BRPI1013187B1 - TABLET AND GRANULATED POWDER - Google Patents

Description

Technical field

The present invention is a tablet containing (1) 6-fluoro3-hydroxy-2-pyrazinecarboxamide or a salt thereof, (2) and a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, and refers to a tablet and a granular powder in which the amount of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof is 50 to 95% of the mass of the tablet or granular powder.

Fundamentals of technique

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (hereinafter, will be referred to as compound A) or a salt thereof is a compound that is used as a treatment such as prevention or therapy of a viral infection or, particularly, a viral flu infection [Patent Document 1].

One to several tablets (s) containing compound A or salt thereof are / are administered orally. To improve adherence to medication, there is a demand for a pill, where the number of pills to be administered is reduced and its intake is easy. Thus, there is a demand for the development of a tablet where the amount of compound A or its salt is high and the size of the tablet is in a size to be able to be easily ingested.

There is also a demand for a mixed powder for making tablets for making the tablet as such.

In the manufacture of tablets, it is essential that the powder mixed for tablet production has a compression molding property. When the compression molding property of the mixed powder is low, the hardness of the tablet becomes low. In this case, there is a possibility that the tablets will be broken during the packaging and transportation time or that the tablets will be worn or broken in the coating machine when the tablets are film-coated.

On the other hand, when the cohesive strength of the powder mixed to produce tablets is strong, fluidity is poor and it is difficult to supply a predetermined amount of the powder mixed to produce tablets to a degree under tablet production. Therefore, discrepancies in the tablet masses become large and the quality is deteriorated.

It has been reported that the size of an easily swallowed circular tablet has a diameter of 7 to 8 millimeters and that the size of an easily swallowed elliptical tablet has a diameter greater than 9 millimeters [Non-patent document 1]. A tablet in a large size is difficult to ingest due to the feeling of resistance and the sensation of compression not only for small children and patients having difficulty swallowing, but also for adult patients in general, and causing a decrease in adherence to the drug. The size of the tablet is preferred to be no larger than 9 millimeters.

Compound A or a salt thereof has such a property that no compression molding properties are available, specific volume is large, cohesive strength is strong and fluidity is low. It is difficult that a tablet containing a large amount of compound A or a salt thereof and being in an easily ingestible size is manufactured by a conventional method.

A method has been reported where an additive having a high molding property such as crystalline cellulose is mixed to make a mixed powder for producing tablets having a high compression molding property where a tablet having the required hardness is prepared. [Non-patent document 2].

However, in order to manufacture a tablet containing compound A or a salt thereof where the necessary hardness is available, it is necessary that the amount of the additive contained therein is not less than 50% or, preferably, not less than 60% of the tablet's mass. Because of this reason, the size of a tablet becomes large.

As for a method where the cohesive strength of the mixed powder to produce tablets is decreased and fluidity is improved, a method has been reported where the fluidity promoter is mixed [Non-patent document 3].

However, it is not possible to improve the cohesive strength of compound A or its salt only by mixing a fluidity promoter. The powder mixed to produce tablets having low fluidity shows a low loading property to a degree to produce tablets. Therefore, discrepancies in the tablet masses become large and the quality is deteriorated.

On the other hand, a method is known in which a binder is used and granulation is carried out by means of a dry or wet granulation method where the bond strength between the particles in the tablets is improved. However, although the required hardness is achieved by this method, the dissolution property decreases due to the appearance of the bond strength between the particles.

So far, there is no known tablet in which the amount of compound A or its salt contained therein is high, the size is an easily digestible size, the dissolution property is excellent and the hardness is durable against the film coating, packaging and transport whereby the tablet is stable for a long period of time.

State of the art documents

Patent documents

Patent document 1: Publication of international application WO 00/10569.

Non-patent documents

Non-patent document 1: Iryo Yakugaku (= Jpn.J.Pharm.

Health Care Scí), volume 32, pages 842 to 848, 2006.

Non-patent document 2: “Development of Pharmaceuticals” edited by Hisashi Ichibangase and two others, volume 12, first edition, published by K.K. Hirokawa Shoten, volume 12, published on October 15, 1990, pages 178 to 185.

Non-patent document 3: “Development of Pharmaceuticals” edited by Hisashi Ichibangase and two others, volume 12, first edition, published by K.K. Hirokawa Shoten, volume 12, published on October 15, 1990, pages 166 to 167.

Summary of the invention

Problem to be solved by the invention

There has been a demand for a tablet in which the amount of compound A or salt contained therein is high, the size is an easily digestible size, the dissolution property is excellent and the hardness is durable against the film coating, packaging and transport in which the tablet is stable for a long period of time and also by a powder mixed to produce a tablet for making the tablet as such.

Means for solving problems

Under such circumstances, the present inventors have repeatedly carried out intensive studies and, as a result, have revealed a tablet in which the amount of compound A or a salt thereof is high, the size is an easily digestible size, the dissolution property is excellent and the hardness is durable against the film coating, packaging and transportation where the tablet is stable for a long period of time.

They further revealed a mixed powder for tablet production being excellent as an intermediate product for making the tablet as such and also disclosed a granular powder being excellent for manufacturing the mixed powder for producing the tablet on which the present invention was obtained.

Advantages of the invention

The tablet of the present invention is a tablet containing (1) compound A or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) binder, wherein the amount of compound A or a salt thereof contained in this is 50 to 95% of the mass of the tablet.

In the tablet of the present invention, the amount of compound A or a salt thereof is high, the size is an easily digestible size, the dissolution property is excellent and the hardness is durable against the film coating, packaging and transport.

The tablet of the present invention is useful as a tablet containing a high amount of compound A or a salt thereof.

The granulated powder of the present invention is a granular powder containing (1) compound A or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) binder, wherein the amount of compound A or a salt the same contained in this is 50 to 95% of the granulated powder.

The granulated powder of the present invention contains a high amount of compound A or a salt thereof and is useful as a granular powder for the manufacture of a tablet containing a high amount of compound A or a salt thereof.

Mode of carrying out the invention

The present invention will now be more specifically illustrated as below.

The term% used in this report means the percentage by mass unless otherwise stated.

Compound A or a salt thereof used in the present invention is capable of being produced by a process mentioned, for example, as in the publication of the international application WO 00/10569.

The amount of compound A or a salt thereof can be 50 to 95%, preferably 60 to 90%, or more preferably, 70 to 85% of the weight of the tablet or the granulated powder.

The substituted lower hydroxypropyl cellulose or croscarmellose sodium used in the present invention is capable of being mixed inside and / or outside the granulated powder.

The amount of substituted hydroxypropyl cellulose or croscarmellose sodium contained therein may be 2 to 20%, preferably 2.5 to 15%, or more preferably 5 to 10% of the weight of the tablet.

Substituted hydroxypropyl cellulose is preferred.

There is no particular limitation for the binder used in the present invention and examples thereof include povidone, hydroxypropyl cellulose, hypromellose, sodium carmelose, methyl cellulose, polyvinyl alcohol, gum arabic and dextrin. One of these binders can be used or two or more of them can be used in combination.

As a preferred binder, povidone can be exemplified.

Examples of povidone include povidone K 17, povidone K 25, povidone K30 and povidone K90.

The amount of povidone contained therein may be 1 to 20%, or preferably 2.5 to 10% of the weight of the tablet or the granulated powder.

It is preferred that a lubricant is added to the tablet and granular powder of the present invention.

Examples of the lubricant which is used in the present invention when necessary include sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talc and sucrose fatty acid ester.

Examples of the preferred lubricant include sodium stearyl fumarate and talc and the most preferred one is sodium stearyl fumarate.

The amount of the lubricant contained therein is 0.1 to 5%, preferably 0.2 to 2% or, more preferably, 0.2 to 1% of the mass of the tablet or the granulated powder.

It is preferred that silicon dioxide is added to the tablet and granular powder of the present invention.

Examples of the silicon dioxide which is used in the present invention on need include hydrated silicon dioxide and light anhydrous silicic acid.

The amount of silicon dioxide contained therein is 0.5 to 15%, preferably 2 to 10% or, more preferably 3 to 5% of the mass of the tablet or the granulated powder.

It is possible that a disintegrating agent is still added to the tablet and granular powder of the present invention upon need.

There is no particular limitation for the disintegrating agent used in the present invention in need and examples thereof include carmellose, calcium carmellose, sodium carboxymethyl starch, crospovindone and partially pregelatinized starch. more of it can be used in combination. Crospovindone is preferred.

The disintegrating agent can be mixed inside and / or outside the granulated powder.

The granulometry of crospovindone is preferred to be 100 gm or less. When crospovidone whose particle size is greater than 100 pm is used, it may be the case that small convex projections are found on the tablet surface over time. In addition, when crospovidone having a small particle size is used, its dissolution property is improved much more.

The amount of crospovidone contained therein can be 1 to 10% or, preferably 2 to 5% of the weight of the tablet or the granulated powder.

An excipient can be added to the tablet and granular powder of the present invention.

Examples of the excipient used in the present invention in need include sugar alcohol such as erythritol, mannitol, xylitol and sorbitol; saccharide such as sucrose, powdered sugar, lactose and glucose; cyclodextrin such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β-cyclodextrin and sulfobutyl ether β-cyclodextrin; cellulose such as crystalline cellulose and microcrystalline cellulose; and starch such as corn starch, potato starch and partially pregelatinized starch. With respect to these excipients, one can be added or two or more of them can be added in combination.

There is no particular limitation on adding quantity of the excipient, but an amount required depending on the object can be appropriately mixed together.

In the tablet and granular powder of the present invention, an additive which has been commonly used in the pharmaceutical industry can be used within such a range that the effect of the present invention is not thereby impaired.

Examples of the additive include a corrector, a coloring agent, a flavoring agent, a surfactant, a coating agent and a plasticizer.

Examples of the broker include aspartame, saccharin, stevia, thaumatin and acesulfame potassium.

Examples of the coloring agent include titanium dioxide, red ferric oxide, yellow ferric oxide, black iron oxide, edible red n ° 102, edible yellow n ° 4, and edible yellow n ° 5.

Examples of the flavoring agent include essential oils such as orange oil, lemon oil, mint oil and pineapple oil;

essence such as orange essence and mint essence; flavors such as cherry flavor, vanilla flavor and fruit value; powdered flavors such as micronized yogurt, micronized apple, micronized banana, micronized peach, micronized strawberry and micronized orange; vanillin and ethyl vanillin.

Examples of the surfactant include sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polysorbate and hydrogenated polyoxyethylene castor oil.

Examples of the coating agent include hypromellose, aminoalkyl E methacrylate copolymer, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose phthalate-acetate, methyl cellulose hydroxypropyl phthalate, L methacrylic acid copolymer, LDL copolymer and LDH copolymer. of methacrylic acid S, polyvinyl alcohol hydroxypropyl methyl cellulose acetate-succinate.

Examples of the plasticizer include triethyl citrate, Macrogol, triacetin and propylene glycol.

With respect to these additives as such, one of them can be used or two or more of them can be used in combination. There is no particular limitation on the amount of mixing of the same, but the additives can be appropriately mixed depending on the object so that the effect is well achieved.

When administering the tablet of the present invention, the method, dose and frequency of the same are able to be appropriately selected depending on the age, body weight and symptom of the patient, and generally, the dose at which the pharmaceutical effect is capable of being obtained can be administered or once a day or several times in installments a day. Generally, 10 to 5,000 mg or, preferably 200 to 2,400 mg as compound A can be administered to an adult daily once or several times in installments.

With respect to the method for making the tablet of the present invention, a method can be exemplified in which a granulated powder is manufactured by a wet or dry granulation method followed, if necessary, by the addition of an excipient, a disintegrating agent and / or a lubricant therefrom and the resulting mixed powder to produce the tablet is made into tablets.

In the method of making the granulated powder of the present invention, a wet granulation method can be exemplified as a preferred granulation method.

Examples of the wet granulation method include a fluidized bed granulation method, a centrifugal turbination granulation method, a mixing / agitation granulation method, a high speed mixing / agitation granulation method, a turbination granulation method , a wet grinding granulation method and an extrusion granulation method.

Examples of the preferred wet granulation method include a fluidized bed granulation method, a centrifugal turbination granulation method, a mixing / agitation granulation method, a high speed mixing / agitation granulation method, a turbination granulation and a wet grinding granulation method and, among them, a fluidized bed granulation method is more preferred. When a fluidized bed granulation method is adopted, a granular powder having a large mass is prepared and, when compared to other granulation methods, a granulated powder having a high compression molding property is able to be prepared.

Examples of the method for adding the binder during granulation include (1) a method in which a binder dissolved in water is sprayed onto a mixed powder comprising compound A or a salt thereof, a disintegrating agent, etc., and (2) a method in which water is sprayed on a mixture of compound A or a salt thereof, a disintegrating agent and a binder.

Examples of the addition of silicon dioxide include (1) a method in which pulverized silicon dioxide is added to a mixed powder comprising compound A or a salt thereof, a disintegrating agent, etc. and (2) a method in which silicon dioxide and a binder are dispersed in water and then sprayed on a mixed powder. Method (2) is a preferred addition method since the compression molding property and the dissolution property when producing in tablets are then improved when compared to method (1).

Usefulness of the tablet of the present invention will now be illustrated by means of the following test examples.

Test Example 1

With respect to the samples, the uncoated flat tablets of Examples 1 and 19 and Comparative Examples 1, 2 and 3 and the uncoated flat tablets as well as their film-coated tablets of Examples 2 and 3 and Comparative Examples 4 and 5 were used.

In the measurement of hardness, a portable PC evaluator (Okada Seiko) or an automatic measuring device for the characteristics of the TM 3-3 tablet (Kikusui Seisakusho) was used.

The dissolution test was conducted by a pudding method for a dissolution test according to the Japanese pharmacopoeia. Pudding revolutions were 50 rpm. A sample was poured into 900 ml of an acetate buffer (pH 4.5) followed by stirring for 15 minutes. The test solution was collected and the dissolution rate (%) of compound A was determined using an absorbance method.

In the measurement of hardness, the central tablets were used at all times. In the dissolution test, tablets from Examples 1 and 19 and Comparative Examples 1, 2 and 3 and film-coated tablets from Examples 2 and 3 and Comparative Examples 4 and 5 were used. The result is shown in table 1.

Table 1

Ex 1 Ex2 Ex 3 Ex 19 EC 1 EC2 EC3 EC4 EC 5 Compound A 210.0 205.3 223.5 242.3 250.0 236.2 224.2 216.3 223.5 Hydroxypropyl cellulose substituted lower 26.3 25.6 0.0 5.5 0.0 0.0 0.0 0.0 0.0 Croscarmellose sodium 0.0 0.0 5.6 0.0 0.0 0.0 0.0 0.0 0.0 Crospovidone 0.0 0.0 0.0 0.0 0.0 0.0 0.0 13.5 0.0 Starch sodium carboxymethyl 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5.6 Povidona K 30 12.4 12.8 14.0 4.2 0.0 12.5 12.3 13.5 14.0 Silicon dioxide 0.0 5.1 5.6 2.4 0.0 0.0 12.3 5.4 5.6 Sodium stearyl fumarate 1.3 1.2 1.3 0.6 0.0 1.3 1.2 1.3 1.3 Opradry 0.0 10.0 10.0 0.0 0.0 0.0 0.0 10.0 10.0 Total mass (mg) 250.0 260.0 260.0 255.0 250.0 250.0 250.0 260.0 260.0 Hardness (N) 87 81 121 53 MI 83 66 113 109 Dissolution rate (%) 91.3 93.5 86.7 93.9 MI 5.3 4.5 76.3 63.6

EC: Comparative example

MI: Measurement impossible

The preparation (Comparative example 1) using neither binders nor disintegrating agents was unable to be produced in tablets where measurement of the tablet's hardness and dissolution rate was not possible.

Preparations (Comparative Examples 2 and 3) not using disintegrating agent showed very low dissolution property.

In preparations (Comparative Examples 4 and 5) using crospovidone or sodium carboxymethyl starch as a disintegrating agent, their dissolution rates after 15 minutes were not as low as greater than 85%.

In contrast, in preparations (Examples 1, 2 and 19) using a substituted lower hydroxypropyl cellulose as a disintegrating agent and in the preparation (Example 3) using croscarmellose sodium as a disintegrating agent, its dissolution rates after 15 minutes were as excellent as not less than 85%.

The tablets in which compound A, povidone K30 and substituted lower hydroxypropyl cellulose or croscarmellose sodium were mixed together were excellent as the tablets where a high amount of compound A was contained here and an excellent dissolution property and required hardness were available.

Test example 2

As for the samples, uncoated flat tablets and their film-coated tablets from Examples 4 to 10 and the tablet from Example 11 were used.

Hardness measurement and dissolution testing were performed in the same manner as in Test Example 1.

For the measurement of hardness, tablets were used at all times. For the dissolution test, the tablet of Example 11 and the film-coated tablets of Examples 4 to 10 were used. The result is shown in Table 2.

Table 2

Ex4 Ex5 Ex 6 Ex7 Ex 8 Ex9 Ex 10 Ex 11 Compound A 200.0 200.0 200.0 200.0 200.0 200.0 200.0 209.4 Hydroxypropyl cellulose substituted lower 25.0 25.0 25.0 25.0 25.0 25.0 25.0 26.2 Povidona K30 12.5 0.0 0.0 0.0 0.0 0.0 0.0 13.1 Polyvinyl alcohol 0.0 12.5 0.0 0.0 0.0 0.0 0.0 0.0 Hypromellose 2910 0.0 0.0 12.5 0.0 0.0 0.0 0.0 0.0 Hydroxypropyl cellulose (HPC-L) 0.0 0.0 0.0 12.5 0.0 0.0 0.0 0.0 Hydroxypropyl cellulose (HPCSSL) 0.0 0.0 0.0 0.0 12.5 0.0 0.0 0.0 Methyl cellulose 0.0 0.0 0.0 0.0 0.0 12.5 0.0 0.0 Gum arabic 0.0 0.0 0.0 0.0 0.0 0.0 12.5 0.0 Silicon dioxide 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Sodium stearyl fumarate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 1.3 Opadry 7.5 7.5 7.5 7.5 7.5 7.5 7.5 0.0 Total mass (mg) 258.0 258.0 258.0 258.0 258.0 258.0 258.0 258.0 Hardness (N) 94 82 75 72 72 75 69 74 Dissolution rate (%) 95.1 99.7 99.7 96.3 98.4 99.0 98.9 91.5

In the preparations (Examples 4 to 11) using povidone K30, polyvinyl alcohol, hypromellose 2910, hydroxypropyl cellulose, methyl cellulose and gum arabic as a binder, its dissolution rates after 15 minutes were as excellent as not less than 90%.

The tablets in which compound A, a binder and a hydroxypropyl substituted lower cellulose were mixed were excellent as were the tablets where a high amount of compound A was contained therein and an excellent dissolution property and required hardness were available.

Test example 3

The tablets of Examples 11 to 16 were used as test samples.

I

Measurements of the hardness of the core tablets and their dissolution tests were carried out in the same manner as in the

Test example 1. The result is shown in Table 3.

Table 3

Exll Ex 12 Ex 13 Ex 14 Ex 15 Ex 16 Compound A 209.4 207.3 205.3 203.1 199.0 189.1 Hydroxypropyl cellulose substituted lower 26.2 25.9 25.6 25.4 24.9 23.6 Povidona K30 13.1 13.0 12.8 12.7 12.4 12.5 Silicon dioxide 0.0 2.6 5.1 7.6 12.4 12.5 Sodium stearyl fumarate 1.3 1.2 1.2 1.2 1.3 1.2 Total mass (mg) 250.0 250.0 250.0 250.0 250.0 250.0 Hardness (N) 74 75 75 82 78 85 Dissolution rate (%) 91.5 90.8 93.5 97.1 99.6 98.9

Any of the above tablets showed excellent dissolving properties. Tablets (Examples 13 to 16) containing no less than 2% silicon dioxide showed a much better dissolving property and tablets (Examples 14 to 16) containing no less than 3% silicon dioxide still showed a dissolving property much better.

The tablets in which compound A, povidone K, substituted lower hydroxypropyl cellulose and silicon dioxide were mixed together were excellent as the tablets where a high amount of compound A was contained therein and an excellent dissolution property and required hardness were available.

Test example 4

The tablets and film-coated tablets of the same ones manufactured in Examples 17 and 18 were used as test samples.

Measurement of the hardness of the core tablets and the dissolution tests of the film-coated tablets were carried out in the same manner as in Test Example 1. The result is shown in

Table 4.

Table 4

Example 17 Example 18 Compound A 200.0 200.0 Hydroxypropyl cellulose substituted lower 26.2 25.0 Povidona K30 11.5 12.5 Silicon dioxide 11.5 12.5 Crospovidone 5.3 0.0 Sodium stearyl fumarate 0.5 0.5 Opadry 8.0 10.0 Total mass (mg) 263.0 260.5 Hardness (N) 61 46 Dissolution rate (%) 96.9 91.1

Any of the tablets manufactured by a fluidized bed granulation method which is a wet granulation method (Example 17) and the tablet manufactured by a high speed mixing / stirring granulation method (Example 18) showed excellent dissolution property and they were excellent as the pills.

Examples

The present invention will now be illustrated by means of the following Examples and Comparative Examples although the present invention is not limited to them.

Compound A was used after finely ground.

As for the coating agent, Opadry 03A42214 (containing 79.2% hypromellose 2910, 10% titanium oxide, 10% talc and 0.75% yellow iron sesquioxide, manufactured by Nippon Colorcon) was used.

Conditions for producing tablets in each of the Examples and Comparative Examples were DR 8.5 mm from a punch and 10 kN of pressure to produce the tablet unless otherwise mentioned.

Example 1

Compound A (6 g) and 0.75 g of a substituted lower hydroxypropyl cellulose (L-HPC LH-11), manufactured by Shin Etsu Chemical) were mixed in a grain. To this mixed powder was added 1.75 g of a 20% aqueous solution of povidone K 30 (Plasdone K 29/32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 2

Compound A (5g), 0.63 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.13 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed in a gral. To this mixed powder was added 1.55 of a 20% aqueous solution of povidone K 30 (Plasdone K 29/32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 μητ and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg. The tablet was coated with 10 mg of a coating agent to provide a film-coated tablet.

Example 3

Compound A (5 g), 0.13 g of croscarmellose sodium (Ac-DiSol, manufactured by FMC BioPolymer) and 0.13 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed in a gral. To this mixed powder was added 1.55 of a 20% aqueous solution of povidone K 30 (Plasdone K 29/32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg. The tablet was coated with 10 mg of a coating agent to provide a film-coated tablet.

Example 4

Compound A (5g), 0.63 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical) and 0.375 g of povidone K 30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) mixed in a gral. To this mixed powder was added 1.67 g of pure water followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 5

Compound A (6 g), 0.75 g and 0.13 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical) and 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed in a gral. To this mixed powder was added 1.86 of a 20% aqueous solution of polyvinyl alcohol (Gohsenol RG-05, manufactured by Nippon Synthetic Chemical Industry) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 6

Compound A (6 g), 0.75 g and 0.13 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical), 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 0.375 g of hypromellose 2910 (TC-5RW, manufactured by Shin Etsu Chemical) were mixed in a grain. To this mixed powder was added 1.85 g of water, followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 7

Compound A (6 g), 0.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical), 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 0.375 g hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) were mixed in a grain. To this mixed powder was added 1.92 g of pure water followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 8

Compound A (6 g), 0.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical), 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 0.375 g hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda) were mixed in a grain. To this mixed powder was added 2.0 g of pure water followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 9

Compound A (6 g), 0.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical), 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 0.375 g methyl cellulose (Metolose SM-4, manufactured by Shin Etsu Chemical) were mixed in a grain. To this mixed powder was added 2.08 g of pure water followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 10

Compound A (6 g), 0.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical), 0.375 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 0.375 g powdered acacia (manufactured by Wako Pure Chemical Industries) were mixed in a grain. To this mixed powder was added 2.07 g of pure water followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 7.5 mg of a coating agent to provide a film-coated tablet.

Example 11

Compound A (30 g) and 3.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) were mixed in a grain. To this mixed powder were added 9.49 g of a 20% aqueous solution of povidone K 30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 12

Compound A (5 g), 0.63 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.06 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) mixed in a gral. To this mixed powder was added 1.55 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 13

Compound A (5 g), 0.63 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.13 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) mixed in a gral. To this mixed powder was added 1.56 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 14

Compound A (5 g), 0.63 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.19 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) mixed in a gral. To this mixed powder was added 1.55 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 15

Compound A (5 g), 0.63 g of substituted lower hydroxypropyl cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.31 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) mixed in a gral. To this mixed powder was added 1.55 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 16

Compound A (6 g), 0.75 g of hydroxypropyl substituted lower cellulose (L-HPC LH-B1, manufactured by Shin Etsu Chemical) and 0.75 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) mixed in a gral. To this mixed powder was added 2.01 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Example 17

Povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) (430 g) was added and dissolved in 8.170 g of pure water. In addition, 430 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were added to it and dispersed in it to provide a binder solution. Separately, 7,400 g of compound A and 970 g of a substituted lower hydroxypropyl cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical) were mixed in a fluid bed granulation dryer. The binder solution was sprayed onto this mixed powder followed by granulation and drying. The resulting granulated powder was sieved through a 1.9 mm sieve. To 249.25 mg of the resulting powder, crospovidone (Polyplasdone XL-10, manufactured by Intemational Specialty Products) was added in an amount corresponding to 5.25 mg and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% followed by mixing and tablet production to provide core tablets each weighing 250 mg. Each tablet was coated with 8 mg of a coating agent to provide a film-coated tablet.

Example 18

Compound A (160 g), 20 g of a hydroxypropyl cellulose substituted lower (L-HPC LH-B1, manufactured by Shin Etsu Chemical), 10 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) and 10 g of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) were mixed in a high speed agitation granulator (VG-01, manufactured by Powrex Products) and pure water was dripped into it to granulate. The resulting granulated powder was sieved through a 3.9 mm sieve and dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250.5 mg. The tablet was coated with 10 mg of a coating agent to provide a film-coated tablet.

Example 19

Compound A (5.74 g), 0.13 g of hydroxypropyl substituted lower cellulose (L-HPC LH-11, manufactured by Shin Etsu Chemical) and 0.03 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil ) were mixed in a gral. To this mixed powder was added 0.5 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 gm and silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) in an amount corresponding to 0.5% and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and tabletting to provide core tablets each weighing 255 mg.

Comparative Example 1

Compound A (250 mg) was made into a tablet.

Comparative Example 2

Compound A (12 g) was placed in a grade and 3.2 g of a 20% aqueous solution of povidone K 30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) was added thereto followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.5% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Comparative Example 3

Compound A (6 g) and 0.34 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed to one degree. To this mixed powder was added 1.65 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg.

Comparative Example 4

Compound A (4 g), 0.25 g of crospovidone (Kollidon CL-SF, manufactured by BASF) and 0.1 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed to one degree. To this mixed powder was added 1.25 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 μηι and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production of pills to provide pills each weighing 250 mg. The tablet was coated with 10 mg of a coating agent to provide a film-coated tablet.

Comparative Example 5

Compound A (5 g), 0.13 g of sodium carboxymethyl starch (Primojel, manufactured by Matsutani Chemical Industry) and 0.13 g of silicon dioxide (Aerosil 200, manufactured by Nippon Aerosil) were mixed in one degree. To this mixed powder was added 1.56 g of a 20% aqueous solution of povidone K30 (Plasdone K29 / 32, manufactured by Intemational Specialty Products) followed by granulation. The resulting granulated powder was dried overnight at 40 ° C. The resulting granulated powder was passed through a sieve having an opening size of 500 pm and sodium stearyl fumarate (PRUV, manufactured by JRS Pharma) in an amount corresponding to 0.2% was added to the resulting powder followed by mixing and production tablet to provide core tablets each weighing 250 mg. The tablet was coated with 10 mg of a coating agent to provide a film-coated tablet.

Industrial Applicability

The tablet of the present invention is a tablet containing (1) compound A or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, wherein the amount of compound A or a salt of the same contained in this is 50 to 95% of the mass of the tablet.

In the tablet of the present invention, the amount of compound A or a salt thereof is high, the size is an easily ingestible size, the dissolution property is excellent and the hardness is durable against film coating, packaging and transportation.

The tablet of the present invention is useful as a tablet containing a high amount of compound A or a salt thereof.

The granulated powder of the present invention is a granulated powder containing (1) compound A or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, wherein the amount of compound A or a salt thereof contained in this is 50 to 95% of the mass of the granulated powder.

The granulated powder of the present invention contains a high amount of compound A or a salt thereof and is useful as a granular powder for the manufacture of a tablet containing a high amount of compound A or a salt thereof.

Claims (16)

1. Tablet, characterized by the fact that it contains (1) 6 fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, in which the amount of 6-fluoro-3-hydroxy-2 pyrazinecarboxamide or a salt thereof is 50 to 95% of the weight of the tablet. 2. Tablet according to claim 1, characterized in that the substituted lower hydroxypropyl cellulose or croscarmellose sodium is a substituted lower hydroxypropyl cellulose. 3. Tablet according to claim 1 or 2, characterized by the fact that it still contains silicon dioxide. 4. Tablet according to claim 3, characterized by the fact that the amount of silicon dioxide contained therein is 2 to 10% of the mass of the tablet. Tablet according to any one of claims 1 to 4, characterized in that it still contains a lubricant. 6. Tablet according to claim 5, characterized in that the lubricant is a sodium stearyl fumarate. Tablet according to any one of claims 1 to 6, characterized in that the production of tablets is carried out using a granulated powder manufactured by a wet granulation method. Tablet according to any one of claims 1 to 6, characterized in that the production of tablets is conducted using a granulated powder manufactured by a fluidized bed granulation method. 9. Granulated powder, characterized by the fact that it contains (1) 62 fluoro-3-hydroxy-2-pyrazinecarboxamide or a salt thereof, (2) a substituted lower hydroxypropyl cellulose or croscarmellose sodium and (3) a binder, in that the amount of 6-fluoro-3-hydroxy-2 pyrazinecarboxamide or a salt thereof is 50 to 95% of the granulated powder. Granulated powder according to claim 9, characterized in that the substituted lower hydroxypropyl cellulose or croscarmellose sodium is a substituted lower hydroxypropyl cellulose. Granulated powder according to claim 9 or 10, characterized in that it still contains silicon dioxide. Granulated powder according to claim 11, characterized in that the amount of silicon dioxide contained therein is 2 to 10% of the mass of the granulated powder. Granulated powder according to any one of claims 9 to 12, characterized in that it still contains a lubricant. Granulated powder according to claim 13, characterized by the fact that the lubricant is sodium stearyl fumarate. Granular powder according to any one of claims 9 to 14, characterized in that it is manufactured by a wet granulation method. Granulated powder according to any one of claims 9 to 14, characterized in that it is manufactured by a fluidized bed granulation method.