VITAMIN-CONTAINING GRANULES AND PRODUCTION THEREOF

Abstract: A vitamin-containing granule substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt and a binding agent, said compound or compounds ac­ counting for 90 to 99 weight % on a dry basis can be prepared by spray-coating the powders of said compound or com­ pounds with a solution containing a binder while maintaining the powders in a fluidized state in a fluidized-bed granulation apparatus. The granules are of high flowability and blend well with other medicaments, granules, additives, and so on. In addi­ tion to this, the granules are excellent in compressibility so that they can be processed into tablets with small amounts of excipients and the tablets therefrom have satisfactory high hardness.

Description: The present invention relates to a granule for direct compression containing one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt, a process for preparation thereof, and tablets produced therefrom. Vitamin B₆, vitamin B₂, nicotinamide and calcium pantothenate are often administered alone or in combination with other vitamins and/or drugs in the form of tablets. Tablets are generally prepared by compression of powders as such or after preliminary granulation. It would be expedient if tablets could be produced directly from powders without preliminary granulation. However, vitamin B₆, vitamin B₂, nicotinamide and calcium pantothenate are lacking in flowability and compressibility which are necessary for tableting and, therefore, cannot be compressed directly from powders. For this reason, vitamin B₆, vitamin B₂, nicotinamide, and calcium pantothenate are granulated in combination with other vitamins, pharmacollogically active substances and/or excipients by a conventional wet kneading granulation process and, then, compressed into tablets from the resulting granules. The wet granulation of vitamin B₆, vitamin B₂, nicotinamide and calcium pantothenate can hardly give a homogenous granule. The granules so produced are not very good in flowability. Tablets obtained therefrom are not satisfactory in mechanical strength. Furthermore, granules obtained by the wet granulation demand a large amount of excipient in the tableting step and this leads to a great increase in the tablet weight, resulting in difficulty in taking the tablet. US-A-3,308,217 describes a granulation method involving the uniform mixing of dry particles of a physiologically active material liable to damage at elevated temperatures with dry particles of a physiologically inactive but compatible thermoplastic material which softens at a temperature below the temperature at which the active material is damaged, heating the resulting mixture above the softening temperature of the thermoplastic material but below the temperature at which damage would be caused to the active material to cause agglomeration of the two sets of particles and cooling the resulting powdered agglomerates to a temperature below the softening point of the thermoplastic material so as to form a granulate which can be directly pressed into tablets. Amongst the physiologically active materials described are riboflavin (vitamin B₂) and pyridoxine hydrochloride (vitamin B₆). US-A-4372968 and EP-A-178138 describe the formation of granules containing sodium L-ascorbate and a thiamine salt, respectively, in which a powder of the active component is spray coated in a fluidized-bed granulator with a binder such as a water-soluble cellulose. EP-A-178 138 is an intermediate document within the meaning of Art. 54(3)EPC. The present inventors conducted an intensive research to overcome the above-mentioned disadvantages and found that the granulation of powders of vitamin B₆, vitamin B₂, nicotinamide, and calcium pantothenate in a fluidized-bed granulator using a small amount of a water-soluble cellulose as a binding agent can produce granules capable of being tableted with a small quantity of an excipient and the granules give tablets having a satisfactory high hardness. The findings were followed by a further investigation which has resulted in the present invention. Thus, the present invention is concerned with (1) a vitamin-containing granule substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt and a water-soluble cellulose as a binding agent, with said compound or compounds accounting for about 90 to 99 weight percent on a dry basis, (2) a process for the preparation of vitamin-containing granules which comprises fluidizing powders of one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt, at least about 95 weight percent of said powders passing a 100-mesh sieve (JIS) (149 µm sieve opening), in a fluidize-bed granulator, and spraying the powders so fluidized with a solution containing 1 to 10 weight percent of a water-soluble cellulose as a binding agent based on the total dry weight of product granules, and (3) a tablet produced by compressing vitamin-containing granules substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt and a water-soluble cellulose as a binding agent, said compound or compounds accounting for about 90 to 99 weight percent on a dry basis, either alone or in combination with one or more other components for tableting. As examples of said vitamin B₆, there may be mentioned pyridoxine hydrochloride and pyridoxal phosphate. As examples of said vitamin B₂, there may be mentioned riboflavin. The salts of pantothenic acid usable in the present invention are exemplified by calcium pantothenate. The vitamin B₆, vitamin B₂, nicotinamide, and pantothenic acid salt are used in powdery form. Thus, powders such that 95 weight percent or more of the particles pass a 100-mesh sieve (JIS) (149 µm sieve opening) are used. More desirable, are powders such that all the particles pass the 100-mesh sieve (JIS) (149 µm sieve opening) and at least 50 weight percent of the particles pass a 280-mesh sieve (JIS) (53 µm sieve opening). The fluidized-bed granulator is a fluidized-bed dryer fitted with a binder solution spraying means and permits simultaneous granulation and drying operations in a single unit. As examples of such an apparatus, there may be mentioned models available on the market under the names Glatt (Glatt AG in West Germany; Fuzi Powdal Co. in Japan), Aeromatic (Aeromatic AG in Switzerland), Calmic (Calmic Engineering Co. in England), Flow Coater (Freund Industries Co. in Japan) and other machines. The binding agent for spray coating is a water-soluble cellulose binder. The water-soluble celluloses include, for example, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and methylcellulose. The binding agent may be used in a useful and manageable concentration, for example 1 to 15 weight percent and preferably 3 to 10 weight percent. The optimum concentration depends on the combination of binding agent and solvent and is desirably such that it gives a sprayable viscosity which may range from 1 cp (0.001 Pas) to 1000 cps (10 Pas), preferably 10 cps (0.01 Pas) to 500 cps (0.5 Pas). The granulation is carried out by spray-coating vitamin powder with a solution containing the water-soluble cellulose binder, while allowing the powder to fluidize in a fluidized-bed granulator until the amount of the binder has reached 1 to 10 weight percent relative to the vitamin component. The vitamin powders are charged into a fluidized-bed apparatus and fluidized by feeding a dry air normally heated up to 50 to 100°C through the lower part of the apparatus. Then, a solution containing the binder is sprayed from spray nozzles towards the powders in fluidized state. The exhausted air temperature is normally maintained at 30 to 60°C. The conditions for spray-coating and granulation can be controlled by adjusting the air feeding rate, air temperature, solution spray rate, operating time and so on. Granulation is generally complete in 10 minutes to 2 hours. After granulation, drying is carried out in a conventional manner. Thus, they can be dried by continuing the fluidization after completion of spraying until the product temperature reaches a predetermined level. The dried product can be used as final granules but can be adjusted to a desired granule size distribution by milling the granules in a Power mill, Fitz mill or the like. In this manner, vitamin granules containing 90 to 99 weight percent of vitamin B₆, vitamin B₂, nicotinamide and/or pantothenic acid salt on a dry basis can be obtained. Among the vitamin-containing granules according to the present invention, particularly preferred are granules containing 95 to 98 weight percent of at least one compound selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and pantothenic acid salt on a dry basis. While there is no particular limitation on granule size, excessively coarse particles would not be suitable for blending with other particulate components and could cause weight fluctuation in tablet manufacturing. Excessively fine particles would also prove disadvantageous because of their poor flowability in charging into dies in tableting. The desired granule size is such that the proportion of particles which do not pass a 32-mesh sieve (JIS) (500 µm sieve opening is not more than 5 weight percent and that of particles which pass a 145-mesh sieve (JIS) (105 µm sieve opening) is not more than 30 weight percent. The vitamin granules according to the present invention are used as a raw material for the manufacture of tablets containing one or more members of vitamin B₆, vitamin B₂, nicotinamide and pantothenic acid salt. The tabletting of the granules is carried out in accordance with the conventional pharmaceutical procedure under the routine tableting conditions (e.g. 800 to 2500 kg/cm²) in the presence of a lubricating agent and, as required, other drugs and/or excipients (e.g. lactose, sucrose or mannitol ). The lubricating agent may be one used commonly in the manufacture of tablets, such as stearic acid compounds (e.g. magnesium stearate, calcium stearate or stearic acid ), talcs, sucrose fatty acid esters, and so on. The amount and type of lubricating agent are selected so that the resulting tablet will be useful and marketable in respect of strength and disintegrability. Generally, its amount is preferably 0.1 to 7 weight percent based on the active component of the product tablet, and it is preferable that said stearic acid compound is added in a proportion of at least 0.5 percent. The drugs other than the above-mentioned active compounds that can be additionally incorporated include, among others, L-ascorbic acid, sodium L-ascorbate, vitamin B₁ hydrochloride, and so on. These drugs are preferably used in the form of granules, which have been prepared by coating the respective powders with the aid of a binding agent in a fluidized-bed granulator (See U.S. Patents 4, 036, 948 and 4,372,968, and European Patent (Laid-Open) No. 0178138. By the method according to the present invention, there can be obtained granules comprising vitamin B group particles uniformly coated with a small amount of a binding agent and tablets containing vitamin B group compounds in high concentrations can be obtained by a simple procedure comprising mixing said granules with a lubricating agent, and tableting by compressing the mixture. The granules do not include fine dust and have good flowability. This quality is desirable for direct compression, makes for ease of handling, and allows for a minimum of swirling dust. In addition, the granules have good mixability with other ingredients or granules. The granules of the present invention,though having a very low binder content, have good stability even after mixing with other ingredients or granules, show a good bonding property, and have a good compressibility, because the surface of the vitamin powder is uniformly coated. Therefore, the granules require only a small amount of an excipient in the manufacture of tablets and contribute to a reduction in tablet size. This feature is suitable for the manufacture of a multi-vitamin preparation and ensures stability in isolation from the other vitamins. Furthermore, thanks to their improved binding property, the use of these granules ensures the overall hardness of the tablets. Thus, whether the product is a tablet containing vitamin B alone or a tablet containing vitamin B and other medicaments, the required amount of excipient may be only very low (for example, 1 to 10 weight percent based on the total weight of the tablet). Moreover, as these granules are lean in a binder component, the tablets manufactured from the granules can be small in size and yet have sufficient mechanical strength. The disintegration of the tablets is also rapid. Thus, these and other excellent qualities can be ensured. Furthermore, the granules according to the present invention are characterized in that the characteristic bitter taste of vitamin B compounds has been ameliorated. Therefore, the tablets manufactured in accordance with the present invention can be easily ingested. The term "mesh" as used herein means the sieve size according to the classification defined in Japan Industrial Standard (JIS). The relation between mesh designation and sieve size is shown in the following table. Mesh Size of sieve openings (µm) 32 500 100 149 120 125 145 105 200 77 280 53 325 44 Examples The following examples are given to illustrate the present invention in further detail. In the following description, all parts are by weight. Example 1 While 97 parts of pyridoxine hydrochloride powders passing a 100-mesh sieve (JIS) (149 µm opening size) were fluidized in a fluidized-bed granulator using dry air at 80 to 100°C, a 5 weight percent aqueous solution containing hydroxymethylcellulose was sprayed to the fluidized powders up to an amount equivalent to 3 parts on a solid bases, and the granules obtained were allowed to dry in the granulator. The resulting granulation was pulverized in a Fitz mill using a punched screen with openings 1.5 mm in a diameter to give pyridoxine hydrochloride containing granules. The particle size distribution of the resulting granules was such that 5.0% of them remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and another 0.5% of them passed a 120-mesh sieve (JIS) (125 µm sieve opening). As shown in the following table, the bitter taste of the ungranulated material had been mitigated in the product granules. Results of a sensory test of pyridoxine hydrochloride-containing granules: (Evaluation by a panel of 10 tasters) Panelist 1 2 3 4 5 6 7 8 9 10 Overall Granules ± ± ± ± ± ± ± ± ± ± ± Ungranulated material + + + + + + + + + + + Criteria: ± : Almost no bitter taste is felt. + : A bitter taste is felt. Example 2 The procedure of Example 1 was repeated except that a 5 weight % aqueous solution containing hydroxypropylcellulose was used as the binder solution to produce pyridoxine hydrochloride-containing granules. The granule size distribution of the product was such that 5.4% remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and 6.5% passed a 120-mesh sieve (JIS) (125 µm sieve opening). Example 3 While 97 parts of pyridoxal phosphate powders passing 100-mesh sieve (JIS) (149 µm sieve opening) were fluidized in a fluidized-bed granulator using dry air at 80 to 100°C, a 5 weight percent aqueous solution containing hydroxypropylcellulose was sprayed on to the fluidized powders up to an amount equivalent to 3 parts on a solid basis and the granulation was allowed to dry in the granulator. The resulting product was pulverized in a Fitz mill using a 1.5 mm screen to give pyridoxal phosphate-containing granules. These granules were such that 2.5% remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and 7.1% passed a 145-mesh sieve (JIS) (105 µm sieve opening). Example 4 (Only for illustrative purposes - not claimed) While 97 parts of nicotinamide powders passing a 120-mesh sieve (JIS) (125 µm sieve opening) were fluidized in a fluidized-bed granulator using dry air heated up to 80-100°C, a starch paste which had been prepared by dispersing 6 weight percent of corn starch in water and gelatinizing it at 75°C was sprayed on to the fluidized powders up to an amount equivalent to 3 parts on a solid basis and the granulation was dried as such in the granulator. The resulting product was pulverized in a Fitz mill using a punched screen with openings 1.5 mm in diameter to give nicotinamide-containing granules. The particle size distribution was such that 4.5% of the product remains on a 32-mesh sieve (JIS) (500 µm sieve opening) and 2.3% passes a 145-mesh sieve (JIS) (105 µm sieve opening). Example 5 The procedure of Example 4 was repeated except that a 5 weight percent aqueous solution containing hydroxypropylmethylcellulose was used as the binder solution to give nicotinamide-containing granules. The particle size distribution of the product was such that 3.0% remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and 7.4% passed a 145-mesh sieve (JIS) (105 µm sieve opening). Example 6 While 97 parts of calcium pantothenate powders passing a 100-mesh sieve (JIS) (149 µm sieve opening) were fluidized in a fluidized-bed granulator using dry air heated up to 80 to 90°C, a 5 weight percent aqueous solution containing hydroxypropylcellulose was sprayed onto the fluidized powder up to an amount equivalent to 3 parts on a solid basis and the granules were allowed to dry in the granulator. The resulting product was pulverized in a Fitz mill using a punched screen with openings 1.5 mm in diameter to give calcium pantothenate-containing granules. The particle size distribution of the product was such that 2.1% remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and 6.7% passed a 145-mesh sieve (JIS) (105 µm sieve opening). Example 7 While 97 parts of riboflavin powders passing a 100-mesh sieve (JIS) (149 µm sieve opening) were fluidized in a fluidized-bed granulator using dry air heated up to 50 to 100°C, a 5 weight percent aqueous solution containing hydroxypropylmethylcellulose was sprayed on to the fluidized powders up to an amount equivalent to 3 parts on a dry basis, and the granules obtained were allowed to dry in the granulator. The resulting granules were pulverized in a Fitz mill using a punched screen with openings 1.5 mm in diameter to give riboflavin containing granules. The granule size distribution of the resulting granules was such that 3.5% of them remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and another 2.3% of them passed a 145-mesh sieve (JIS) (105 µm sieve opening). Example 8 While 95 parts of pyridoxine hydrochloride powders passing a 100-mesh sieve (JIS) (149 µm sieve opening) were fluidized in a fluidized-bed granulator using dry air heated up to 70 to 100°C, a 10 weight percent aqueous solution containing hydroxypropylmethylcellulose was sprayed on to the fluidized powders up to an amount equivalent to 5 parts on a solid basis, and the granules produced were allowed to dry in the granulator. The resulting product were pulverized in a Fitz mill to give pyridoxine hydrochloride-containing granules. The particle size distribution of the product was such that 4.9% of them remained on a 32-mesh sieve (JIS) (500 µm sieve opening) and 0.4% passed a 120-mesh sieve (JIS) (125 µm sieve opening). Reference Example While 97 parts of calcium ascorbate powders passing a 120-mesh sieve (JIS) (125 µm sieve opening) were fluidized in a fluidize-bed granulator using dry air heated up to 50 to 100°C, a 5 weight percent aqueous solution containing hydroxypropylmethylcellulose was sprayed on to the fluidized powders up to an amount equivalent to 3 parts on a dry basis, and the granules were allowed to dry in the granulator. The resulting granules were pulverized in a Fitz mill using a punched screen with openings 1.5 mm in diameter to give calcium ascorbate-containing granules. The granule size distribution of the resulting granules was such that 0% of them remained on a 16-mesh sieve (JIS) (931 µm sieve opening) and another 4.7% of them passed a 120-mesh sieve (JIS) (125 µm sieve opening). Example 9 To 103.1 parts of the pyridoxine hydrochloride-containing granules as obtained in Example 1 were added 11.8 parts of corn starch and 0.1 part of magnesium stearate. The mixture was compressed into tablets having a diameter of 7.0 mm and weighing 115 mg per tablet. Each tablet contained 100 mg of pyridoxine hydrochloride and had a hardness of 6.2 kg as determined with a Heberlein hardness tester. The disintegration time was 4.5 minutes as measured by the method according to the Japanese Pharmacopeia. Example 10 31.0 parts of the pyridoxine hydrochloride-containing granules as obtained in Example 2 were mixed with 31.0 parts of thiamine nitrate-containing granules (as prepared based on Example 2 of European Patent (Laid-Open) No. 0178138), 7.5 parts of 0.1% vitamin B₁₂ (cyanocobalamin) triburation [Roche, U.S.A.], 7.88 parts of crystalline cellulose, and 0.12 parts of magnesium stearate were mixed. The mixture was compressed into tablets weighing 235 mg per tablet. Each tablet had a diameter of 8.5 mm and contained 100 mg of pyridoxine hydrochloride, 100 mg of thiamine nitrate, and 25 mcg of cyanocobalamin. As determined with a Heberlein hardness tester, the hardness of the tablets was 8.5 kg. The disintegration time determined by the method of the Japanese Pharmacopeia was 9.6 minutes. Example 11 30 parts of pyridoxal phosphate-containing granules as obtained in Example 3, 20 parts of spray-dried lactose, 18.8 parts of corn starch and 0.3 parts of magnesium stearate were mixed. The mixture was compressed into tablets weighing 70 mg per tablet. Each tablet had a diameter of 5.5 mm and contained 30 mg of pyridoxal phosphate. The hardness of the tablet as determined with a Heberlein hardness tester was 4.7 kg and the disintegration time according to the method of Japanese Pharmacopeia was 3.5 minutes. Example 12 22.2 parts of pyridoxine hydrochloride-containing granules as obtained in Example 2, 22.2 parts of calcium pantothenate-containing granules as obtained in Example 6, 22.2 parts of thiamine nitrate-containing granules (prepared according to Example 2 of European Patent (Laid-Open) No. 0178138), 22.2 parts of nicotinamide-containing granules as obtained in Example 4, 0.3 parts of 0.1% cyanocobalamin trituration, 10.4 parts of crystalline cellulose and 0.5 parts of magnesium stearate were mixed. The mixture was compressed into tablets weighing 700 mg per tablet. Each tablet had a diameter of 13.0 mm and contained 150 mg of thiamine nitrate, 150 mg of pyridoxine hydrochloride, 150 mg of nicotinamide, 150 mg of calcium pantothenate, and 150 mcg of cyanocobalamin. The tablet had a hardness of 15 kg as measured with a Heberlein hardness tester and showed a disintegration time of 21 minutes as tested by the method according to the Japanese Pharmacopeia. Example 13 5.4 parts of pyridoxine hydrochloride-containing granules as obtained in Example 1, 5.4 parts of thiamine nitrate-containing granules (prepared based on Example 2 of European Patent (Laid-Open) No. 0178138, thiamine nitrate content 97 weight %, hydroxypropylmethylcellulose content 3 weight %), 5.4 parts of nicotinamide-containing granules as obtained in Example 5, 5.4 parts of riboflavin-containing granules as obtained in Example 7, 51.0 parts of ascorbic acid-containing granules (prepared based on Example 3 of U.S.P. 4,036,948, ascorbic acid content 97 weight %, hydroxypropylmethylcellulose content 3 weight %), 6.7 parts of calcium pantothenate-containing granules as obtained in Example 6, 1.5 parts of 0.1% cyanocobalamin trituration,12.4 parts of crystalline cellulose, 20.3 parts lactose and 0.5 parts of magnesium stearate were mixed. The mixture was compressed into capsular tablets weighing 1140 mg per tablet. Each tablet had a length of 19 mm in major axis and 8 mm in minor axis, and contained 50 mg of thiamine mononitrate, 50 mg of riboflavin, 50 mg of pyridoxine hydrochloride, 50 mg of nicotinamide, 10 mcg of cyanocobalamin, 50 mg of calcium pantothenate and 500 mg of ascorbic acid. The tablet had a hardness of 15.6 kg as measured with a Heberlein hardness tester and showed a disintegration time of 21 minutes as tested by the method according to the Japanese Pharmacopeia. Example 14 0.55 parts of riboflavin-containing granules as obtained in Example 7, 56.5 parts of calcium ascorbate-containing granules as obtained in the Reference Example and 51 parts of ascorbic acid-containing granules (prepared based on Example 3 of U.S.P. 4,036,948, ascorbic acid content 97 weight %, hydroxypropylmethylcellulose content 3 weight %), 11.9 parts of crystalline cellulose, 0.6 parts of magnesium stearate were mixed. The mixture was compressed into tablets having a weight of 121 mg per tablet. The tablet had a diameter of 6.5 mm and contained 100 mg of vitamin C and 5 mg of riboflavin. The hardness of the tablet as determined with a Heberlein hardness tester was 6.5 kg and the disintegration time was 18 minutes according to the method of Japanese Pharmacopeia.

Claims: A vitamin-containing granule substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a pantothenic acid salt and a water-soluble cellulose as a binding agent, said compounds accounting for 90 to 99 weight percent on a dry basis. A vitamin-containing granule substantially comprising one or more compounds selected from the group consisting of vitamin B₆, nicotinamide and a pantothenic acid salt and a water-soluble cellulose as a binding agent, said compounds accounting for 90 to 99 weight percent on a dry basis. A vitamin-containing granule substantially comprising vitamin B₂ and a water-soluble cellulose as a binding agent, said compound accounting for 90 to 99 weight percent on a dry basis. A vitamin-containing granule as claimed in any of Claims 1 to 3, wherein the water-soluble cellulose is hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or methylcellulose. A process for preparation of a vitamin-containing granule which comprises fluidizing powders of one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a salt of pantothenic acid, at least 95 weight percent of which pass a 100-mesh sieve (Japan Industrial standard), (149 µm sieve opening) in a fluidized-bed granulator, and spraying the fluidized powders with a solution containing a water soluble cellulose as a binding agent corresponding to 1 to 10 weight percent of the total dry weight of the preparation to give granules. A process as claimed in Claim 5, wherein the concentration of the binder in the solution is 1 to 15 weight percent. A tablet produced by compressing vitamin granules substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide, and a salt of pantothenic acid and a water-soluble cellulose as a binding agent, said compound or compounds accounting for 90 to 99 weight percent on a dry basis, either as they are or after the addition of one or more other components for tableting. A vitamin-containing granule substantially comprising one or more compounds selected from the group consisting of vitamin B₆, vitamin B₂, nicotinamide and a panthotenic acid salt accounting for 90 to 99 weight percent on a dry basis characterised in that it is obtained by a method which comprises fluidizing the powders of the said one or more compounds at least about 95 weight percent of which is capable of passing through a 149 µm opening size sieve (100-mesh sieve; Japan Industrial Standard), in a fluidized-bed granulator, and spraying the powders with a solution containing a water-soluble cellulose in an amount corresponding to 1 to 10 weight percent of the total dry weight of the granule.

Inventors: IZUHARA, SEIJI, KITAMORI, NOBUYUKI, MAENO, MASAYA
Applicants: TAKEDA CHEMICAL INDUSTRIES, LTD.
Application year: 1986
Main classification: A61K9
IPC codes: A61K31, C07D213, A61K9, A61P25, A61P3