JP6440317B2 - Oral solid tablets - Google Patents

Description

  The present invention relates to an internal solid tablet.

Among non-steroidal anti-inflammatory agents, ibuprofen, aspirin, and the like are widely used as components of analgesics / antipyretics because they have excellent analgesic and antipyretic effects.
Ibuprofen, aspirin, and the like are poorly water-soluble acidic drugs that are difficult to dissolve in water. Therefore, internal solid tablets containing ibuprofen, aspirin, etc. (tablets containing ibuprofen, etc.) are wet-granulated together with excipients such as water-soluble polymer compounds to form granulated particles. Generally, it is compressed into tablets.

In order to improve the immediate effect such as the antipyretic analgesic action of the tablet, it is necessary to improve the disintegration property of the tablet in the body and improve the dissolution property of the drug in the body. However, tablets containing ibuprofen and the like tend to have poor disintegration in the body due to the physicochemical properties inherent to the drug.
On the other hand, for the purpose of improving the dissolution of the drug in the body, an aqueous liquid containing a water-soluble or water-swellable polymer compound is sprayed onto a co-ground product of a poorly water-soluble drug and an excipient. However, a granulated particle obtained by wet granulation and a tablet obtained by mixing and granulating the granulated particle and other raw materials are disclosed (see Patent Document 1).

International Publication No. 2007/126063

  By the way, when producing granulated particles containing a drug, in general, in order to improve the absorbability of the drug in the body and the dosage of tablets, various kinds of additives such as selection of additives and particle coating are available. Consideration is made. In particular, poorly water-soluble drugs such as ibuprofen and aspirin are slowly absorbed into the body. For this reason, when the drug contained in the granulated particles is a poorly water-soluble drug, it has not been possible to improve the immediate effect of the drug simply by improving the disintegration of the tablet.

As a result of investigations, the present inventors have found that increasing the dispersibility in the body of a drug that dissolves from a tablet that has disintegrated in the body is very effective in further improving the immediate effect of the tablet. Obtained knowledge.
However, when trying to improve the dispersibility of the drug in the body, the tablet hardness tends to decrease with time. And there existed a problem that a tablet cracks or lacks by the vibration at the time of conveyance, or the actual use by the fall of the tablet hardness accompanying time.

  The present invention has been made in view of the above circumstances, and an object of the present invention is an internal solid tablet having high dispersibility of a drug in the body and in which a decrease in tablet hardness with time is suppressed.

As a result of intensive studies, the present inventors have made the poorly water-soluble drug highly dispersible in the body by combining the poorly water-soluble drug and excipient such as ibuprofen and aspirin with a carbonate or bicarbonate. It was found that the immediate effect of the drug is improved. In addition, by combining a specific water-soluble powder, it has been found that the poorly water-soluble drug is further dispersible in the body and the tablet hardness is maintained over time, and the present invention has been completed.
That is, the internal solid tablet of the present invention includes the following aspects.
[1] A poorly water-soluble drug (a1) having a solubility in water at 20 ° C. of 5 mg / mL or less, a water-swellable polymer compound having a molecular weight of 1000 or more, and a solubility in water at 20 ° C. of 1 mg / mL or more. One or more polymer compounds (a2) selected from the group consisting of water-soluble polymer compounds having a molecular weight of 1000 or more, and a water-soluble powder having a solubility in water at 20 ° C. of more than 5 mg / mL and a molecular weight of less than 1000 It consists of granulated particles (A) containing the body (a3) (excluding the following particles (B)), and one or more compounds selected from the group consisting of bicarbonate (b1) and carbonate (b2) An internal solid tablet containing particles (B).
[2] The internal solid tablet according to [1], wherein the content of the water-soluble powder (a3) in the granulated particles (A) is 10% by mass or more.
[3] The internal solid tablet according to [1] or [2], wherein the particle (B) contains the bicarbonate (b1) and the carbonate (b2).
[4] The bicarbonate (b1) is sodium bicarbonate, and the carbonate (b2) is at least one carbonate selected from the group consisting of sodium carbonate and calcium carbonate, The internal solid tablet according to [3], wherein the mass ratio represented by b1) / carbonate (b2) is 2 or less.
[5] The internal solid tablet according to any one of [1] to [4], wherein the particle (B) has a volume average particle diameter of 10 to 1000 μm.

  According to the internal solid tablet of the present invention, the dispersibility of the drug in the body is high, and the decrease in tablet hardness with time is suppressed.

It is a photograph which shows the state (appearance) of the PTP package after performing a preservation | save test in an Example.

(Internal solid tablets)
The internal solid tablet of the present invention contains granulated particles (A) and particles (B) composed of one or more compounds selected from the group consisting of bicarbonate and carbonate.
Hereinafter, the granulated particles (A) and the particles (B) are also referred to as (A) component and (B) component, respectively.

<Granulated particles (A)>
The component (A) in the present invention comprises a poorly water-soluble drug (a1) having a solubility in water at 20 ° C. of 5 mg / mL or less, a water-swellable polymer compound having a molecular weight of 1000 or more, and a solubility in water at 20 ° C. of 1 mg / mL. One or more polymer compounds (a2) selected from the group consisting of water-soluble polymer compounds having a molecular weight of 1000 or more and a molecular weight of 1000 or more, and solubility in water at 20 ° C. is more than 5 mg / mL, and the molecular weight is Granulated particles containing less than 1000 water-soluble powder (a3) (excluding the following particles (B)).
Hereinafter, the poorly water-soluble drug (a1), the polymer compound (a2), and the water-soluble powder (a3) are also referred to as component (a1), component (a2), and component (a3), respectively.
Although content of the (A) component in an internal solid tablet is not specifically limited, For example, 0.1-90 mass% is preferable with respect to the total mass of an internal solid tablet, and 1-80 mass% is more preferable. If the content of the component (A) is not less than the above preferable lower limit, sufficient medicinal effects can be easily obtained, and if it is not more than the above preferable upper limit, the moldability of the tablet becomes better.

≪Liquid poorly soluble drug (a1) ≫
The component (a1) in the present invention is a drug having a solubility in water at 20 ° C. of 5 mg / mL or less. Among these, a preferable component (a1) is a drug having a solubility of 0 to 5 mg / mL.
The component (a1) is not particularly limited, and examples thereof include nonsteroidal anti-tumor agents such as ibuprofen, aspirin, naproxen, ketoprofen, indomethacin, bufexamac, diclofenac, alclofenac, etodolac, flurbiprofen, mefenamic, and piroxicam. Inflammatory agents: Hypnotics and sedatives such as nitrazepam, triazolam, phenobarbital, amibarbital, and allylisopropylpropyrea; antiepileptics such as phenytoin, primidone, clonazepam, carbamazepine, valproic acid; antidepressants such as meclizine hydrochloride Neuropsychiatric agents such as haloperidol, chlordiazepoxide, diazebam and sulpiride; antisedatives such as atropine; cardiotonic agents such as digoxin; arrhythmic agents such as pindolol and disopyramide; Diuretics such as thiazide, spironolactone, triamterene, furosemide, bumetanide; antihypertensives such as prazosin hydrochloride; coronary vasodilators such as isosorbide nitrate, nifedipine, dipyridamole; antitussives such as noscapine, turopterol, tranilast; expectorants such as bromhexine hydrochloride Antibiotics such as erythromycin, josamycin, chloramphenicol, rifampicin, griseofulvin; antihistamines such as clemastine fumarate; steroids such as dexamethasone, betamethasone, prednisolone, danazol, chlormadinone acetate; vitamins A, folic acid (vitamins M) Vitamins such as Famotidine, Metoclopramide, Omeprazole, Trepibuton, Sucralfate, etc. Treatment for digestive system diseases; Clofibrate, Mel Putopurin, methotrexate, aluminum hydroxide, synthetic hydrotalcite, magnesium oxide, and magnesium hydroxide.
In addition, as for (a1) component, if there exists a commercial item, it may be used, or what was synthesize | combined suitably by the well-known method from the raw material compound may be used.

As the component (a1), one type may be used alone, or two or more types may be used in combination.
Among the above, as the component (a1), a nonsteroidal anti-inflammatory agent is preferable because the effect of the present invention is particularly remarkable. Among non-steroidal anti-inflammatory agents, one or more selected from the group consisting of ibuprofen, aspirin, naproxen and ketoprofen is more preferable, and ibuprofen and aspirin are particularly preferable.

The content of the component (a1) in the component (A) can be an effective amount in each poorly water-soluble drug. Although content of this (a1) component is not specifically limited, For example, 0.1-80 mass% is preferable with respect to the total mass of (A) component, 1-65 mass% is more preferable, 5-50 mass % Is more preferable.
If content of this (a1) component exists in the said preferable range, the further improvement of the dispersibility of the (a1) component in a body can be aimed at. Moreover, if this content is more than the said preferable lower limit, sufficient medicinal effect will be acquired, and if it is below the said preferable upper limit, the moldability of a tablet will become more favorable.

≪Polymer compound (a2) ≫
The component (a2) in the present invention has a water-swellable polymer compound having a molecular weight of 1000 or more (hereinafter also referred to as “(a21) component”) and water solubility at 20 ° C. of 1 mg / mL or more, and has a molecular weight. One or more polymer compounds selected from the group consisting of 1000 or more water-soluble polymer compounds (hereinafter also referred to as “component (a22)”). In an internal solid tablet, the component (a2) is a component that mainly functions as a binder.
In this specification, the molecular weight of the component (a2) means a weight average molecular weight, and is measured by gel permeation chromatography (GPC). The (a2) component has a weight average molecular weight of 1000 or more, preferably 5000 or more, more preferably 10,000 or more, and even more preferably 30,000 to 130,000, both of the component (a21) and the component (a22).
Regarding the component (a21), “water swellability” means that when water is added, it swells and exhibits a transparent, turbid or suspended viscous liquid property.
The component (a22) is a polymer compound having a solubility in water of 20 ° C. of 1 mg / mL or more. Among these, a preferable component (a22) is a polymer compound having a solubility of 100 mg / mL or more, and more preferably a polymer compound having 200 mg / mL or more.

Examples of the component (a21) include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, etc. Among them, low-substituted hydroxypropylcellulose is preferable.
In the low-substituted hydroxypropyl cellulose, the “low-substituted” means that the molar substitution degree of the substituent (hydroxypropyl group) is 5 to 16, preferably about 7 to 12.

Examples of the component (a22) include carmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gum arabic, carboxyvinyl polymer, popidone, polyvinyl alcohol, polyacrylic acid, among others, hydroxypropylcellulose, hydroxypropylmethylcellulose. , Methyl cellulose and polyvinyl alcohol are preferable, and hydroxypropyl cellulose is more preferable.
The polyvinyl alcohol preferably has a saponification degree of 96 mol% or less.

As the component (a2), one type may be used alone, or two or more types may be used in combination.
As a preferable component (a2), the viscosity at 20 ° C. of a 2 mass% aqueous solution is less than 6.0 mPa · s, more preferably 1 to 5.5 mPa · s, and still more preferably 1. It is a thing of 2-5.0 mPa * s, Most preferably, it is a thing of 1.5-4.0 mPa * s. If the viscosity is not less than the above preferred lower limit, the granulation property of the component (A) becomes better, and if it is not more than the preferred upper limit, the dispersibility of the component (a1) in the body is further increased. .
In the present specification, “viscosity of 2 mass% aqueous solution of component (a2)” is a single cylindrical rotational viscometer (“LVDV-II + Pro” manufactured by Brookfield, spindle No. ULA, rotation speed: 60 rpm, measurement time) : Measured for 4 minutes, measurement temperature: 20 ° C.).

 Among these, as the component (a2), the low-substituted hydroxypropyl cellulose as the component (a21), the hydroxypropyl cellulose as the component (a22), or a combination thereof is preferable. Among them, the combination of the low-substituted hydroxypropyl cellulose as the component (a21) and the hydroxypropyl cellulose as the component (a22) is particularly preferable.

Although content of (a2) component in (A) component is not specifically limited, 5-45 mass% is preferable with respect to the total mass of (A) component, for example, and 15-35 mass% is more preferable.
If the content of the component (a2) is not less than the preferable lower limit value, the granulation property of the component (A) is further improved. If the content is not more than the preferable upper limit value, the component (a1) in the body. The dispersibility of is further increased.

≪Water-soluble powder (a3) ≫
The component (a3) in the present invention is a powder having a solubility in water at 20 ° C. of more than 5 mg / mL. Among these, a preferable component (a3) is a powder having a solubility of 10 mg / mL or more, and more preferably a powder having a solubility of 13 to 1000 mg / mL.
In addition, the component (a3) is a powder having a molecular weight of less than 1000. Among these, a preferable component (a3) is a powder having a molecular weight of 50 or more and less than 1000, and more preferably a powder having a molecular weight of 100 to 500.
However, the compound corresponding to the component (B) is not included in the component (a3).
Examples of the component (a3) include mannitol (molecular weight 182.2), lactose, lactose hydrate (molecular weight 360.3), sugars such as sucrose and fructose; erythritol (molecular weight 122.12), xylitol, sorbitol and the like. Sugar alcohols: anhydrous potassium dihydrogen phosphate (molecular weight 136.1), sodium chloride (molecular weight 58.4), inorganic salts such as potassium chloride; acetaminophen (molecular weight 151.2), anhydrous caffeine (molecular weight 194) 19), water-soluble active drugs such as caffeine hydrate.

As the component (a3), one type may be used alone, or two or more types may be used in combination.
Among these, as the component (a3), lactose or a hydrate thereof, and a water-soluble active drug are preferable because a decrease in tablet hardness with time is further suppressed. Among these, at least one selected from the group consisting of lactose or a hydrate thereof, mannitol and acetaminophen is more preferable, and at least one selected from the group consisting of mannitol and acetaminophen is more preferable.

The content of the component (a3) in the component (A) is preferably 10% by mass or more, more preferably 10 to 90% by mass, and still more preferably 20 to 50% by mass with respect to the total mass of the component (A). 30-40 mass% is especially preferable.
If content of this (a3) component is more than the said preferable lower limit, the wettability of a tablet will be improved and the dispersibility of the (a1) component in a body will increase more. In addition, a decrease in tablet hardness with time is further suppressed. On the other hand, if it is below the above-mentioned preferable upper limit value, since the content ratio of the component (a1) increases, the dose per one time of the internal solid tablet can be reduced, and the dosing property becomes better.

The content of the component (a3) in the internal solid tablet is, for example, preferably 0.5 to 81% by mass and more preferably 1 to 45% by mass with respect to the total mass of the internal solid tablet.
If content of this (a3) component is more than the said preferable lower limit, the wettability of a tablet will be improved and the dispersibility of the (a1) component in a body will increase more. In addition, a decrease in tablet hardness with time is further suppressed. On the other hand, if it is below the above-mentioned preferable upper limit value, since the content ratio of the component (a1) increases, the dose per one time of the internal solid tablet can be reduced, and the dosing property becomes better.

The average particle size of the component (a3) is preferably 5 to 500 μm, more preferably 10 to 300 μm. If the average particle size of the component (a3) is not less than the above-mentioned preferred lower limit value, the fluidity of the component (a3) will be good, handling at the time of production will be further improved, and if it is not more than the above preferred upper limit value. In addition, the dispersibility of the component (a3) during granulation increases, and the particle diameter of the component (A) after granulation hardly occurs.
In this specification, the “average particle diameter” means a volume average particle diameter (hereinafter also simply referred to as “average particle diameter”), and indicates a value measured by a laser diffraction / scattering method.

  The mass ratio of the (a1) component and the (a3) component ((a3) component / (a1) component) is preferably 0.1 to 50, more preferably 0.2 to 10, and still more preferably 0.3 to 3.5. When the mass ratio (component (a3) / component (a1)) is within the above preferred range, the decrease in tablet hardness with time is further suppressed. In addition, since the content ratio of the component (a1) is increased, the dose per time of the internal solid tablet can be reduced, and the dosing property becomes better.

≪Other ingredients (a4) ≫
The component (A) includes other components (a4) (hereinafter also referred to as “component (a4)”) as necessary in addition to the components (a1), (a2) and (a3). But you can.

<Particles (B) composed of one or more compounds selected from the group consisting of bicarbonate and carbonate>
The particles (B) are composed of one or more compounds selected from the group consisting of bicarbonate (b1) and carbonate (b2). Hereinafter, the bicarbonate (b1) and the carbonate (b2) are also referred to as the component (b1) and the component (b2), respectively.
The component (b1) and the component (b2) are components that are blended mainly in order to improve the dispersibility of the component (a1) in the body.

  (B) As for the average particle diameter of component, 10-1000 micrometers is preferable, 30-1000 micrometers is more preferable, 70-900 micrometers is further more preferable. If the average particle size of the component (B) is not less than the above-mentioned preferred lower limit value, the fluidity of the component (B) will be good, and it will be easy to handle during production. The dispersibility of the component (a1) is further increased.

  The content of the component (B) in the internal solid tablet is preferably 0.5 to 20% by mass, more preferably 1 to 15% by mass, and further preferably 2 to 11% by mass with respect to the total mass of the internal solid tablet. 4 to 9.5% by mass is particularly preferable. If the content of the component (B) is not less than the above preferable lower limit, the effect of improving the dispersibility of the component (a1) in the body can be more easily obtained, and if it is not more than the above preferable upper limit, The stability of the component (a1) in the tablet becomes better.

  The mass ratio (component (a3) / component (B)) between the component (a3) and the component (B) in the internal solid tablet is preferably 0.2 to 40, more preferably 0.7 to 20, and still more preferably. Is 1.5-10. If the mass ratio (component (a3) / component (B)) is not less than the above-mentioned preferred lower limit value, a decrease in tablet hardness with time is further suppressed, and if it is not more than the preferred upper limit value, The dispersibility of the component (a1) is further increased.

≪Bicarbonate (b1) ≫
Examples of the hydrogen carbonate in the component (b1) include sodium hydrogen carbonate, potassium hydrogen carbonate, ammonium hydrogen carbonate and the like. As the component (b1), one type may be used alone, or two or more types may be used in combination. Among these, as the component (b1), sodium hydrogen carbonate and potassium hydrogen carbonate are preferable, and sodium hydrogen carbonate is more preferable because the effect of improving the dispersibility of the component (a1) in the body is higher.
The content ratio of the component (b1) in the internal solid tablet is not particularly limited, but is preferably, for example, 0.05 to 15% by mass, more preferably 0.1 to 6% by mass with respect to the total mass of the internal solid tablet. 0.3-2 mass% is further more preferable, and 0.5-1.5 mass% is especially preferable. If the content rate of (b1) component in a tablet is more than the said preferable lower limit, the dispersibility of (a1) component in a body will improve. On the other hand, when the content ratio of the component (b1) in the tablet is equal to or less than the preferable upper limit value, a decrease in tablet hardness with time is suppressed.
(B1) The average particle diameter (volume average particle diameter) of the particle group of a component has preferable 30-1000 micrometers, More preferably, it is 70-500 micrometers, More preferably, it is 120-300 micrometers. If the average particle size of the particle group of the component (b1) is equal to or more than the preferable lower limit value, the handling property at the time of producing the tablet is further improved, while the average particle size of the particle group of the component (b1) is If it is below the preferable upper limit, the dispersibility of the component (a1) in the body is further improved.

≪Carbonate (b2) ≫
Examples of the carbonate in the component (b2) include sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like. As the component (b2), one type may be used alone, or two or more types may be used in combination. Among these, as the component (b2), sodium carbonate or calcium carbonate is preferable, and sodium carbonate is more preferable. When sodium carbonate is used, sodium carbonate hydrate may be used, and anhydrous sodium carbonate may be used, but it is preferable to use anhydrous sodium carbonate.
Although the content rate of (b2) component in a tablet is not specifically limited, For example, 1-10 mass% is preferable with respect to the total mass of an internal solid tablet, 3-9 mass% is more preferable, and 5-9 mass% is More preferably, 7-8 mass% is especially preferable. When the content ratio of the component (b2) in the tablet is equal to or greater than the preferable lower limit, the swelling of the drug storage part of the package with time is small, and the dispersibility of the component (a1) in the body is further improved. On the other hand, when the content ratio of the component (b2) in the tablet is equal to or less than the preferable upper limit value, the tablet can be easily downsized and the dosage can be easily improved.
The average particle size (volume average particle size) of the particle group (b2) is preferably 30 to 1000 μm, more preferably 100 to 900 μm, still more preferably 250 to 800 μm, and particularly preferably 400 to 600 μm. (B2) By making the average particle diameter of the particle group of a component in the said preferable range, it becomes difficult to produce the expansion | swelling with time of the drug storage part of a package.

 In the present invention, the component (B) preferably contains at least one component (b1) and at least one component (b2). When the component (B) includes both the component (b1) and the component (b2), the dispersibility is good, the decrease in tablet hardness with time is further suppressed, and the expansion of the drug container of the package can also be suppressed.

  When an internal solid tablet contains both the component (b1) and the component (b2), the mass ratio of the component (b1) and the component (b2), that is, the mass ratio represented by the component (b1) / (b2) (Hereinafter also referred to as “b1 / b2 ratio”) is 2 or less, preferably 0.01 to 2, more preferably 0.03 to 1.0, and still more preferably 0.07 to 0.2. If b1 / b2 ratio is below the said upper limit, it will become difficult to produce the expansion | swelling with time of the drug storage part of a package. When the b1 / b2 ratio is equal to or greater than the preferable lower limit, the dispersibility of the component (a1) in the body is further improved. Moreover, the fall of tablet hardness is further suppressed by setting b1 / b2 ratio to a suitable range.

<Other components (C)>
The internal solid tablet of the present invention may contain other components (C) (hereinafter also referred to as “component (C)”) as necessary, in addition to the components (A) and (B) described above.
(C) As a component, surfactant, a disintegrating agent, an excipient | filler, a lubricant, a fragrance | flavor, a sweetener, a sour agent, etc. are mentioned, for example.

-Surfactant The internal solid tablet of the present invention may further contain a surfactant in addition to the above-described components (A) and (B). By further containing the surfactant, the wettability of the tablet is mainly improved, and the dispersibility of the component (a1) in the body is further improved.
The surfactant is not particularly limited, and examples thereof include an anionic surfactant, a nonionic surfactant, a cationic surfactant, and an amphoteric surfactant that are generally used in oral preparations.

  Anionic surfactants include alkyl sulfate salts such as sodium lauryl sulfate; alkyl ether sulfates, alkyl ether carboxylates, N-acyl sarcosine salts, N-acyl glutamates, N-acyl-N-methyl β-alanine salts N-acyl amino acid salts such as alkyl polyoxyethylene sulfate, α-olefin sulfonate, N-acyl-N-methyl taurate, alkyl sulfosuccinate, alkyl phosphate, polyoxyethylene alkyl ether phosphate Examples include salts. Among them, alkyl sulfate ester salts are preferable, and sodium lauryl sulfate is particularly preferable.

Nonionic surfactants include polyoxyethylene (2) alkyl ether, polyoxyethylene (9) alkyl ether, polyoxyethylene (21) alkyl ether, polyoxyethylene (25) alkyl ether, polyoxyethylene (5) alkyl. Phenyl ether, polyoxyethylene (10) alkylphenyl ether, polyoxyethylene (15) alkylphenyl ether, polyoxyethylene (10) polyoxypropylene (4) alkyl ether, polyoxyethylene (40) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (80) hydrogenated castor oil, polyoxyethylene Nglycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene (10) sorbitan fatty acid ester, polyoxyethylene (20) sorbitan fatty acid ester, polyoxyethylene (30) sorbit fatty acid ester, polyoxyethylene (40) Sorbit fatty acid ester, polyoxyethylene (60) sorbite fatty acid ester, polyoxyethylene (10) sterol, polyoxyethylene (20) sterol, polyoxyethylene (30) sterol, hydrogenated sterol, polyethylene glycol (1) fatty acid ester, Polyethylene glycol (2) fatty acid ester, polyethylene glycol (4) fatty acid ester, polyethylene glycol (10) fatty acid ester, polyethylene Glycol (25) fatty acid ester, polyethylene glycol (40) fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene (6) beeswax derivative, polyoxyethylene (20) beeswax derivative, polyoxyethylene (5 ) Alkylamine, polyoxyethylene (10) alkylamine, polyoxyethylene (15) alkylamine, polyoxyethylene (5) fatty acid amide, polyoxyethylene (10) fatty acid amide, polyoxyethylene (15) fatty acid amide, alkyl Examples include diethanolamine, alkyl glucoside, alkyl maltoside, alkyl polyglucoside, sucrose fatty acid ester, methyl glucoside ester, and methyl glucamide. Of these, sucrose fatty acid esters are preferred.
In addition, the numerical value in the bracket | parenthesis in the description of the nonionic activator of the said illustration represents the average addition mole number of ethylene oxide (EO).

Examples of the cationic surfactant include N-acylaminoethyldiethylamine salt, N-acylguanidine salt, alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkylbenzyldimethylammonium salt and the like.
Amphoteric surfactants include soy phospholipids, hydrogenated soybean phospholipids, egg yolk phospholipids, hydrogenated egg yolk phospholipids, lecithin derivatives such as phosphatidylcholine, N-alkyldimethylamine oxide, N-alkyl-β-iminodipropionic acid Examples thereof include salts, N-alkyldimethylbetaine, N-acyl-dimethylbetaine, N-acylamidopropyldimethylbetaine, 2-alkylimidazoline derivatives, N-alkylsulfobetaine glucamine, and N-alkylcarboxybetaine glucamine.

As the surfactant, one type may be used alone, or two or more types may be used in combination.
Among these, as the surfactant, an anionic surfactant and a nonionic surfactant are preferable, and an anionic surfactant is more preferable because dispersibility of the component (a1) in the body is further increased.
The content of the surfactant in the internal solid tablet is preferably 0.1 to 10% by mass, more preferably 0.3 to 5% by mass, and 0.5 to 5% by mass with respect to the total mass of the internal solid tablet. Further preferred. If the content of the surfactant is not less than the above-mentioned preferred lower limit value, the effect of improving the dispersibility of the component (a1) in the body can be more easily obtained. The stability of the component (a1) in the inside becomes better.

-Disintegrating agent The internal solid tablet of this invention may contain the disintegrating agent further in addition to the above-mentioned (A) component and (B) component. By further containing the disintegrant, the disintegration property of the tablet is mainly improved, and the dispersibility of the component (a1) in the body is further improved.
Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, crospovidone and the like.
The disintegrant may be used alone or in combination of two or more.
The content of the disintegrant in the internal solid tablet is preferably 0.1 to 10% by mass, more preferably 0.3 to 5% by mass, and further preferably 0.5 to 5% by mass with respect to the total mass of the internal solid tablet. preferable. If the content of the disintegrant is not less than the above-mentioned preferred lower limit value, the effect of improving the dispersibility of the component (a1) in the body can be more easily obtained. The stability of the component (a1) is improved.

  When a surfactant and a disintegrant are used in combination as the component (C), the mass ratio of the surfactant to the disintegrant in the internal solid tablet (surfactant / disintegrant) is preferably 0.05 to 20. More preferably, it is 0.1-10. If the mass ratio (surfactant / disintegrant) is not less than the above-mentioned preferred lower limit value, the dispersibility of the component (a1) in the body is further increased, and if it is not more than the preferred upper limit value, in the tablet The stability of the component (a1) is improved.

-Excipient The internal solid tablet of the present invention may further contain an excipient in addition to the components (A) and (B) described above. By further containing the excipient, the dispersibility of the component (a1) in the body is improved, and the moldability during tableting is improved.
Examples of the excipient include sugar alcohols such as maltitol, erythritol and mannitol; and sugars such as lactose, sucrose and reduced lactose. Among these, mannitol and lactose are preferable, and mannitol is more preferable.
These excipients may be used alone or in combination of two or more.
As for content of the excipient | filler in an internal use solid tablet, 5-80 mass% is preferable with respect to the total mass of an internal use solid tablet. If the content of the excipient is not less than the above-mentioned preferable lower limit value, the moldability during tableting is further improved, and if it is not more than the above-described preferable upper limit value, dispersion of the component (a1) in the body. Sexuality increases.

-Lubricant The internal solid tablet of the present invention may further contain a lubricant in addition to the above-described components (A) and (B).
Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester. Among these, magnesium stearate is preferable.

-Fragrance | flavor In addition to the above-mentioned (A) component and (B) component, the internal solid tablet of this invention may further contain a fragrance | flavor.
Examples of the fragrances include menthol, limonene, plant essential oils (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.

-Sweetener, acidulant The internal solid tablet of this invention may further contain a sweetener or an acidulant in addition to the above-mentioned (A) component and (B) component.
Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, and salts thereof.

<Method for producing solid tablets for internal use>
The internal solid tablet of this invention can be manufactured with the manufacturing method which has a granulation process and a tableting process, for example.

≪Granulation process≫
In the granulation step, granulated particles (component (A)) containing the component (a1), the component (a2) and the component (a3) are produced. Granulation can be performed by, for example, a dry granulation method or a wet granulation method.
In the wet granulation method, for example, using a fluidized bed granulator, an aqueous solution or dispersion containing the component (a2) while mixing the component (a1) and the component (a3) It is granulated while spraying (which may be added) (fluidized bed granulation method).
The concentration of the aqueous solution or dispersion containing the component (a2) is appropriately determined depending on the type of the component (a1) or the component (a2), and is preferably 1 to 20% by mass, more preferably 3 to 15% by mass. is there.
The average particle size of the component (A) obtained after granulation is preferably 100 to 1000 μm and more preferably 150 to 700 μm because dispersibility of the component (a1) in the body is further increased.

When the component (a1) is not a desired particle size as a raw material, the component (a1) may be charged into a pulverizer and pulverized under conditions of, for example, a rotational speed of 5000 to 20000 rpm (pulverized product may be obtained). processing). During the pulverization, an optional component other than the component (a1) may be charged into the pulverizer.
The average particle size of the pulverized product after the pulverization treatment is preferably 0.01 to 50 μm, more preferably 0.01 to 35 μm, still more preferably 0.1 to 30 μm, and particularly preferably 0.1 to 25 μm. When the average particle size of the pulverized product is not less than the above-mentioned preferable lower limit value, the handleability of the component (a1) is improved during granulation, and when the average particle size is not more than the above-described preferable upper limit value, ) Dispersibility of the component is further increased.

In the pulverization treatment, it is preferable to co-grind the component (a2) together with the component (a1). By co-pulverizing the component (a1) and the component (a2), the component (a1) is pulverized well. Thereby, the surface area of (a1) component particle becomes larger, and the dispersibility of (a1) component in a body further increases.
As the component (a2) here, it is preferable to use low-substituted hydroxypropylcellulose. In this case, the content of the low-substituted hydroxypropyl cellulose in the component (A) is preferably 5 to 45% by mass, more preferably 10 to 35% by mass with respect to the total mass of the component (A). is there. When the content is equal to or more than the preferable lower limit, when mixed with the component (a1), adhesion of the component (a1) to the mixer or pulverizer is suppressed, and the mixing efficiency and grindability are further improved. To do. On the other hand, if it is below the said preferable upper limit, the dispersibility of the (a1) component in a body will increase more.

  The mixing ratio of the component (a1) to the low-substituted hydroxypropyl cellulose ((a1) component: (low-substituted hydroxypropyl cellulose)) is preferably 1: 0.01 to 1:10, more preferably, by mass ratio. It is 1: 0.05-1: 5, More preferably, it is 1: 0.05-1: 2. If the mass ratio is equal to or greater than the above-mentioned preferable lower limit value, the mixing efficiency and grindability are further improved since the adhesion of the component (a1) to the mixer or grinder is easily suppressed when both are mixed. To do. On the other hand, if it is below the preferable upper limit, the dispersibility of the component (a1) in the body is further enhanced.

≪Tabletting process≫
In the tableting process, the granulated particles (component (A)) prepared in the granulation process, the component (B), and the component (C) as necessary are mixed and tableted to obtain a tablet. .

Examples of the mixing method of each component include powder mixing.
For powder mixing, a general mixer such as a Bole container mixer (manufactured by Bole Kotobuki Kogyo Co., Ltd.), a V-type mixer (manufactured by Dalton Co., Ltd.), a ribbon mixer (manufactured by Dalton Co., Ltd.) or the like can be used. .
The mixing order is not particularly limited, and for example, all the components may be charged into a mixer and mixed, or each component may be sequentially added to the mixer and mixed.
The mixing time is not particularly limited, and is a time during which each component can be dispersed approximately uniformly.

The tableting method is not particularly limited, and examples thereof include a method using a conventionally known tableting machine, such as a rotary tableting machine.
The tableting conditions are not particularly limited, and are appropriately determined in consideration of the hardness required for the tablets.

  After tableting, the tablet may be subjected to a coating treatment as necessary for the purpose of improving the storage stability of the tablet. The coating treatment is not particularly limited, and a conventionally known method can be applied. For example, a method of applying a coating agent (an aqueous solution of a polymer, a plasticizer, etc.) to the surface of a molded article after tableting and then drying is mentioned. It is done.

  The internal solid tablet of the present invention preferably has a tablet hardness of about 55 to 100N, more preferably about 65 to 90N. By setting the hardness of the initial product to the above preferable lower limit value or more, it is possible to easily prevent tablet breakage or chipping in vibration or actual use during transfer, and by setting the hardness to the above preferable upper limit value or less, Tablet disintegration is better.

Since the internal solid tablet of the present invention described above contains the component (B), the dispersibility of the component (a1) in the body is increased, and the immediate effect of the drug is improved.
Moreover, since the (a1) component is granulated by combining the (a2) component and the (a3) component, the dispersibility of the (a1) component in the body is further enhanced.
In addition, a decrease in tablet hardness with time is also suppressed. It is estimated that the decrease in tablet hardness is caused by the reaction between the component (a1) and the component (B) in the tablet. In the present invention, the reaction between the component (a1) and the component (B) is less likely to occur by granulating the component (a1). For this reason, it is thought that tablet hardness is maintained over time.

EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated more concretely, this invention is not limited to the following Example. In the examples, “%” means “% by mass” unless otherwise specified.
The raw materials used in this example are as follows.

・ Granulated particles (A)
..Slightly water-soluble drugs (a1)
Ibuprofen, trade name “Ibuprofen 25” (BASF). Solubility in water at 20 ° C. 0.077 mg / mL.

..Polymer compound (a2)
Hydroxypropyl cellulose, trade name “HPC-SSL” (manufactured by Nippon Soda Co., Ltd.). Weight average molecular weight 40000, viscosity of 2 mass% aqueous solution at 20 ° C. 2.45 mPa · s.
Low-substituted hydroxypropyl cellulose, trade name “LH-31” (manufactured by Shin-Etsu Chemical Co., Ltd.). Weight average molecular weight 100,000.

..Water-soluble powder (a3)
Acetaminophen, trade name “Piretinol” (Iwaki Pharmaceutical Co., Ltd.). Solubility in water at 20 ° C. 14 mg / mL, molecular weight 151.2 Average particle size 30 μm.
Mannitol, trade name “Pearlitol 50C” (manufactured by Rocket). Solubility 200 mg / mL in water at 20 ° C., molecular weight 182.2, average particle diameter 50 μm.
Lactose hydrate, trade name “Pharmacatose 50M” (manufactured by DFE Pharma). Solubility in water at 20 ° C. 161 mg / mL, molecular weight 360.3, average particle size 50 μm.

.. Water-insoluble powder (a3 ′): Comparative component of component (a3) Crystalline cellulose, trade name “Theorus PH-302” (manufactured by Asahi Kasei Chemicals Corporation). Solubility in water at 20 ° C. is 0.0001 mg / mL or less, molecular weight 16200-48700, average particle size 90 μm.

-Particles (B) composed of one or more compounds selected from the group consisting of bicarbonates and carbonates
..Bicarbonate (b1)
Sodium bicarbonate, trade name “sodium bicarbonate KF” (Asahi Glass Co., Ltd.). Average particle size 110 μm.
..Carbonates (b2)
Anhydrous sodium carbonate, trade name “dry sodium carbonate” granule grade (manufactured by Takasugi Pharmaceutical Co., Ltd.). Average particle size 564 μm.
Anhydrous sodium carbonate, trade name “dry sodium carbonate” powder grade (manufactured by Takasugi Pharmaceutical Co., Ltd.). Average particle size 45 μm.
Calcium carbonate, trade name “Calcium carbonate” (manufactured by Wako Pure Chemical Industries, Ltd.). Average particle size 90 μm.
Magnesium carbonate, trade name “magnesium carbonate” (manufactured by Kyowa Chemical Industry Co., Ltd.). Average particle size 100 μm.
Potassium carbonate, trade name “potassium carbonate” (manufactured by Wako Pure Chemical Industries, Ltd.). Average particle size 120 μm.

・ Other ingredients (C)
Sodium lauryl sulfate, trade name “SLS” (manufactured by Nikko Chemicals Co., Ltd.).
Crospovidone, trade name “Kollidon CL-SF” (manufactured by BASF).
Mannitol, trade name “Pearlitol 200SD” (manufactured by Rocket).
Magnesium stearate, trade name “magnesium stearate” (manufactured by Taihei Chemical Industrial Co., Ltd.).

<Method for producing solid tablets for internal use>
First, granulated particles 1 to 7 each including (a1) component, (a2) component, and (a3) component or (a3 ′) component were produced. Next, each granulated particle, component (B), and other components were mixed and tableted to obtain an internal solid tablet.

≪Granulation process≫
According to the composition (blending components, content (mass%)) shown in Table 1, granulated particles were produced by the following production methods. In Table 1, the content of the blending component indicates a pure equivalent amount.
The average particle size of the granulated particle group was measured using a laser diffraction / scattering particle size distribution measuring device “LS230 type” (manufactured by Beckman Coulter).
“Mass ratio (a3) / (a1)” described in Table 1 means the mass ratio of the content of component (a3) to the content of component (a1) in the granulated particles. About the granulated particle 7, the mass ratio of content of (a3 ') component with respect to content of (a1) component in granulated particle is meant.

(Production of granulated particles 1)
2145 g of ibuprofen (component (a1)) and 858 g of low substituted hydroxypropylcellulose (component (a2)) were mixed to obtain a mixture. Next, the mixture was put into a pulverizer Coroplex (manufactured by POWREC Co., Ltd., 160Z type) and pulverized under the condition of a rotational speed of 12000 rpm to obtain a pulverized product. The average particle size of the pulverized product was 12 μm.
Next, 1365 g of the pulverized product was put into a preheated Spiraflow (Freund Sangyo Co., Ltd., SFC-5 type), the supply air temperature was 55 ° C., the exhaust air flow rate was 2.7 m ³ / min, and the rotor rotation speed was 200 rpm. The flow started under the conditions of
After confirming that the exhaust temperature was 43 ° C. or higher, 6000 g of an aqueous solution (HPC-SSL: purified water = 150: 2350 (mass ratio)) of hydroxypropylcellulose (component (a2)) was added to a two-fluid nozzle ATF type ( Spraying was performed using a hole diameter of φ1.8 mm.
After the spraying, the supply air temperature was changed to 65 ° C. and drying was performed. When the exhaust temperature reached 43 ° C., drying was finished and a granulated product was obtained.
The obtained granulated product was sieved using a sieve having an opening of 850 μm, whereby granulated particles 1 were obtained. The average particle diameter of the particle group of the granulated particles 1 was 182 μm.

(Production of granulated particles 2)
In the same manner as in the production of the granulated particles 1, a pulverized product of ibuprofen and low-substituted hydroxypropylcellulose was obtained.
Next, 1365 g of the pulverized product and a predetermined amount of the component (a3) were charged into the preheated spira flow, and flow was started in the same manner as in the production of the granulated particles 1.
Thereafter, spraying, drying, and sieving were performed in the same manner as in the production of the granulated particles 1 so that the composition shown in Table 1 was obtained, whereby granulated particles 2 were obtained. Table 1 shows the average particle diameter of the particle group of the granulated particles 2.

(Production of granulated particles 3-6)
According to the composition shown in Table 1, granulated particles 3 to 6 were obtained in the same manner as in the production of the granulated particle 2 except that the type of component (a3) and the blending amount of each component were changed. Table 1 shows the average particle diameters of the particle groups of the granulated particles 3 to 6.

(Production of granulated particles 7)
According to the composition shown in Table 1, granulated particles 7 were obtained in the same manner as in the production of the granulated particles 2 except that the component (a3) was changed to the component (a3 ′). Table 1 shows the average particle diameter of the particle group of the granulated particles 7.

(Granulation of (b2))
What was produced by the method shown below was used for the sodium carbonate used in Examples 31-33.
Anhydrous sodium carbonate having an average particle size of 45 μm and 1 kg of a trade name “dry sodium carbonate” powder grade were charged into a stirring granulator (High Speed Mixer FS-10, manufactured by Fukae Pautech Co., Ltd.). 50 g of water was added thereto, and the mixture was stirred and granulated at an agitator rotation speed of 300 rpm and a chopper rotation speed of 1500 rpm. The powder in the stirring granulator was collected and dried in a thermostatic bath. The dried powder was classified for each predetermined particle size with a sieve to obtain an anhydrous sodium carbonate particle group having an average particle size shown in Table 6.

≪Tabletting process≫
According to the composition shown in Tables 2 to 6 (formulation components, content (mg / tablet)), each internal solid tablet was produced by the following production method. The content (mg / tablet) of each component described in Tables 2 to 6 is the mass of each compounding component per tablet. In Tables 2-6, content of a compounding component shows a pure conversion amount.
In Tables 2 to 3, “component (A ′)” indicates that it is a comparative component of component (A).
“Total (mg)” described in Tables 2 to 6 is the sum of the masses of the ingredients per tablet. “Mass ratio (a3) / (B)” means the mass ratio of the content of the component (a3) to the content of the component (B) in one tablet.

(Examples 1-33, Comparative Examples 1-3)
In a blender (Boule Container Mixer “LM20” manufactured by Kotobuki Industries Co., Ltd., “MC20” manufactured by Kotobuki Industries Co., Ltd.) so that the composition per tablet is as shown in Tables 2 to 6, (A ) Component or (A ′) component, (B) component, and (C) component were added. The total mass of the charged powder was about 2 kg. After adding each compounding component, mixing was performed at a rotation speed of 21 rpm for 20 minutes to obtain a mixed powder.
Subsequently, using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., Libra), the tableting pressure of the obtained mixed powder was set so that the tablet hardness was about 78.5 N. An internal solid tablet was obtained.

<Evaluation>
About the internal solid tablet of each case, the dispersibility evaluation test and the tablet hardness test which are shown below were performed, respectively.

[Dispersibility evaluation test]
A dispersibility evaluation test was conducted using a paddle dissolution tester (Toyama Sangyo Co., Ltd.).
Two tablets are added to the stomach model solution (sodium chloride and hydrochloric acid are dissolved in water and the pH is adjusted to 1.8) so that the stirring blades of the paddle are sufficiently hidden. The mixture was stirred so as not to disperse in the liquid.
Five minutes after adding 2 tablets to the gastric model solution, the solution was collected and transferred to a vial, and acetonitrile and acetic acid were added to dissolve ibuprofen.
After dissolving ibuprofen, it was filtered with a 0.45 μm filter, and the amount of ibuprofen was measured by high performance liquid chromatography. From the measurement result of the high performance liquid chromatography, the amount of ibuprofen dispersed from the tablet into the test solution was calculated backward.
The dispersion ratio after 5 minutes from the addition of the tablet was calculated by determining the ratio (%) of the mass of ibuprofen dispersed from the tablet to the total mass of ibuprofen in the added tablet.
In this example, if the dispersion ratio is 50% or more, it can be said that the dispersibility of ibuprofen in the body is sufficiently high. In addition, when the dispersion ratio is 70% or more, it can be said that the dispersibility of ibuprofen in the body is remarkably high, and when it is 80% or more, the dispersibility of ibuprofen in the body is extremely remarkably high.

[Tablet hardness test]
The hardness of the tablet was measured using a tablet hardness breaking measuring machine (TH-203CP, manufactured by Toyama Sangyo Co., Ltd.).
As samples for measurement, 10 tablets each of a tablet immediately after production (initial product) and a tablet immediately after production stored at 50 ° C. for 24 hours (preserved product) were used. And each hardness of 10 tablets was measured and the average value of these was determined.
As the difference in tablet hardness between the initial product and the stored product is smaller, the decrease in tablet hardness with time is suppressed. The difference in tablet hardness is preferably 10N or less, more preferably 6N or less, and even more preferably 5N or less.

[Evaluation of the effect of suppressing the expansion of the drug container in the package]
As a PTP (press-through package), a plastic sheet (thickness 0.30 μm, VSL-4610N, manufactured by Sumitomo Bakelite Co., Ltd.) on which a pocket (drug container) having a diameter of 11.5 mm and a depth of 7 mm was molded was used.
Each tablet of each example was accommodated in the PTP drug container, and an aluminum film was heat sealed to the PTP so as to close the drug container, thereby preparing a PTP package. A plastic film having a distance of 4 mm from the edge of the drug container to the perforation (adjacent package) of the plastic sheet was used.
Next, the obtained PTP package was stored for 2 weeks under conditions of a temperature of 50 ° C. and a relative humidity of 75% RH. And according to the following evaluation criteria, the effect which suppresses the expansion | swelling of the medicine accommodating part in a package was evaluated.
FIG. 1 is a photograph showing the state (appearance) of a PTP package after the above-mentioned storage, and is an example of a PTP package showing the states of the following evaluation criteria (I, II, III, IV). is there.
In the PTP package shown in FIG. 1, tablets are accommodated in a drug container 1 having a substantially circular shape in plan view, and an aluminum film 2 is provided so as to close the drug container 1.
Evaluation criteria I: Neither swelling of the drug container 1 nor peeling of the aluminum film 2 was observed (no swelling at all).
II: Slight expansion of the drug container 1 was observed, but peeling of the aluminum film 2 from the plastic sheet was not observed (there was swelling and no seal peeling).
III: The drug container 1 was expanded and the aluminum film 2 was peeled off from the plastic sheet, but did not reach the perforation (swelled and seal peeled off).
IV: The drug container 1 was expanded, and the aluminum film 2 was peeled off from the plastic sheet and reached the perforation (the seal peeled off and reached the perforation).

From the results shown in Tables 2 to 6, the internal solid tablets of Examples 1 to 33 to which the present invention was applied had higher dispersibility of the drug in the body than the internal solid tablets of Comparative Examples 1 to 3, and It can be confirmed that the decrease in tablet hardness with time is suppressed.
Further, the hydrogen carbonate (b1) contains sodium hydrogen carbonate, the carbonate (b2) contains sodium carbonate or calcium carbonate, and the mass ratio represented by the hydrogen carbonate (b1) / carbonate (b2) is 2 or less. In Examples 22 to 33, it can be confirmed that the expansion of the drug container of the package is suppressed.

Claims (5)

  A poorly water-soluble drug (a1) having a solubility in water at 20 ° C. of 5 mg / mL or less, a water-swellable polymer compound having a molecular weight of 1000 or more, and a solubility in water at 20 ° C. of 1 mg / mL or more, and a molecular weight of 1000 or more. And one or more polymer compounds (a2) selected from the group consisting of water-soluble polymer compounds, and water-soluble powders (a3) having a solubility in water at 20 ° C. of more than 5 mg / mL and a molecular weight of less than 1000 ) (Excluding the following particles (B)), and particles (B) made of one or more compounds selected from the group consisting of hydrogen carbonate (b1) and carbonate (b2) And an internal solid tablet.   The internal solid tablet of Claim 1 whose content of the said water-soluble powder (a3) in the said granulated particle (A) is 10 mass% or more.   The internal solid tablet according to claim 1 or 2, wherein the particles (B) contain the bicarbonate (b1) and the carbonate (b2).   The bicarbonate (b1) is sodium bicarbonate, the carbonate (b2) is at least one carbonate selected from the group consisting of sodium carbonate and calcium carbonate, and the bicarbonate (b1) / The internal use solid tablet of Claim 3 whose mass ratio represented by carbonate (b2) is 2 or less.   The internal solid tablet as described in any one of Claims 1-4 whose volume average particle diameter of the said particle | grain (B) is 10-1000 micrometers.