JP2020094023A - Excipient granules, tablet and method for producing tablet - Google Patents

Abstract

To provide excipient granules that ensure sufficient tablet hardness even at a low tableting pressure and, when put into a tablet, show excellent quick collapsibility and can be taken with a good feeling, a tablet including the excipient granules and a method of producing the same.SOLUTION: Excipient granules contain cellulose, and partially pregelatinized starch. A tablet contains the excipient granules, and active ingredients. A method for producing a tablet uses the excipient granules.SELECTED DRAWING: None

Description

The present invention relates to excipient granules, tablets and methods for making tablets.

BACKGROUND ART Conventionally, tablets, capsules, granules, powders and the like are known as dosage forms of oral solid preparations in the fields of pharmaceuticals, foods, and other chemical industries. In particular, recent tablets can be taken without water as a dosage form that is easier to take even for the elderly, children, and patients with weak swallowing ability.When taken in the mouth or put in water, saliva and small amounts Development of an orally disintegrating tablet that rapidly disintegrates with water is expected.
Orally disintegrating tablets, in addition to the property of rapidly disintegrating in the oral cavity, as well as ordinary tablets, at the time of production, transportation, use, may also have sufficient hardness to withstand physical impact such as no abrasion. is needed.
In addition, it is desirable from the viewpoint of medication compliance that the unpleasant taste and irritation are suppressed and that the mouthfeel is good when contained in the mouth.

In recent years, in the production of orally disintegrating tablets, a method of producing by compression-molding a drug-free granule and a drug or a drug-containing granule has been reported.
Patent Document 1 discloses drug-free granules containing crystalline cellulose having a bulk density of 0.23 g/cm ³ or less, sugar alcohol and pregelatinized starch, and an orally disintegrating tablet obtained by compression-molding a drug or drug-containing granules, and Its manufacturing method is described. It is described that the orally disintegrating tablet described in Patent Document 1 rapidly disintegrates when contained in the mouth or when placed in water, and has sufficient hardness for ordinary production, transportation and use. ..

JP, 2017-008112, A

However, with the drug-free granules described in Patent Document 1, in order to obtain a tablet having sufficient hardness, the tablet must be compressed with a high pressing pressure, the core remains in the center of the tablet, and the feeling of ingestion is poor. Further, in order to accelerate the disintegration time, it is usually added a disintegrant, but the disintegrant causes the tablet to swell during storage and causes abrasion of the tablet, so it can be added to the orally disintegrating tablet as much as possible. A small amount is preferred. There is also a vicious circle in which the tablet formability is generally deteriorated when a large amount of a disintegrant is added.

The present invention has been made in view of the above circumstances, a sufficient tablet hardness can be obtained even at a low pressing pressure, an excipient granule excellent in fast disintegration and a feeling of taking when formed into a tablet, and the above-mentioned excipient. Provided are a tablet using shaped granules and a method for producing the same.

As a result of intensive studies to solve the above problems, the present inventors have found that by blending cellulose and partially pregelatinized starch in the excipient granules, sufficient tablet hardness can be obtained even at low pressing pressure, and rapid disintegration is achieved. Further, they have found that a tablet having an excellent feeling of ingestion can be obtained, and have completed the present invention.

That is, the present invention includes the following aspects.
The excipient granules according to the first aspect of the present invention include cellulose and partially pregelatinized starch.
The excipient granules according to the first aspect may further include a water-soluble excipient.
The content of the water-soluble excipient may be 1% by mass or more and 90% by mass or less based on the total mass of the excipient granules.
The excipient granules according to the first aspect may further include a binder.
The binder may be a water-soluble polymer.
The content of the binder may be 1% by mass or more and 20% by mass or less based on the total mass of the excipient granules.
The content of the cellulose may be 1% by mass or more and 90% by mass or less based on the total mass of the excipient granules.

The tablet according to the second aspect of the present invention contains the excipient granules according to the first aspect and an active ingredient.
The tablet according to the second aspect may further include a disintegrant.

The method for producing a tablet according to the third aspect of the present invention is a method using the excipient granules according to the first aspect.

According to the excipient granules of the above aspect, sufficient tablet hardness can be obtained even at a low pressing pressure, and it is possible to provide an excipient granule that is excellent in fast disintegration when formed into a tablet and has a feeling of ingestion. According to the tablet of the above aspect and the method for producing the tablet, sufficient tablet hardness can be obtained even at a low pressing pressure, and a tablet excellent in rapid disintegration and ingestion feeling can be obtained.

Hereinafter, modes for carrying out the present invention (hereinafter, sometimes simply referred to as “the present embodiment”) will be described in detail. The following embodiments are examples for explaining the present invention, and are not intended to limit the present invention to the following contents. The present invention can be appropriately modified and implemented within the scope of the gist.

<<Excipient granules>>
The excipient granules of this embodiment include cellulose and partially pregelatinized starch.
The “excipient granule” in the present specification is mainly granulated by granulating an excipient. The excipient granules are preferably free of active ingredients. By not containing the active ingredient, it functions as a skeleton of the preparation capable of imparting desirable disintegrating properties and moldability as an orally disintegrating tablet, regardless of the properties peculiar to the active ingredient. However, the active ingredient may be contained in a small amount so as not to impair the function of the excipient granules.

The excipient granules of the present embodiment have the above-mentioned constitution, and therefore, sufficient tablet hardness can be obtained even at a low pressing pressure, and to provide the excipient granules which are excellent in rapid disintegration and a feeling of ingestion when formed into a tablet. You can

<Cellulose>
As used herein, "cellulose" is a naturally-derived, water-insoluble fibrous substance containing cellulose. In the excipient granules of the present embodiment, for example, wood pulp, non-wood pulp, straw, rice straw, cotton, cotton linter, hemp, ramie, bagasse, kenaf, beet, squirts, hydrolyzed from a cellulose raw material such as bacterial cellulose. Cellulose obtained by treatment or the like can be used. These cellulose raw materials may be used alone or in combination of two or more. Among them, as the cellulose raw material, wood pulp or non-wood pulp is preferable, wood bleached pulp (BP), wood dissolving pulp (DP) or cotton linter pulp is more preferable, and wood bleached kraft pulp (BKP) or wood dissolved kraft pulp ( DKP) is more preferred.

Among them, cellulose powder is preferable as the cellulose contained in the excipient granules of the present embodiment. Generally, "cellulose powder" is referred to as crystalline cellulose, powdered cellulose, etc., and is preferably used as a pharmaceutical additive or food additive. In addition, those treated with an additive such as silicic acid-treated crystalline cellulose (SMCC) described in Pharmaceutical Additives Standard 2018 may be used.
Among them, crystalline cellulose is preferable as the cellulose powder. The crystalline cellulose is at least one that meets the confirmation test of microcrystalline cellulose described in Food Additives Official Publication No. 9th Edition, and one that meets the confirmation test of crystalline cellulose described in Japanese Pharmacopoeia 17th revision. More preferable.

The content of cellulose in the excipient granules of the present embodiment is preferably 1% by mass or more and 90% by mass or less, more preferably 1% by mass or more and 70% by mass or less, more preferably 3% by mass based on the total mass of the excipient granules. The content is more preferably from 70% by mass to 70% by mass, particularly preferably from 5% by mass to 60% by mass, and most preferably from 10% by mass to 50% by mass. When the content of cellulose is at least the above lower limit, the tablet is more excellent in moldability and disintegration. Further, when the content of cellulose is not more than the above upper limit value, the feeling of ingestion as an orally disintegrating tablet tends to be more excellent.

When using cellulose powder for the excipient granules of the present embodiment, the average particle size of the cellulose powder is 10 μm or more and 200 μm or less, preferably 15 μm or more and 150 μm or less, more preferably 15 μm or more and 130 μm or less, and further preferably 15 μm or more and 120 μm or less. It is preferably 15 μm or more and 100 μm or less. When the average particle size of the cellulose powder is at least the above lower limit value, it is more effective in preventing tableting troubles. When the average particle size is within the above range, the tablet is more excellent in the balance between moldability and disintegration.
The average particle size of the cellulose powder is a low tap type sieve shaker (manufactured by Hiraiko Seisakusho, Sieve Shaker A type), and JIS standard sieve openings 212 μm, 177 μm, 150 μm, 106 μm, 75 μm, 63 μm, 45 μm. And 10 μg of the cellulose powder were sieved for 15 minutes using a 38 μm sieve, and the mass percentage (%) of the powder on each sieve and passed through the 38 μm sieve was determined. Particles when the cumulative mass percentage was 50% Expressed in diameter.

The loose bulk density of the cellulose powder is preferably 0.10 g/cc or more and 0.34 g/cc or less, more preferably 0.11 g/cc or more and 0.33 g/cc or less, and 0.12 g/cc or more and 0.30 g/cc or less. Is more preferable. When the loose bulk density is at least the above lower limit value, the compression moldability can be further improved. On the other hand, when the loose bulk density is not more than the above upper limit, the mass uniformity of the tablet becomes better. The loose bulk density of the cellulose powder can be measured by the method described in Examples described later.

The bulk density of the cellulose powder is preferably 0.25 g/cc or more and 0.60 g/cc or less, more preferably 0.26 g/cc or more and 0.58 g/cc or less, and 0.27 g/cc or more and 0.57 g/cc or less. Is more preferable. When the bulk density is within the above range, handleability becomes better. The bulk density of the cellulose powder can be measured by the method described in Examples below.

The compressibility of the cellulose powder is preferably 21% or more and 70% or less, more preferably 23% or more and 60% or less, and further preferably 25% or more and 57% or less. When the compressibility is within the above range, the fluidity of the cellulose powder itself is better, and this is preferable from the viewpoint of tablet mass uniformity.
The compressibility can be calculated from the loose bulk density (A) and the solid bulk density (P) according to the formula shown below.

Compression rate (%) = {(P-A)/P} x 100

The water absorption of the cellulose powder is preferably 160% or more and 360% or less, more preferably 160% or more and 350% or less, further preferably 190% or more and 320% or less, particularly preferably 200% or more and 310% or less, and 205% or more 310%. The following are the most preferable. The “water absorption amount” in the present specification is an index of how much water the cellulose powder absorbs, based on the weight of the cellulose powder. When the amount of water absorption is within the above range, the disintegration in tablets is improved.
The water absorption of the cellulose powder can be calculated using the method described below. Using a dried sample, weigh 1 g of cellulose powder into a plastic 50 mL centrifuge tube (Nalgene ^TM High-Speed Round-Bottom PPCO Centrifuge Tubes, product number: 3110-0500) (actually weigh the mass “Wi” (g)) and pure water: 30 mL are added, and dispersed with stirring with a spoon so that the whole cellulose powder is immersed in pure water. After standing for 30 minutes, centrifugation (centrifugal force: 2000 G, time: 10 minutes, temperature: 20° C.) is performed to precipitate a solid content. Tilt the mouth of the centrifuge tube downward so as not to destroy the precipitated cellulose layer, remove the supernatant liquid, and tilt the mouth of the centrifuge tube 30° downward from the horizontal on a table lined with paper towels. Drain excess water by letting it sit for a minute. Then, the mass (Wf(g)) of the water-absorbed cellulose powder is measured. Using the obtained Wi and Wf, the water absorption amount (%) is calculated by the formula shown below.

Water absorption (%) = {(Wf-Wi)/Wi} x 100

The ratio of the major axis (L) to the minor axis (D) of the cellulose particles, that is, the aspect ratio (L/D) is preferably 1.5 or more and 3.5 or less, more preferably 1.7 or more and 3.5 or less, and 1 0.8 or more and 3.5 or less are more preferable, and 2.0 or more and 3.5 or less are especially preferable. When the aspect ratio is within the above range, the compatibility with the active ingredient and other components is better, the entanglement of the elongated particles is appropriate, and the moldability and disintegration are more excellent in balance. In addition, it is more excellent in the feeling of taking a tablet.
The aspect ratio (L/D) of the cellulose powder can be measured by the method described in Examples described later.

The lower limit of the angle of repose of the cellulose particles is preferably 30°, more preferably 32°, further preferably 33°, particularly preferably 34°. On the other hand, the upper limit of the angle of repose is not particularly limited, but is theoretically less than 90°, preferably 80°, more preferably 70°, and further preferably 60°.
That is, the angle of repose of the cellulose particles is preferably 30° or more and less than 90°, more preferably 32° or more and 80° or less, further preferably 33° or more and 70° or less, and particularly preferably 34° or more and 60° or less.
The angle of repose is a fluidity index generally used in the field of powder.The lower the angle of repose, the better the fluidity, and the more uniform mixing with partially pregelatinized starch, active ingredients and other ingredients. It will be easier.
The angle of repose of the cellulose powder can be measured using a cellulose powder having a water content of 3.5% by mass or more and 4.5% by mass or less. For the angle of repose of the cellulose powder, a Sugihara-type repose angle measuring instrument (slit size: depth 10 × width 50 × height 140 mm, protractor installed at a position of width 50 mm) was used, and the cellulose powder was measured with a constant-volume feeder at 50 cc/min. It is determined by measuring the dynamic self-fluidity when dropped into the slit at the speed of. The angle between the bottom of the device and the formation layer of cellulose powder is the angle of repose. The measurement is performed 5 times, the average value is obtained, and the obtained value can be used as the angle of repose.

<Partially pregelatinized starch>
The partially pregelatinized starch is preferably used as a pharmaceutical additive or a food additive, and one that conforms to the confirmation test of the partially pregelatinized starch described in the pharmaceutical additive standard 2018 is preferable. Examples of such partially pregelatinized starch include commercially available partially pregelatinized starch (PCS (registered trademark) manufactured by Asahi Kasei).

The content of partially pregelatinized starch in the excipient granules of the present embodiment is preferably 1% by mass or more and 80% by mass or less, and more preferably 1% by mass or more and 70% by mass or less, based on the total mass of the excipient granules. It is more preferably 2% by mass or more and 70% by mass or less, particularly preferably 3% by mass or more and 70% by mass or less, and most preferably 5% by mass or more and 65% by mass or less. When the content of partially pregelatinized starch is at least the above lower limit, the tablet is more excellent in ingestion feeling. Further, when the content of cellulose is not more than the above upper limit value, the moldability and disintegration of tablets tend to be more excellent.

The average particle size of the partially pregelatinized starch is preferably 10 μm or more and 80 μm or less, more preferably 20 μm or more and 70 μm or less, further preferably 30 μm or more and 70 μm or less, particularly preferably 30 μm or more and 60 μm or less, and most preferably 40 μm or more and 60 μm or less. When the average particle size of the partially pregelatinized starch is equal to or more than the above lower limit, the tablet is more excellent in ingestion feeling. On the other hand, when the average particle diameter is not more than the above upper limit value, the tablet formability is more excellent.
The average particle size of the partially pregelatinized starch is a particle size with a cumulative volume of 50% measured by a laser diffraction type particle size distribution meter (LA-950 V2 type (trade name), manufactured by Horiba Ltd.).

The loose bulk density of the partially pregelatinized starch is preferably 0.10 g/cc or more and 1.0 g/cc or less, more preferably 0.10 g/cc or more and 0.8 g/cc or less, and 0.2 g/cc or more and 0.8 g or less. /Cc or less is more preferable. When the loose bulk density is at least the above lower limit, the balance between the moldability and the disintegration of the tablet is more excellent. On the other hand, when the loose bulk density is not more than the above upper limit, the mass uniformity of the tablet becomes better.
The loose bulk density can be measured by using a partially pregelatinized starch having a water content of 5.5% by mass or more and 6.5% by mass or less and a method similar to that of the loose bulk density of cellulose powder. .. Further, the water content of the partially pregelatinized starch can also be measured using the same method as the water content of the cellulose powder.

The lower limit of the angle of repose of the partially pregelatinized starch is preferably 25°, more preferably 28°, further preferably 30°, particularly preferably 32°. On the other hand, the upper limit of the angle of repose is not particularly limited, but is theoretically less than 90°, preferably 70°, more preferably 60°, and further preferably 50°.
That is, the angle of repose of the partially pregelatinized starch is preferably 25° or more and less than 90°, more preferably 28° or more and 70° or less, further preferably 30° or more and 60° or less, and particularly preferably 32° or more and 50° or less.
The angle of repose is an index of fluidity generally used in the field of powder, and the lower the angle of repose is, the more excellent the fluidity is, and the more easily it is mixed with cellulose, the active ingredient, and other ingredients more uniformly.
The angle of repose can be measured by using a partially pregelatinized starch having a water content of 5.5% by mass or more and 6.5% by mass or less and using the same method as the angle of repose of cellulose powder.

The amount of the water-soluble component of the partially pregelatinized starch is not particularly limited, but is preferably 0.1% by mass or more and 8% by mass or less, more preferably 0.1% by mass or more and 7% by mass or less, and 0.1% by mass or more 6 The content is more preferably not more than mass%, particularly preferably not less than 0.1 mass% and not more than 5 mass%. The smaller the content of the water-soluble component, the better the moldability of the tablet.
The amount of water-soluble components of partially pregelatinized starch can be measured using the following method. The water content of the partially pregelatinized starch is measured in advance. The water content can be measured by the same method as the water content of the cellulose powder, and the water content is 5.5% by mass or more and 6.5% by mass or less (the water content is defined as “W1 (%) )) partially pregelatinized starch. Next, a partially pregelatinized starch is weighed out into a plastic 50 mL centrifuge tube (Nalgene ^™ High-Speed Round-Bottom PPCO Centrifuge Tubes, product number: 3110-0500) so that the solid content becomes 1 g (here, The mass of the partially pregelatinized starch actually weighed is defined as M1 (g), that is, the mass M1 (g) can be calculated by "formula: solid content 1 g x (1-W1/100)". .. Partial pregelatinized starch: M2g (M2 (g) = 40-M1 (g)) of pure water is added to M1g at room temperature (20°C), and the partially pregelatinized starch dispersion liquid is dispersed with stirring with a spatula. Soak pure water in the whole starch. Then, after standing for 10 minutes, the dispersion liquid is centrifuged (centrifugal force: 2000 G, time: 15 minutes, temperature: room temperature (20° C.)) to precipitate a solid content. The mouth of the centrifuge tube is tilted down so as not to break the precipitated partially pregelatinized starch layer, and the supernatant liquid is put into a weighing bottle whose dry mass (T1 (g)) has been measured in advance. In order to evaporate the supernatant liquid to dryness, a weighing bottle containing the supernatant liquid is placed in a dryer (temperature: 105° C., time: 16 hours or more) and dried. After the supernatant liquid is dried, the weighing bottle is put in a desiccator and cooled to room temperature, and after measuring the mass (T2 (g)), the amount of water-soluble component (mass %) can be calculated by the formula shown below. ..

Amount of water-soluble components (mass %) = {(T2-T1)/solid content (1g)} x 100

Portion swelling degree of pregelatinized starch is preferably ^{2 cm} 3 / g or more 15cm ³ / g or less, more preferably ^{3 cm} 3 / g or more 13cm ³ / g or less, more preferably ^{5 cm} 3 / g or more 13cm ³ / g or less, It is particularly preferably 5 cm ³ /g or more and 10 cm ³ /g or less.
When the degree of swelling is at least the above lower limit, the tablet disintegration is more excellent. On the other hand, when the degree of swelling is not more than the above upper limit, the tablet tends to have a better feeling of ingestion.
The degree of swelling of partially pregelatinized starch can be measured using the following method. 1 g of partially pregelatinized starch is put into 75 mL of pure water at a temperature of 25° C., and stirred with a stirrer for 10 minutes to disperse. The total amount of the dispersion liquid is put into a 100-mL graduated cylinder with a tight stopper, and pure water is put into the graduated cylinder to adjust the volume to 100 mL. The graduated cylinder containing the dispersion liquid is shaken up and down 5 times, the partially pregelatinized starch is again dispersed, and the mixture is left standing for 16 hours or more. The volume (cm ³ /g) after standing is the swelling degree. The measurement is performed 5 times, the average value is obtained, and the obtained value can be used as the swelling degree.

The water absorption of the partially pregelatinized starch is preferably 300% or more and 700% or less, more preferably 400% or more and 700% or less, and further preferably 450% or more and 700%. When the water absorption amount is at least the above lower limit, the tablet disintegration is more excellent. On the other hand, when the water absorption amount is not more than the above upper limit value, the tablet is more excellent in ingestion feeling.
The water absorption can be measured by the same method as the water absorption of the cellulose powder.

As the degree of pregelatinization of the partially pregelatinized starch, starch having various degrees of pregelatinization can be used, but 40% or more and 80% or less is preferable, 45% or more and 80% or less is more preferable, and 45% or more and 75% or less is preferable. More preferably, 50% or more and 75% or less is particularly preferable. When the degree of gelatinization is within the above range, the moldability and disintegration of the tablet are better, and the tablet is more comfortable to take.
The degree of pregelatinization of partially pregelatinized starch is based on the glucoamylase method which is a conventional method (reference: Jiro Nikuni, "Starch Chemistry Handbook", Asakura Shoten, 1977, p.242). It means a required value and can be measured, for example, by the following method.
1 g of glucoamylase is dissolved in 100 mL of water, and the supernatant is used as an enzyme solution. A suspension is prepared by adding 8 mL of water to 100 mg of sample (anhydrous basis). Dispense 2 mL of the suspension into each of two test tubes to give a test solution and a complete α-test solution. 2 mol/L acetate buffer (pH 4.8): 1.6 mL, water: 0.4 mL, and enzyme solution: 1 mL are added to the test solution. 10N NaOH: 0.2 mL, 2 mol/L acetic acid: 1.6 mL, water: 0.2 mL, and enzyme solution: 1 mL are added to the complete α-ized test solution. These test solutions are reacted at 37° C. for 60 minutes. To each reaction solution: 0.5 mL, 25 mmol/L HCl: 10 mL is added to terminate the reaction. Supernatant: 0.5 mL is collected, and water: 0.5 mL and Somogyi reagent: 1.0 mL are added. The solution is heated in boiling water for 10 minutes and then cooled. Add 3 mL of Nelson reagent, and after 3 minutes, bring the total volume to 10 mL with purified water, and measure the absorbance at a wavelength of 660 nm. Using the obtained absorbance, the degree of alphalation is calculated by the following formula. In the formula, “Aa” is the absorbance of the test liquid, “Ab” is the absorbance of the completely α-ized test liquid, and “A ₀ ”is the absorbance of the blank.

Degree of alpha (%) = {(Aa-Ao)/(Ab-Ao)} x 100

<Other ingredients>
[Excipients other than cellulose]
The excipient granules of the present embodiment may include an excipient other than cellulose and partially pregelatinized starch in addition to cellulose and partially pregelatinized starch. As the excipient other than cellulose and partially pregelatinized starch, those which are compatible with the pharmacopoeias of Japan, Europe and the United States can be usually used, and may be an organic excipient or an inorganic excipient. May be. Further, it may be a water-soluble excipient or a water-insoluble excipient. Examples of organic excipients include sugars, sugar alcohols, starches other than partially pregelatinized starch, and cellulose derivatives. Examples of saccharides include lactose, sucrose, fructooligosaccharides, glucose, palatinose, maltose, reduced maltose, powdered sugar, powdered candy, fructose, isomerized lactose, honey sugar and the like. These saccharides may be used alone or in combination of two or more. Examples of sugar alcohols include D-mannitol, erythritol, xylitol, maltitol, sorbitol and the like. These sugar alcohols may be used alone or in combination of two or more. Examples of the starches include corn starch, potato starch, rice starch and the like. These starches may be used alone or in combination of two or more. Examples of the cellulose derivative include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, croscarmellose sodium and the like. These cellulose derivatives may be used alone or in combination of two or more.
Examples of the inorganic excipient include synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminate silicate, magnesium hydroxide and the like. These inorganic excipients may be used alone or in combination of two or more.
Among them, as the excipient other than cellulose and partially pregelatinized starch, a water-soluble excipient is preferable, a sugar alcohol is more preferable, and D-mannitol is further preferable.

When sugar alcohol is used as the excipient, the particle size is preferably 10 μm or more and 300 μm or less, more preferably 20 μm or more and 150 μm or less. The particle size of sugar alcohol can be measured by a laser diffraction type particle measuring method. Commercially available sugar alcohols can be appropriately used.

When the excipient other than cellulose and partially pregelatinized starch is a water-soluble excipient, the content of the water-soluble excipient can be appropriately selected, and the content is 1 with respect to the total mass of the excipient granules. The content is preferably from mass% to 90 mass%, more preferably from 1 mass% to 85 mass%, even more preferably from 1 mass% to 83 mass%, particularly preferably from 2 mass% to 73 mass%. When the content is within the above range, the tablet is more excellent in the balance between moldability and disintegration.

[Binder]
The excipient granules of this embodiment may include a binder in addition to cellulose and partially pregelatinized starch. As the binder, a water-soluble polymer is preferable. Examples of the water-soluble polymer include polyvinylpyrrolidone, pregelatinized starch, acacia, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl. Examples include alcohol and macrogol. These binders may be used alone or in combination of two or more.
Among them, as the water-soluble polymer, polyvinylpyrrolidone, pregelatinized starch or hydroxypropylcellulose is preferable, and polyvinylpyrrolidone or pregelatinized starch is more preferable, since the tablet has more excellent moldability and disintegration property.
The content of the binder is preferably 1% by mass or more and 20% by mass or less, more preferably 1% by mass or more and 10% by mass or less, and more preferably 1% by mass or more and 6% by mass or less with respect to the total mass of the excipient granules. More preferable. When the content of the binder is within the above range, the tablet formability and disintegration are more excellent.

[Disintegrant]
The excipient granules of this embodiment may include a disintegrant in addition to cellulose and partially pregelatinized starch. Examples of the disintegrating agent include those classified as "disintegrating agents" in "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo Co., Ltd.) such as celluloses, starches, and synthetic polymers. Examples of celluloses include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose and the like. Examples of the starches include sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, pregelatinized starch and the like. Examples of the synthetic polymer include crospovidone and crospovidone copolymer. These disintegrants may be used alone or in combination of two or more.
The content of the disintegrant is preferably 0.5% by mass or more and 30% by mass or less, more preferably 1% by mass or more and 20% by mass or less, and more preferably 1% by mass or more and 10% by mass with respect to the total mass of the excipient granules. The following is more preferable. When the content of the disintegrant is at least the above lower limit, the balance between moldability and disintegration of the tablet is excellent, while when it is at most the above upper limit, the storage stability of the tablet is excellent.

<Method of manufacturing excipient granules>
Examples of the method for producing the excipient granules of the present embodiment include dry granulation, wet granulation, heat granulation, spray granulation, and microencapsulation. Specific examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a crush granulation method, and a tumbling granulation method. In the fluidized bed granulation method, the fluidized powder is granulated by spraying the binding liquid onto the fluidized powder in a fluidized bed granulator. In the stirring granulation method, powder is mixed, kneaded and granulated simultaneously in a closed structure by rotating a stirring blade in a mixing tank while adding a binding solution. In the extrusion granulation method, the wet mass kneaded by the addition of the binding solution is forcibly extruded from a screen having an appropriate size by a screw method, a basket method, or the like for granulation. In the crushing and granulating method, the wet mass kneaded by the addition of the binding solution is sheared and crushed by the rotary blade of the granulator, and the centrifugal force ejects it from the outer peripheral screen to granulate. In the rolling granulation method, the particles are rolled by the centrifugal force of the rotating rotor, and the binding liquid sprayed from the spray gun at this time grows spherical granules with a uniform particle size in a snowball manner. ..
As a method for producing the excipient granules of the present embodiment, any method can be applied, but the present inventors have found that when the granules are produced by the fluidized bed granulation method, they are formed into tablets. It was found that an excipient granule having a better balance of disintegration property and disintegration property and an excellent feeling of ingestion can be obtained.

The binder solution sprayed by the fluidized bed granulation method is prepared by appropriately dispersing or dissolving the above binder in a solvent such as water, ethanol or methanol. The conditions for adjusting the binding solution can be appropriately selected.
The method of spraying the binding solution is, for example, a method of spraying the binding solution using a pressure nozzle, a two-fluid nozzle, a four-fluid nozzle, a rotating disk, an ultrasonic nozzle, a method of dropping the binding solution from a tubular nozzle, or a continuous spraying method. Alternatively, a drying step or a shaking step may be provided in the middle of the granulation step, and after spraying for a certain period of time, an intermittent spraying method of repeating a cycle such as drying for a certain period of time may be mentioned. There is no particular limitation as long as a granulated product can be obtained.
The amount of the binding solution sprayed is not particularly limited as long as it can be granulated. Further, the spraying speed is not particularly limited as long as it can be granulated. For example, the spray rate at the time of producing a 1 kg granulated product can be 3 g/min or more and 30 g/min or less.

Excipient granules can also be dried after granulation. The drying method is not particularly limited as long as it is a method of usually pharmaceutically drying, and examples thereof include hot air heating type, conduction heat transfer type and freeze drying. In the hot air heating type, hot air is brought into direct contact with the additive to simultaneously remove evaporated water. Specific examples of the hot air heating type include shelf drying, vacuum drying and fluidized bed drying. In the conductive heat transfer type, the additive is indirectly heated through the heat transfer wall. Specific examples of the conductive heat transfer type include a pan type, a shelf box type, and a drum type. In freeze-drying, the additives should be frozen at -10°C or higher and 40°C or lower, and then heated under high vacuum (1.3×10 ^-5 MPa or more and 2.6×10 ^-4 MPa or less). To sublimate and remove water.

The drying time can be appropriately adjusted depending on the drying temperature and the amount of excipient granules. For example, when a 1 kg granulated product is dried in a fluidized bed at a drying temperature of 80° C., the drying time can be 10 minutes or more and 60 minutes or less. Also, the water content of the excipient granules can be appropriately adjusted by the balance between the drying time and the temperature.

<<Tablet>>
The tablet of this embodiment contains the above-mentioned excipient granules and an active ingredient.
Since the tablet of the present embodiment contains the above-mentioned excipient granules, sufficient tablet hardness can be obtained even with a low pressing pressure, and a tablet excellent in fast disintegration and ingestion feeling can be obtained. Moreover, the tablet of this embodiment is suitable as an orally disintegrating tablet.

In the tablet of the present embodiment, the compounding amount of the excipient granules may be any ratio, but a practically preferable range is 95% by mass or less based on the mass of the entire tablet. The lower limit is practically 0.1% by mass. In the case of a tablet containing a large amount of active ingredients, the blending amount of the excipient granules is preferably 0.1% by mass or more and 80% by mass or less, more preferably 1% by mass or more and 70% by mass or less, and 5% by mass or more. 60 mass% or less is more preferable, and 5 mass% or more and 55 mass% or less is especially preferable.

<Active ingredient>
In the present specification, the "active ingredient" is added to the mixed powder, molded product, processed product or the like in order to exert the intended function or effect in the fields of medicines, health foods, foods, industrial fields, etc. Say. For example, an active ingredient in the pharmaceutical field is a medicinal active ingredient.

Examples of suitable active ingredients contained in the tablet of the present embodiment are shown below.
As the medicinal active ingredient, an active ingredient of an orally administered medicinal product is preferable. Examples of the orally administered drug include, for example, antipyretic and analgesic anti-inflammatory drug, hypnotic sedative, drowsiness preventive, analgesic, pediatric analgesic, stomachic, antacid, digestive, cardiotonic, arrhythmic drug, antihypertensive drug, and antihypertensive drug. Examples include vasodilators, diuretics, anti-ulcer agents, intestinal agents, osteoporosis remedies, antitussive expectorants, antiasthma agents, antibacterial agents, frequent urine improving agents, nutritional tonics, vitamins and the like. These medicinal ingredients may be used alone or in combination of two or more.

Specific examples of the medicinal properties of pharmaceuticals include, for example, aspirin, aspirin aluminum, acetaminophen, etenzamid, sazapyrine, salicylamide, lactylphenetidine, isothibenzyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, and hydrochloric acid. Tripelenamine, tonzylamine hydrochloride, phenetazine hydrochloride, metzilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, mebuhydroline teoclate dimethyric acid, maleic acid dimethyline dihydrochloride, dimethyric acid diamine salicylate, maleic acid carboxinate Phenylamine, chlorpheniramine d-maleate, difeterol phosphate, aloclamide hydrochloride, cloperastine hydrochloride, pentoxyberine citrate (carbetapentane citrate), tipepidine citrate, sodium dibnate, dextromethorphan hydrobromide, Dextromethorphan phenolphthalic acid, hibendate acid tipepidine, fendizoate cloperastine, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, potassium guaiacolsulfonate, guaifenesin, Sodium Benzoate Caffeine, Caffeine, Anhydrous Caffeine, Vitamin B1 and its Derivatives and Their Salts, Vitamin B2 and Their Derivatives, Their Salts, Vitamin C and Their Derivatives, Their Salts, Hesperidin and Its Derivatives and Their Salts, vitamin B6 and its derivatives and salts thereof, nicotinamide, calcium pantothenate, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetic acid salt (aluminum glycinate) ), aluminum hydroxide gel (as dry aluminum hydroxide gel), dry aluminum hydroxide gel, aluminum hydroxide/magnesium carbonate mixed dry gel, coprecipitation product of aluminum hydroxide/sodium hydrogen carbonate, aluminum hydroxide/calcium carbonate -Magnesium carbonate coprecipitation product, magnesium hydroxide/potassium aluminum sulfate coprecipitation product, magnesium carbonate, magnesium aluminometasilicate, ranitidine hydrochloride , Cimetidine, famotidine, naproxen, diclofenac sodium, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, promethazine hydrochloride, meclizine hydrochloride, dimenhydrinate, tannic acid diphenhydramine, tanenoic phenetane acid Diphenylpyraline, diphenhydramine fumarate, promethazine methylene disalicylate, sporocollamine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methylatropine bromide, methylanisotopine bromide, methylspocoramine bromide, bromide Methyl-1-hyoscyamine, methylbenactidium bromide, belladonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid, cesium oxalate, ethyl piperidylacetylaminobenzoate, aminophylline, Diprophylline, theophylline, sodium hydrogen carbonate, fursultiamine, isosorbide dinitrate, ephedrine, cephalexin, ampicillin, sulfixazole, sucralfate, allylisopropylacetylurea, bromvalerylurea, ephedra, nantenzitsu, spruce, rondy, licorice, kyoto, chazenshi, Chazensou, Senega, Fritillaria, Fennel, Oubaku, Ouren, Gautu, Chamomile, Keihi, Gentiana, Gooh, Beast (including Yutan), Shajin, Gyoza, Sojutsu, Clove, Chinpi, Byakujutsu, Chiryu, Chikusetsunjin, "Japanese Pharmacopoeia", "Japanese Pharmacopoeia Standards (Outside Base)", "US Pharmacopoeia" (carrot, valerian, button pipi, salamander, insulin, vasopressin, interferon, urokinase, seratiopeptidase, somatostatin, etc.) USP)”, “National Medicines Collection (NF)”, “European Pharmacopoeia (EP)”, and the like. These medicinal ingredients may be used alone or in combination of two or more.

The active ingredient for health food is not limited as long as it is an ingredient to be added for the purpose of enhancing health. Specifically as active ingredients for health foods, for example, green juice powder, aglycone, agarix, Ashwagandha, astaxanthin, acerola, amino acid, alginic acid, ginkgo leaf extract, sardine peptide, turmeric, uronic acid, echinacea, eleuthero, oligosaccharides. , Oleic acid, nucleoprotein, cuticle peptide, catechin, potassium, calcium, carotenoid, garcinia, L-carnitine, chitosan, conjugated linoleic acid, kidati aloe, Gymnema sylvestre extract, citric acid, cumistin, glyceride, grisenol, glucagon, curcumin, glucosamine , N-acetylglucosamine, L-glutamine, chlorella, cranberry extract, cat's claw, germanium, enzyme, ginseng extract, coenzyme Q10, collagen, collagen peptide, coleus forskolin, chondroitin, psyllium husk powder, hawthorn extract, saponin, lipid , L-cystine, perilla extract, citrimax, fatty acid, plant sterol, seed extract, spirulina, squalene, white willow, ceramide, selenium, St. John's wort extract, soybean isoflavone, soybean saponin, soybean peptide, soybean lecithin, simple sugar, protein, Chest tree extract, iron, copper, docosahexaenoic acid, tocotrienols, nattokinase, Bacillus natto culture extract, niacin sodium, nicotinic acid, disaccharide, lactic acid bacterium, garlic, saw palmetto, germinated rice, coix extract, herb extract, valerian extract, pantothene. Acid, hyaluronic acid, biotin, chromium picolinate, vitamin A, vitamin A2, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, hydroxytyrosol, bifidobacteria, brewer's yeast , Fructooligosaccharides, flavonoids, butchers bloom extract, black cohosh, blueberries, prune extract, proanthocyanidin, protein, propolis, bromelain, probiotics, phosphatidylcholine, phosphatidylserine, β-carotene, peptide, safflower extract, maitake extract, maca extract, magnesium , Silybum marianum, manganese, mitochondria, minerals, mucopolysaccharide, melatonin, meshimakobu, melilot extract powder, molybdenum, vegetable powder, folic acid, lactose, lycopene, linoleic acid, lipoic acid, phosphorus (phosphorus), lutein, lecithin And rosmarinic acid, royal jelly, DHA, EPA and the like. Examples of the amino acid include valine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, histidine, cystine, tyrosine, arginine, alanine, aspartic acid, seaweed powder, glutamine, glutamic acid, glycine, proline, and serine. Be done. These active ingredients for health foods may be used alone or in combination of two or more.

The active ingredient may be water-soluble or sparingly soluble. "Slightly soluble" means that the amount of water required to dissolve 1 g of solute is 30 mL or more in the 17th revised Japanese Pharmacopoeia.
Examples of the poorly water-soluble solid active ingredient include, for example, acetaminophen, ibuprofen, benzoic acid, etenzamid, caffeine, camphor, quinine, calcium gluconate, dimethylcaprol, sulfamine, theophylline, theopromine, riboflavin, mephenesin, and pheno. Barbital, aminophylline, thioacetazone, quercetin, rutin, salicylic acid, theophylline sodium salt, pirapital, quinine hydrochloride, irgapyrin, dichitoxin, griseofulvin, phenacetin, etc. , Antihistamines, etc.; acetylspiramycin, ampicillin, erythromycin, xatamycin, chloramphenicol, triacetyloleandomycin, nystatin, colistin sulfate, and other antibiotics; methyltestosterone, methylandrostetrondiol, progesterone, estradiol benzoate, ethini Steroid hormone agents such as restradiol, deoxycorticosterone acetate, cortisone acetate, hydrocortisone, hydrocortisone acetate, and brednisolone; dientstrol, hexastrol, diethylstilbestrol, diethylstilbesterol dibrothionate, chlorotrianisene Nonsteroidal egg yolk hormone agents such as; and other medicinal ingredients such as fat-soluble vitamins described in “Japanese Pharmacopoeia”, “External Group”, “USP”, “NF”, “EP”, etc. .. These poorly water-soluble solid active ingredients may be used alone or in combination of two or more.

The active ingredient may be poorly water-soluble and may be oily or liquid. Examples of the poorly water-soluble, oily or liquid active ingredients include, for example, teprenone, indomethacin farnesyl, menatetrenone, phenypentol, phytonadione, vitamins, higher unsaturated fatty acids, coenzyme Qs, oil-soluble flavoring agents, etc. Examples include the pharmacologically active ingredient of medicines described in “Pharmacopoeia”, “External Group”, “USP”, “NF”, and “EP”. Examples of vitamins include vitamin A oil, vitamin D, vitamin E and the like. Vitamin E has various homologues and derivatives, but is not particularly limited as long as it is liquid at room temperature. Specific examples of vitamin E include dl-α-tocopherol, dl-α-tocopherol acetate, d-α-tocopherol, and d-α-tocopherol acetate. Examples of the higher unsaturated fatty acids include DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and liver oil. Examples of the oil-soluble flavor include orange oil, lemon oil, peppermint oil and the like. These poorly water-soluble, oily or liquid active ingredients may be used alone or in combination of two or more.

The active ingredient may be sparingly water-soluble and semi-solid. Examples of the poorly water-soluble and semi-solid active ingredient include herbs or herbal extracts, oyster meat extracts, propolis and propolis extracts, coenzyme Qs and the like. The herbs or herbal extracts include, for example, earth dragon, licorice, cinnamon, peony, button piper, valerian, salamander, ginger, chinpi, maoh, nantenjitsu, halibut, onji, kyokyo, shazenshi, shazenso, gypsum, seneca, Fritillaria, fennel, oleander, laurel, zedoary, chamomile, gentian, gou, animal gall, shazin, ginger, ginseng, clove, chinhi, juniper, chikusettsu ginseng, carrot, kakkonto, keishito, kososan, purple Examples include Kokeishi-to, Shoji-ko-to, Shoseiryu-to, Bakumondo-to, Hangekoboku-to, Mao-to. These poorly water-soluble semisolid active ingredients may be used alone or in combination of two or more.

The active ingredient may be sublimable. The “sublimable active ingredient” in the present specification is not particularly limited as long as it has sublimability, and may be solid at room temperature or liquid. It may be semi-solid. As the sublimable active ingredient, for example, benzoic acid, etenzamid, caffeine, camphor, salicylic acid, phenacetin, ibuprofen, etc., "Japanese Pharmacopoeia", "External Group", "USP", "NF", "EP" And sublimable medicinal properties and the like. These sublimable active ingredients may be used alone or in combination of two or more.

These active ingredients may be blended with excipient granules in the tablet of the present embodiment in a finely divided state. For example, as the average particle size of the active ingredient used in the tablet of the present embodiment, for the purpose of improving the dispersibility of the active ingredient, or improving the mixing uniformity of the active ingredient having a medicinal effect in a trace amount. Is preferably 1 μm or more and 40 μm or less, more preferably 1 μm or more and 20 μm or less, still more preferably 1 μm or more and 10 μm or less.

(Granule containing active ingredient)
The active ingredient used in the tablet of this embodiment may be in the form of granules. The active ingredient-containing granules can be produced, for example, by a conventional extrusion granulation method, a mixed stirring granulation method, a high speed stirring granulation method, a fluidized bed granulation method, a rolling granulation method, or the like.

(coating)
The active ingredient or the active ingredient-containing granules can be coated to control unpleasant tastes such as bitterness and irritancy, odor masking, and elution properties. For the coating, a coating agent and a plasticizer described later can be used appropriately. The coating method is performed by using, for example, a fluidized bed granulating/coating machine, a rolling fluidized bed granulating/coating machine, a centrifugal fluidized granulating/coating machine, or a Wurster type fluidized bed granulating/coating machine. Further, a waxy substance is heated and melted, and an active ingredient and, if necessary, components such as sugar alcohol, synthetic aluminum silicate, and hydrous silicon dioxide are added and dispersed or dissolved, and then the dispersion or solution. It is also possible to carry out spray granulation to obtain active ingredient-containing granules with unpleasant taste and odor masking.

Examples of the coating agent include ethyl cellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkylmethacrylate copolymer RS, aminoalkylmethacrylate copolymer RS, acrylic acid. Examples thereof include ethyl/methyl methacrylate copolymer, polyvinyl acetal/diethylaminoacetate, polyvinyl acetate resin and the like. These coating agents may be used alone or in combination of two or more.

Examples of the plasticizer to be combined with the coating agent include diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol, triacetin and the like. These plasticizers may be used alone or in combination of two or more.

<Other additives>
The tablet of the present embodiment may further contain other additives, if necessary. Other additives include, for example, an excipient, a disintegrant, a binder, a fluidizing agent, a lubricant, a corrigent, a fragrance, a coloring agent, a sweetener and the like.

Examples of excipients include starch acrylate, L-aspartic acid, aminoethylsulfonic acid, aminoacetic acid, candy (powder), gum arabic, gum arabic powder, alginic acid, sodium alginate, pregelatinized starch, pumice granules, inositol. , Ethyl cellulose, ethylene vinyl acetate copolymer, sodium chloride, olive oil, kaolin, cacao butter, casein, fructose, pumice stone, carmellose, carmellose sodium, hydrous silicon dioxide, dry yeast, dry aluminum hydroxide gel, dry sodium sulfate, dry sulfuric acid Magnesium, agar, agar powder, xylitol, citric acid, sodium citrate, disodium citrate, glycerin, calcium glycerophosphate, sodium gluconate, L-glutamine, clay, clay 3, clay granules, croscarmellose sodium, crospovidone, Magnesium aluminate silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, light liquid paraffin, cinnamon powder, crystalline cellulose, crystalline cellulose/carmellose sodium, crystalline cellulose (grains), silicic acid treated crystalline cellulose (SMCC) , Phellinus linteus, synthetic aluminum silicate, synthetic hydrotalcite, sesame oil, wheat flour, wheat starch, wheat germ flour, rice rice, rice starch, potassium acetate, calcium acetate, cellulose acetate phthalate, safflower oil, salix beeswax, zinc oxide , Titanium oxide, magnesium oxide, β-cyclodextrin, dihydroxyaluminum aminoacetate, 2,6-di-butyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, gypsum sucrose, sucrose fatty acid ester, hydroxylation Alumina magnesium, aluminum hydroxide/gel, aluminum hydroxide/sodium hydrogen carbonate coprecipitate, magnesium hydroxide, scrawan, stearyl alcohol, stearic acid, calcium stearate, polyoxyl stearate, magnesium stearate, soybean hydrogenated oil, purified gelatin, Purified shellac, purified sucrose, purified sucrose spherical granules, cetostearyl alcohol, polyethylene glycol 1000 monocetyl ether, gelatin, sorbitan fatty acid ester, D-sorbitol, tricalcium phosphate, soybean oil, soybean unsaponifiables, soybean lecithin, skim milk powder, Talc, ammonium carbonate, calcium carbonate, magnesium carbonate, neutral anhydrous sodium sulfate, low substituted hydr Loxypropyl cellulose, dextran, dextrin, natural aluminum silicate, corn starch, tragacanth powder, silicon dioxide, calcium lactate, lactose, lactose granules, perfiller 101, white shellac, white petrolatum, hakudo, white sugar, sucrose/starch spherical Granules, Hadakamugi green leaf extract powder, naked malt leaf green juice dry powder, honey, paraffin, potato starch, semi-digested starch, human serum albumin, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl Methyl cellulose phthalate, phytic acid, glucose, glucose hydrate, partially pregelatinized starch, pullulan, propylene glycol, powdered reduced maltose starch syrup, powdered cellulose, pectin, bentonite, sodium polyacrylate, polyoxyethylene alkyl ether, polyoxyethylene hardening Castor oil, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, sodium polystyrene sulfonate, polysorbate 80, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, polyethylene glycol, Maltitol, maltose, D-mannitol, starch syrup, isopropyl myristate, anhydrous lactose, anhydrous calcium hydrogen phosphate, anhydrous calcium phosphate granules, magnesium aluminometasilicate, methyl cellulose, cottonseed powder, cottonseed oil, mokuro, monostearic acid Aluminum, glycerin monostearate, sorbitan monostearate, medicinal carbon, peanut oil, aluminum sulfate, calcium sulfate, granular corn starch, liquid paraffin, dl-malic acid, calcium phosphate-hydrogen phosphate, calcium hydrogen phosphate, phosphate As excipient for "Pharmaceutical Additives" (issued by Yakuji Nippo Co., Ltd.) such as calcium hydrogen granules, sodium hydrogen phosphate, potassium dihydrogen phosphate, calcium dihydrogen phosphate, sodium dihydrogen phosphate, etc. Some are classified. These may be used alone or in combination of two or more.

Examples of the disintegrant include those classified as "disintegrants" in the "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo Co., Ltd.) such as cellulose derivatives, starches, and synthetic polymers. Examples of the cellulose derivative include croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose and the like. Examples of the starches include sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch and the like. Examples of the synthetic polymer include crospovidone and crospovidone copolymer. These disintegrants may be used alone or in combination of two or more.

The blending amount of the disintegrant is preferably 0.5% by mass or more and 15% by mass or less, more preferably 1% by mass or more and 10% by mass or less, further preferably 2% by mass or more and 5% by mass or less with respect to the mass of the entire tablet. preferable.

As the binding agent, the binding agent is a "pharmaceutical additive encyclopedia" (published by Yakuji Nippo Co., Ltd.) such as sugars, sugar alcohols, water-soluble polysaccharides, celluloses, starches, synthetic polymers, and inorganic compounds. There are those classified as. Examples of saccharides include sucrose, glucose, lactose, fructose and the like. Examples of sugar alcohols include mannitol, xylitol, maltitol, erythritol, sorbitol and the like. Examples of the water-soluble polysaccharides include gelatin, pullulan, carrageenan, locust bean gum, agar, glucomannan, xanthan gum, tamarind gum, pectin, sodium alginate, gum arabic and the like. Examples of celluloses include crystalline cellulose, powdered cellulose, hydroxypropyl cellulose, methyl cellulose and the like. Examples of the starches include pregelatinized starch, partially pregelatinized starch, starch paste and the like. Examples of synthetic polymers include polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol and the like. Examples of the inorganic compounds include calcium hydrogen phosphate, calcium carbonate, synthetic hydrotalcite, magnesium aluminate silicate, and the like. These binders may be used alone or in combination of two or more.

Examples of the fluidizing agent include those classified as a fluidizing agent in "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo Co., Ltd.) such as silicon compounds. Examples of silicon compounds include hydrous silicon dioxide and light anhydrous silicic acid. These fluidizing agents may be used alone or in combination of two or more.

Lubricants that are classified as "lubricants" in the "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo) such as magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc, and sodium stearyl fumarate Is mentioned. These lubricants may be used alone or in combination of two or more.
The blending amount of the lubricant is preferably 0.1% by mass or more and 5% by mass or less, more preferably 0.1% by mass or more and 3% by mass or less, and 0.1% by mass or more 1 with respect to the mass of the entire tablet. It is more preferably not more than mass%.

Examples of the corrigent include "encyclopedia of pharmaceutical additives" such as glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol (Yakuji Nippo ) Issued) are classified as flavoring agents. These flavoring agents may be used alone or in combination of two or more.

Examples of the fragrance include oils, green tea powder, and the like, which are classified as fragrances and fragrances in the “Pharmaceutical Additives Dictionary” (published by Yakuji Nippo). Examples of the oils include orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, peppermint oil and the like. These fragrances may be used alone or in combination of two or more.

Examples of the coloring agent include food coloring agents, sodium copper chlorophin, titanium oxide, riboflavin, and the like which are classified as coloring agents in the "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo). Examples of food dyes include Food Red No. 3, Food Yellow No. 5, Food Blue No. 1, and the like. These colorants may be used alone or in combination of two or more.

Examples of sweeteners include those classified as sweeteners in the "Pharmaceutical Additives Dictionary" (published by Yakuji Nippo Co.) such as aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and end of armature. Can be mentioned. These sweeteners may be used alone or in combination of two or more.

<Tablet manufacturing method>
The tablet manufacturing method of the present embodiment is a method using the above-mentioned excipient granules.
It is obtained by tableting a mixture of one or more active ingredients or active ingredient-containing granules and the above-mentioned excipient granules. The tablet manufacturing method of the present embodiment is illustrated below, but this is an example, and the tablet manufacturing method of the present embodiment is not limited to the following method.

Examples of the method for producing the tablet of the present embodiment include a method in which the active ingredient or the active ingredient-containing granules are mixed with the above-mentioned excipient granules, followed by compression molding. At this time, in addition to the active ingredient or the active ingredient-containing granules, other additives may be added, if necessary. Examples of the other additives include the same as those exemplified in the above "other additives".

In the tablet manufacturing method of the present embodiment, the order of addition of the respective components is not particularly limited, and examples thereof include the method shown in i) or ii) below.
i) A method in which the active ingredient or the active ingredient-containing granules, the above-mentioned excipient granules, and, if necessary, other additives are mixed together and compression-molded;
ii) Active ingredient or active ingredient-containing granules, at least one additive of a fluidizing agent and a disintegrant agent, and the like are pretreated and mixed, and the above excipient granules and, if necessary, other additives are mixed. And then compression molding

Among them, the addition order of each component is preferably i) from the viewpoint of easy operation. It is also possible to add a lubricant to the mixed powder for compression molding obtained in i) and ii), further mix, and then perform compression molding. The addition method of each component is not particularly limited as long as it is a commonly used method, but for example, a small suction transportation device, an air transportation device, a bucket conveyor, a pressure transportation device, a vacuum conveyor, a vibrating quantitative feeder, a sprayer. , May be added continuously using a funnel or the like, or may be added all at once.

The mixing method is not particularly limited as long as it is a commonly used method, for example, a container rotary mixer, a stirring mixer, a high-speed fluid mixer, a drum mixer, a fluidized bed mixer, etc. It may be used and mixed. Examples of the container rotary type mixer include a V type, W type, double cone type, container tuck type mixer, and the like. Examples of the agitation type mixer include a high speed agitation type, a universal agitation type, a ribbon type, a pug type, and a Nauta type mixer. A container shaking type mixer such as a shaker can also be used.

The tablet compression molding method is not particularly limited as long as it is a commonly used method, for example, a method of compression molding into a desired shape using a die and a pestle, and a desired shape after compression molding into a sheet shape in advance. Examples thereof include a method of cutting into a shape. Examples of the compression molding machine include a compression machine such as a static pressure press machine, a roller type press machine, a single punch tableting machine and a rotary tableting machine. Examples of the roller type press include a briquetting roller type press and a smooth roller type press.

As a method for forming a tablet, for example, a mixture of an active ingredient and the above-mentioned excipient granules, or one or more active ingredients and the above-mentioned excipient granules, and if necessary, other additives, A semi-direct compression method of compression-molding a mixture of the above, a mixture of active ingredient-containing granules and the above excipient granules, or one or more active ingredient-containing granules and the above excipient granules, if necessary. Correspondingly, there may be mentioned a wet granule compression method in which a mixture of other additives is compression molded. In addition, you may use the manufacturing method of the multi-nuclear tablet which makes a tablet compression-molded beforehand the inner core, the manufacturing method of the multilayer tablet which piles up a several compact previously compressed, and compresses again. Among them, a semi-direct compression method is preferable as a method for forming tablets in terms of productivity and process control, and a wet granule compression method is preferable for uniformization of various components.

The compression-molded tablets may be further coated. Examples of the coating agent used in this case include coating agents described in "Encyclopedia of Pharmaceutical Additives" (published by Yakuji Nippo). These coating agents may be used alone or in combination of two or more.

Hereinafter, the present embodiment will be described in detail with reference to Examples and Comparative Examples, but the present embodiment is not limited thereto. The physical properties of the cellulose powder, the measuring method thereof, and the tablet evaluation method are as follows.

<Measurement method>
The physical properties of the cellulose powder were measured using the methods described below.

[Physical Properties 1] Loose Bulk Density A Scott volume meter (model ASTM B-329-85, manufactured by Tsutsui Rikagaku Kikai) is used to measure the loose bulk density of the cellulose powder, and each sample of 25 cc is passed through a sieve (opening 1 mm). It was filled in a cylindrical metal container. Each sample contained in a 25 cc cylindrical metal container was scraped off, and the mass (g) of each sample contained in the container was divided by 25 cc to determine the loose bulk density. The measurement was performed 3 times and the average value was calculated. When measuring the loose bulk density of each sample, a sample having a water content adjusted to 3.5% by mass or more and 4.5% by mass or less was used. The water content of each sample was measured for 3 g of the sample using an infrared moisture meter (FD-240, manufactured by Kett Science Laboratories) in an automatic measurement mode (105° C., monitoring time 60 seconds). The water content was measured twice and the average value was calculated.

[Physical Properties 2] Hardness Bulk Density A hardness density (bulk apparent specific gravity) (g/cc) of the cellulose powder was calculated using a powder physical property measuring device (PT-R, manufactured by Hosokawa Micron). The sieve used had an opening of 710 μm, and the funnel used had a metal inner diameter of 0.8 cm. VIBRATION was carried out at 2.0 (power supply: AC100V, 60Hz). For the measurement, a cellulose powder having a water content adjusted to 3.5% by mass or more and 4.5% by mass or less was used.

[Physical Properties 3] Aspect Ratio Cellulose powder was dispersed on a glass plate and photographed at a magnification of 500 times using a microscope (VHX-1000, manufactured by Keyence Corporation). The captured image is analyzed by the following procedure using image processing analysis system software (Image HyperII, manufactured by DigiMo), and the aspect ratio of particles (ratio of major axis (L) to minor axis (D); L/D). Was measured. At least 50 particles were measured and an average value was obtained.
(1) Procedure 1: Binarization processing An image taken with a microscope was loaded in monochrome in analysis software, and the scale of the image was set by the two-point distance method. Next, "Otsu method" was selected in the binarization process, and the threshold value was set. Since the optimum threshold differs for each image, the threshold was selected so as to match the shape of the original particle as much as possible while comparing with the original image.
(2) Step 2: Binarization Correction While comparing with the captured original image, appropriate measurement results can be obtained such as particles overlapping each other, particles protruding from the screen, particles with blurred and blurred outlines, etc. Particles not found were deleted and excluded from measurement targets.
(3) Procedure 3: Filling in holes In the "filling in holes" mode, "8" was selected for "nearby" and "filling in holes" was executed. Next, the “binary image hand correction” was again performed to compare with the original image to confirm whether the correction was performed normally. If it was not corrected normally, the hand correction was performed again.
(4) Procedure 4: Image measurement After setting the number of deleted pixels to "1,000" and selecting "8" for "vicinity", "image measurement" was executed. The measurement results of "major axis" and "minor axis" for each measured particle are displayed on the personal computer. The value obtained by dividing the "major axis" by the "minor axis" was taken as the aspect ratio.

<Evaluation method>
The tablets obtained in Examples and Comparative Examples were evaluated using the methods described below.

[Evaluation 1] Hardness of tablet The hardness of the tablet was measured with a hardness meter (DR.SCHLEUNIGER Tablet Tester 8M) 20 hours or more and 48 hours or less immediately after tableting. The average value of 10 tablets was taken as the hardness of the tablets.

[Evaluation 2] Disintegration time of tablets For tablets, using an orally disintegrating tablet tester (manufactured by Toyama Sangyo Co., Ltd., model ODT-101), test liquid: water (37±1°C), weight diameter φ20 mm, weight weight The tablet was set to the left end of the central hole of the sample fixing frame under the conditions of 20 g and a rotation speed of 140 rpm, and the disintegration time was measured. The average value of 6 tablets was taken as the tablet disintegration time.

[Evaluation 3] Feeling of Taking Tablets With respect to the tablets, the feeling of taking each tablet in the oral cavity was sensory evaluated by using 10 healthy adult men and women as panelists. If you feel a powdery feeling, there is "moisturizing". If you do not feel a powdery feeling, "no moisturizing". If you feel a grain residue in the oral cavity, "grainy". If it does not feel, it is "no roughness", "smooth" if the tablet disintegrates so that it dissolves on the tongue, "not smooth" if it does not disintegrate unless the tablet is rolled in the oral cavity, oral cavity when the tablet disintegrates If there is a core remaining inside, there is a core remaining, and if there is no core remaining in the oral cavity when the tablet disintegrates, then there is no core remaining, and each item has 4 levels (◎: very good, ○: good) , (Normal, × Poor).

<Manufacture of excipient granules>
[Example 1] Production of excipient granule A D-mannitol (manufactured by SPI Pharma): 125 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D3.5, angle of repose 57°: 435 g, and partially pregelatinized starch (Asahi Kasei Co., Ltd., PCS PC-10, water-soluble component 3 mass% or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. I got A.

[Example 2] Production of excipient granule B D-mannitol (manufactured by SPI Pharma): 524 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 36 g, and partially pregelatinized starch (Asahi Kasei Co., Ltd., PCS PC-10, water-soluble component 3 mass% or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. B was obtained.

[Example 3] Production of Excipient Granule C D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. I got C.

[Example 4] Production of excipient granules D D-mannitol (manufactured by SPI Pharma): 19 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceorus KG-1000, average particle size 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 471 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. I got D.

[Example 5] Production of excipient granule E D-mannitol (manufactured by SPI Pharma): 454 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 36 g were mixed in a polyethylene bag for 1 minute and charged into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. I got E.

[Example 6] Production of excipient granules D D-mannitol (manufactured by SPI Pharma): 375.2 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle size 50 µm, loose bulk density 0.12 g/ cc, water absorption 291%, L/D 3.5, angle of repose 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ^{3 ).} /G or more and 9 cm ³ /g or less, alpha degree 55% or more and 70% or less): 140 g are mixed in a polyethylene bag for 1 minute, and put into a fluidized bed granulator (manufactured by Paulec, multiplex, MP-01 type). did. Next, 252 g of purified water was sprayed into the fluidized bed granulator and dried to obtain Excipient Granules F.

[Example 7] Production of excipient granule G D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Then, a liquid prepared by dissolving 25.2 g of hydroxypropyl cellulose (Nisso HPC SL, Nippon Soda Co., Ltd.) in purified water: 226.8 g is sprayed in a fluidized bed granulator and then dried to obtain Excipient Granules G. Obtained.

[Example 8] Production of excipient granules H D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceorus KG-1000, average particle diameter 50 µm, loose bulk density 0.12 g/cc, Water absorption 291%, L/D 3.5, repose angle 57°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, a liquid prepared by dispersing 25.2 g of pregelatinized starch (Awaka Kasei Co., Ltd., SWELSTAR PD-1) in purified water: 226.8 g is sprayed in a fluidized bed granulator and then dried to obtain Excipient Granules H. Obtained.

[Example 9] Production of excipient granules I D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., CEOLUS PH-101, average particle diameter 50 µm, loose bulk density 0.29 g/cc, Water absorption 195%, L/D 1.8, repose angle 45°: 210 g, and partially pregelatinized starch (PCS PC-10 manufactured by Asahi Kasei Corporation, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. Got I.

[Example 10] Production of excipient granule J D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-802, average particle diameter 50 µm, loose bulk density 0.21 g/cc, Water absorption 226%, L/D 2.8, angle of repose 49°: 210 g, and partially pregelatinized starch (Asahi Kasei Co., Ltd., PCS PC-10, water-soluble component 3 mass% or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. Got J.

Example 11 Production of Excipient Granule K D-mannitol (manufactured by SPI Pharma): 350 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras UF-702, average particle diameter 90 μm, loose bulk density 0.29 g/cc, Water absorption 235%, L/D 2.6, angle of repose 34°: 210 g, and partially pregelatinized starch (Asahi Kasei Co., Ltd., PCS PC-10, water-soluble component 3 mass% or less, swelling degree 8 cm ³ /g). Above 9 cm ³ /g or less, degree of alphalation 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. I got K.

[Example 12] Production of excipient granule L D-mannitol (manufactured by SPI Pharma): 340.2 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras UF-711, average particle size 50 µm, loose bulk density 0.22 g/ cc, water absorption 239%, L/D 2.8, angle of repose 42°: 210 g, and partially pregelatinized starch (Asahi Kasei Co., Ltd., PCS PC-10, water-soluble component 3% by mass or less, swelling degree 8 cm ^{3 ).} /G or more and 9 cm ³ /g or less, alpha degree 55% or more and 70% or less): 140 g are mixed in a polyethylene bag for 1 minute, and put into a fluidized bed granulator (manufactured by Paulec, multiplex, MP-01 type). did. Next, a solution of polyvinylpyrrolidone (PVP K-30, Gokyo Sangyo Co., Ltd.: 35 g) dissolved in purified water: 315 g was sprayed in a fluidized bed granulator and dried to obtain excipient granules L. ..

Comparative Example 1 Production of Excipient Granules M D-mannitol (manufactured by SPI Pharma): 560 g, and partially pregelatinized starch (manufactured by Asahi Kasei Corporation, PCS PC-10, water-soluble component 3% by mass or less, swelling degree) 8 cm ³ /g or more and 9 cm ³ /g or less, degree of gelatinization 55% or more and 70% or less): 140 g were mixed in a polyethylene bag for 1 minute, and fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type) It was thrown in. Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 25.2 g dissolved in purified water: 226.8 g is sprayed into a fluidized bed granulator and then dried to obtain excipient granules. M was obtained.

[Comparative Example 2] Production of Excipient Granule N D-mannitol (manufactured by SPI Pharma): 490 g, and crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., Ceoras KG-1000, average particle size 50 µm, loose bulk density 0.12 g/ cc, water absorption 291%, L/D 3.5, angle of repose 57°): 210 g were mixed in a polyethylene bag for 1 minute and put into a fluidized bed granulator (manufactured by Paulec, Multiplex, MP-01 type). .. Then, polyvinylpyrrolidone (PVP K-30, manufactured by Gokyo Sangyo Co., Ltd.): a solution of 25.2 g dissolved in 226.8 g of purified water was sprayed in a fluidized bed granulator and then dried to obtain excipient granules N. Got

<Production of tablets>
[Examples 13 to 24 and Comparative Examples 3 to 4] Production of tablets T-a1 to T-a12 and T-b1 to T-b2 (1) Production of active ingredient-containing granules N-acetylglucosamine (Yaizu Suisan Chemical Industry Co., Ltd. Company made, Marine Sweet YSK): 640 g and D-mannitol (made by SPI Pharma): 160 g were mixed in a polyethylene bag for 1 minute, and then mixed in a fluidized bed granulator (made by Paulec, multiplex, MP-01 type). I put it in. Next, polyvinylpyrrolidone (manufactured by Gokyo Sangyo Co., Ltd., PVP K-30): 28.8 g dissolved in purified water: 259.2 g is sprayed into a fluidized bed granulator and then dried to dry the active ingredient-containing granules. Got

(2) Production of tablets Tablets were produced using the excipient granules A to N obtained in Examples 1 to 12 and Comparative Examples 1 and 2. Specifically, the active ingredient-containing granules produced in the above (1): 423 g, excipient granules of any of excipient granules A to N: 450 g, and crospovidone (manufactured by BASF, Kollidon CL-SF. ): 27 g were mixed in a polyethylene bag for 1 minute to obtain a mixture. After mixing 900 g of the obtained mixture with sodium stearyl fumarate (Nisso Shoji Co., Ltd.): 4.5 g, using a rotary tableting machine (manufactured by Kikusui Seisakusho, LIBRA2, 6 punches, 5 skips, 30 rpm turntable) Tablets were obtained to obtain tablets T-a1 to T-a12 and T-b1 to T-b2 (tablet diameter 8 mmφ-12R, mass 185 mg). The tableting pressure was appropriately set so that the hardness of the obtained tablet was 45 N or more and 55 N or less.

[Comparative Example 5] Production of tablet T-b3 N-acetylglucosamine (manufactured by Yaizu Suisan Chemical Co., Ltd., Marine Sweet YSK): 327 g, D-mannitol (manufactured by SPI Pharma): 329 g, crystalline cellulose (manufactured by Asahi Kasei Co., Ltd., CEOLUS KG-1000, average particle size 50 μm, loose bulk density 0.12 g/cc, water absorption 291%, L/D 3.5, repose angle 57°: 130 g, partially pregelatinized starch (PCS PC, Asahi Kasei Corporation) -10, water-soluble component 3% by mass or less, swelling degree 8 cm ³ /g or more 9 cm ³ /g or less, alpha degree 55% or more 70% or less): 87 g, and crospovidone (BASF, Kollidon CL-SF) : 27 g were mixed in a polyethylene bag for 1 minute to obtain a mixture. After mixing 900 g of the obtained mixture with sodium stearyl fumarate (Nisso Shoji Co., Ltd.): 4.5 g, using a rotary tableting machine (manufactured by Kikusui Seisakusho, LIBRA2, 6 punches, 5 skips, 30 rpm turntable) The mixture was compressed to give tablets T-b3 (tablet diameter 8 mmφ-12R, mass 185 mg). The tableting pressure was appropriately set so that the hardness of the obtained tablet was 45 N or more and 55 N or less.

Various evaluations were performed on the obtained tablets T-a1 to T-a12 and T-b1 to T-b3 using the above methods. The results are shown in Table 1 below.

From Table 1, the tablets T-a1 to T-a12 (Examples 13 to 24) using the excipient granules A to L (Examples 1 to 12) containing cellulose and partially pregelatinized starch have low pressing pressure. A tablet of sufficient hardness was obtained. Also, by making the excipient into granules, the occurrence of roughness and roughness is improved, and by compression molding with low pressing pressure, a core is not formed in the center of the tablet, resulting in a smooth and very comfortable feeling. A tablet was obtained.
Moreover, in tablets T-a1 to 3 (Examples 13 to 15) using excipient granules A to C (Examples 1 to 3) having different cellulose contents, a lower pressing pressure was obtained due to an increase in the cellulose content. A tablet with sufficient hardness can be obtained, and there is a tendency that the disintegration time is shortened and the smoothness and core retention tend to be better, while the decrease in the cellulose content results in better roughness and roughness. A trend was seen.
Further, in tablets T-a3 to T-a5 (Examples 15 to 17) using excipient granules C to E (Examples 3 to 5) having different partially pregelatinized starch contents, the partially pregelatinized starch content was An increase in the value tended to result in better smoothness, while a decrease in the partially pregelatinized starch content tended to result in a higher hardness and a better roughness.
Further, in tablets T-a3 and T-a6 (Examples 15 and 18) using excipient granules C and F (Examples 3 and 6) with or without the inclusion of a binder, by containing a binder, The tendency was to improve the roughness and roughness.
Moreover, tablets T-a3, T-a7 and T-a8 (Examples 15, 19 and 20) using excipient granules C, G and H (Examples 3, 7 and 8) having different kinds of binders were used. In, the use of polyvinylpyrrolidone or pregelatinized starch as a binder tended to improve smoothness and core retention.
Further, in tablets T-a3 and T-a9 to T-a12 (Examples 15 and 21 to 24) using excipient granules C and I to L having different types of cellulose, the larger L/D is, The core remnant tended to be better, and the smaller the angle of repose, the better the roughness, and the smaller the average particle size, the better the roughness. ..

On the other hand, the tablet T-b1 (Comparative Example 3) using the excipient granules M (Comparative Example 1) that does not contain cellulose but partially gelatinized starch has a purpose of not being compressed at a high compression pressure of 6 kN. It was not possible to obtain tablets having a hardness of 45 N or more and 55 N or less. Further, it was confirmed that when the tableting was carried out with a high tableting pressure, a core was formed in the center of the tablet, the disintegration time was delayed to 34 seconds, the feeling of ingestion was left unremoved, and the smoothness was not felt.
Similarly, tablet T-b2 (Comparative Example 4) using Excipient Granule N (Comparative Example 2) containing cellulose but not partially pregelatinized starch also exhibited a slow disintegration time of 33 seconds and felt smoothness. It was confirmed that it was not possible.
Further, tablet T-b3 (Comparative Example 5) obtained by tableting without granulating an excipient gives a tablet having a high hardness with a low tableting pressure, but when disintegrated in the oral cavity, it is moisturized. , And it was rough, and the feeling of ingestion was poor.

From these, by using the excipient granules of the present embodiment, the tablet shows sufficient hardness even at low pressing pressure, exhibits good rapid disintegration, and is an orally disintegrating tablet excellent in the feeling of taking. It became clear that it was obtained.

According to the excipient granules of the present embodiment, sufficient tablet hardness can be obtained even with a low pressing pressure, and it is possible to provide excipient granules that are excellent in rapid disintegration when formed into tablets and have a feeling of ingestion.

Claims (10)

Excipient granules comprising cellulose and partially pregelatinized starch. The excipient granules according to claim 1, further comprising a water-soluble excipient. The excipient granules according to claim 2, wherein the content of the water-soluble excipient is 1% by mass or more and 90% by mass or less based on the total mass of the excipient granules. Excipient granules according to any one of claims 1 to 3, further comprising a binder. The excipient granule according to claim 4, wherein the binder is a water-soluble polymer. The excipient granules according to claim 4 or 5, wherein the content of the binder is 1% by mass or more and 20% by mass or less based on the total mass of the excipient granules. The excipient granules according to any one of claims 1 to 6, wherein the content of the cellulose is 1% by mass or more and 90% by mass or less based on the total mass of the excipient granules. A tablet comprising the excipient granule according to any one of claims 1 to 7 and an active ingredient. The tablet according to claim 8, further comprising a disintegrant. A method for producing a tablet, which uses the excipient granules according to any one of claims 1 to 7.