WO1999058114A1

WO1999058114A1 - Sustained release tablets, additive compositions therefor and process for producing the same

Info

Publication number: WO1999058114A1
Application number: PCT/JP1999/002408
Authority: WO
Inventors: Fujio Sekigawa; Takeshi Homma
Original assignee: Freund Industrial Co., Ltd.
Priority date: 1998-05-11
Filing date: 1999-05-10
Publication date: 1999-11-18
Also published as: JP2000034224A

Abstract

Additive compositions for producing sustained release tablets which show a good fluidity in the tabletting step and enable accurate control of the elution speed of the drug ingredients. Compositions characterized by consisting fine granules which contain 50 to 100 % by weight of a hydrophilic matrix base and 0 to 50 % by weight of an inert pharmaceutical filler and have a loose apparent density of 0.35 g/ml or more and a repose angle of 40° or less; and sustained release tablets containing the above compositions and the principal agents.

Description

Description Sustained-release tablets, their additive compositions, and their manufacturing methods

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 sustained-release tablet containing the additive composition. The present invention relates to a release tablet and a method for producing the tablet. Background art

Sustained-release preparations have been developed for the purpose of improving compliance with a decrease in the number of administrations and reducing the fluctuation range of blood concentration to prevent side effects and expect stable therapeutic effects. Various formulations are on the market. Above all, sustained-release tablets using a hydrophilic matrix base have simple structures and manufacturing processes, 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 a hydrophilic matrix base using a binder is used. There is a wet granule compression method in which a drug powder is wet granulated, and the resulting granules are tableted with other additives or lubricants. Sustained-release tablets obtained in this way form a continuous gel layer on the tablet surface when contacted with water, delaying the penetration of water into the tablet, and maintain their shape without disintegration for a long time it can. The dissolution of the drug is controlled by the rate of water penetration and exhibits a sustained release effect.

The following are known as sustained-release tablets using a hydrophilic matrix base produced by the direct powder compression method.

(1) Japanese Patent Publication No. 4-52008 discloses that the average molecular weight is 50,000 or more, that is, the viscosity of a 2% aqueous solution at 20 ° C is about 800 cP or more. The use of hydroxypropylmethylcellulose (hereinafter referred to as HPMC) having a methoxyl group content of 16 to 24% by weight and a hydroxypropoxyl group of 4 to 32% by weight up to 25% of the tablet weight is described. ing.

(2) Japanese Patent Publication No. 5-9394 discloses that the average molecular weight is 23,000 or less. That is, it describes an HPMC using a 2% aqueous solution at 20 ° C. having a viscosity of about 50 cP or less and a hydroxypropoxyl group of 9 to 12% by weight.

(3) Japanese Patent Publication No. 7-5151 / 16 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, A description is given of the use of an HPMC having a hydroxyproboxyl group content of 7 to 12% by weight and having a particle size of 95% by weight or more through a 100-mesh sieve.

(4) Japanese Patent Application Laid-Open No. 6-172121 discloses that the viscosity of a 2% aqueous solution at 20 ° C is 14 or more, and that the methoxyl group content is 19 to 24. The use of an HPMC prepared in such a manner that the amount of hydroxypropoxyl groups is 4 to 12% by weight and the particle size of the mesh passes through a sieve having a mesh size of 100% or more by 95% by weight or more is described. I have.

(5) Patent No. 2 686 215 discloses that a 2% aqueous solution at 20 ° C. has a viscosity of not less than 1,000 cP and a methoxyl group content of 19 to 30. 4 to 12% by weight of hydroxypropoxyl group, and can pass through 95% or more of a sieve with a particle size of 100 mesh, and a loose apparent density of 0.35 gZml or less. Using an HPMC prepared to give

The following are known as examples of sustained release tablets using a hydrophilic matrix base produced by the wet granulation compression method.

(6) Japanese Patent Publication No. 4-164025 discloses that a base drug and an excipient are mixed with methylcellulose having a 2% aqueous solution viscosity of 80 cP or more at 20 ° C and water or water. It describes a method using granules obtained by adding and kneading a water-containing organic solvent.

(7) In Japanese Patent Application Laid-Open No. 5-255125, a partial wet granulation method is used, in which HPMC or a water-soluble component is mixed with drug granules obtained by wet granulation of a drug using a binder. It describes that a tablet is prepared to produce a sustained-release tablet in which the drug is released according to a predetermined relational formula.

Further, the following are known as additive compositions which are excellent in fluidity and can be directly hit by using a wet granule compression method.

(8) Japanese Patent Publication No. 6-25073 discloses that a heteropolysaccharide is crosslinked with a heteropolysaccharide. Use is made of granules comprising from 20 to 60% by weight of a hydrophilic material comprising a polysaccharide material which can be removed and from 40 to 80% by weight of an inert drug filler.

(9) JP-A-4-1313252 discloses that HPMC is suspended in hot water having a dissolution temperature or higher, and tannic acid, acrylic acid / methyl methacrylate / dimethyl methacrylate / dimethylaminoethyl copolymer or methacrylic acid / acrylic acid is used. It describes that a composition obtained by spray-drying after adding an acid ester copolymer is used.

(10) Japanese Patent Application Laid-Open No. 6-23964 describes a composition using a composition obtained by spray-drying an aqueous solution of HPMC in which microcrystalline cellulose is dispersed.

However, powders of hydrophilic matrix bases (such as cellulose ethers) represented by HPMC, which are often used for the production of sustained-release tablets as described above, have poor fluidity during tableting. Are known, and the physical properties of the high viscosity type (high molecular weight) are more remarkable.

In the methods described in the publications (1) to (5) using the direct powder compression method, the total weight of the tablets becomes uneven, or the miscibility with the drug or other excipients deteriorates. However, it is difficult to accurately control the dissolution rate of the active ingredient. Depending on the prescription, production on a rotary tableting machine may not be possible. 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 at the time of hydration is small, so that the tablet form is formed before the gel layer is sufficiently formed. Even if it collapses or the 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, and there is a problem that the diameter of the whole tablet becomes large and it becomes difficult to take it.

On the other hand, in the case of the production method by the wet granule compression method, in the method (7) described in Japanese Patent Application Laid-Open No. 5-255125, only the production of granules mainly containing a drug is carried out. Although it may be effective for drugs that have difficulty in mixing, mixing, and compression molding, it has no relation to the physical properties of HPMC, and therefore has the same drawbacks as the direct powder compression method described above. On the other hand, the method (6) described in Japanese Patent Application Laid-Open No. H4-164025 discloses a method in which a drug or an excipient is mixed with methylcellulose and water or a water-containing organic solvent is added. Since the granules obtained by kneading are used, the properties of methylcellulose seem to be improved. However, drugs that are unstable to water have concerns about degradation, etc., so it is preferable to mix and disintegrate them in the untreated state.Slow release is possible except for drugs with tableting disorders It is difficult to say that granulation with the base is appropriate.

Therefore, an additive composition having excellent fluidity, which can obtain a sustained-release tablet simply by mixing it with a drug powder, is desired. However, the method described in Japanese Patent Publication No. 6-25073 discloses a method ( In 8), since the additive composition contains natural gums such as tragacanth and acacia, the quality may vary between lots. JP-A-4-3 1 2 5 2 2

(9) and the method described in Japanese Patent Application Laid-Open No. 6-23964 (10) both involve spray drying, and the methods for preparing the additive composition include cost and productivity. This is not desirable in terms of Regarding the physical properties of the obtained composition, those described in JP-A-6-239764 have a small apparent density despite the low HPMC content (20%) in the composition. (0.20 _g // ml), the amount of filling can be limited when making tablets with a rotary tableting machine.

An object of the present invention is to provide an additive composition having excellent fluidity at the time of tableting and a method for producing the same, which are useful for producing a sustained release tablet in which the dissolution rate of a medicinal ingredient is accurately controlled. It is in.

In particular, the present invention is excellent in terms of sustained release, such as high gel strength during hydration and requiring a small amount of addition to tablets, but is poor in fluidity and mixing properties in tableting. The need for advanced technology for granulation is one of the factors that hinders the spread. Despite containing as a main component a high-viscosity type hydrophilic matrix base such as HPMC, it has fluidity and miscibility. It is an object of the present invention to provide an additive composition for a sustained-release preparation comprising fine granules excellent in quality 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. Disclosure of the invention

The additive composition for producing the sustained-release tablet of the present invention, which has been achieved to achieve the above object, comprises a hydrophilic matrix base or a hydrophilic matrix base. The mixture of the active pharmaceutical filler is wet-granulated using a solvent or a binder, and mainly includes the following inventions.

(1) 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 Zm 1 or more and a repose angle of 4 An additive composition for a sustained release tablet, comprising fine particles having a temperature of 0 ° or less.

(2) The hydrophilic matrix base according to the above (1), wherein the hydrophilic matrix base material contains at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium. The additive composition for sustained-release tablets according to the above.

(3) The inert pharmaceutical filler contains at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. The additive composition for sustained release tablets according to the item (1) or (2).

(4) A hydrophilic matrix characterized by wet granulating a composition of a hydrophilic matrix base or a hydrophilic matrix base and the inert drug filler using a solvent or a binder. Base 50-100% by weight and inert pharmaceutical filler 0-

A process for producing an additive composition for sustained-release tablets comprising 50% by weight, fine particles having a loose apparent density of 0.35 g / m 1 or more and an angle of repose of 40 ° or less.

(5) To the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inactive drug filler, an organic solvent containing water at a ratio not more than the ratio at which the hydrophilic matrix base starts dissolving is added and kneaded. 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 inactive pharmaceutical filler, add an organic solvent containing water at a ratio not more than a ratio at which the hydrophilic matrix base starts dissolving and stir. The method for producing an additive composition for sustained-release tablets according to item (4), wherein granulation is performed.

(7) Wet granulation of the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inactive drug filler with hot water or a hydrated organic solvent at a temperature equal to or higher than the dissolution temperature of the hydrophilic matrix base. The sustained release tablet according to the above (4), characterized in that: A method for producing an additive composition for an agent.

(8) The method according to item (4), wherein the hydrophilic matrix is sprayed on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose which has been infiltrated by adding water, and wet granulation is performed. A method for producing the additive composition for sustained-release tablets according to the above.

(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 which has been impregnated by adding water, and centrifugally tumbling and granulating. 5. The method for producing the additive composition for sustained release tablets according to the above.

(10) The inert pharmaceutical filler contains at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. Features,

(4) The method for producing an additive composition for sustained-release tablets according to any one of the above items (7) to (7).

(11) The hydrophilic matrix base comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium,

(4) The method for producing the additive composition for sustained-release tablets according to any one of the above items (4) to (10).

(12) Consisting of 50-100% by weight of a hydrophilic matrix base and 0-50% by weight of an inert pharmaceutical filler, having a loose apparent density of 0.35 g / m1 or more and a repose angle of 40 °. A sustained release tablet comprising an additive composition for sustained release tablet comprising the following fine granules and a main drug component.

(13) The additive composition for sustained-release tablets comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium. (12) The sustained release tablet according to the above (12), characterized in that the tablet is contained as a base.

(14) The additive composition for sustained release tablets contains 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 above item (12) or (13), which is contained as an active pharmaceutical filler. (15) The additive composition for sustained release tablets comprises a solvent or a binder prepared by mixing 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 (12) to (14), characterized in that the sustained release tablet is manufactured by wet granulation using the tablet.

(16) The additive composition for sustained-release tablets is prepared by adding the hydrophilic matrix base or the mixture of the hydrophilic matrix base and the inert drug filler to the hydrophilic matrix base. (1 2) characterized in that it is produced by adding an organic solvent containing water at a ratio below the rate at which dissolution starts, kneading the mixture, and sieving the kneaded product with a crusher. Item-The sustained-release tablet according to any one of items 14 to 14.

(17) The additive composition for sustained-release tablets is prepared by adding the hydrophilic matrix base or the mixture of the hydrophilic matrix base and the inert drug filler to the hydrophilic matrix base. (12) to (12), characterized in that they are produced by adding an organic solvent containing water at a ratio not more than the ratio at which dissolution is started and performing stirring granulation.

(14) The sustained release tablet according to any one of the above (14).

(18) The additive composition for sustained-release tablets comprises the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert drug filler, the hydrophilic matrix base comprising: (12) to (14), characterized by being produced by wet granulation with hot water or a water-containing organic solvent having a temperature equal to or higher than the dissolution temperature of Sustained release tablets.

(19) The additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler composed of crystalline cellulose or powdered cellulose impregnated with water. The sustained-release tablet according to any one of (12) to (14), which is manufactured by wet granulation.

(20) The additive composition for sustained-release tablets 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 (12) to (14), characterized in that it is a tablet.

(21) Consisting of 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 / m 1 or more and a repose angle of 40. ° The main drug is added as is to the additive composition for sustained release tablets consisting of A method for producing a sustained-release tablet, characterized by tableting, or tableting, or adding fine particles obtained by granulating the main drug with other additives.

(22) The additive composition for sustained-release tablets comprises, in the composition, at least one hydrophilic selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium. (21) The method for producing a sustained release tablet according to the above (21), comprising a matrix base.

(23) The additive composition for sustained release tablets is selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol in the composition. The method for producing a sustained-release tablet according to the item (21) or (22), comprising at least one inert drug filler.

(24) The additive composition for sustained-release tablets contains 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 in that the tablet is produced by wet granulation.

(25) The additive composition for sustained-release tablets comprises a hydrophilic matrix base, or a mixture of a hydrophilic matrix base and the inert drug filler, and a hydrophilic matrix base. Characterized in that it is manufactured by adding an organic solvent containing water at a ratio of not more than the rate at which dissolution starts, kneading the mixture, and sizing the kneaded product with a crusher.

(21) The method for producing a sustained-release tablet according to any one of the above (23) to (23).

(26) The additive composition for sustained-release tablets contains the hydrophilic matrix, or a mixture of the hydrophilic matrix and the inert drug filler, and a hydrophilic matrix. (21)-characterized in that it is produced by adding an organic solvent containing water at a ratio below which the base starts dissolving and performing stirring granulation.

(23) The method for producing a sustained-release tablet according to any one of the above (23).

(27) The additive composition for sustained release tablets comprises the hydrophilic matrix base, or a mixture of the hydrophilic matrix base and the inert drug filler, comprising the hydrophilic matrix base. Wet granulation with hot water or a water-containing organic solvent above the melting temperature of The method for producing a sustained-release tablet according to any one of (21) to (23), characterized in that the tablet is produced.

(28) The additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base onto an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose impregnated with water to form a wet matrix. The method for producing a sustained-release tablet according to any one of (21) to (23), wherein the tablet is produced by granulation.

(29) The additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base on an inert pharmaceutical filler composed of crystalline cellulose or powdered cellulose impregnated with water. The method for producing a sustained-release tablet according to any one of (21) to (23), wherein the method is produced by centrifugal tumbling granulation.

(30) The additive composition for sustained release tablets comprises lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol as the inert pharmaceutical filler. (24) The method according to any one of the above items (24) to (27), which is manufactured using at least one selected from inert pharmaceutical fillers. Method for producing sustained release tablets.

(31) The additive composition for sustained release tablets comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium as the hydrophilic matrix base. The method for producing a sustained-release tablet according to any one of the above items (24) to (30), characterized by being manufactured using a hydrophilic matrix base consisting of:

The term “loose apparent density” here refers to the value obtained by the following measurement method. Using a Kaza specific gravity measuring instrument (manufactured by Kuramochi Kagaku Kikai Seisakusho Co., Ltd.) manufactured based on the Japanese Industrial Standards and Vinyl Chloride Resin Test Method (JISK 6721), insert a predetermined amount of sample into a damper. Put the sample into the funnel, immediately pull out the damper, and let the sample fall naturally continuously into a receiver with an internal volume of 100 ml. After the sample raised from the receiver is scraped off with a glass rod, the weight of the receiver containing the sample is measured to calculate the density. The “angle of repose” indicates the value obtained by the injection method. That is, a predetermined amount of the sample is dropped on a measuring table by vibration using an electromagnetic vibration type repose angle measuring device (manufactured by Tsutsui Rikakiki Co., Ltd.), and the process is continued until the sample starts to spill from around the table. A slanted deposit is formed, and the inclination angle is read with a protractor. BRIEF DESCRIPTION OF THE FIGURES

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

FIG. 2 is a view showing a drug dissolution 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 the sustained release tablet of the present invention.

FIG. 5 is a diagram 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 difendipine in the sustained-release tablet of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

The hydrophilic matrix base used in the additive composition was selected from hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, and a mixture of two or more thereof. And those containing seeds.

In the case of HPMC, there is HPPMC228 of the Japanese Pharmacopoeia (13th revision). For example, there is a product marketed by Shin-Etsu Chemical Co., Ltd. under the trade name of METROLOS. . Among them, 90 SH—4000, 90 SH—150 000, 90 SH—300 000 are high-viscosity types in which the viscosity of a 2% aqueous solution at 20 ° C. is 4,000 cP or more. , Such as 90 SH-10000, which are particularly poor in the mixing property with the drug and the fluidity at the time of tableting can be used. Similarly, HPC has a viscosity of more than 1,000 cP (HPC-H, manufactured by Nippon Soda Co., Ltd.), and methylcellulose has a viscosity of more than 1,500 cP. Things (SM-1 500, SM-400, SM-800, Shin-Etsu Chemical Co., Ltd.).

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. No.

The method for producing an additive composition for tablets of the present invention improves the disadvantageous physical properties of the hydrophilic matrix base in terms of tableting, and basically comprises a hydrophilic matrix base, or It is characterized by adding a solvent or a binder to a mixture of a hydrophilic matrix base and an inert pharmaceutical filler, kneading the mixture, and granulating the mixture. As a solvent to be added at the time of granulation, an organic solvent containing water at a ratio below which the hydrophilic matrix base starts dissolving is suitable. For example, 90 PM of HPMC2208 is dissolved when the water ratio exceeds 30%. When a water-containing organic solvent of 35% or more is used, HPMC immediately gels and becomes highly viscous, making it difficult to spread the liquid throughout the powder layer. And only a non-uniform powder consisting of untreated powder can be obtained.

The ratio at which the hydrophilic matrix base starts dissolving means the following. That is, a hydrophilic matrix base is previously added to an organic solvent in a sufficiently small amount of about 0.1%, and the mixture is stirred and dispersed. Add a certain amount of water to this and continue dispersing. When the dispersion is stopped and 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 uniform 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 mixed with a hydrous organic solvent. In addition, it is desirable to use a stirring granulation method in which high-speed stirring is performed, or a crushing granulation method in which the mixture is kneaded in a kneader, sized with a pulverizer (pulverizer), and then dried in a fluidized bed. When the fluidized bed granulation method is used, only a part of the particle surface in the powder bed is bonded. Since the mixture does not adhere, tertiary particles are formed without consolidation, and only bulky granules can be obtained. When the composite fluidized bed granulation method is used, it is easy to spread the solvent all over the powder bed, so that the particles can be somewhat compacted. However, since many of the above hydrophilic matrix bases are fibrous particles, it is necessary to consolidate the particles by entanglement of the particles, and the granulated material which imparts the desired fluidity and apparent density is obtained. In order to obtain a powder, a stirring granulation method is preferable, and a crushing granulation method is most preferable.

In addition, when an inert pharmaceutical filler rich in water absorption and plastic deformation (plasticity) such as crystalline cellulose or powdered cellulose (hereinafter, referred to as cellulose) is used, exceptionally, it can be produced only with water. A method in which cellulose is charged into a centrifugal tumbling granulator, water is sprayed while rotating a rotating disk to infiltrate the cellulose, and then a hydrophilic matrix base is sprayed, and further water is sprayed to perform granulation. It is. In this method, despite the granulation of water alone, the hydrophilic matrix base does not gel or agglomerate because the water absorption of the cellulose is assisted, and the growth of the composite particles proceeds uniformly. If you want to obtain more compact granules, add water to cellulose using a kneader and knead, then scatter the hydrophilic matrix base gradually and continue kneading until 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 in accordance with the dose of the active ingredient from the sustained-release tablet produced using the additive composition. For a drug such as chlorpheniramine maleate or difendipine, which is administered in a single dose of several mg, it is possible to use a hydrophilic matrix base content of 50% by weight or more. Although it does not matter, for a substance that requires several hundred mg per dose, such as acetaminophendetophylline, the content of the hydrophilic matrix base should be 8 to avoid an increase in tablet weight and tablet diameter. It is preferable to use 0% by weight or more of the composition.

Regarding the particle size of the additive composition, it is usually a material capable of passing through a No. 18 sieve, preferably a material capable of passing through a No. 30 sieve, and most preferably a material capable of passing through a No. 42 sieve. When particles remaining on the sieve of No. 18 are used, the distribution in the tablets is not so tight even if they are compressed, due to the small surface area of the particles. Is difficult. For this reason, water is infiltrated in a state where a continuous gel layer is hardly formed, and the tablet may be disintegrated at an early stage of dissolution, which is not preferable. The particle size referred to here is the value obtained by using the standard screen sieve specified in Japanese Industrial Standards / Test Sieve (JISZ8801) and by the general rules for sieving test method (JISZ8815). Point to.

The additive composition obtained by this method may be mixed with the power of directly adding and mixing the active ingredient or the fine granules obtained by adding other additives to the active ingredient and mixing. After adding a lubricant and the like, tablets can be made into sustained-release tablets by a tableting machine according to a conventional method.

The additive composition has excellent mixability with the main drug and other excipients, and when mixed by a V-type mixer, there is little variation in which the drug content becomes constant immediately after mixing.

Also, since the angle of repose is less than 40 °, the fluidity is excellent and the tablet has a very small coefficient of weight variation. Therefore, it is possible to accurately control the content of the hydrophilic matrix base and the active drug in the tablet, and to easily adjust and set the dissolution rate of the active ingredient. Further, the loose apparent density is, for example, 0.35 g / m 1 or more for a composition comprising 100% by weight of a hydrophilic matrix base such as HPMC (90SH-400). Since the composition comprising 50% by weight of the hydrophilic matrix base and 50% by weight of the inert pharmaceutical filler is 0.45 gZm 1 or more, the tablet composition is filled into a tableting machine to a desired tablet weight. be able to.

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 matrix base, the solubility of the medicinal component in water and digestive juices, and the desired sustained release performance. It is 5 to 90% by weight, preferably 20 to 60% by weight. If the content is less than 5% by weight, it may not be possible to obtain a sufficient sustained-release performance, which is not preferable.

The additive composition of the present invention has an increased 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 hydrophilic matrix base particles swollen during the drying step, and the crystal structure is increased. This is because the swelling property becomes larger during rehydration. result As a result, adhesion to the inner wall of the digestive tract is increased, and the residence time in the digestive tract can be prolonged. In addition, by imparting swelling properties, the collapse of the gel layer, which is a concern when using a high-viscosity type hydrophilic matrix base, is extremely delayed, and the remaining amount of the medicinal component is reduced. Occasionally, the dissolution rate is not reduced.

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

H PMC (Metrose, 90 SH—400 000, manufactured by Shin-Etsu Chemical Co., Ltd.) 500 g and lactose (DMV, Pharmatose, 350 ML actose) 500 g, 8 liter capacity (Available from Fukae Kogyo Co., Ltd.), and 1.0 kg of a mixed solution of water / ethanol = 25/75 was added and kneaded for 15 minutes. The kneaded material is sized with a crusher equipped with a 3 mm diameter screen (Dalton Co., Ltd., Power Mill P-3 type), and then a fluidized bed granulator (Freund Sangyo Co., Ltd., FLO-5 type) ) And the dried granules were sieved and sized using a No. 30 sieve. This operation was repeated three times to obtain 2.2 kg of fine granules. Table 1 shows the angle of repose and the apparent density of looseness.

Comparative Example 1

100 g of HPMC (90 SH-40000) and 100 g of lactose were charged into a fluid bed granulator (Freund Sangyo Co., Ltd., FL-MINI type), and water / ethanol =

A 200 g mixture of 25/75 was sprayed at a rate of 30 mLZ (spray pressure: 0.1 MPa, intake temperature: 70-75 ° C, exhaust temperature: 30-35) ° C). After drying,

The resulting mixture was sieved and sized using a No. 30 sieve to obtain 178 g of fine granules. The angle of repose and apparent density of looseness are as shown in Table 1.

Comparative Example 2

250 g of H PMC (90S H-4000) and 250 g of lactose were charged into a combined fluidized bed granulator (SFC-MINI type, manufactured by Freund Corporation), and water / ethanol = 25 Z 500 g of the mixture of 75 was sprayed at a rate of 80 ml / min (spray pressure: 0.2 MPa, mouth rotation speed: 300 rpm, agitator rotation speed: 500 rpm, air supply) Temperature: 70-75 ° C, exhaust temperature: 30-35 ° C). After drying, The mixture was sieved with a No. 30 sieve to obtain 339 g of fine granules. Table 1 shows the angle of repose and apparent density of looseness.

:table 1

Example 2

Charge 800 g of H PMC (90 S H-400 0) and 200 g of lactose into a stirrer, add 1.2 kg of a 20/80 mixed solution of water / ethanol, and knead for 15 minutes did. Thereafter, sizing, drying and sieving were carried out under the same operating conditions as in Example 1 to obtain 752 g of fine granules. Table 2 shows the angle of repose and loose apparent density.

Comparative Example 3

96 g of HPMC (90 SH-400 0) and 24 g of lactose were charged into a fluid bed granulator (Fuchiint Sangyo Co., Ltd., FL_MINI type), water / ethanol = 20/80 Of the mixture was sprayed at a rate of 20 m / min (spray pressure: 0.1 MPa, intake temperature: 70-75 ° C, exhaust 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 apparent density of looseness.

Comparative Example 4

240 g of H PMC (90S H-4000) and 60 g of lactose were charged into a complex fluidized bed granulator (SFC-MINI type, manufactured by Freund Corporation), and water / ethanol = 20/80 37.5 g of the mixture was sprayed at a rate of 54 ml / min. One pressure: 0.2 MPa, rotor one revolution: 300 rpm, agitator revolution: 500 rpm, supply temperature: 70-75 t :, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved and sized using a No. 30 sieve to obtain 173 g of fine granules. The angle of repose and apparent density of looseness are as shown in Table 2.

[Table 2]

Example 3

1.0 kg of HPMC (90 SH-40000) 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 carried out 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 density of looseness.

Comparative Example 5

120 g of H PMC (90SH-40000) is charged into a fluidized bed granulator (FL-MINI type, manufactured by Freund Industry Co., Ltd.), and a mixed liquid of water / ethanol = 2080 150 g was sprayed at a rate of 20 m1 / min (spray pressure: 0.1 MPa, intake temperature: 70-75 ° C, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved and sized with a No. 30 sieve to obtain 8 lg of fine granules. Table 3 shows the angle of repose and loose apparent density.

Comparative Example 6

300 g of HPMC (90 SH-4000) was charged into a combined fluidized bed granulator (SFC-MINI type, manufactured by Freund Sangyo Co., Ltd.), and water / ethanol = 20 / 37.5 g of the mixed solution of 80 was sprayed at a rate of 54 ml (spray pressure: 0.2 MPa, rotation per mouth: 300 rpm, rotation per agitator: 500 rpm, (Supply temperature: 70-75 ° C, exhaust temperature: 30-35 ° C). After drying, the mixture was sieved and sized with a sieve No. 30 to obtain 153 g of granules. Table 3 shows the angle of repose and loose apparent density.

Comparative Example 7

The angle of repose and the apparent apparent density of untreated HPMC (90SH-40000) were measured. Table 3 shows the results.

[Table 3]

Various granulation methods were used to manufacture additive compositions with varying PMC content ratios.As shown in Tables 1-3, after kneading with a kneader, sizing with a crusher. The crushing-granulation method performed was most suitable for obtaining a product with a large loose apparent density, a small angle of repose and good fluidity.

Example 4

To 800 g of the additive composition (HPMCZ lactose (50Z50)) obtained in Example 1, lactose for direct hitting (Fruit Sangyo Co., Ltd., Dilact Touzou S) (155 g) and chlorpheniramine maleate 40 g (Fukuju Pharmaceutical Co., Ltd.) was added, and the mixture was charged into a V-type mixer (V-10 type, manufactured by Tokuju Kousaku Co., Ltd.). During mixing, resampling is performed at three points in the mixer over time, and the amount of chlorpheniramine maleate is determined using a spectrophotometer (U best — 35, manufactured by JASCO Corporation). To evaluated. The results are shown in Figure 1. Immediately after mixing, the content of the drug is constant and the blackness is small, indicating that the additive composition of the present invention is excellent in mixing properties.

Comparative Example 8

V-type mixture of unprocessed HPMC (90SH-4000) 400 g and lactose for direct hitting (Freund Sangyo Co., Ltd., Dila Touzo S) 5.55 g and chlorpheniramine maleate 40 g The mixture was charged in the same machine and the mixing properties were examined in the same manner as in Example 4. The results are shown in Figure 1. Even after 20 minutes of mixing, the drug content was not constant, and the dispersion was large.

Example 5

To the mixture prepared in Example 4 was added 0.5% of magnesium stearate, and tableting was performed using a tablet-to-tablet machine (HT_30 type, manufactured by Hata Ironworks Co., Ltd.). The tablet weight of the obtained tablet was 20 O mg, the coefficient of weight variation was as small as 1.6%, and the tablet hardness was as high as 9.7 kcm 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

Using a single-shot tableting machine (Fuji Pharmaceutical Co., Ltd., FY-MCU-T type), chlorpheniramine maleate (6 mg) and the additive composition prepared in Example 1 H PMCZ lactose (50/50) ) 500 tablets of 8 mm diameter containing 35% HPMCC were prepared by adding lactose for direct compression and magnesium stearate to a tablet weight of 200 mg, containing 14 Omg. 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 Pharmacopoeia dissolution test method 2 (paddle method), use 90 Om1 of purified water as the test solution, add the required amount of tablets at a liquid temperature of 37 ° C and a paddle rotation speed of 100 rpm. went. The result is shown in figure 2.

Example 7

Using a single-shot tableting machine, containing 6 mg of chlorpheniramine maleate and 160 mg of the additive composition HPMC / lactose (50-50) prepared in Example 1, for direct compression Lactose and magnesium stearate were added to make the tablet weight 200 mg, and 500 tablets of 8 mm in diameter containing 40% of HPMC were produced. The drug elution pattern from the obtained tablets was examined under the same conditions as in Example 6. The result is shown in figure 2.

Example 8

Using a single-shot tableting machine, containing chlorpheniramine maleate 6 mg and the additive composition H PMCZ lactose (550 0) 18 O mg prepared in Example 1, lactose for direct compression and stearic acid Magnesium was added to make the tablet weight 200 mg, and 500 tablets of 8 mm in diameter containing 45% of HPMC were produced. The drug elution pattern from the obtained tablets was examined under the same conditions as in Example 6. The result is shown in figure 2.

As shown in FIG. 2, 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 a medicinal component.

Example 9

Using the tablet obtained in Example 7, the effect of the test solution on the dissolution pattern was examined. Three types of test solutions were used: purified water, the first solution (artificial gastric juice, pH 1.2), and the second solution (artificial intestinal fluid, pH 6.8). The results are shown in Figure 3. As shown in FIG. 3, the sustained-release tablet using the product of the present invention can elute a pharmaceutically active ingredient without being affected by liquidity.

Example 10

Using a single-shot tableting machine, containing acetaminophen fine granules (acetominofenno lactose = 70/30) (143 mg) and the single granulated HPMC prepared in Example 3 (100 mg), direct compression Lactose for use and magnesium stearate were added to make the tablet weight 250 mg, and 500 tablets of 9 mm diameter containing 40% of HPMC were produced. Acetaminophen fine granules were separately granulated by stirring with a high speed mixer (Fukae Kogyo Co., Ltd., FMD-25J type) and sieved and sized using a No. 30 sieve. . The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester. According to the Japanese Dissolution Test Method 2 (paddle method), 90 Om1 of purified water was used as the test solution at a liquid temperature of 37 ° C and a pesticide rotation speed of 100 rpm. Fig. 4 shows the results. Example 1 1

Theophylline fine granules (theophylline / lactose = 70 3 0) HP PMC containing 100 mg of a single granulated product of 144 mg and the HPMC prepared in Example 3, and added lactose for direct injection and magnesium stearate to make the tablet weight 250 mg. Of 950 tablets of 9 mm diameter containing 40% was prepared. Theophylline fine granules were separately stirred and granulated 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. According to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), 900 ml of purified water was used as the test solution, and the test was performed at a liquid temperature of 37 and a rotational speed of 100 rpm. Figure 5 shows the results.

Example 1 2

Using a single-shot tableting machine, difedipin fine granules (difedipinnocarboxymethylethylcellulose (manufactured by Freund Corporation) / lactose = 10/20/70) 100 mg and Example 2 The excipient composition prepared in (1) containing 87.5 mg of PMC / lactose (80Z20), added lactose for direct injection and magnesium stearate to a tablet weight of 20 Omg, and 35% of HPMC 500 tablets of 8 mm in diameter were produced. The fine particles of nifendipine were separately granulated by a combined fluidized-bed granulator (FFC-MINI type, manufactured by Freund Corporation) and sieved and sieved with a No. 30 sieve. The drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester. In accordance with the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method), use the Japanese Disintegration Test Method Test Solution No. 2 Liquid 900 m1 as the test solution, at a liquid temperature of 37 ° C and a pedal rotation speed of 100 rpm. The required amount of tablets was charged. Fig. 6 shows the results.

Example 13

Crystalline cellulose (manufactured by Asahi Kasei Kogyo Co., Ltd., Avicel, PH-101) (1,000 g) was charged into a die, 740 g of water was added, and the mixture was kneaded for 15 minutes. The kneaded material was halved, and kneading was continued using a screw feeder while spraying 500 g of HPMC (90SH-40000) at a rate of 50 gZ. The minute kneading was continued. This kneaded material is sized with a crusher equipped with a 3 mm diameter screen (manufactured by Dalton Co., Ltd., Power Mill Model P-3), and then centrifugally tumbled and granulated by Freund Sangyo Co., Ltd. CF-360), spraying 270 g of water at a speed of 10 m1 while rotating the rotating disk (rotor rotation speed: 200-400, spray air pressure: 0) 1 MPa, spray air volume: 15 liters, slit empty Volume: 150 to 400 liters per Z minute). After drying, the dried granules were sieved using a No. 42 sieve to obtain 778 g of fine granules. The angle of repose of the fine grains was 38 ° and the loose apparent density was 0.38 gZml. Industrial applicability

As described above, according to the present invention, as shown in, for example, FIGS. 4 to 6, even with various drugs having different solubility in water, a sustained-release tablet using the product of the present invention shows that Eluted butter can be easily obtained.

Claims

The scope of the claims

1. Hydrophilic matrix base 50-100% by weight and inert pharmaceutical filler 0-

An additive composition for a sustained-release tablet, comprising fine particles having a loose apparent density of not less than 0.35 g / m1 and an angle of repose of not more than 40 °. .

2. The hydrophilic matrix base according to claim 1, characterized in that the hydrophilic matrix base comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcell mouth-sunatium. An additive composition for sustained release tablets.

3. The inert pharmaceutical filler comprises at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. Item 10. The additive composition for sustained release tablets according to Item 1 or 2.

4. A hydrophilic matrix base comprising 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. 1100% by weight and inert pharmaceutical filler 0 550% by weight, loose apparent density from 0.35 g Zm 1 or more and repose angle from 40 ° or less A method for producing an additive composition for sustained release tablets comprising:

5. To the hydrophilic matrix base or the composition containing the hydrophilic matrix base and the inactive drug filler, add an organic solvent containing water at a ratio at which the hydrophilic matrix base starts dissolving or less. 5. The method for producing an additive composition for sustained-release tablets according to claim 4, wherein the kneaded product is sized by a crusher.

6. To the composition containing the hydrophilic matrix base or the hydrophilic matrix base and the inactive drug filler, an organic solvent containing water at a ratio at which the hydrophilic matrix base starts dissolving is added. The method for producing an additive composition for sustained-release tablets according to claim 10, wherein the granulation is performed by stirring.

7. The composition containing the hydrophilic matrix base or the hydrophilic matrix base and the inactive pharmaceutical filler is wet-formed 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. 5. The method according to claim 4, wherein the particles are granulated. A method for producing an additive composition for sustained release tablets.

8. The method of claim 4, wherein the hydrophilic matrix base is sprayed on an inert pharmaceutical filler consisting of a crystal cell mouth or powdered cellulose infiltrated by adding water to perform wet granulation. 5. The method for producing the additive composition for sustained release tablets according to the above.

9. The centrifugal tumbling granulation by spraying the hydrophilic matrix base on an inert pharmaceutical filler made of crystalline cellulose or powdered cellulose impregnated with water to add water. A method for producing the additive composition for sustained-release tablets according to the above.

10. The inert pharmaceutical filler contains 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, characterized in that:

11. The hydrophilic matrix base material comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose. 10. The method for producing the additive composition for sustained-release tablets according to any one of items 10 to 10.

12. Hydrophilic matrix base 50 to 100% by weight and inert pharmaceutical filler 0 to 50% by weight, loose apparent density of 0.35 g Zm 1 or more and angle of repose A sustained-release tablet comprising: an additive composition for sustained-release tablets comprising fine particles having a particle size of not more than 40 ° and a main ingredient.

13. The sustained release tablet additive composition comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium. The sustained-release tablet according to claim 12, characterized in that the tablet is contained as an agent.

14. The additive composition for sustained release tablets is at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol. 14. The sustained-release tablet according to claim 12 or claim 13, wherein the sustained-release tablet comprises:

15. The sustained release tablet additive composition is prepared by wet-forming a composition containing a hydrophilic matrix base or 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, characterized in that it is manufactured by granulating.

16. The additive composition for sustained-release tablets contains the hydrophilic matrix base, or a mixture of the hydrophilic matrix base and the inert drug filler, and the hydrophilic matrix base. 12. The method according to claim 12, wherein the kneaded product is produced by adding and kneading an organic solvent containing water at a ratio not more than a ratio at which dissolution is started, and sizing the kneaded product with a crusher. -The sustained-release tablet according to any one of Items 1 to 15.

17. The sustained release tablet additive composition is added to the hydrophilic matrix base, or a mixture of the hydrophilic matrix base and the inert drug filler, to the hydrophilic matrix base. Wherein the mixture is produced by adding an organic solvent containing water at a ratio of not more than a rate at which dissolution starts and performing stirring granulation, wherein: 3. The sustained-release tablet according to 1.).

18. The additive composition for sustained-release tablets contains the hydrophilic matrix base, or a mixture of the hydrophilic matrix base and the inert drug filler, with the hydrophilic matrix base. The sustained-release according to any one of claims 12 to 15, characterized by being produced by wet granulation with hot water or a water-containing organic solvent having a dissolution temperature or higher. Tablets.

19. The additive composition for sustained-release tablets is prepared by spraying the hydrophilic matrix base onto an inert pharmaceutical filler composed of crystalline cellulose or powdered cellulose impregnated with water and wet-molding. The sustained-release tablet according to any one of claims 12 to 15, characterized in that the sustained-release tablet is manufactured by granulating.

20. The above-mentioned additive composition for sustained-release tablets is produced by a method of spraying a hydrophilic matrix base onto crystalline cellulose or powdered cellulose infiltrated with water and centrifugally tumbling and granulating. The sustained-release tablet according to any one of claims 12 to 15, characterized in that it is a tablet.

21. Consisting of 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 / m1 or more and a repose angle of The main drug is added as is to an additive composition for sustained release tablets consisting of fine granules of 40 ° or less. Or a tablet obtained by adding granules obtained by adding another additive to the main drug and compressing the granules.

22. The additive composition for sustained-release tablets comprises at least one hydrophilic compound selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium in the composition. The method for producing a sustained-release tablet according to claim 21, characterized in that the tablet comprises a hydrophilic matrix base.

23. The additive composition for sustained release tablets was 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 at least one 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, wherein

25. In the additive composition for sustained release tablets, the hydrophilic matrix base starts dissolving in 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 not more than the desired ratio is added and kneaded, and the kneaded product is produced by sizing with a crusher, wherein The method for producing a sustained release tablet according to any one of the above.

26. In the additive composition for sustained release tablets, the hydrophilic matrix base starts dissolving in the hydrophilic matrix base or a mixture of the hydrophilic matrix base and the inert pharmaceutical filler. 25.The method according to claim 21, wherein the mixture is produced by adding an organic solvent containing water at a ratio of not more than a predetermined amount and performing stirring granulation. Method for producing release tablets.

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. 25.The method according to claim 21, wherein the product is produced by wet granulation with the above-mentioned hot water or a water-containing organic solvent. The method for producing the sustained-release tablet according to any one of claims 1 to 10.

28. The additive composition for sustained-release disintegrant is obtained by spraying the hydrophilic matrix base on an inert pharmaceutical filler composed of crystalline cellulose or powdered cellulose soaked with water. The method for producing a sustained-release tablet according to any one of claims 21 to 24, characterized in that the tablet is produced by wet granulation.

29. 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 soaked with water and centrifuging. The method for producing a sustained-release tablet according to any one of claims 21 to 24, characterized by being produced by tumbling granulation.

30. The additive composition for sustained-release tablets is selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol as the inert pharmaceutical filler. The sustained release according to any one of claims 24 to 28, characterized in that the sustained release is manufactured using at least one inert pharmaceutical filler. For the production of dispersible tablets.

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