WO1999058114A1 - Comprimes a liberation prolongee, compositions d'addition et procede de production desdites compositions - Google Patents

Comprimes a liberation prolongee, compositions d'addition et procede de production desdites compositions Download PDF

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Publication number
WO1999058114A1
WO1999058114A1 PCT/JP1999/002408 JP9902408W WO9958114A1 WO 1999058114 A1 WO1999058114 A1 WO 1999058114A1 JP 9902408 W JP9902408 W JP 9902408W WO 9958114 A1 WO9958114 A1 WO 9958114A1
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Prior art keywords
sustained
hydrophilic matrix
matrix base
additive composition
release
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PCT/JP1999/002408
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English (en)
Japanese (ja)
Inventor
Fujio Sekigawa
Takeshi Homma
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Freund Industrial Co., Ltd.
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Application filed by Freund Industrial Co., Ltd. filed Critical Freund Industrial Co., Ltd.
Publication of WO1999058114A1 publication Critical patent/WO1999058114A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • 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.
  • 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.
  • 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.
  • sustained-release tablets using a hydrophilic matrix base produced by the direct powder compression method.
  • 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.
  • HPMC hydroxypropylmethylcellulose
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sustained release tablets using a hydrophilic matrix base produced by the wet granulation compression method are known as examples of sustained release tablets using a hydrophilic matrix base produced by the wet granulation compression method.
  • 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.
  • a partial wet granulation method 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.
  • additive compositions which are excellent in fluidity and can be directly hit by using a wet granule compression method.
  • 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.
  • 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.
  • 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.
  • 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.
  • HPMC hydrophilic matrix bases
  • the physical properties of the high viscosity type high molecular weight
  • the hydrophilic matrix base 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • An additive composition for a sustained release tablet comprising fine particles having a temperature of 0 ° or less.
  • 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 inert pharmaceutical filler contains at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol.
  • lactose sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol.
  • 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.
  • 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.
  • the sustained release tablet according to the above (4) characterized in that: A method for producing an additive composition for an agent.
  • the inert pharmaceutical filler contains at least one selected from lactose, sucrose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdered cellulose, mannitol, xylitol and sorbitol.
  • the hydrophilic matrix base comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium,
  • a sustained release tablet comprising an additive composition for sustained release tablet comprising the following fine granules and a main drug component.
  • the additive composition for sustained-release tablets comprises at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the additive composition for sustained-release tablets comprises, in the composition, at least one hydrophilic selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium.
  • 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 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 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.
  • 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.
  • 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.
  • 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 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 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.
  • the additive composition for sustained release tablets comprises at least one selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose and carboxymethylcellulose sodium as the hydrophilic matrix base.
  • loose apparent density here refers to the value obtained by the following measurement method.
  • a Kaza specific gravity measuring instrument manufactured by Kuramochi Kagaku Kikai Seisakusho Co., Ltd.
  • JISK 6721 Japanese Industrial Standards and Vinyl Chloride Resin Test Method
  • 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.
  • 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.
  • HPMC there is HPPMC228 of the Japanese Pharmacopoeia (13th revision).
  • HPPMC228 of the Japanese Pharmacopoeia (13th revision).
  • METROLOS a product marketed by Shin-Etsu Chemical Co., Ltd. under the trade name of METROLOS.
  • 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.
  • 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.
  • 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.
  • 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.
  • 90 PM of HPMC2208 is dissolved when the water ratio exceeds 30%.
  • 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.
  • 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.
  • pulverizer pulverizer
  • the composite fluidized bed granulation method 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.
  • cellulose crystalline cellulose or powdered cellulose
  • inert pharmaceutical filler rich in water absorption and plastic deformation plasticity
  • plasticity such as crystalline cellulose or powdered cellulose
  • cellulose crystalline cellulose or powdered cellulose
  • 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.
  • 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.
  • a drug such as chlorpheniramine maleate or difendipine, which is administered in a single dose of several mg
  • a hydrophilic matrix base content 50% by weight or more.
  • 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.
  • the particle size of the additive composition 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.
  • a material capable of passing through a No. 18 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.
  • 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.
  • 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.
  • 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.
  • H PMC Metal, 90 SH—400 000, manufactured by Shin-Etsu Chemical Co., Ltd.
  • DMV Pharmatose, 350 ML actose
  • 500 g, 8 liter capacity Available from Fukae Kogyo Co., Ltd.
  • 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.
  • 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.
  • Example 4 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.
  • HT_30 type manufactured by Hata Ironworks Co., Ltd.
  • Example 2 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 2 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.
  • the elution of the drug was delayed by increasing the amount of the additive composition.
  • the product of the present invention it is easy to accurately control the dissolution rate of a medicinal component.
  • Example 7 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.
  • 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.
  • FFC-MINI type combined fluidized-bed granulator
  • the drug dissolution pattern from the obtained tablets was examined using an automatic dissolution tester.
  • 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.
  • 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.
  • HPMC 90SH-40000
  • 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
  • a sustained-release tablet using the product of the present invention shows that Eluted butter can be easily obtained.

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Abstract

L'invention concerne des compositions d'addition qui permettent de produire des comprimés à libération prolongée présentant une bonne fluidité au stade de la mise en comprimés et un contrôle précis de la vitesse d'élution des ingrédients du médicament. Ces compositions se caractérisent par des granules fines qui contiennent 50 à 100 % en poids d'une base de matrice hydrophile et 0 à 50 % en poids d'une charge pharmaceutique inerte, et présentent une densité apparente lâche d'au moins 0,35 g/ml et un angle de repos d'au plus 40°. L'invention concerne en outre des comprimés à libération prolongée contenant lesdites compositions et lesdits principaux agents.
PCT/JP1999/002408 1998-05-11 1999-05-10 Comprimes a liberation prolongee, compositions d'addition et procede de production desdites compositions WO1999058114A1 (fr)

Applications Claiming Priority (4)

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JP10/142074 1998-05-11
JP14207498 1998-05-11
JP11101515A JP2000034224A (ja) 1998-05-11 1999-04-08 徐放性錠剤、その添加剤組成物及びそれらの製造方法
JP11/101515 1999-04-08

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BR112012028788A2 (pt) 2010-05-10 2016-07-19 Euro Celtique Sa fabricação de grânulos sem ativos
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CA2909370A1 (fr) 2013-04-16 2014-10-23 Murray And Poole Enterprises Limited Formulations de colchicine a liberation prolongee et procedes d'utilisation de ces dernieres

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WO2004024184A1 (fr) * 2002-09-11 2004-03-25 Takeda Pharmaceutical Company Limited Preparation a liberation prolongee
WO2004080439A1 (fr) * 2003-03-12 2004-09-23 Takeda Pharmaceutical Company Limited Composition de medicament comportant un principe actif adhere en concentration elevee a un noyau spherique
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