Solid matrix pharmaceutical preparation

[0001] The present invention relates to a solid pharmaceutical product.

BACKGROUND OF THE INVENTION [0002] In the medical field, many attempts have been made to control the release of an active substance and to maintain the active substance concentration in the blood at an appropriate level over a long period of time. In order to maintain the concentration of the active substance in the blood at an appropriate level over a long period of time, it is necessary to maintain the adsorption of the active substance over a long period of time pharmaceutical methods (sustained release techniques) are used. Orally administered solid products eventually move from the upper gastrointestinal tract (stomach and upper small intestine) to its lower part (lower small intestine and large intestine); and often the adsorption capacity of the active substance is lower in the lower gastrointestinal tract compared to its upper sections. Thus, the most important consideration is developing a strategy that allows continuous adsorption of the active substance in the lower sections of the gastrointestinal tract where the solid medicinal product will remain the longest.

[0003] Known sustained release techniques include, for example, sustained release techniques based on controlled diffusion, that is, by using film-coated medicinal products in which core compositions or core tablets that contain therapeutic substances are coated with water-insoluble polymeric membranes; matrix products are made together with water insoluble polymers, waxes and the like; and the like. However, according to these techniques, because the release rate of the active substance decreases as the release progresses, the release rate of the active substance is insufficient in the lower parts of the gastrointestinal tract to which the medicinal product reaches several hours after administration. As a result, the concentration of the active substance in the blood is difficult to maintain.

[0004] Other known sustained release techniques utilize pharmaceutical methods for releasing the active substance in the lower gastrointestinal tract (e.g., products coated with a gastric acid protective layer in which the compositions of the core directly releasing the active substance are coated with protective membranes gastric juice). However, such techniques control the release of the active substance by means of membranes and therefore require the use of membrane coating procedures. For this reason, the process of producing a pharmaceutical product becomes complicated.

[0005] On the other hand, it is known that sustained-release matrix products are made using enteric polymers based on methacrylic acid. The enteric polymer is an insoluble substance at pH values ​​lower than the pH at which the enteric polymer can dissolve, and it becomes soluble at pH values ​​higher than the pH at which the enteric polymer can dissolve. Thus, the matrix of the enteric polymer containing product can inhibit the release of the active substance in the upper gastrointestinal tract and quickly release the active substance in the lower gastrointestinal tract. In other words, the sensitivity of the intestinal polymer to the pH value makes it possible to obtain sustained-release products with precise control of the release of the active substance.

[0006] For example, patent documents 1, 2, 3 and 4 show products with matrices containing enteric polymers obtained by mixing the enteric polymer and the active substance, and then combining them by crushing (extruding tablets). However, the release of the active substance from the product matrix is ​​usually considered to be dependent on the size of the surface of the pharmaceutical product, and such product matrices obtained by extrusion of tablets have small values ​​of the surface size that contact the solvent. For poorly soluble active substances with a low dissolution rate, the small surface area of ​​the pharmaceutical product causes a deficiency in the release of the active substance.

[0007] On the contrary, patent document 5 describes products obtained by wet kneading a powder mixture containing a copolymer of methacrylic acid with ethanol, followed by extrusion. Such a product is formed into sustained release tablets by wet kneading and extrusion. Such a product (tablets, granules and powder are referred to as multi-unit type products) can have a larger surface area and can be used for active substances with poor solubility. In addition, compared to single-unit type products, such tablets obtained by extrusion of tablets, i.e. multi-unit type products, in the form of tablets have a moderate ability to disintegrate in the gastrointestinal tract. Therefore, such tablets can reduce patient-dependent changes in the absorption of the active substance to a greater extent than conventional tablets.

[0008] Patent document 6 describes sustained release multiparticles that are substantially free of a lubricant. The multiparticles are obtained by extrusion from a mixture containing a pharmaceutically active ingredient in which the plasticizing additive is used in an amount sufficient to act as a plasticizer and also as a lubricant.

[0009] Patent Document 7 describes oxycodone multiparticles that can be obtained by extrusion of a mixture comprising (a) oxycodone, (b) a water-insoluble ammonium methacrylate copolymer, (c) a plasticizer, (d) a lubricant, and (e) a modifying agent water permeability.

[0010] Patent document 8 shows an inert copolymer of poly (ethyl acrylate, methyl methacrylate) which is used as a carrier in the process of making pharmaceutical products containing the active ingredient.

[0011] Patent Document 9 discloses sustained release gel coated compositions in which the gel coatings comprise a pharmaceutically acceptable mixture of gelatin and a hydrophobic polymer.

[0012] In addition, non-patent document 1 presents a multi-unit type product containing a methacrylic acid copolymer S, methacrylic acid LD copolymer, active substance, polyvinylpyrrolidone and triethyl citrate as a plasticizer. The products are obtained by wet kneading with water, followed by extrusion and spherical forming.

Patent Document 1: Investigated Japanese Patent Description, published under number 1992-43049.

Patent document 2: Unexamined Japanese patent publication, published after 1994-199657.

Patent document 3: patent description Ser. Americas number 4 968 508.

Patent document 4: patent description Ser. Of America, published after number 2006-0159753.

Patent Document 5: Unexamined Japanese Patent Publication, Published Number 1994-24991.

<td>Patent Document 2006/024881 A.</td><td> 6:</td><td>international</td><td>description</td><td>patent,</td><td>number</td><td>WO</td>

<td>Patent Document 2005/000310 A.</td><td> 7:</td><td>international</td><td>description</td><td>patent,</td><td>number</td><td>WO</td>

<td>Patent Document 2005/079760 A.</td><td> 8:</td><td>international</td><td>description</td><td>patent,</td><td>number</td><td>WO</td>

<td>Patent Document</td><td> 9:</td><td>international</td><td>description</td><td>patent,</td><td>number</td><td>WO</td>

03/082204 A.

Non-Patent Document 1: International Journal of Pharmaceutics, 2001, volume 213, pages 7-12.

Disclosure of the Invention [0013] However, as outlined below, the process of making tablets or granules is accompanied by problems associated with processing the mixture containing the above-mentioned enteric polymer by extrusion and spherical forming.

[0014] First, the enteric polymer based on methacrylic acid is a hard enteric polymer, which is associated with its high glass transition temperature, not lower than 160 ° C. For this reason, if matrix products containing enteric polymers based on methacrylic acid are produced by extrusion and transformation into spherical forms, the wet kneaded product must be further enriched with plasticizing agents so that extrusion can proceed smoothly.

[0015] Although the amount of methacrylic acid S copolymer in the pharmaceutical composition prepared according to the method set out in patent document 5 is 5% by weight, the amount of methacrylic acid S copolymer in the composition must be increased in order to increase the response of the obtained pharmaceutical product to the pH value. However, increasing the amount of methacrylic acid S copolymer in the composition does not provide effective plasticization, which creates difficulties in the process of producing a matrix product containing enteric polymers containing methacrylic acid, by extrusion and spherical forming. More specifically, such insufficient plasticity increases the resistance during wet extrusion. As a result, extrusion cannot be carried out.

[0016] On the other hand, Non-Patent Document 1 describes a pharmaceutical composition which contains 77% by weight of methacrylic acid copolymer, and about 11% by weight of triethyl citrate, added as a plasticizer, to provide the plasticity necessary for extruding the wet kneaded product. However, according to this method, the intestinal glass transition temperature of the methacrylic acid based polymer is lowered due to the addition of a plasticizer, which causes metamorphosis and deformation of the intestinal methacrylic acid based polymers. Accordingly, the film may form inside the extruder screen mesh, which may cause blockage or damage. In addition, metamorphosis and deformation of intestinal methacrylic acid polymers may occur as well as changes in the solubility of the products obtained over time due to the plasticizer remaining in the products. In addition, the method presented in Non-patent Document 1 is characterized by uncertainty due to possible incompatibility with active substances.

[0017] Thus, a plasticizer is necessary to increase the amount of intestinal methacrylic acid polymer in the extruded product, while the addition of the plasticizer causes the disadvantages described above. In other words, the problem difficult to solve is to increase the amount of intestinal polymer in the product obtained by extrusion, while solving the problems arising from the addition of a plasticizer.

[0018] The present invention provides a solid pharmaceutical product that is devoid of the above-mentioned problems associated with conventional manufacturing methods, also with such amounts of intestinal methacrylic acid polymer that will allow a good response to the pH value, thereby giving the final product a sustained capacity release.

[0019] More specifically, it is an object of the present invention to provide a solid matrix product that overcomes all of the above problems caused by the addition of a plasticizer, providing increased control over release, by suppressing the release of the active substance in the upper gastrointestinal tract and the immediate release of the active substance in the the lower part of the gastrointestinal tract.

[0020] The inventors of the present invention have conducted extensive research to solve the above problems, and have found that desired products with solid type matrices can be obtained by using a combination of intestinal methacrylic acid based polymer and sugar and / or sugar alcohol with specific properties. The present invention is based on these findings.

[0021] The present invention relates to a solid pharmaceutical matrix type product as defined in items 1 to 13 below.

[0022] Item 1: A matrix type solid pharmaceutical product comprising: (a) an enteric polymer based on methacrylic acid; and (b) sugar and / or sugar alcohol, wherein 1 g sugar and / or sugar alcohol (b) may be dissolved in not more than 4 g of water at a water temperature between 20 and 25 ° C.

[0023] Item 2: A solid pharmaceutical product according to item 1, wherein the amount of sugar and / or sugar alcohol is from 0.1 to 10 parts by weight with respect to 1 part by weight of the intestinal methacrylic acid polymer.

[0024] Item 3: A solid pharmaceutical product according to item 1 or 2, wherein the sugar and / or sugar alcohol has a melting point of 140 ° C or lower.

[0025] Item 4: A solid pharmaceutical product according to item 1 or 2 that does not contain a plasticizer.

[0026] Item 5: A solid pharmaceutical product according to item 3 that does not contain a plasticizer.

[0027] Item 6: A solid pharmaceutical product according to item 1 or 2, which is prepared by a method comprising an extrusion process.

[0028] Item 7: A solid pharmaceutical product according to item 3, which is prepared by a method comprising an extrusion process.

[0029] Item 8: A solid pharmaceutical product according to any one of items 1 to 7, wherein the sugar and / or sugar alcohol is at least one compound selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose and maltose, dextrose, fructose and maltitol.

[0030] Item 9: A solid pharmaceutical product according to item 1, wherein the content of the intestinal methacrylic acid polymer ranges from 6 to 50% by weight.

[0031] Item 10: A solid pharmaceutical product according to item 1, wherein the enteric polymers based on methacrylic acid dissolve at pH values ​​of 5.5 or higher.

[0032] Item 11: A solid pharmaceutical product according to item 1, wherein the enteric polymer based on methacrylic acid has a glass transition temperature not lower than 100 ° C.

[0033] Item 12: A solid pharmaceutical product according to any one of items 1 to 11, wherein the enteric polymer based on methacrylic acid is at least one polymer selected from the group consisting of methacrylic acid L copolymer, methacrylic acid LD copolymer and methacrylic acid S copolymer.

[0034] Item 13: A solid pharmaceutical product according to item 1 containing an active substance selected from the group consisting of cilostazol, tolvaptan, phenytoin, aspirin and naproxen.

Solid pharmaceutical product [0035] The matrix-type solid pharmaceutical product of the present invention comprises (a) an enteric polymer based on methacrylic acid, and (b) sugar and / or sugar alcohol.

[0036] Sugar and / or sugar alcohol (b) has the property that its 1 g dissolves in no more than 4 g of water at a water temperature between 20 and 25 ° C.

[0037] In addition to the above components (a) and (b), the pharmaceutical solid product of the present invention may contain other ingredients, preferably (c) active substance and (d) a drug-retaining substance. The pharmaceutical solid product does not contain a plasticizer.

[0038] The pharmaceutical solid product is preferably of the matrix type product and is a sustained release pharmaceutical solid product.

(a) Enteric methacrylic acid polymer [0039] According to the invention, as the enteric polymer based on methacrylic acid (a), many known enteric polymers based on methacrylic acid can be used if they are soluble in an environment with a pH value corresponding to the prevailing conditions. in the small intestine and in the large intestine. Suitable intestinal methacrylic acid polymers dissolve at a pH of 5.5 or higher, more preferably 6.0, and a pH of 7.5 or lower. If the pH of dissolution is within this range, the enteric polymer dissolves in the small intestine and / or the large intestine, which allows the active substance to be quickly released from the pharmaceutical product in the lower gastrointestinal tract.

[0040] Furthermore, according to the invention, the enteric glass transition temperature of the methacrylic acid-based polymer is usually 100 ° C or higher, preferably 105 ° C or higher, more preferably 130 ° C or higher. The glass transition temperature is preferably 200 ° C or less. If the glass transition temperature is within the given range, there is no deformation and metamorphosis at room temperature, which results in less effect on changes in product dissolution over time. Another benefit is that extrusion can be carried out without overloading the extruder.

[0041] Suitable specific examples of the intestinal methacrylic acid polymer include methacrylic acid LD copolymer, methacrylic acid L copolymer, methacrylic acid S copolymer and the like. The methacrylic acid LD copolymer is preferably used in the form of powders. Powdered LD methacrylic acid copolymer means polymer in both liquid and suspension form containing 30% solids. Furthermore, the methacrylic acid LD copolymer according to the present invention can be used in dry form or, if it contains some moisture, it can be used in powder form. Additionally, such a powdered LD methacrylic acid copolymer is sometimes referred to herein as a dry LD methacrylic acid copolymer.

[0042] As enteric polymers based on methacrylic acid, any products of this type readily available commercially can be used. For example, "Eudragit L100D55" (Degussa AG) can be used as the dry LD copolymer of methacrylic acid, "Eudragit L100" (Degussa AG) can be used as the L copolymer of methacrylic acid, and "Eudragit S100" (Degussa AG) can be used as the S copolymer methacrylic acid. Such enteric polymers can be used alone or in combination of two or more of them.

[0043] The mixing of two or more of these intestinal polymers can by any method determine a pH value in the range from 5.5 to 7 at which the product dissolves in the lower parts of the small intestine and in the large intestine (pH of the intestinal polymer dissolution). For example, if the pH of the intestinal dissolution of the polymer is by any method determined in the range of

5.5 to 6, the ratio of methacrylic acid LD copolymer to methacrylic acid L copolymer may range from 1:99 to 99: 1. In addition, if the pH of the intestinal dissolution of the polymer is by any method within the range of

5.5 to 7, the ratio of methacrylic acid LD copolymer to methacrylic acid S copolymer may range from 1:99 to 99: 1. In addition, if the pH of the intestinal dissolution of the polymer by any method is in the range of 6 to 7, then the ratio of methacrylic acid L copolymer to methacrylic acid S copolymer may range from 1:99 to 99: 1.

[0044] According to the present invention, the amount of enteric polymer contained in the product usually ranges from 1 to 50% by weight, preferably in the range from 3 to 45% by weight, more preferably in the range from 6 to 40% by weight, and even more preferably in the range of 10 to 35% by weight. The intestinal polymer content maintained in this range is advantageous due to the variability of the release conditions of the active substance and due to the requirements of the manufacturing process (satisfactory extrusion). Thus, meeting the conditions set by the variability of the release conditions of the active substance means that the product can easily provide the intended release of the active substance.

[0045] The intestinal methacrylic acid polymer that is used to obtain the solid pharmaceutical product of the present invention is preferably dissolved at a pH value of 5.5 or above. The pH value affecting the solid pharmaceutical product of the present invention is appropriately selected depending on the active substances listed below, the desired pharmacological effects and the like. The pH response can also be controlled by selecting various intestinal methacrylic acid polymers, selecting the amount of intestinal polymer used in the product and the like.

For example, certain products are preferably intended for the slow release of the active substance in the upper gastrointestinal tract (stomach and upper small intestine), in addition to the function of these products of continuous adsorption in the lower gastrointestinal tract (lower sections of the small intestine and large intestine). In such cases, it is desirable to mitigate the pH response of the solid pharmaceutical product. This is especially achieved by reducing the amount of methacrylic acid based enteric polymer with a solid pharmaceutical product. In addition, if we increase the product's ability to continuously adsorb in the lower gastrointestinal tract, it is desirable to shorten the response range to the pH of the solid pharmaceutical product. Especially when the amount of intestinal methacrylic acid polymer in the solid pharmaceutical product becomes larger.

(b) Sugar and / or sugar alcohol [0047] The sugar and / or sugar alcohol used in the present invention have particular water solubility. The amount of water needed to dissolve 1 g sugar and / or sugar alcohol at a water temperature between 20 and 25 ° C is usually 4 g or less, preferably 3.5 g or less. In addition, the amount of water needed to dissolve 1 g sugar and / or sugar alcohol at a water temperature between 20 and 25 ° C is preferably 1 g or more. If the amount of water required for dissolution varies within said range, adequate plasticity is provided to the kneaded mixture prior to product manufacture.

[0048] More preferably, the sugar and / or sugar alcohol have a melting point of 140 ° C or lower, preferably is 130 ° C or lower, more preferably is 125 ° C or lower, and a melting point of 90 ° C or higher. Sugar and / or sugar alcohol exhibiting a melting point in the said range assume a solid form at room temperature, which allows easy manufacturing operations. Another advantage is that the hardness of the sugar and / or sugar alcohol does not affect the extrusion process.

[0049] As sugar and / or sugar alcohol that can be used in accordance with the present invention, they are substances with the given properties, and they may exist in the form of hydrate (s). Examples of such substances include at least one substance selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose, dextrose, fructose, maltitol. Preferable examples include at least one substance selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose, dextrose, fructose, maltitol. More preferably the sugars and / or sugar alcohols may be at least one substance selected from the group consisting of erythritol, xylitol, lactitol, sorbitol, trehalose, maltose. Even more preferred sugars and / or sugar alcohols may be at least one substance selected from the group consisting of erythritol, lactitol monohydrate, trehalose dihydrate and maltose monohydrate. Such even more preferred sugars and / or sugar alcohols have reasonable solubilities and corresponding melting points as well as less dependence on hygroscopicity. They are also satisfactory in terms of stability during longer storage.

[0050] Sugar and sugar alcohol can be selected from various commercial products. Examples are more detailed below.

(Bi) Erythritol and its hydrates [0051] Erythritol, i.e., sugar alcohol, is produced from glucose by an enzymatic reaction. The melting point of erythritol is 119 to 122 ° C and the amount of water (at 25 ° C) necessary to dissolve 1 g of erythritol is 3.3 g (Nikken Chemicals Co., Ltd., Erythritol Technical Data). As erythritol, a commercial product called "Erythritol 100M" (Nikken Chemicals Co., Ltd.) can be used.

(B-ii) Xylitol and its hydrates [0052] Xylitol, i.e., sugar alcohol, is produced by converting various cellulosic waste substances into xylose by hydrolysis and subsequent hydrogenation. Xylitol has some hygroscopic abilities. The amount of water needed to dissolve 1 g of xylitol at 20 ° C is 1.6 g (Handbook of Pharmaceutical Excipients, 2001,

Japan Pharmaceutical Excipients Council). In addition, the melting point of xylitol is from 93 to 95 ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). As xylitol, commercial products such as "Xylitol P" (Nikken Fine Chemical Co., Ltd.), "XYLISORB" (Roquette), and "Xylit P" (Towa Chemical Industry Co., Ltd.) can be used.

(B-iii) Lactitol and its hydrates [0053] Lactitol, i.e., sugar alcohol, is produced by catalytic hydrogenation of lactose. Examples of lactitol include anhydride, monohydrate, dihydrate and trihydrate. Of these, non-hygroscopic monohydrate is preferably used. The melting point of lactitol monohydrate is 97 ° C (Merck Index, 12th edition), and the amount of water needed at 20 ° C to dissolve 1 g of lactitol is 1.8 g (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council) . As lactitol monohydrate, the commercially available product under the name "Lactitol LC-1" (Nikken Fine Chemical Co., Ltd.) can be used.

(B-iv) Sorbitol and its hydrates [0054] Sorbitol, i.e., sugar alcohol, is produced from glucose or corn syrup by high pressure hydrogenation or by electrolytic reduction. Sorbitol is characterized by high hygroscopicity. The amount of water at 25 ° C necessary to dissolve 1 g sorbitol is 0.5 ml (g) (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). In addition, the melting point of sorbitol ranges from 97 to 112 ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council; Journal of Thermal Analyze 18 sis and Calorimetry, vol. 73, pages 615-621). As sorbitol, commercial products such as "Sorbitol SP" (Nikken Fine Chemical Co., Ltd.), "NEOSORB Powder" (Roquette) and "Sorbitol DP-10M" (Towa Chemical Industry Co., Ltd.) can be used.

(Bv) Trehalose and its hydrates [0055] Trehalose dihydrate, i.e., the sugar component, is a disaccharide in which two glucose molecules are bound, similar to maltose. The trehalose pharmaceutical additive is prepared from a starch product that has undergone partial enzymatic degradation using trehalose-producing bacteria. Although trehalose dihydrate is not non-hygroscopic, it has low hygroscopic properties. The melting point of trehalose dihydrate is 97 ° C and the amount of water at 20 ° C necessary for dissolving 1 g of trehalose dihydrate is 1.2 g (Trehalose Technical Data, Hayashibara Biochemical Labs., Inc.). As trehalose dihydrate, commercial products such as "Trehalose P" (Asahi Kasei Chemicals Corp.) and "Treha" (Hayashibara Co., Ltd) can be used.

(B-vi) Maltose and its hydrates [0056] Maltose monohydrate, i.e., its sugar component, is a disaccharide carbohydrate that is produced by enzymatic hydrolysis of starch. If the content of maltose is 90% or more, it can also be used in pharmaceutical products as a syrup from maltose powder in the form of a pharmaceutical additive. Maltose is used as the anhydride and monohydrate, with the monohydrate showing low hygroscopicity. The amount of water at 20 ° C necessary to dissolve 1 g of maltose monohydrate is

1.2 g (New Food Industry, Vol. 31, No. 4, pp. 17-22). In addition, the melting point (decomposition temperature) of maltose monohydrate ranges from 102 to 103 ° C (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council). As maltose monohydrate, commercial products such as "Sunmalt-S" (Sanwa Cornstarch Co., Ltd.) and "Nisshoku Crystal Maltose" (Nihon Shokuhin Kako Co., Ltd.) can be used.

[0057] In accordance with the present invention, a mixture of sugar and / or sugar alcohol (b) can increase the plasticity of a kneaded mixture containing intestinal methacrylic acid polymers without using a plasticizer. Since no plasticizer is used according to the method of the invention, various harmful effects caused by the use of a plasticizer can be avoided. Accordingly, the stability of the product can be improved and the dissolution ability of the medicinal product can be easily controlled.

[0058] In accordance with the present invention, in order to maintain an appropriate ratio of intestinal methacrylic acid polymer to sugar and / or sugar alcohol, the sugar and / or sugar alcohol content is usually from 0.01 to 20 parts by weight, preferably from 0.1 to 10 parts by weight, more preferably from 0.2 to 5 parts by weight, based on 1 part by weight of the intestinal methacrylic acid polymer. The amount of sugar and / or sugar alcohol in this range is advantageous because the product is easy to obtain and handle, the plasticity of the kneaded mixture increases and the production is easy to carry out the manufacturing process (ease of manufacture).

[0059] With respect to other sugar and / or sugar alcohol detailed above, the melting point and the amount of water needed to dissolve 1 g of sugar and / or sugar alcohol are: temperature from 160 to 186 ° C and 0.5 g water for sucrose, melting point 83 ° C and 1 g water for dextrose, melting point 102 to 105 ° C and 0.3 g water for fructose, and melting point from 148 up to 151 ° C and high solubility for maltitol (Handbook of Pharmaceutical Excipients, 2001, Japan Pharmaceutical Excipients Council).

(c) Active substances [0060] Any active substances such as those used as active ingredients in medicinal products intended for the treatment or prevention of diseases may be used. Such active substances can be used in the form of free compounds, their salts, solvates (hydrate, ethanol solvate and the like), or in crystalline polymorphic forms. Suitable active substances for use in accordance with the method of the present invention are those for which the occurrence of side effects is reduced by means of a sustained release technique, the method of the present invention to increase therapeutic efficacy. In addition, suitable active substances are those which, by releasing the active substance, increase the therapeutic efficacy in Crohn's disease, ulcerative colitis, irritated colitis, colon cancer and the like with damage to the lower gastrointestinal tract.

[0061] The active substances may be in crystalline form or in non-crystalline form. The active substances may be water-soluble or fat-soluble, as well as may have poor water solubility. The active substances are preferably weakly basic, neutral or acidic.

[0062] If active substances with poor solubility are used, nanomization, micronization, amorphization and the like pharmaceutical methods can be used to improve such low solubility. However, according to the wet kneading technique with ethanol, which is outlined in Patent Document 5, ethanol has the potential to cause problems related to crystallization or crystal growth of the active substance.

[0063] Examples of active substances used in the method of the invention include, 5-aminosalicylic acid, acyclovir, aspirin, acetylsalicylic acid, acetaminophen, aripiprazole, ampicillin, isoniazid, ibuprofen, indometacin, etenzamide, enalapril, erythromycin, omeprazole, ketocamone , salazosulfapridine, salazopyrine, diazepam, diclofenac, diclofenac sodium, dipyridamole, cimetidine, cilostazol, simvastatin, sucralfate, sulpiride, sulfasalazine, celecoxib, tacrolimus, theophylline, tegafur, dexamethasone, dextromethorphan, tetomilast, terfenadine, doxorubicin, triamcinolone, tolvaptan, nadifloxacin, naproxen, nifedipine, urea, sodium valpronate, haloperidol, valaciclovir, paliperidone, hydroportatin, phenophenacin, famocortinone sodium, fluorouracil, prednisolone, prednisone, furosemide, probucol, wesnarinone, penicillin, perphenazine, chlorfeniramine maleate, midazolam, doxazosin mesylate, methotrexate, morphine, ranitidine, lansoprazole, lisinopril, risperidone, lidocaine, rebamipid, levodopa, rotigotine, lovastatin, lorazepam, warfarin, ambroxol hydrochloride, cartolol hydrochloride, diphenhydramine hydrochloride, hydrochloride hydrochloride, hydrochloride mozavaptan hydrochloride, ranitidine hydrochloride, levocarnitine hydrochloride, cortisone acetate, salbutamol sulfate and the like.

[0064] Preferred active substances are 5-aminosalicylic acid, acyclovir, aspirin, acetylsalicylic acid, acetaminophen, aripiprazole, ibuprofen, indomethacin, etenzamide, omeprazole, salazosulfapridine, salazopyrine, diazepam, diclofenac, ticlofenac sodium tegafur, tetomilast, doxorubicin, tolvaptan, haloperidol, paliperidone, hydrocortizone, phenytoin, budesonide, pravastatin, fluorouracil, prednisolone, prednisone, furosemide, probucol, wesnarinone, lansoprazole, risperidone, rebamipide, levodopa, rotigotine, lovastatin, carteolol hydrochloride, nicardipine hydrochloride, procaterol hydrochloride, mozavaptan hydrochloride, cortisone acetate, salbutamol sulfate and the like. More preferred active substances are cilostazol, tolvaptan, phenytoin, aspirin and naproxen.

[0065] The amount of such active substances in a pharmaceutical product is usually from 1 to 90% by weight, preferably from 5 to 80% by weight, more preferably from 10 to 70% by weight. In the pharmaceutical product of the present invention, such active substances can be used alone or in combination of two or more of them.

[0066] According to the present invention, sustained release solid products are prepared using such active substances that can be administered twice daily. For example, tolvaptan is antagonistic to vasopressin: vasodilating ability, ability to lower blood pressure, ability to inhibit the release of sugars in the liver, ability to inhibit the growth of renal connective tissue cells, diuretic capacity, ability to inhibit platelet sticking, ability to inhibit vomiting, ability to promote urea secretion, inhibit factor VIII secretion, ability to promote activity the heart, the ability to inhibit the compression of glomerular connective tissue cells, inhibiting the ability to produce sugars in the liver, inhibiting the ability to secrete aldosterone, inhibiting the ability to produce endothelin, regulating renin secretion, ability to regulate memory, ability to regulate, ability to regulate the process of producing prostaglandins and the like. Tolvaptan preferably serves as a vasodilator, antihypertensive agent, diuretic, platelet sticking inhibitor, urea secretion promoter, agent used for heart damage, agent used for kidney damage and the like; and is effective in the prevention and / or treatment of hypertension, edema, ascites, heart disease, kidney problems, vasopressin parody secretion syndrome (SIADH), liver cirrhosis, blood sodium deficiency, blood calcium deficiency, diabetes, circulatory disorders, kinetosis , disorders of water metabolism, kidney damage, various ischemia related diseases and the like. In addition, tolvaptan exhibits the following antagonistic properties of oxytocin: inhibitory effect on uterine smooth muscle contraction, inhibitory effect on milk secretion, inhibitory effect on prostaglandin synthesis and secretion, and vasodilatory ability; moreover, it is effective in preventing and / or treating oxytocin-related diseases, especially in cases of premature delivery, dysmenorrhea or stopping preparation for caesarean section and in such cases. Tolvaptan is also effective for the prevention and / or treatment of polycystic kidney disease. The use of such drug substances in accordance with the sustained release technique of the present invention allows the production of medicinal products that can be administered only once a day.

(d) Substances allowing to maintain the form of the drug [0067] According to the present invention, the substances to maintain the form of the drug (d) may be substances that maintain the desired physical form of the product during manufacture at various stages of manufacture. Preferably, these substances allow the pharmaceutical product to be kept by extrusion and spherical forming. [0068] In accordance with the present invention, the desired drug form retainers (d) are water retaining, raising, and plasticizing substances. Examples of used drug retention agents include hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose and the like water-soluble cellulose derivatives; crystalline cellulose, weakly substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl ethylcellulose, ethylcellulose, hypromellose phthalate, water phthalate acetate and cellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate, cellulose acetate, polyvinylpyrrolidone, polyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol (partially or fully saponified), and similar water-soluble synthetic polymers; crospovidone, polycarbophil, calcium polycarbophil, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid S copolymer, LD methacrylic acid copolymer, dry methacrylic acid LD copolymer, polyvinylacetal polymer, diethylamino sol wheat starch, rice starch, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, dextrin, αcyclodextrin, β-cyclodextrin, maltodextrin, isomalt, hydroxypropyl starch, carboxymethyl starch and sodium starch; gum arabic, gum arabic powder, agar, powdered agar, gelatin, purified gelatin, chitosan, xanthan gum, pectin, sodium alginate, locust bean gum, guar gum, and similar natural polymer compounds; stearic acid, monoglycerol stearate, carnauba wax, stearyl alcohol, cetanol, macrogol 1500, macrogol 4000, macrogol 6000, and similar low melting substances; and the like. Such drug-retaining substances are used singly or in combinations of two or more.

[0069] Preferred substances that retain the form of the drug are substances that are insoluble in water and have little disintegration effect. Examples of such drug retaining substances include crystalline cellulose, chitosan, sodium alginate, polycarbophil, calcium polycarbophil and the like. Crystalline cellulose is most preferred.

[0070] As crystalline cellulose, commercial products such as "Ceolus PH-101", "Ceolus PH-102", "Ceolus PH-301", "Ceolus PH-302" and "Ceolus KG-802" (Asahi Kasei Chemicals Corp.), "Avicel PH-200" (FMC Corporation), "VIVAPUR 12" (JRS) and the like.

[0071] The amount of such drug retaining substances in a pharmaceutical product usually ranges from 1 to 90% by weight, preferably from 3 to 80% by weight, more preferably from 5 to 50% by weight.

Other Ingredients [0072] The pharmaceutical product of the present invention may contain, for example, additives, binders, pH adjusting agents, absorption enhancers, glidants, coloring agents, medicinal product flavor correctors, flavors, capsules and the like various additives that can be mixed with a solid pharmaceutical product. Such ingredients can be mixed in the pharmaceutical product of the present invention in an amount that does not affect the effects of the present invention.

[0073] The solid pharmaceutical product of the present invention is preferably prepared by extrusion and spherical molding methods. Powders, lozenges and capsules are preferably used as the dosage form. In addition, the solid pharmaceutical product of the present invention can be prepared in such a way that the above-mentioned powders and granules are contained in tablets, as are the tablets of the granule type described in Advancing Medication, Forefront of DDS, 2002, Yoshiharu Kaneo, page 22, Hirokawa Publishing Co. More preferably dosage forms of the solid pharmaceutical product include granules, capsules and tablets containing granules. Dosage forms for capsules or tablets containing granules are preferred because the solid pharmaceutical product is easy to prepare and administer. In addition, due to the improved tablet strength and moisture content, tablets containing granules can be film coated without compromising the advantages of the present invention.

[0074] If the solid pharmaceutical product of the present invention is used in the form of a powder or granules, due to the use of the extrusion step in the production process, the grain size of the powder or granules preferably ranges from 0.3 to 3 mm.

[0075] If the solid pharmaceutical product of the present invention is used in the form of capsules, because of the ease of manufacture and administration, the size of the capsules is preferably numbered from 5 to 00.

[0076] When the solid pharmaceutical product of the present invention is used in the form of tablets containing granules, due to the manufacture and ease of use and administration of the medicinal product, the tablets are preferably made in the form of a round or distycha, with a diameter or larger axis preferably containing tablets in the range of 6 to 30 mm.

Method of producing a solid pharmaceutical product according to the present invention [0077] A method of producing a solid pharmaceutical product according to the present invention, in particular a method of producing powders, granules and capsules is provided below, but they do not limit the scope of the invention.

[0078] The solid pharmaceutical product of the present invention can be made by various industrial methods. If powders, granules and capsules are produced that are the preferred dosage forms of the present invention, the method of manufacture preferably includes at least an extrusion process. In addition to the extrusion process, the manufacturing process preferably includes a wet kneading process and a spherical forming process.

[0079] The solid pharmaceutical product of the present invention is preferably prepared by a wet kneading process, extrusion process, spherical forming process, drying process and optionally screening process. In accordance with the present invention, such processes are preferably carried out in the order following wet kneading, extrusion, sphericalization and drying. [0080] If the solid pharmaceutical product of the present invention is prepared in the form of capsules, after the screening process, sliding screening and subsequent encapsulation are carried out.

[0081] If the solid pharmaceutical product of the present invention is produced in the form of tablets containing granules, then after the screening process, the granules are mixed with suitable additives, glidants and tableted. In addition, if necessary, film coating may be carried out after tabletting.

Wet kneading process [0082] The wet kneading process is a wet kneading process of the above ingredients with other ingredients, such as a binder, which allows wetting of each ingredient. At this stage, the sugar and / or sugar alcohol (b) component may be used in the form of a powder or in the form of a solution, as this component is dissolved in water. [0083] Wet kneading is performed mainly based on the wet granulation method using a high shear method. Examples of equipment used in the wet kneading process include "New Speed ​​Kneader" (Okada Seiko Co., Ltd.), "Vertical Granulator" (Powrex Corp.), "High Speed ​​Mixer" (Fukae Powtec Co., Ltd.), " High Speed ​​Mixing-Type Mixer / Granulator NMG "(Nara Machinery Co., Ltd.)," Diosna Mixer Granulator "(Mutual Corporation)," Aeromatic-Fielder "(Spectrium) and the like.

Extrusion process [0084] The extrusion process is a process of extruding the mixture obtained by wet kneading through screens to obtain cylindrical fibers. The type of device used for extrusion is not limited, it can be of any type, such as, for example, devices provided with a method of extrusion type screw, gravity type and piston type. Examples of the screw type extruder include "Dome Gran DG-L1", "Twin-Dome Gran TDG-80" and "Twin Dome Gran TDG-110", (Fuji Paudal Co., Ltd.) and the like. Examples of the extruder provided with gravity-type extrusion include "Gear Pelletizer GCS" (Hosokawa Micron Corp.) gear type, "FG type Cylindrical Extruder" radiation type (Fukae Powtec Co., Ltd.) and the like.

[0085] If powders are produced, the screen pore size ranges from 0.3 to 0.5 mm. If granules and capsules are produced, the screen pore size may range from 0.3 to 3 mm.

The process of imparting a spherical form [0086] The process of imparting a spherical form is a process of cutting cylindrical fibers obtained in the process of extrusion into pieces of suitable dimensions, and giving them a spherical form adapted for use in the form of a drug. Examples of devices used in the process of spherical form include "New Speed ​​Kneader" (Okada Seiko Co., Ltd.), "Marumerizer QJ" (Fuji Paudal. Co., Ltd.), "CF Granulator" and "Granurex GX" (Freund Co., Ltd.) and the like.

Drying process [0087] The drying process is a process of drying the particles obtained in the process of producing spherical forms to remove moisture. Drying can be carried out by direct drying or indirect drying. During direct drying, for example, a disc oven, a fluid bed dryer and the like can be used. During intermediate drying, for example, a vacuum dryer, microwave dryer, infrared dryer and the like can be used. Specific examples of equipment used in the drying process include "Glatt Fluid Bed Granulator WST" and "Multiplex" (Powrex Corporation), "Box Aeration Parallel Flow Dryer" and "Midget Dryer" (Fuji Paudal Co., Ltd.), "Slit Flow FBS "(Okawara Mfg. Co., Ltd.), "Flow Dryer NFOD" (Freund Corporation), "Vibration Dryer" (Chuo Kakohki Co., Ltd.), "SPHH-200" (Tabai Espec Corp.) and the like.

Screening process [0088] The screening process is a process of selecting dry particles of a certain size. For example, the use of sieves is a suitable method for this purpose.

The slip mixing process [0089] The slip mixing process is the process of adding a lubricant to the particles after the screening process and homogeneously mixing the particles and the lubricant. For example, the diffusion and mixing method (rotary container method) is suitable for a slip mixing process.

Capsule filling process [0090] The capsule filling process is the process of filling capsules with particles containing a lubricant. Examples of the device used to fill capsules include "LIQFIL super" (Qualicaps Co., Ltd.), "GKF" (Bosch Packaging Technology), "ZANASI", "MATIC" (IMA) and the like.

Advantages of the Invention [0091] In accordance with the present invention, the use of sugar and / or sugar alcohol which exhibit specific properties may impart suitable plasticity to a kneaded mixture with a high content of intestinal methacrylic acid polymer. Thus, it is not necessary to add a plasticizer to the solid pharmaceutical product of the present invention, and thus it is free from the following disadvantages caused by the addition of a plasticizer: mixing with a plasticizer promotes metamorphosis and deformation of the intestinal methacrylic acid polymer, making it susceptible to film formation enteric polymer on the inside of the screen. Such films can cause screen clogging and extruder damage. In addition, the plasticizer remaining in the solid product simultaneously promotes metamorphosis and deformation of the intestinal methacrylic acid polymer. As a result of these changes, changes in the process of dissolution of the active substance in relation to time are unavoidable.

[0092] Since the solid pharmaceutical product of the present invention may contain large amounts of intestinal methacrylic acid polymer without the use of a plasticizer, the product exhibits a high level of release control ability that limits the release of the active substance in the upper gastrointestinal tract and rapidly accelerates the release of the active substances in the lower sections of the gastrointestinal tract.

[0093] The solid pharmaceutical product of the present invention contains intestinal methacrylic acid polymers with good pH response, thus showing high release control capacity. Accordingly, a coating process is not necessary that is carried out to produce gastroresistant products, products that release the active substance depending on time, products adapted to release in the colon, and the like. For this reason, according to the present invention, solid pharmaceutical products having the desired sustained release capacity can be produced inexpensively and very efficiently.

Brief Description of the Drawings [0094] Figure 1 shows the dissolution test results of the products obtained in the additional examples that illustrate the dissolution test results obtained for the products according to examples 24, 25 and 26.

Figure 2 shows the results of a study on changes in blood concentration after pre-food administration, based on the example of tolvaptan serum concentration after pre-food administration.

Figure 3 shows the change in blood concentration after administration after food, as exemplified by the serum concentration of tolvaptan after administration after food.

Figure 4 shows the in vitro correlation of in vivo results (level B) for additional examples, which is shown by plotting the relationship between mean residence time (MRT) and release time of 50% active substance (T50) for products according to examples 24-26 (in vitro correlation - in vivo).

Most Preferred Embodiment of the Present Invention Examples [0095] In the following, the present invention will be explained below in more detail in examples and comparative examples.

Example 1 [0096] Cilostazol (100 g), 15 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g Eudragit S100 (S methacrylic acid copolymer; Degussa AG) and 10 g Ceolus PH-301 ( crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 10 g of purified water are added as binding solutions and wet kneaded over 180 seconds. The kneaded product is gradually introduced into the Dome Gran DGL1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times at a rotation speed of 40 rpm to produce fine sliced ​​of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (spherical device; Fuji Paudal Co., Ltd.) equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 20 seconds at a rotation speed of about 1000 rpm, granules are obtained. The wet granules are dried in an SPHH-200 oven (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0097] The fine cut-off extrudates obtained in the above extrusion process significantly affect the quality and performance of the solid pharmaceutical product of the present invention. On a small scale, because the amount of kneaded product passed through the sieves is small, the pressure used for extruding the product is low during one run and the process efficiency is difficult to assess. Accordingly, if the yield is judged on the basis of a small amount of kneaded product, the kneaded product is passed through the screen of the device several times and thus the conditions generated by the solid composition accumulated in the gap between the screen and the screw are stabilized. Under these conditions, yield is preferably evaluated. In the examples below, one kneaded product is extruded three times and the temperature of the extruded product is measured after each extrusion. The plasticity of the kneaded product is determined depending on these temperature values.

[0098] Using an IR-101 non-contact infrared thermometer (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 1

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 24,2^aboutC</td>

<td>After the first extrusion</td><td> 31,3^aboutC</td>

<td>After the second extrusion</td><td> 33,0^aboutC</td>

<td>After the third extrusion</td><td> 33,0^aboutC</td>

<td>Temperature difference before and</td><td>Δ 7.1^aboutC</td>

<td>after the first extrusion</td><td></td>

[0099] These results indicate that by adding maltose monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 2 [0100] Cilostazol (100 g), 15 g Erythritol 100M (erythritol; Nikken Chemicals Co., Ltd.), 30 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH-301 ( crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water are added as binding solutions and wet kneaded over 160 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times at a screw rotation speed of 40 rpm to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 15 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0101] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 2

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 24,3^aboutC</td>

<td>After the first extrusion</td><td> 31,2^aboutC</td>

<td>After the second extrusion</td><td> 33,6^aboutC</td>

<td>After the third extrusion</td><td> 34,6^aboutC</td>

<td>Temperature difference before and</td><td>Δ 6.9^aboutC</td>

<td>after the first extrusion</td><td></td>

[0102] These results indicate that the addition of erythritol can give moderate plasticity to a wet kneaded product containing a large amount of methacrylic acid based copolymer S.

Example 3 [0103] Cilostazol (100 g), 15 g Sorbitol SP (sorbitol; Nikken Chemicals Co., Ltd.), 30 g Eudragit S100 (S copolymer with methacrylic acid; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 8 g of purified water and wet kneaded over 90 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times at a screw rotation speed of 40 rpm to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (spherical form making machine; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 20 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0104] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 3

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 24,4^aboutC</td>

<td>After the first extrusion</td><td> 30,3^aboutC</td>

<td>After the second extrusion</td><td> 34,6^aboutC</td>

<td>After the third extrusion</td><td> 38,0^aboutC</td>

<td>Temperature difference before and</td><td>Δ 5.9^aboutC</td>

<td>after the first extrusion</td><td></td>

[0105] These results indicate that by adding sorbitol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 4 [0106] Cilostazol (100 g), 15 g Lactitol LC-1 (lactitol monohydrate; Nikken Chemicals Co., Ltd.), 30 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH -301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water and wet kneaded are added as binding solutions, for 170 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times at a screw rotation speed of 40 rpm to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 25 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0107] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 4

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 3,6^aboutC</td>

<td>After the first extrusion</td><td> 31,6^aboutC</td>

<td>After the second extrusion</td><td> 34,6^aboutC</td>

<td>After the third extrusion</td><td> 38,2^aboutC</td>

<td>Temperature difference before and</td><td>Δ 8.0^aboutC</td>

<td>after the first extrusion</td><td></td>

[0108] These results indicate that by adding lactitol monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 5 [0109] Cilostazol (100 g), 15 g Trehalose P (trehalose dihydrate; Hayashibara Biochemical Laboratories, Inc.), 30 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH-301 ( crystalline cellulose; Asahi Kasei

Chemicals Corp.) is introduced into the Speed ​​Kneader

NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) aqueous solution are added as binding solutions, and 8.5 g of purified water and wet kneaded over 140 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times at a screw rotation speed of 40 rpm to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules. [0110] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 5

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 23,1^aboutC</td>

<td>After the first extrusion</td><td> 32,8^aboutC</td>

<td>After the second extrusion</td><td> 37,8^aboutC</td>

<td>After the third extrusion</td><td> 43,2^aboutC</td>

<td>Temperature difference before and</td><td>Δ 9.7^aboutC</td>

<td>after the first extrusion</td><td></td>

[0111] These results indicate that by adding trehalose dihydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 6 [0112] Cilostazol (100 g), 15 g Xylitol P (xylitol; Nikken Fine Chemicals Co., Ltd.), 30 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 8.5 g of purified water are added as binding solutions, and wet kneaded over 115 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times at a screw rotation speed of 40 rpm to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed in 25 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0113] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 6

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 23,1^aboutC</td>

<td>After the first extrusion</td><td> 31,3^aboutC</td>

<td>After the second extrusion</td><td> 33,3^aboutC</td>

<td>After the third extrusion</td><td> 37,6^aboutC</td>

<td>Temperature difference before and</td><td>Δ 8.2^aboutC</td>

<td>after the first extrusion</td><td></td>

[0114] These results indicate that by adding xylitol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Comparative Example 1 [0115] Cilostazol (100 g), 15 g Wyndale Lactose 200M (lactose monohydrate; The Lactose Company of New Zealand Limited), 30 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH -301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 10 g of purified water and wet kneaded over 240 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out twice at a screw rotation speed of 40 rpm; however, the third extrusion stops due to significant deposition on the DG-L1, which significantly changes the engine's operation.

[0116] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 7

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 3,5^aboutC</td>

<td>After the first extrusion</td><td> 51,7^aboutC</td>

<td>After the second extrusion</td><td> 56,0^aboutC</td>

<td>After the third extrusion</td><td>Not extruded</td>

<td>Temperature difference before and</td><td>Δ 28.2^aboutC</td>

<td>after the first extrusion</td><td></td>

[0117] These results indicate that when adding lactose monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer cannot be given.

Comparative Example 2 [0118] Cilostazol (100 g), 15 g Pearlitol 50C (D-mannitol; Roquette), 30 g Eudragit S100 (S copolymer with methacrylic acid; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose ; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 10 g of purified water and wet kneaded for 300 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out twice at a screw rotation speed of 40 rpm; however, the third extrusion stops due to the significant deposition of the mixture on the DG-L1, which significantly changes the engine operation.

[0119] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 8

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 24,3^aboutC</td>

<td>After the first extrusion</td><td> 42,7^aboutC</td>

<td>After the second extrusion</td><td> 53,2^aboutC</td>

<td>After the third extrusion</td><td>Not extruded</td>

<td>Temperature difference before and</td><td>Δ 18.4^aboutC</td>

<td>after the first extrusion</td><td></td>

[0120] These results indicate that the addition of D-mannitol cannot give moderate plasticity to a wet kneaded product containing a large amount of methacrylic acid based copolymer S.

Example 7 [0121] Cilostazol (100 g), 25 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH- 301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 18 g of purified water and wet kneaded over 320 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 20 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0122] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

Table 9

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 5,6^aboutC</td>

<td>After the first extrusion</td><td> 30,3^aboutC</td>

<td>After the second extrusion</td><td> 32,5^aboutC</td>

<td>After the third extrusion</td><td> 34,7^aboutC</td>

<td>Temperature difference before and</td><td>Δ 4.7^aboutC</td>

<td>after the first extrusion</td><td></td>

[0123] These results indicate that by adding maltose monohydrate, moderate plasticity of a wet kneaded product containing a high amount of methacrylic acid-based S copolymer can be imparted.

Example 8 [0124] Cilostazol (100 g), 25 g Erythritol 100M (erythritol; Nikken Fine Chemicals Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 15 g of purified water and wet kneaded over 100 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times, at a screw speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0125] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 10</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 22,9^aboutC</td>

<td>After the first extrusion</td><td> 32,6^aboutC</td>

<td>After the second extrusion</td><td> 34,3^aboutC</td>

<td>After the third extrusion</td><td> 38,7^aboutC</td>

<td>Temperature difference before and</td><td>Δ 9.7^aboutC</td>

<td>after the first extrusion</td><td></td>

[0126] These results indicate that by adding erythritol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 9 [0127] Cilostazol (100 g), 25 g Lactitol LC-1 (lactitol monohydrate; Nikken Fine Chemicals Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) aqueous solution are added as binding solutions, and 16.5 g of purified water and wet kneaded over 140 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules. [0128] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 11</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 25,0^aboutC</td>

<td>After the first extrusion</td><td> 31,0^aboutC</td>

<td>After the second extrusion</td><td> 3 6,5^aboutC</td>

<td>After the third extrusion</td><td> 3 9,5^aboutC</td>

<td>Temperature difference before and</td><td>Δ 6.0^aboutC</td>

<td>after the first extrusion</td><td></td>

[0129] These results indicate that by adding lactitol monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 10 [0130] Cilostazol (100 g), 25 g Sorbitol SP (sorbitol; Nikken Fine Chemicals Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 15 g of purified water and wet kneaded over 50 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ku50 production device; Fuji Paudal Co., Ltd.), equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 25 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0131] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 12</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 22,5^aboutC</td>

<td>After the first extrusion</td><td> 33,0^aboutC</td>

<td>After the second extrusion</td><td> 33,5^aboutC</td>

<td>After the third extrusion</td><td> 35,0^aboutC</td>

<td>Temperature difference before and</td><td>Δ 10.5^aboutC</td>

<td>after the first extrusion</td><td></td>

[0132] These results indicate that by adding sorbitol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 11 [0133] Cilostazol (100 g), 25 g Trehalose P (trehalose dihydrate; Hayashibara Biochemical Laboratories, Inc.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 ( crystalline cellulose; Asahi Kasei

Chemicals Corp.) is introduced into the Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) aqueous solution are added as binding solutions, and 16.5 g of purified water and wet kneaded over 110 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules. [0134] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 13</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 23,8^aboutC</td>

<td>After the first extrusion</td><td> 32,5^aboutC</td>

<td>After the second extrusion</td><td> 34,8^aboutC</td>

<td>After the third extrusion</td><td> 36,8^aboutC</td>

<td>Temperature difference before and</td><td>Δ 8.7^aboutC</td>

<td>after the first extrusion</td><td></td>

[0135] These results indicate that by adding trehalose dihydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 12 [0136] Cilostazol (100 g), 25 g Xylitol P (xylitol; Nikken Fine Chemicals Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 15 g of purified water and wet kneaded over 50 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (spherical form making machine; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed in 20 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0137] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 14</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 22,2^aboutC</td>

<td>After the first extrusion</td><td> 29,3^aboutC</td>

<td>After the second extrusion</td><td> 3 0,5^aboutC</td>

<td>After the third extrusion</td><td> 31,6^aboutC</td>

<td>Temperature difference before and</td><td>Δ 7.3^aboutC</td>

<td>after the first extrusion</td><td></td>

[0138] These results indicate that by adding xylitol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Comparative Example 3 [0139] Cilostazol (100 g), 25 g micronized sucrose in a hammer mill (granulated CH sugar; Ensuiko Sugar Refining Co., Ltd.), 60 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into the Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 30 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 17 g of purified water and wet kneaded over 90 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out twice at a screw rotation speed of 40 rpm; however, the third extrusion stops due to significant deposition on the DG-L1, which significantly changes the engine's operation.

[0140] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 15</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 3,6^aboutC</td>

<td>After the first extrusion</td><td> 42,7^aboutC</td>

<td>After the second extrusion</td><td> 50,3^aboutC</td>

<td>After the third extrusion</td><td> 55,2^aboutC (suspended)</td>

<td>Temperature difference before and</td><td>Δ 19.1^aboutC</td>

<td>after the first extrusion</td><td></td>

[0141] These results indicate that when adding sucrose, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer cannot be given.

Reference Example 1 [0142] Amorphous tolvaptan is prepared by the following method: 7-chloro-5-hydroxy-1- [2-methyl-4- (255 methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzoazepine (100 g) and 50 g hydroxypropyl cellulose (HPC-SL, with a hydroxypropoxyl content of 53 to 78% by weight; Nippon Soda Co., Ltd.) is dissolved in a mixture of methylene chloride (1390 g) and ethanol (350 g). The solution is then dried using a spray dryer (type ODT-8; Ohkawara Kakohki Co., Ltd.) and then dried using a vacuum dryer (LCV-232; Tabai Espec Corp.) to obtain an amorphous powder (amorphous tolvaptan) .

Example 13 [0143] Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 15 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g Eudragit S100 (S copolymer with methacrylic acid; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 15 g of purified water and wet kneading are added as binding solutions, in a wet condition for 110 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 device (device for producing ku56 list form; Fuji Paudal Co., Ltd.), equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extruded product is processed in 25 seconds, with rotation speeds of about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0144] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 16</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 23,2^aboutC</td>

<td>After the first extrusion</td><td> 2 8,0^aboutC</td>

<td>After the second extrusion</td><td> 27,7^aboutC</td>

<td>After the third extrusion</td><td> 2 9,5^aboutC</td>

<td>Temperature difference before and</td><td>Δ 4.8^aboutC</td>

<td>after the first extrusion</td><td></td>

[0145] These results indicate that by adding maltose monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 14 Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 15 g Erythritol 100M (erythritol; Nikken Fine Chemicals Co., Ltd.), 30 g Eudragit S100 (copolymer S with methacrylic acid; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 20 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 13 g of purified water and wet kneading are added as binding solutions, in 90 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (spherical form making machine; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed in 20 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0147] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 17</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 23,1^aboutC</td>

<td>After the first extrusion</td><td> 2 9,5^aboutC</td>

<td>After the second extrusion</td><td> 30,4^aboutC</td>

<td>After the third extrusion</td><td> 31,8^aboutC</td>

<td>Temperature difference before and</td><td>Δ 6.4^aboutC</td>

<td>after the first extrusion</td><td></td>

[0148] These results indicate that by adding erythritol, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 15 [0149] Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 15 g Lactitol LC-1 (lactitol monohydrate; Nikken Fine Chemicals Co., Ltd.), 30 g Eudragit S100 ( S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 13 g of purified water are added as binding solutions, and wet kneaded over 120 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming machine; Fuji Paudal Co., Ltd.), equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0150] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 18</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 24,2^aboutC</td>

<td>After the first extrusion</td><td> 30,3^aboutC</td>

<td>After the second extrusion</td><td> 31,2^aboutC</td>

<td>After the third extrusion</td><td> 3 6,5^aboutC</td>

<td>Temperature difference before and</td><td>Δ 6.1^aboutC</td>

<td>after the first extrusion</td><td></td>

[0151] These results indicate that by adding lactitol monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Example 16 [0152] Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 15 g Trehalose P (trehalose dihydrate; Hayashibara Biochemical Laboratories, Inc.), 30 g Eudragit

S100 (S-methacrylic acid copolymer; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.) . Then, 20 g of a 5% (w / v) aqueous HPC-L solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 14.5 g of purified water are added as binding solutions, and wet kneaded over 130 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw rotation speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 20 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 to 3 hours to obtain dried granules.

[0153] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 19</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 22,9^aboutC</td>

<td>After the first extrusion</td><td> 28,1^aboutC</td>

<td>After the second extrusion</td><td> 29, 1^aboutC</td>

<td>After the third extrusion</td><td> 31,5^aboutC</td>

<td>Temperature difference before and</td><td>Δ 5.2^aboutC</td>

<td>after the first extrusion</td><td></td>

[0154] These results indicate that by adding trehalose dihydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer can be imparted.

Comparative Example 4 [0155] Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 15 g Lactose 200M Vandals (lactose monohydrate; The Lactose Company of New Zealand Limited), 30 g Eudragit S100 (copolymer S with methacrylic acid; Degussa AG), and 10 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) HPC-L aqueous solution (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 17.5 g of purified water and wet kneaded over 140 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out twice at a screw rotation speed of 40 rpm; however, it stops during the third extrusion due to significant deposition on the DG-L1, which significantly changes the engine's operation.

[0156] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>bale 20</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 3,6^aboutC</td>

<td>After the first extrusion</td><td> 42,6^aboutC</td>

<td>After the second extrusion</td><td> 49,2^aboutC</td>

<td>After the third extrusion</td><td> 56,5^aboutC (suspended)</td>

<td>Temperature difference before and</td><td>Δ 19.0^aboutC</td>

<td>after the first extrusion</td><td></td>

[0157] These results indicate that when adding lactose monohydrate, moderate plasticity of a wet kneaded product containing a large amount of methacrylic acid-based S copolymer cannot be given.

Example 17 [0158] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 54 g Eudragit S100 ( S-methacrylic acid copolymer; Degussa AG), and 18 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then 60 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., is added as binding solutions.

Ltd.), and 11 g of purified water and wet kneaded in 180 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out six times, at a screw speed of 40 rpm, to produce fine cuttings of about 2 to 4 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain matrix granules. The matrix granules are sieved to obtain a granule fraction with dimensions from 600 to 1000 gm.

1. Measurement of particle size distribution [0159] The particle size of the matrix granules (about 5 g) is measured with a Robot Shifter RPS-95 (Seishin Enterprise Co., Ltd.) based on a particle size measurement method (dry screening method) defined in General Tests at Japanese Pharmacopoeia. The average particle size for matrix granules is 770 gm.

2. Decomposition measurement [0160] Matrix granules (140.4 g) obtained by the method of Example 17 are thoroughly mixed with 0.6 g anhydrous silicic acid (Adsolider-101; YKF Inc.). The mixture is filled into a size 3 hypromellose capsule (QUALI-V capsules; Qualicaps Co., Ltd.), introducing an amount corresponding to 60 mg of tolvaptan. Capsules containing matrix granules are placed in plastic containers and stored at 60 ° C for two weeks.

[0161] The above-mentioned matrix granules are powdered in a mortar and an equivalent amount of 30 mg tolvaptan is obtained. Then, methanol is added and sonicated to completely disintegrate the granules. Methanol is then added and the mixture is filtered through a membrane filter with a pore size of approximately 0.5 gm. The filtrate obtained is determined using the LC-2010 CT (liquid pressure chromatography; Shimadzu Corp.) system by measuring at 254 nm and using a mobile phase (acetonitrile, water and phosphoric acid in a volume ratio of 500: 500: 1) at a rate of about 1 ml flow. The test is conducted to detect the presence of a certain degradation product, which in this specification is referred to as degradation product A. The concentration of the degradation product A is calculated by means of a percentage assessment of the surface area (ratio of the peak area corresponding to the degradation product A to the surface of the tolvaptan peak).

[0162] Examination of the degradation product A concentration before and after storage, it was found that the concentration of degradation product A was 0.01% immediately after manufacture, and 0.02% after storage at 60 ° C during two weeks. This means that the formation of decomposition products is limited.

3. Active substance release study [0163] Using the release process study system - DT-610 (Jasco Corp.), a tolvaptan release study from capsules containing matrix granules is performed according to a second release test method (agitator method) according to Japanese Pharmacopoeia. Polysorbate 80 is added to a diluted McIlvaine buffer, pH 7.4, to provide a concentration of 1% w / v. This solution (900 ml) is used as a solution for testing the release process. The agitator rotational speed is 50 rpm and measurements are made at 268 nm and 350 nm wavelengths.

[0164] The following table shows the release amount and the differences in release amount before and after storage at 60 ° C during two weeks (the value defined as "Δ release rate" is calculated by subtracting the value obtained after storage at 60 ° C within two weeks of the value obtained immediately after the manufacturing process).

Table 21

<td>Sampling time</td><td>Directly after manufacturing</td><td>After storage during 2 weeks at 60^aboutC</td><td>Δ size release</td>

<td>0.5 hours</td><td> 20,9%</td><td> 20,4%</td><td> 0,5%</td>

<td>1 hour</td><td> 58,4%</td><td> 58,6%</td><td> -0,2%</td>

<td>2 hours</td><td> 88,3%</td><td> 92,6%</td><td> -4,3%</td>

[0165] Table 21 shows that slight changes in the amount of tolvaptan release occur when testing capsules containing matrix granules, obtained according to example 17, measured immediately after manufacture, and after storage at 60 ° C for two weeks. This clearly demonstrates the stability of the solid product of the present invention.

Comparative Example 5 [0166] Amorphous tolvaptan (45 tolvaptan content of 30 g), obtained by the method of reference example 1, 45 g Pearlitol 50C (D-mannitol; Roquette), 30 g Eudragit S100 (copolymer S with methacrylic acid; Degussa AG), and 10 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into the NMG1L (Nara Model High Shear Miner Granulator; Nara Machinery Co., Ltd.). Then, 40 g of a mixture (1: 1 weight ratio) with 4% (w / v) aqueous HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 4% w / v aqueous polysorbate solution are added as binding solutions. 80 (polysorbate 80 (HM); NOF Corporation) and wet kneaded for 30 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out twice, with a screw rotation speed of 40 rpm, to obtain sliced ​​type extrusions with a length of about 2 to 4 cm. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 60 seconds at a rotation speed about 1000 rpm, with wet granules being obtained. The wet granules are dried with an SPHH-200 apparatus (taco oven; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain matrix granules. The matrix granules are sieved to obtain a granule fraction with dimensions from 355 to 850 μη.

[0167] The particle size distribution is measured in a manner identical to that described in Example 17, and the average particle size for the matrix granules is 690 μη.

[0168] After measuring the particle size and conducting the dissolution test, the amount of degradation product A is determined in the matrix granules immediately after manufacture, and in the matrix granules placed in an airtight (airtight) container, stored for one year at room temperature. Measurement of particle size and dissolution test and amount of degradation product A are carried out on these granules after storage for one year at room temperature. The matrix granules stored for one year at room temperature are again placed in a glass, sealed container and further stored at 60 ° C for two weeks. The measurement and testing of the solubility of the degradation product A are then carried out on the matrix granules after two weeks storage at 60 ° C. The measurement of the degradation product A is carried out in the same way as in Example 17. The solubility test is carried out according to the following method.

Active substance release test [0169] Using the DT-610 dissolution test system (Jasco Corp.), the release of tolvaptan from matrix granules is determined according to a second release test method (stirrer method) according to Japanese Pharmacopoeia. Polysorbate 80 to 68 is added to a diluted McIlvaine buffer, pH 7.0, to bring the concentration value to 1% by weight / volume. This solution (900 ml) is used as a solution in the release test. The speed of rotation of the stirrer was 100 rpm, the measurement was made at a wavelength of 268 nm and 350 nm.

[0170] Table 22 shows the results of measuring the amount of degradation product A.

<td>this</td><td>bale 22</td>

<td>A sample</td><td>The amount of resulting product</td>

<td></td><td>distribution A.</td>

<td>Immediately after manufacture</td><td> 0,01%</td>

<td>After storage during 1</td><td> 0,13%</td>

<td>a year at room temperature</td><td></td>

<td>After two weeks,</td><td> 0,48%</td>

<td>bursts at 60^aboutC</td><td></td>

[0171] Table 23 shows the results of the release study. In the table, the term "Δ release value" was calculated by subtracting the release amount after two weeks storage at 60 ° C from the release amount obtained after one year storage at room temperature.

Table 23

<td>Time</td><td>Directly</td><td>After time 1</td><td>After time 2</td><td>Δ</td><td>large-</td>

<td>bierania</td><td>after producing</td><td>year</td><td>weeks</td><td>COMPONENTS</td><td>release</td>

<td>samples</td><td>NIU</td><td>wailing at room temperature</td><td>storing in temperature 60^aboutC</td><td colspan="2">nanny</td>

<td>0.5 hours</td><td> 53,4%</td><td> 56,2%</td><td> 34,2%</td><td colspan="2"> 22,0%</td>

<td>1 hour</td><td> 98,0%</td><td> 81,4%</td><td> 52,9%</td><td> 28,5%</td>

<td>2 hours</td><td> 99,7%</td><td> 92,7%</td><td> 67,7%</td><td> 25,0%</td>

[0172] If the matrix granules contain a plasticizer (polysorbate 80), the amount of degradation product A formed increases significantly and the amount of release decreases significantly. In addition, during storage for one year at room temperature, the amount of decomposition product A formed increases, and the amount of release remains constant. These results show that the matrix granules obtained by the method of Comparative Example 5 give much worse results due to the amount of release of the active substance over time.

Example 18 [0173] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 18 g Eudragit S100 ( S-methacrylic acid copolymer; Degussa AG), and 18 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 60 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) is added as binding solutions, and 15 g of purified water and wet kneaded over 250 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out five times, at a screw speed of 60 rpm, to produce fine cuttings of the sliced ​​type about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed within 50 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules. The dried granules are sieved through sieves separating particles from 600 gm to 1000 gm. The dried granules contain 7.4% by weight of methacrylic acid based copolymer S.

Example 19 [0174] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g Eudragit S100 ( S-methacrylic acid copolymer; Degussa AG), and 18 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 60 g of a 5% (w / v) aqueous HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) solution is added as binding solutions, and 8 g of purified water and wet kneaded over 160 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out six times at a rotational speed of 60 revolutions per minute to produce fine cuttings of about 10 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed in 25 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules. The dried granules are sieved through sieves separating particles from 600 gm to 1000 gm. The dried granules contain 11.7% by weight of methacrylic acid based copolymer S.

Example 20 [0175] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 54 g Eudragit S100 (S -methacrylic acid copolymer; Degussa AG), and 18 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 60 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 11 g of purified water and wet kneaded over 180 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome-shaped matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out six times, at a screw speed of 60 rpm, to produce fine cuttings of the slice type about 3 to 5 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules. The dried granules are sieved through sieves separating particles from 600 gm to 1000 gm. The dried granules contain 19.2% by weight of methacrylic acid S copolymer.

Comparative Example 6 [0176] Amorphous tolvaptan (90 g tolvaptan content of 60 g), obtained by the method of reference example 1, 12.9 g Sunmalt-S (maltose monohydrate;

Sanwa Cornstarch Co., Ltd.), and 18 g of Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.) . Then, 30 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) and 6 g of purified water are added as binding solutions, and wet kneaded over 210 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome-shaped matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out five times at a screw speed of 60 rpm to produce fine cuttings of about 1 to 2 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 60 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules. The dried granules are sieved through sieves separating particles from 600 μη to 1000 μη. The dried granules do not contain methacrylic acid based S copolymer.

Release test [0177] Using the DT-610 release test system (Jasco Corp.), tolvaptan dissolution test from matrix granules is performed according to a second release test method (agitator method) according to Japanese Pharmacopoeia. The following solutions were used: test solution 1 and 2.

[0178] Test solution 1: 900 ml solution in which Polysorbate 80 was added to the first solution (pH 1.2) as a solution for dissolution testing according to the 15th edition of Japanese Pharmacopoeia, to bring the concentration to 1% by weight.

[0179] Test solution 2: 900 ml solution in which Polysorbate 80 was added to diluted McIlvaine buffer (pH 7.4) to bring the concentration to 1% w / v.

[0180] The stirrer rotation speed for both solutions was 50 rpm and measurements were made at wavelengths of 268 nm and 350 nm.

[0181] Table 24 shows the results of the release test for test solution 1. The numerical values ​​in this table are presented as the average value for the three tests.

<td colspan="3">Table 24</td><td colspan="2"></td>

<td>Download time</td><td>Example</td><td>Example</td><td>Example</td><td>Example</td>

<td>rania</td><td>comparative</td><td> 18</td><td> 19</td><td> 20</td>

<td>samples</td><td> 6</td><td></td><td></td><td></td>

<td>0.5 hours</td><td> 6,5%</td><td> 6,1%</td><td> 6,8%</td><td> 6,9%</td>

<td>1 hour</td><td> 11,6%</td><td> 10,8%</td><td> 11,9%</td><td> 11,6%</td>

<td>2 hours</td><td> 19,3%</td><td> 17,3%</td><td> 19,8%</td><td> 18,7%</td>

[0182] Under acidic conditions, at pH 1.2, no difference was observed in the release of the active substance from the granules, nor any difference in the content of the methacrylic acid-based polymer.

[0183] Table 25 shows the results of the release test obtained using test solution 2. The results in the table are mean values ​​for the three determinations.

Table 25

<td>Download time</td><td>Example</td><td>Example</td><td>Example</td><td>Example</td>

<td>rania</td><td>comparative</td><td> 18</td><td> 19</td><td> 20</td>

<td>samples</td><td> 6</td><td></td><td></td><td></td>

<td>0.5 hours</td><td> 6,3%</td><td> 9,8%</td><td> 12,7%</td><td> 31,9%</td>

<td>1 hour</td><td> 11,5%</td><td> 18,5%</td><td> 30,1%</td><td> 72,1%</td>

<td>2 hours</td><td> 18,8%</td><td> 30,2%</td><td> 54,3%</td><td> 97,6%</td>

[0184] In the area of ​​pH values ​​in which polymers based on methacrylic acid dissolve, the release of the active substance accelerates to the given values; however, the product obtained according to Comparative Example 6 shows exactly the same release capabilities that it exhibited under acidic conditions.

Example 21 [0185] Phenytoin (100 g, Sigma-Aldrich), 60 g Erythritol (erythritol; Nikken Fine Chemicals Co., Ltd.), 15 g Eudragit S100 (S-methacrylic acid copolymer; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 40 g of a 5% (w / v) HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) aqueous solution are added as binding solutions, and 9.5 g of purified water and wet kneaded over 150 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a hatched plate in which the jumps are separated by 3 mm intervals, the extrudate is processed for 10 seconds at a speed of about 1000 rpm , wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules.

[0186] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>balls 26</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 2 4,9^aboutC</td>

<td>After the first extrusion</td><td> 26,8^aboutC</td>

<td>After the second extrusion</td><td> 27,1^aboutC</td>

<td>After the third extrusion</td><td> 27,0^aboutC</td>

<td>Temperature difference before and</td><td>Δ 1.9^aboutC</td>

<td>after the first extrusion</td><td></td>

Example 22 [0187] Aspirin (acetylsalicylic acid, 100 g, Wako Pure Chemical Industries, Ltd.), 10 g Lactitol LC-1 (lactitol; Nikken Fine Chemicals Co., Ltd.), 40 g Eudragit S100 (dry copolymer S with methacrylic acid; Degussa AG), and 20 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 40 g of a 5% (w / v) HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) aqueous solution are added as binding solutions, and 9 g of purified water and wet kneaded over 130 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 19.3%. Extrusion is carried out three times, at a screw speed of 40 rpm, to produce fine cuttings of about 2 to 3 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules.

[0188] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>balls 27</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 25,0^aboutC</td>

<td>After the first extrusion</td><td> 32,6^aboutC</td>

<td>After the second extrusion</td><td> 34,6^aboutC</td>

<td>After the third extrusion</td><td> 34,6^aboutC</td>

<td>Temperature difference before and</td><td>Δ 7.6^aboutC</td>

<td>after the first extrusion</td><td></td>

Example 23 [0189] Naproxen (15 g, Sigma-Aldrich), 30 g Trehalose P (trehalose dihydrate; Hayashibara Biochemical Laboratories, Inc.), 40 g Eudragit L100D55 (dry LD copolymer with methacrylic acid; Degussa AG), and 30 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) is introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Oka78 da Seiko Co., Ltd.). Then, 20 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 4.5 g of purified water and wet kneaded over 140 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome matrix having 0.6 mm pores and a gap size of 22.6%. Extrusion is carried out three times, at a screw speed of 40 rpm, to produce fine cuttings of about 4 to 5 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 30 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 2 hours to obtain dried granules.

[0190] Using a non-contact infrared thermometer, type IR-101 (Technoline Ltd.), the temperature of the kneaded product after kneading is measured, and the temperature of the kneaded product after each extrusion. The results are given in the table below.

<td>this</td><td>balls 28</td>

<td>Wet kneaded product</td><td>Measured temperature</td>

<td>After wet kneading</td><td> 25,0^aboutC</td>

<td>After the first extrusion</td><td> 34,5^aboutC</td>

<td>After the second extrusion</td><td> 35,9^aboutC</td>

<td>After the third extrusion</td><td> 36,4^aboutC</td>

<td>Temperature difference before and</td><td>Δ 9.5^aboutC</td>

<td>after the first extrusion</td><td></td>

Example 24 [0191] The dried granules (196 g) obtained by the method of Example 20 are mixed with 0.8 g Adsolider-101 (silicon dioxide; YKF Inc.), and 141 mg of the obtained granules are filled into a hypromellose capsule size 3. The capsule contains 60 mg tolvaptan.

Example 25 [0192] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 30 g Eudragit S100 (S -methacrylic acid copolymer; Degussa AG), and 18 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 60 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 3 g of purified water and wet kneaded over 180 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome-shaped matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out four times at a screw rotation speed of 60 rpm to produce fine cuttings of about 2 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 60 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 4 hours to obtain dried granules. The dried granules are sieved through sieves separating particles of 780 μη. The granules (179 g) are mixed with 0.8 g Adsolider-101 (silicon dioxide; YKF Inc.), and the resulting granules in the amount of 129 mg are filled into a hypromellose capsule size 3. The capsule contains 60 mg tolvaptan.

Example 26 [0193] Amorphous tolvaptan (180 g tolvaptan content of 120 g), obtained by the method of reference example 1, 25.8 g Sunmalt-S (maltose monohydrate; Sanwa Cornstarch Co., Ltd.), 54 g Eudragit S100 (S -methacrylic acid copolymer; Degussa AG), and 30 g Ceolus PH-301 (crystalline cellulose; Asahi Kasei Chemicals Corp.) are introduced into a Speed ​​Kneader NSK-150 (mixing granulator; Okada Seiko Co., Ltd.). Then, 60 g of a 5% (w / v) aqueous solution of HPC-L (hydroxypropyl cellulose; Nippon Soda Co., Ltd.) are added as binding solutions, and 16 g of purified water and wet kneaded over 180 seconds. The kneaded product is gradually introduced into the Dome Gran DG-L1 (extruder; Fuji Paudal Co., Ltd.) equipped with a dome-shaped matrix having 0.8 mm pores and a gap size of 22.5%. Extrusion is carried out four times, at a screw speed of 60 rpm, to produce fine extrudates of the sliced ​​type about 2 cm in length. Using the Marumerizer QJ-400 (ball forming device; Fuji Paudal Co., Ltd.), equipped with a dashed plate in which the jumps are separated by 3 mm intervals, the extruded product is processed for 60 seconds at a speed of about 1000 rpm, wet granules are obtained. The wet granules are dried using an SPHH-200 apparatus (tray furnace; Tabai Espec Corp.) at 70 ° C for 4 hours to obtain dried granules. The dried granules are sieved through sieves separating particles of 780 pm. The granules (217 g) are mixed with 0.9 g Adsolider-101 (silicon dioxide; YKF Inc.), and the resulting granules in an amount of 147 mg are filled into a number 3 hypromellose capsule. This capsule contains 60 mg of tolvaptan.

Method of testing the active substance release process [0194] Using the NTR-6200A active substance release testing system (Toyama Sangyo Co., Ltd.), the release of tolvaptan from capsules obtained by the methods set out in Examples 24, 25 and 26 according to the second test method release (stirrer method) according to Japanese Pharmacopoeia. The following test solution was used.

[0195] Test solution: 900 ml of the solution in which polysorbate 80 is added to the second solution (pH 6.8) as a test release solution according to the 15th edition of Japanese Pharmacopoeia to obtain a concentration of 1% w / v.

Measurements at wavelength: λ1 - 268 mm; λ2 - 350 nm.

Agitator rotation speed: 100 rpm.

Number of samples: n = 6.

Sampling time: 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours.

Calculation of time for 50% release (T50) of the active substance [0196] The time needed for the 50% release of tolvaptan is determined from Figure 1.

Table 29

Release time for 50% tolvaptan from products obtained according to examples 24, 25 and 26 (T.₅₀)

<td></td><td>Example 24</td><td>Example 25</td><td>Example 26</td>

<td>^T50</td><td>3.72 hours</td><td>4.28 hours</td><td>7.03 hours</td>

Study after oral administration [0197] To confirm the effect of sustained release from the solid pharmaceutical product of the present invention, a study was conducted after oral administration to healthy volunteers. Eighteen healthy men and women (aged 18 to 45) were randomly divided into three groups of six people - group A, group B and group C. An incomplete cross-trial with three groups in four stages is carried out according to the following scheme.

Table 30

<td>sch</td><td colspan="2">dosage emat in the study of</td><td colspan="2">orally</td>

<td>Group</td><td>1st stage</td><td>2nd stage</td><td>3rd stage</td><td>4th stage</td>

<td>AND</td><td>Tablets from</td><td>Example</td><td>Example</td><td>Example</td>

<td></td><td>release</td><td>24, delivery</td><td>25</td><td>25, giving</td>

<td></td><td>direct,</td><td>not before</td><td>not before</td><td>after</td>

<td></td><td>served before</td><td>meal</td><td>meal</td><td>meal</td>

<td></td><td>a double meal</td><td>once a day</td><td>once a day</td><td>once a day</td>

<td></td><td>fold in time</td><td></td><td></td><td>BE</td>

<td></td><td>day</td><td></td><td></td><td></td>

<td>B</td><td>Tablets from release direct, served before twice a day</td><td>Example 26, administration before meal once a day</td><td>Example 24, administration before meal once a day</td><td>Example 24, administration after meal once a day</td>

<td>C</td><td>Tablets from</td><td>Example</td><td>Example</td><td>Example</td>

<td></td><td>release</td><td>25</td><td>26, delivery</td><td>26, giving</td>

<td></td><td>direct,</td><td>not before</td><td>not before</td><td>after</td>

<td></td><td>served before</td><td>meal</td><td>meal</td><td>meal</td>

<td></td><td>a double meal</td><td>once a day</td><td>once a day</td><td>once a day</td>

<td></td><td>fold in time</td><td></td><td></td><td>BE</td>

<td></td><td>day</td><td></td><td></td><td></td>

[0198] In the first step, immediate-release tablets are administered to volunteers from each group before meals, twice a day. Two tablets, including 45 mg tolvaptan in total (one 30 mg tablet and one 15 mg tablet), are administered orally, before eating early in the morning; and the 15 mg tablet is given orally after 8 hours. The daily dose of tolvaptan is 60 mg. In a second step, different capsules obtained by the methods of examples 24, 25 and 26 before a meal are orally administered to volunteers from each group. In the third stage, capsules obtained by the methods of Examples 24, 25 and 26, other than those administered in the second stage, were orally administered to volunteers from each group before meals. In the fourth step, the same capsules obtained by the methods of Examples 24, 25 and 26 as administered in the third step are administered orally after a meal. The meals were high-fat foods prepared according to the US FDA guide (Non-Patent Document 2). Capsules obtained according to the methods of Examples 24, 25 and 26 were administered orally after 30 minutes, after each meal. The number of cases where the immediate release tablets and capsules obtained according to the methods of Examples 24, 25 and 26 were administered before a meal were 18 and 12, respectively, and in six cases, the capsules obtained by the methods of Examples 24, 25 and 26 were given after a meal. The following are compositions for direct release tablets.

[0199] Non-patent document 2: guide - Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies., US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER), December 2002.

Comparative Example 7 mg tablets (immediate release tablets) [0200] Amorphous tolvaptan (112.5 g; tolvaptan amount: 75 g) obtained by the method of reference example 1, 185 g lactose monohydrate, 50 g corn starch and 50 g crystalline cellulose is mixed in a fluidized bed granulating dryer (Multiplex MP-01; Powrex Corporation). Granulation and drying in a fluidized bed is carried out using 200 g of a 5% w / v aqueous hydroxypropyl cellulose solution containing hydroxypropoxy groups in an amount of 53 to 78% by weight to obtain a granulated product. Granulated products are mixed with

22.5 g LH-11 (low substituted hydroxypropyl cellulose) and 5 g magnesium stearate to obtain granules for the preparation of tablets. Granules, using a rotary tableting machine (12HUK-AWC; Kikusui Seisakusho Ltd.), using a pressure of 900 kg and at a speed of 40 rpm extruded tablets that have a mass of about 174 mg, have a diameter of 8 mm and contain 30 mg of tolvaptan.

Comparative example 8 mg tablets (immediate release tablets) [0201] Amorphous tolvaptan (56.3 g; with the amount of tolvaptan:

37.6 g) obtained by the method of reference example 1, 256.3 g lactose monohydrate, 50 g corn starch and 50 g crystalline cellulose are mixed in a fluidized bed granulating dryer (Multiplex MP-01; Powrex Corporation). Granulation and drying in a fluidized bed is carried out using 200 g of a 5% w / v aqueous hydroxypropyl cellulose solution containing hydroxypropoxy groups in an amount of 53 to 78% by weight to obtain a granulated product. Granulated products are mixed with

22.5 g LH-11 (low substituted hydroxypropyl cellulose) and 5 g magnesium stearate to obtain granules for the preparation of tablets. The granules, using a rotary tableting machine (12HUK-AWC; Kikusui Seisakusho Ltd.), using a pressure of 1000 kg and a speed of 50 rpm, tablets are extruded which have a mass of about 180 mg, have a diameter of 8 mm and contain 15 mg of tolvaptan.

Test [0202] Blood samples are taken periodically and tolvaptan concentration is determined in serum. The pharmacokinetic parameter is calculated using the WinNonlin program (ver. 4.0; Pharsight Corporation) and the PSAG-CP program (Asmedica Co.).

[0203] Figure 2 shows the serum concentration of tolvaptan after administration of test products before meals.

Figure 3 shows the serum concentration of tolvaptan after food administration.

Table 31

<td colspan="2">Pharmacokinetic parameters for</td><td>each sweat</td><td colspan="2">oral ana</td>

<td>Pharmacological parameter</td><td>Tablets from</td><td>Example</td><td>Example</td><td>Example</td>

<td>kinetic</td><td>direct</td><td> 24,</td><td> 25,</td><td> 26,</td>

<td></td><td>release</td><td>60 mg</td><td>60 mg</td><td>60 mg</td>

<td></td><td>45 mg + 15</td><td></td><td></td><td></td>

<td></td><td>mg</td><td></td><td></td><td></td>

<td colspan="5">Administration before a meal (immediate-release tablets,</td>

<td>n = 18; examples 24</td><td>-26, n = 12)</td><td></td><td></td><td></td>

<td>Cmax (ng / ml)</td><td> 414±96,3</td><td> 375±168</td><td> 385±175</td><td> 441±168</td>

<td>AUC</td><td> 4840±1520</td><td> 5660±1730</td><td> 6300±2510</td><td> 5950±1990</td>

<td>(Ng.h / ml)</td><td></td><td></td><td></td><td></td>

<td>t1 / 2 (h)</td><td> 7,6±1,9</td><td> 9,2±1,9</td><td> 10,1±3,0</td><td> 10,2±3,1</td>

<td>C24h (ng / ml)</td><td> 49,5±26,5</td><td> 88,1±41,0</td><td> 102,8±38,6</td><td> 113,3±90,4</td>

<td>MRT_t (H)</td><td>_-</td><td> 15,91±3,64</td><td> 15,84±1,75</td><td> 15,22±2,60</td>

<td colspan="5">Administration after a meal (n = 6)</td>

<td>Cmax (ng / ml)</td><td></td><td> 505±80,8</td><td> 507±185</td><td> 588±102</td>

<td>AUC</td><td></td><td> 5300±1580</td><td> 6349±2870</td><td> 7710±2430</td>

<td>(Ng.h / ml)</td><td></td><td></td><td></td><td></td>

<td>t1 / 2 (h)</td><td></td><td> 7,7±1,4</td><td> 7,5±3,1</td><td> 8,0±1,8</td>

<td>C24h (ng / ml)</td><td></td><td> 63,9±34,9</td><td> 90,3±40,7</td><td> 164,6±83,9</td>

<td>MRT_t (H)</td><td></td><td> 12,61±1,90</td><td> 13,91±1,23</td><td> 15,65±2,82</td>

[0204] Figure 4 schematically shows the relationship between mean residence time (MRT) and release time of 50% active substance (T50) for products according to examples 24-26 (in vitro correlation - in vivo). Level B indicates a good relationship between MRT and T50 according to the US FDA guide (Non-Patent Document 3).

[0205] Non-patent document 3: guide - Guidance for Industry Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / In Vivo Correlations, US Department of Health and Human Services, Food and Drug Administration, and Center for Drug Evaluation and Research (CDER), September 1997.

Examination of color changes during long-term storage of samples obtained according to the tested methods [0206] Granules obtained by the methods of examples 13, 14, and 16 were enclosed in polyethylene bags and stored at room conditions for one year or more. Under these conditions, temperature and humidity were not controlled. Color changes were visually assessed before and after storage. In addition, the hardness of the granules was assessed manually.

<td>A sample</td><td>Sugar / Sugar Sugar</td><td>tint</td><td>Hardness</td>

<td></td><td>cow</td><td></td><td>pellets</td>

<td>Example 13</td><td>Maltose monohydrate</td><td>No change</td><td>No change</td>

<td>Example 14</td><td>erythritol</td><td>No change</td><td>No change</td>

<td>Example 15</td><td>Lactitol monohydrate</td><td>No change</td><td>No change</td>

<td>Example 16</td><td>Trehalose dihydrate</td><td>No change</td><td>No change</td>

[0207] No change in the color or hardness of the granules obtained according to the methods of examples 13 to 16 was observed.

Industrial use [0208] The solid pharmaceutical product of the present invention can be used in many medical applications. Particularly, a solid product, without the use of a plasticizer, can provide excellent plasticity to kneaded products during manufacture. In addition, the product avoids problems resulting from the addition of a colorizer; pro88 duct is therefore very useful. In addition, the product has a high utility value as a solid pharmaceutical product with sustained release of the active substance for oral administration.