophilic matrix base is sprayed on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been infiltrated by adding water to perform wet granulation. A method for producing the additive composition for sustained-release tablets according to the above. 9. The method according to claim 1, wherein the hydrophilic matrix base is sprayed on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been impregnated with water to perform centrifugal tumbling granulation. 5. The method for producing the additive composition for sustained-release tablets according to 4. 10. The inert pharmaceutical filler comprises at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. A method for producing the additive composition for sustained release tablets according to any one of claims 4 to 7. 11. The method according to claim 4, wherein the hydrophilic matrix base contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. 13. The method for producing the additive composition for sustained-release tablets according to the above item. 12. A hydrophilic matrix base 50 to 100.
% By weight and 0-50% by weight of an inert pharmaceutical filler,
A sustained-release tablet comprising an additive composition for a sustained-release tablet comprising fine granules having a loose apparent density of 0.35 g / ml or more and an angle of repose of 40 ° or less, and a main ingredient. 13. The sustained-release tablet additive composition is characterized in that it contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose as a hydrophilic matrix base. The sustained release tablet according to claim 12, 14. The additive composition for sustained release tablets according to claim 1, wherein the lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol,
14. The sustained-release tablet according to claim 12, comprising at least one selected from xylitol and sorbitol as an inert pharmaceutical filler. 15. The sustained release tablet additive composition is prepared by wet granulating a hydrophilic matrix base or a composition comprising a hydrophilic matrix base and an inert pharmaceutical filler using a solvent or a binder. The sustained release tablet according to any one of claims 12 to 14, wherein the sustained release tablet is manufactured by the following method. 16. The additive composition for sustained release tablets starts dissolving the hydrophilic matrix base in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. The kneaded product is manufactured by adding and kneading an organic solvent containing water at a ratio of not more than a predetermined amount, and sizing the kneaded product with a crusher. Item 20. The sustained-release tablet according to item 18. 17. The hydrophilic matrix base starts dissolving in the sustained release tablet additive composition in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. The sustained-release tablet according to any one of claims 12 to 15, characterized in that the sustained-release tablet is produced by adding an organic solvent containing water at a ratio of not more than and performing stirring granulation. 18. The method according to claim 18, wherein the additive composition for a sustained release tablet is prepared by mixing the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler with the hydrophilic matrix base at a dissolving temperature or higher. The sustained-release tablet according to any one of claims 12 to 15, wherein the tablet is produced by wet granulation with hot water or a water-containing organic solvent. 19. The wet-molding method, wherein the additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose impregnated with water. The sustained release tablet according to any one of claims 12 to 15, which is manufactured by granulating. 20. The sustained-release tablet additive composition is produced by a method of sprinkling a hydrophilic matrix base on crystalline cellulose or powdered cellulose impregnated with water and performing centrifugal tumbling granulation. The sustained-release tablet according to any one of claims 12 to 15, which is characterized in that: 21. A hydrophilic matrix base 50 to 100.
% By weight and 0-50% by weight of an inert pharmaceutical filler,
The active ingredient is added as it is to the additive composition for sustained release tablets consisting of fine granules having a loose apparent density of 0.35 g / ml or more and the angle of repose of 40 ° or less, or by adding other additives to the active ingredient. A method for producing a sustained-release tablet, characterized by adding fine granules obtained by granulation and tableting. 22. The additive composition for sustained release tablets according to claim 1, wherein said composition comprises a hydrophilic matrix base comprising at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. 22. The method for producing a sustained-release tablet according to claim 21, wherein the method comprises: 23. The additive composition for sustained release tablets according to claim 1, wherein said composition comprises at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. The method for producing a sustained-release tablet according to claim 21 or 22, wherein the method comprises one kind of an inert pharmaceutical filler. 24. The additive composition for sustained release tablets is produced by wet granulating a hydrophilic matrix base, a hydrophilic matrix base and an inert pharmaceutical filler using a solvent or a binder. The method for producing a sustained-release tablet according to any one of claims 21 to 23, characterized in that the tablet has been prepared. 25. The additive composition for a sustained release tablet according to claim 1, wherein the hydrophilic matrix base starts dissolving in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. 22. A kneaded product obtained by adding and kneading an organic solvent containing water at a ratio of not more than 30%, and sizing the kneaded product with a crusher.
25. The method for producing a sustained-release tablet according to any one of items 24 to 24. 26. The sustained release tablet additive composition, wherein the hydrophilic matrix base starts dissolving in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. The sustained release tablet according to any one of claims 21 to 24, characterized in that the tablet is produced by adding an organic solvent containing water at a ratio of not more than and performing stirring granulation. Production method. 27. The additive composition for sustained-release tablets according to claim 1, wherein the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler is mixed with the hydrophilic matrix base at a temperature not lower than the melting temperature of the hydrophilic matrix base. The method for producing a sustained-release tablet according to any one of claims 21 to 24, wherein the tablet is produced by wet granulation with hot water or a water-containing organic solvent. 28. The sustained release tablet additive composition is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose impregnated with water. The method for producing a sustained-release tablet according to any one of claims 21 to 24, characterized by being produced by granulating. 29. The sustained release tablet additive composition is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been impregnated with water and centrifuged. 3. It is manufactured by dynamic granulation.
5. The method for producing the sustained release tablet according to any one of 4. 30. The additive composition for sustained release tablets, wherein the inert pharmaceutical filler is selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. 29. The method for producing a sustained-release tablet according to any one of claims 24 to 28, wherein the method is produced using at least one inert drug filler. 31. The additive composition for sustained-release tablets, wherein the hydrophilic matrix comprises, as the hydrophilic matrix base, at least one hydrophilic matrix selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. 31. The method for producing a sustained-release tablet according to any one of claims 24 to 30, wherein the tablet is produced using a base.