JP5576907B2 - Sustained release tablets - Google Patents

Description

  The present invention relates to a tablet excellent in hardness and sustained release properties. Specifically, the present invention relates to a sustained-release tablet having excellent hardness, containing a medicinal component and containing sustained-release particles, an antistatic agent and an excipient.

  Since sustained-release preparations continuously release medicinal ingredients, when sustained-release preparations are administered orally, stable treatment should be performed without causing rapid fluctuations in the concentration of medicinal ingredients in the blood. In addition, demand is increasing in recent years because the burden on patients can be reduced by reducing the number of administrations.

  Conventionally, as a sustained-release preparation, a preparation in which the release of an active agent is controlled by a multilayer structure in which a layer such as a delay jacket, a semipermeable membrane and an enteric skin is provided around a solid containing the active agent is known. (See Patent Document 1).

  In addition, a tablet is known in which coated granules in which a medicinal component is coated with a component that imparts sustained release properties, together with physiologically inert excipients and the like (see, for example, Patent Document 2). Such tablets are excellent in the stability of the release of medicinal ingredients and are expected to be used further.

  However, when the coated granules and excipients are molded together, the strength tends to be low, so a tablet having sufficient strength that does not break during manufacturing, packaging, transportation, storage, etc. In order to manufacture, it is necessary to disperse the coated granules in an excessive amount of excipients and to mold them, and there is a problem that enlargement of the tablets cannot be avoided. In addition, when the conventional tablet is simply downsized without changing the composition, the hardness of the tablet decreases, and when a large amount of binder is added to the excipient to improve the hardness of the tablet, There has been a problem that the sustained release of the medicinal component is greatly reduced. Furthermore, when the pressure in compression molding is increased to improve the hardness of the tablet, the coated granules and excipients are bound excessively, resulting in decreased sustained release, or the coated granule particles are broken and released. There was a problem that the characteristics changed.

  On the other hand, in Patent Document 3, a coated granule in which an elementary granule containing a physiologically active substance is coated in multiple layers with a coating agent containing a hydrophobic substance and an excipient having a disintegrating property such as corn starch are both compression-molded. Small tablets have been proposed. The coated granule in this tablet hardly releases the physiologically active substance by itself, and elutes the physiologically active substance from a broken portion such as a crack formed in the coating of the coated granule when compression-molded with a disintegrating excipient. However, this tablet has a problem that it is difficult to control the elution degree of the physiologically active substance.

Therefore, there is a strong demand for tablets containing coated particles having sustained release properties, which have excellent moldability, sufficient strength, excellent sustained release properties, and miniaturized tablets. It was.
As a result of diligent research in view of such circumstances, the present inventor found that a tablet comprising sustained-release coated particles and an antistatic agent such as an excipient and silicon dioxide has a low compression molding pressure. Was found to have high hardness and excellent sustained release properties, and the present invention was completed.

  Patent Document 4 discloses a tablet containing a bioactive substance, baracyclobeer, a filler, a binder, a lubricant, and colloidal silicon dioxide. Although tablets containing an agent and silicon dioxide have been proposed and described as having high hardness, the granules are generally formed in the tablet manufacturing process and do not have sustained release properties. Does not have sustained release.

JP-A-7-2648 Japanese Patent Laid-Open No. 11-171775 JP 2002-179571 A Japanese National Patent Publication No. 10-512564

  The present invention is a tablet obtained by compression molding particles having a sustained release of medicinal ingredients, an antistatic agent and an excipient, and has excellent sustained release and sufficient hardness, and is downsized. Even in such a case, an object is to provide a sustained-release tablet having sufficient strength that does not break during production, packaging, transportation, storage and the like.

The sustained-release tablet of the present invention contains a sustained-release particle comprising a core material containing a medicinal ingredient and a coating layer for controlling the release of the medicinal ingredient from the core material, an antistatic agent, and an excipient. Features.
In the sustained-release tablet of the present invention, the sustained-release particles are preferably 50% by mass or more of the tablet mass. Further, the coating layer of the sustained release particles is preferably a cellulosic polymer, and the coating layer is preferably in the range of 0.1 to 5% by mass of the mass of the sustained release particles.

The sustained-release tablet of the present invention preferably contains an antistatic agent in an amount of 0.5% by mass or less of the tablet mass, more preferably in the range of 0.005 to 0.2% by mass of the tablet mass. preferable.
In the present invention, the antistatic agent is at least one selected from the group consisting of silicon dioxide (including hydrous silicon dioxide), anhydrous silicon, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate, and a surfactant. Preferably there is.

  In addition, the tablet of the present invention may contain various excipients commonly used in preparations, such as binders, disintegrants, lubricants, emulsifiers, stabilizers, surfactants and the like. Furthermore, the sustained-release tablet of the present invention may be provided with a coating commonly used in tablets as necessary.

The sustained-release tablet of the present invention preferably has a tablet strength of 6 Kp or more, although it varies depending on its shape and size.
Furthermore, the present invention comprises mixing and compression-molding a core material containing a medicinal component and a sustained-release particle comprising a coating layer for controlling the release of the medicinal component from the core material, an antistatic agent and an excipient. The present invention relates to a method for producing a sustained-release tablet.

  ADVANTAGE OF THE INVENTION According to this invention, the sustained release tablet which contains many sustained release particle | grains containing a medicinal component, and has the outstanding sustained release property and sufficient hardness is provided. Further, according to the present invention, it is possible to provide a sustained-release tablet having sufficient strength that does not break during manufacture, packaging, transportation, storage, etc. even when it is downsized. Provided is a small sustained-release tablet that is excellent in releasability and easy for patients to take orally.

FIG. 1 is a graph showing the tablet hardness of Examples 4 to 6 and Comparative Example 2. Figure 2 is a graph showing the dissolution characteristics of Comparative Example 3 and Example 7.

Hereinafter, the present invention will be specifically described.
The sustained release tablet of the present invention is compression-molded together with sustained release particles comprising a core material containing a medicinal ingredient and a coating layer for controlling the release of the medicinal ingredient from the core material, an antistatic agent, and an excipient. Do it.

Sustained-release particles The sustained-release particles according to the present invention have a core material containing a medicinal component and a coating layer that covers the core material and controls the release of the medicinal component from the core material.

  The core material of sustained release particles according to the present invention contains at least one medicinal component. The kind of the medicinal component contained in the core material is not particularly limited, and any known physiologically active substance suitable for oral administration can be used, and these can be used in combination as desired. .

  Examples of such medicinal ingredients include chemotherapeutic agents, calcium antagonists, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents, autonomic nerve agents, psychiatric nerve agents, local anesthetics, muscle relaxation Agents, digestive tract drugs, antihistamines, addiction treatments, hypnotic sedatives, antiepileptics, antipyretics, analgesics, anti-inflammatory agents, cardiotonic agents, antiarrhythmic agents, diuretics, vasodilators, antilipidemic agents, nourishing tonics Alter, anticoagulant, liver drug, hypoglycemic agent, antihypertensive agent, anticolitis agent, antiasthma agent, antianginal agent, antiemetic, glucocorticoid, ulcerative colitis or Crohn's disease Drugs, antifungal agents, arteriole sclerosis treatment agents, enzyme inhibitors, gout treatment agents, antiparkinson agents, migraine treatment agents, proteins, peptides and the like.

  These medicinal ingredients include, for example, perapamil hydrochloride, nicardipine, nitrendipine, nimodipine, theophylline, trimethyol, IGF-I, PTH (1-34) and analogs thereof, TGFα, TGFβ1, TGFβ2, TGFβ3, IFNα, Hybrid IFNα, IFNγ, N-hydroxy-N ((6-phenoxy-2H-1-benzopyran-3-yl) methyl) -urea, 4- [5- [4- (aminoiminomethyl) phenoxy] pentoxy] -3 -Methoxy-N, N-bis (1-methylethyl) -benzamide- (2) -2-butenedioate, N- [2-[[2-[[4- (4-fluorophenyl) phenyl] methyl] 1,2,3,4-tetrahydro-1-oxo-6-isoquinolinyl] oxy] ethyl] -N-hydroxy Urea, 1- (1-benzo [b] thie-2-ylethyl) -1-hydroxyurea, 5- [2- (2-carboxyethyl) -3- {6-p-methoxyphenyl} -5E-hexenyl] Oxyphenoxy] valeric acid, hirudin, heparin, calcitonin, 5-aminosalicylic acid, beclomethasone dipropionate, betamethasone-17-valerate, prednisolone, metasulfobenzoate, thixcortol pivalate, budesonide, Fluticasone, metoprolol fumarate, metoprolol tartrate, tetrahydroaminoacridine (THA), galanthamine, ursodiol ), Clomipramine hydrochloride, terbutaline sulfate, aminoglutethimide, defloxamine mesylate, estradiol, isoniazid, methyltestosterone, metyrosine, sophanpine, beclomethasone dipropionate, betamethasone, cortisone acetate, fludrozone acetate Cortisone, hydrocortisone, triamcinolone acetate, parameterzonezone acetate, dexamethasone, triamcinolone, methylprednisolone, amcinonide, prednisolone valerate, diflucortron valerate, dexamethasone valerate, betamethasone valerate, diflorazone acetate, dexamethasone acetate, hydroprednisone acetate acetate , Difluprednate, betamethazol dipropionate , Triamcinolone acetonide, halcinonide, flumethasone pivalate, budesonide, fluocinide, fluocinolone acetonide, fluorometholone, fludroxycortide, alcromethasone propionate, clobetasol propionate, dexamethasone propionate, hydroprothone dipropionate, clobetasone butyrate propanoate And hydrocortisone butyrate propionate.

  Examples of proteins and peptides include transforming growth factor (TGF), immunoglobulin E (IgE) binding factor, interleukin, interferon (IFN), insulin-like growth factor (IGF), milk growth factor, anticoagulation. Examples include substances and parathyroid hormone (PTH).

  In the present invention, as the medicinal component, for example, theophylline, 5-aminosalicylic acid, beclomethasone dipropionate, betamethasone-17-valerate, prednisolone metasulfobenzoate, thixocortol pivalate, budesonide, fluticasone, and metoprolol are preferable. .

The core material of the sustained-release particles may contain a penetrant that induces penetration into the core material in order to achieve a desired medicinal component release behavior. The penetrant can be appropriately selected depending on the type of medicinal component, and for example, sodium chloride, potassium chloride, magnesium chloride, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium hydrogen phosphate, and hydrogen hydrogen phosphate. Inorganic salts such as potassium;
Salts of organic acids such as sodium alginate, sodium aocorbate, sodium benzoate, sodium citrate, edetate disodium, sodium fumarate, sodium acetate, potassium acetate, and magnesium succinate;
Organic acids such as alginic acid, ascorbic acid, citric acid, edetic acid, malic acid, and sorbic acid;
Sugars such as dextrate, sorbitol, xylitol, malt, arabinose, ribose, xylose, glucose, dextrose, fructose, galactose, mannose, sucrose, maltose, lactose, and raffinose;
Water-soluble amino acids such as glycine, leucine, alanine and methionine;
Other examples include magnesium sulfate, magnesium carbonate, urea, saccharin, sodium saccharin, glycerin, hexylene glycol, polyethylene glycol, propylene glycol; and mixtures thereof.

Moreover, the core material of sustained release particles may contain an excipient, a lubricant, a lubricant, a wetting agent, a binder, an emulsifier, a thickener, a stabilizer, and the like, if desired.
Examples of the excipient include sugars such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate and the like.

  Examples of the lubricant include calcium stearate, glyceryl behenate, hydrogenated vegetable oil, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, and stearic acid subsalt. Is mentioned.

Examples of lubricants include molten or colloidal silicon dioxide, calcium silicate, magnesium silicate, talc and silica hydrogel.
Examples of the wetting agent include benbealkonium chloride, benzethonium chloride, cetylpyridium chloride, docusate sodium, lecithin, nonoxynol 9 or 10, outoxynol 9, poloxamer, polyoxyl 35 Castor oil, polyoxyl 40 hydrogen castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, 40, 60 or 80, sodium lauryl sulfate, sorbitan ester, polyoxyethylene sorbitan fatty acid and Tirokeepol (formaldehyde and oxirane and 4 (1,1,3,3-tetramethylbutyl) Phenol polymer), hydrogenated oil, waxes and the like.

  Examples of the binder include acacia, alginic acid, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmagnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyethylene oxide. , Polyvinyl alcohol, polyvinyl methacrylate, polyacrylate, polyvinyl pyrrolidone, pregelatinized starch, starch, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, macrogol, gum arabic, gelatin, agar, sodium alginate, syrup and Casein etc. That.

  In the preparation of sustained-release particles, the core material is usually granulated by a known method, but it is necessary to prepare by mixing the raw materials constituting the core material, such as when the core material consists only of solid medicinal ingredients. If there is no granulation, granulation is not necessarily performed.

  Granulation of the core material of sustained-release particles is, for example, a composition containing a medicinal component and other raw materials constituting the core material, wet extrusion granulation method, rolling granulation method, fluidized bed granulation method, etc. It can carry out by the method known in the usual formulation method.

In the sustained-release particles of the present invention, the coating layer is a layer that covers the above-described core material, and can control the release of the medicinal component in the core material to give sustained-release properties.
Examples of the coating agent for forming such a coating layer include ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, and the like. Cellulosic polymers of
Methacrylic acid copolymers such as ethyl acrylate / methyl methacrylate copolymer and methacrylic acid copolymer;
Examples thereof include polyethylene, popidone (polyvinylpyrrolidone), and polyvinyl alcohol. The coating layer may contain these coating agents alone, may contain a plurality of combinations, or may be composed of multiple layers.

Of these, the coating layer preferably contains a cellulosic polymer, and particularly preferably contains ethyl cellulose.
The sustained release particles according to the present invention can be prepared by coating the core material described above with a coating agent and forming a coating layer on the core material. In the formation of the coating layer, the coating agent can be used by dissolving or dispersing in a solvent as necessary. Examples of the solvent for dissolving or dispersing the coating agent include water; alcohols such as methanol and ethanol; ketones such as acetone; halogenated hydrocarbons such as chloroform; and mixtures thereof. In addition, the coating layer may contain components other than the above-mentioned coating agents such as organic acids and water repellents if desired, and these components are dissolved or dispersed in a solvent together with the coating agent in forming the coating layer. be able to.

  The coating layer can be formed by a method commonly used in pharmaceutical technology, such as a fluidized bed coating method, a pan coating method, or a rolling fluidized bed coating method. For example, when a coating layer is formed by a fluidized bed coating method, a solution or dispersion containing a coating agent is sprayed on the particulate core material from a spray gun nozzle while the particulate core material is fluidized by air pressure. The coating layer is formed by spraying and drying to obtain sustained-release particles.

Such sustained release particles gradually release medicinal components from the minute gaps of the coating layer.
The mass of the coating layer of the sustained-release particles according to the present invention depends on the desired elution characteristics, medicinal components and the kind of the coating layer, but is 0.1 to 5% by mass of the mass of the sustained-release particles, preferably 0. It is desirable to be 5 to 3% by mass.

Further, the sustained-release particles according to the present invention may be particles having a coating layer on the outer layer of the core material, and the shape and particle diameter thereof are not limited, and any of powder, fine granules, granules, granules, etc. The particle diameter (major axis) of the particles is preferably 0.01 to 5 mm, and preferably about 0.1 to 4 mm.
Such sustained-release particles can be suitably formed into tablets having sustained-release properties by compression molding together with a shaped product to be described later.

Antistatic Agent Usually, an antistatic agent is used to prevent or reduce adhesion or repulsion due to static electricity by preventing or suppressing the charging of the surface of the particles. In the present invention, in addition to this, the hardness of the tablet is improved, and the sustained release property of the ingredient is maintained without affecting the dissolution behavior of the medicinal ingredient.

In the present invention, the antistatic agent varies depending on the material of the sustained-release particle coating layer. For example, silicon dioxide (including hydrous silicon dioxide), silicic anhydride (light silicic anhydride, heavy silicic anhydride) Inorganic antistatic agents such as talc, titanium oxide, aluminum silicate, magnesium aluminate metasilicate, magnesium aluminate hydroxide, ammonium chloride, carbon;
Organic antistatic agents such as stearic acid, magnesium stearate, calcium stearate, polyhydric alcohols;
Cationic surfactants such as alkyltrimethylammonium chloride, distearyldimethylbenzylammonium chloride, stearyltrimethylammonium chloride, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, nonionic surfactants such as lanolin fatty acid polyethylene glycol, etc. Surfactant is mentioned.

These antistatic agents may be used alone or in combination of two or more.
The antistatic agent of the present invention is preferably one or more selected from the group consisting of silicon dioxide, anhydrous silicon, talc, titanium oxide, stearic acid, magnesium stearate, calcium stearate and a surfactant.

Excipient The tablet of the present invention further contains an excipient. Excipients include, for example, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, potato starch, croscarmellose sodium, carboxymethyl starch sodium, sucrose, lactose, mannitol, glucose, calcium phosphate, calcium sulfate, calcium lactate , Povidone, cross-linked povidone and the like, and these can be used alone or in combination of two or more. Among these, it is preferable to contain a cellulose-based excipient, and it is more preferable to contain crystalline cellulose.

  In addition, the excipient of the present invention can be used to prepare drugs for oral administration such as binders, lubricants, anti-aggregation agents, disintegrants, foaming agents, absorption enhancers, stabilizers, solubilizers, plasticizers, etc. Can contain various known additives that are usually used.

Examples of the binder include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, povidone, glucose, sucrose, lactose, maltose, sorbitol, mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogol, gum arabic, Examples include gelatin, agar and starch.
As the lubricant (lubricant), for example, the aforementioned lubricant such as stearic acid is preferably used. Examples of the disintegrant include crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose salt, starch, hydroxypropyl starch, carboxymethyl starch sodium, tragacanth and the like. Examples of the foaming agent include sodium bicarbonate and tartaric acid. Examples of the stabilizer include benzoic acid, sodium benzoate, ethyl paraoxybenzoate, ascorbic acid, sodium ascorbate, α-tocopherol and the like. Examples of solubilizing agents for medicinal ingredients include organic acids such as fumaric acid, succinic acid and malic acid.
In the present invention, the excipient is used in the form of a tablet as it is in powder form, but a part or all of it may be granulated into granules of about 10 to 2000 μm.

Sustained-release tablet The sustained-release tablet of the present invention is formed by compression-molding the above-mentioned sustained-release particles, antistatic agent and excipient. The compression molding can be appropriately performed by a compression molding technique used in normal tablet molding.

The sustained release tablet of the present invention desirably contains sustained release particles in an amount of 50% by mass or more, preferably 50 to 90% by mass, more preferably 60 to 80% by mass of the mass of the sustained release tablet. .
That is, in the present invention, sustained release particles; 50 to 90% by mass, preferably 60 to 80% by mass, antistatic agent; 0.5% by mass or less (but not 0), preferably 0.005 to 0% .2 mass%, more preferably 0.01 to 0.15 mass%, excipient; 10 to 50 mass%, preferably 20 to 40 mass%, mixed and compression-molded to give sustained release tablets Can be manufactured.

The specific amount of the antistatic agent in the present invention can remarkably improve the hardness of the tablet, and hardly affects the dissolution characteristics of the medicinal ingredients.
The sustained-release tablet of the present invention has a sufficient hardness that does not break at the stage before oral intake such as during production, packaging, transportation, and storage. Specifically, it is desirable that the tablet hardness is 4 Kp or more, preferably 6 Kp or more. For example, a sustained-release tablet formed into a circle has a tablet hardness of 4 Kp or more, preferably 6 Kp or more when the tablet diameter is 6 mm. It is desirable to have a tablet hardness of 6 Kp or more, preferably 8 Kp or more when the tablet diameter is 9 mm.

  The compression molding conditions for molding the sustained-release tablet of the present invention are not particularly limited, and may be known conditions for producing tablets by compression molding, but conditions for achieving the desired tablet hardness Is desirable. The tableting pressure may be any pressure that achieves the desired tablet hardness, and depends on the size and shape of the sustained-release tablet. For example, when a round tablet having a diameter of 9 mm is formed, it may be about 400 to 2000 kg. it can. The sustained-release tablet of the present invention can achieve a sufficient tablet hardness according to the formulation without molding at an excessively high tableting pressure.

  Such a sustained-release tablet of the present invention exhibits high tablet hardness even when the molding conditions are equivalent, as compared to the case of producing a similar tablet using an excipient containing no antistatic agent, Furthermore, it has the same medicinal component release properties despite its high hardness. Therefore, according to the present invention, a tablet having a tablet thickness equivalent to that of a tablet containing no antistatic agent, an equivalent medicinal component release property, and high hardness can be suitably obtained.

  This is because the antistatic agent prevents or suppresses the static electricity that tends to occur on the surface of the sustained-release particles, thereby reducing the adhesion and repulsion caused by static electricity. This is considered to be because the proper pressure bonding is achieved.

Therefore, according to the present invention, even when the tablet is downsized, a sufficient tablet hardness and good sustained release properties can be obtained, and an excellent small tablet that can be easily taken orally by the patient is provided.
Further, in the method for producing a sustained-release tablet of the present invention, even when the content of excipients such as a binder and a disintegrant is reduced, good tablet hardness and release of a medicinal component can be obtained. The content of sustained-release particles in the tablet can be relatively increased, and as a result, the tablet can be reduced in size.

EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not limited to these Examples.
In the following examples and comparative examples, tablet hardness and dissolution rate were measured by the following methods. Each material was pharmaceutical grade.

Tablet hardness A tablet hardness meter (type 6D, manufactured by DR. SHHILEUNIGER PHARMARON) was used to measure the breaking strength in the diameter direction of 10 randomly extracted tablets, and the average value was calculated.

The dissolution test was carried out using a phosphate buffer at pH 7.5 in accordance with the second method (paddle method) of the dissolution test method of the 14th revised Japanese Pharmacopoeia. After starting the dissolution test, the absorbance of the test solution at 330 nm was measured over time, and the dissolution rate of the medicinal component (5-aminosalicylic acid) was calculated.

[Preparation Example 1]
・Preparation of sustained - release granules 5-Aminosalicylic acid 1000 g added with 10% aqueous popidone and kneaded, granulated by extrusion granulation method, dried, sized and 10-30 mesh elementary granules (core Agent).

Next, 1000 g of 1% ethylcellulose aqueous solution was sprayed on a fluidized bed to 500 g of the obtained elementary granules, dried and sieved to obtain 10-30 mesh sustained-release granules.
The composition of the obtained sustained-release granules was 5-aminosalicylic acid; 94.0% by mass, popidone: 5.0% by mass, and ethylcellulose: 1.0% by mass.

[ Reference Example 1]
200 g of sustained-release granules obtained in Preparation Example 1, 98.4 g of crystalline cellulose, 0.1 g of silicon dioxide and 1.5 g of magnesium stearate are uniformly mixed, and compression-molded at a pressure of 500 kg using a press machine, A circular tablet having a mass of 300 mg per tablet and a diameter of 9 mm was obtained.

  About 10 tablets randomly extracted from the obtained tablets, the breaking strength in the diameter direction of the tablets was measured using a tablet hardness meter (type 6D, manufactured by DR. SHHILEUNIGER PHARMARON), and the average value was calculated. The results are shown in Table 1.

[ Reference Example 2]
A circular tablet was obtained in the same manner as in Reference Example 1 except that 0.1 g of talc was used instead of silicon dioxide in Reference Example 1.
For 10 tablets randomly extracted from the obtained tablets, the breaking strength was measured in the same manner as in Reference Example 1, and the average value was calculated. The results are shown in Table 1.

[Reference Example 3]
Reference Example 1 in place of the silicon dioxide, except that using stearic acid 0.1 g, to obtain a circular tablet in the same manner as in Reference Example 1.
For 10 tablets randomly extracted from the obtained tablets, the breaking strength was measured in the same manner as in Reference Example 1, and the average value was calculated. The results are shown in Table 1.

[Comparative Example 1]
In Reference Example 1, a circular tablet was obtained in the same manner as in Reference Example 1, except that the amount of crystalline cellulose was 98.5 g and silicon dioxide was not used.
For 10 tablets randomly extracted from the obtained tablets, the breaking strength was measured in the same manner as in Reference Example 1, and the average value was calculated. The results are shown in Table 1.

From Reference Examples 1 to 3 and Comparative Example 1, the tablets of Reference Examples 1 to 3 containing an antistatic agent in the shaped product were compared with the tablet of Comparative Example 1 containing no antistatic agent, and the molding conditions and It can be seen that it has excellent tablet hardness despite the tablet thickness being equal.

[Examples 4 to 6, Comparative Example 2]
After uniformly mixing the sustained release granules, crystalline cellulose and silicon dioxide obtained in Preparation Example 1 in the amounts shown in Table 2, talc and Mg stearate are added in the amounts shown in Table 2 and further mixed. 3000 g of a mixture was prepared. Subsequently, the mixture was compression-molded using a rotary tableting machine at pressures of 400 kg, 800 kg, 1200 kg, 1600 kg, and 2000 kg, respectively, to obtain circular tablets having a mass of 375 mg and a diameter of 9 mm per tablet.

  The tablet hardness of the obtained tablets was determined by the measurement method described above. The results are shown in the graph of FIG.

[Comparative Example 3, Example 7]
After the sustained release granules, crystalline cellulose, anhydrous calcium hydrogen phosphate and silicon dioxide obtained in Preparation Example 1 were uniformly mixed in the amounts shown in Table 3, the amounts of talc and Mg stearate shown in Table 3 were mixed. And mixed further to prepare a 3000 g mixture. Then, so as to obtain tablets having the same hardness, using a rotary tableting machine, in Comparative Example 3 1200 kg, the mixture was compression-molded respectively at a pressure of 800kg Example 7, each weighing mass 375mg A round tablet with a diameter of 8.5 mm was obtained. Each resulting tablets of Comparative Example 3 and Example 7, 8.2Kp, was tablet hardness of 8.5Kp.

The dissolution rate of 5-aminosalicylic acid from the tablet was determined by the measurement method described above.
As a result, the tablets of Example 7 as compared to Comparative Example 3 containing no antistatic agent was comparable dissolution rate. The results are shown in the graph of FIG.

Claims (3)

Sustained release particles comprising a core material containing 5-aminosalicylic acid and a coating layer containing a cellulosic polymer that controls the release of 5-aminosalicylic acid from the core material, talc, magnesium stearate, inorganic antistatic agent (excluding tall h) and a sustained-release tablet containing crystalline cellulose,
The sustained release tablet wherein the sustained release particles are 50% by mass or more of the tablet mass.   The sustained release tablet according to claim 1, wherein the tablet hardness is 6 Kp or more. Sustained release particles comprising a core material containing 5-aminosalicylic acid and a coating layer containing a cellulosic polymer that controls the release of 5-aminosalicylic acid from the core material, crystalline cellulose , talc, magnesium stearate, and inorganic antistatic agent (excluding tall h) tablet hardness method for enhancing mixing, compression molding.