JP2022087085A - Solid preparation containing ibuprofen - Google Patents

Abstract

To provide a solid preparation having excellent dissolution of ibuprofen and a good color tone.SOLUTION: A solid preparation includes a granular product containing the following ingredients (a1), (a2), (a3), and (a4): (a1) ibuprofen or a salt thereof or a solvate thereof; (a2) magnesium oxide; (a3) sodium lauryl sulfate; and (a4) one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium.SELECTED DRAWING: None

Description

The present invention relates to a method for producing a solid preparation and a tablet containing ibuprofen.

Ibuprofen (chemical name: 2- (4-isobutylphenyl) propionic acid) is a drug widely known as a kind of NSAID (Patent Document 1 etc.), but it is said that the elution property becomes low when it is made into tablets. There was a problem.
On the other hand, when a poorly soluble drug such as ibuprofen is granulated together with a basic compound and a disintegrant, the granulated product itself disintegrates at the time of disintegration and the basic compound is dispersed from the vicinity of the poorly soluble drug. Therefore, it was generally thought that an environment suitable for elution of poorly soluble drugs would be lost.
Therefore, as a tablet having improved elution of ibprofen, a granulated product containing magnesium hydroxide and magnesium oxide as basic compounds in addition to ibprofen and sodium lauryl sulfate was prepared without adding a disintegrant. A tablet obtained by adding crospovidone and magnesium stearate to the granulated product and tableting it has been proposed (Patent Document 2).

Japanese Patent Application Laid-Open No. 2002-255802 Japanese Unexamined Patent Publication No. 2014-141518

However, as a result of studies by the present inventors, the ibuprofen-containing granules prepared without the disintegrant compound have a dark color tone, and it is difficult to produce tablets having a good color tone from these granules. found.
In addition, when ibuprofen-containing granules prepared without a disintegrant are mixed with low-replacement hydroxypropyl cellulose and tableted, not only the color tone becomes dark but also the elution property is rather lowered. I understood.
An object of the present invention is to provide a solid preparation having excellent elution of ibuprofen and a good color tone.

Therefore, as a result of diligent studies, the present inventors are selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone and croscarmellose sodium together with ibprofen, magnesium oxide and sodium lauryl sulfate. Surprisingly, it was found that a solid preparation containing a granulated product containing one or more disintegrants has excellent elution of ibprofen and a good color tone, and completed the present invention.

That is, the present invention provides the following <1> to <9>.
<1> A solid preparation containing a granulated product containing the following components (a1), (a2), (a3) and (a4).
(A1) Ibuprofen or a salt thereof or a mixture thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low substitution hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone and croscarmé The solid preparation according to <1>, wherein one or more disintegrants selected from sodium loin <2> are granules, fine granules, powders, tablets, rounds, capsules or dry syrups.

<3> The additive layer and the granulated product dispersed in the additive layer are included, and the granulated product contains the following components (a1), (a2), (a3) and (a4). Solid formulation.
(A1) Ibuprofen or a salt thereof or a solvate thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low substitution hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone and croscarmé One or more disintegrants selected from loin sodium <4> (A) Content mass ratio of (B) additive layer to granulated product [(B) / (A)] is 0.001 to 1.5. The solid preparation according to <3>.
<5> The solid preparation according to <3> or <4>, wherein the dosage form is a tablet.

<6> The disintegrant according to any one of <1> to <5>, wherein the component (a4) is one or more disintegrants selected from low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose and crospovidone. Solid formulation.
<7> The content mass ratio [(a3) / (a1)] of the component (a3) to the component (a1) in the granulated product is 0.0001 to 0.5, of <1> to <6>. The solid formulation according to any.

<8> A tableting step of mixing a granule containing the following components (a1), (a2), (a3) and (a4) with an additive and tableting the obtained mixture is included. How to make tablets.
(A1) Ibuprofen or a salt thereof or a mixture thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low degree of substitution hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone and croscarmé One or more disintegrants selected from sodium loin <9> The component (a4) is one or more disintegrants selected from low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl cellulose, carmellose and crospovidone, <8. > The manufacturing method described in.

According to the production method of the present invention, a tablet having excellent elution of ibuprofen and a good color tone can be produced.
The solid preparation of the present invention has excellent elution of ibuprofen and a good color tone.

<Solid product>
The solid pharmaceutical product of the present invention contains granulated products containing the above-mentioned components (a1), (a2), (a3) and (a4).
First, the components (a1) to (a4) contained in the granulated product will be described.

(Component (a1))
Examples of ibprofen or a salt thereof or a solvent mixture thereof include ibprofen; alkali metal salts of ibprofen such as sodium ibprofen and potassium ibprofen; hydrates and alcoholic sums thereof.
Further, as the ibuprofen or a salt thereof or a solvate thereof, powdery ones are preferable. The average particle size of the powder is preferably 5 to 75 μm, more preferably 15 to 60 μm. The average particle size of the powder can be measured by a laser diffraction method.
Ibuprofen or a salt thereof or a solvate thereof can be produced by a known method, and a commercially available product can also be used.

The content of ibprofen or a salt thereof or a solvate thereof in the granulated product is preferably 5 to 70 with respect to the total mass of the granulated product from the viewpoint of elution of ibprofen and manufacturability at the time of tableting. It is by mass, more preferably 15 to 55% by mass, still more preferably 25 to 50% by mass, and particularly preferably 30 to 45% by mass.

(Component (a2))
The magnesium oxide may be heavy magnesium oxide or light magnesium oxide. The particle size and specific volume of magnesium oxide are not particularly limited, but the specific volume is preferably 1 to 12 mL / g, and more preferably 2 to 10 mL / g.
Magnesium oxide can be produced by a known method, and a commercially available product can also be used.

The content of magnesium oxide in the granulated product is preferably 5 to 30% by mass, more preferably 7.5 to 27% by mass, based on the total mass of the granulated product, from the viewpoints of immediate effect, reduction of unpleasant taste, color tone and the like. It is 5.5% by mass, more preferably 12.5 to 25% by mass, and particularly preferably 15 to 25% by mass.

The mass ratio of the component (a2) to the component (a1) in the granulated product [(a2) / (a1)] is 0.3 to 0 from the viewpoint of immediate effect, reduction of unpleasant taste, color tone, and the like. .7 is preferable.

(Component (a3))
Sodium lauryl sulfate is an anionic surfactant represented by CH ₃ (CH ₂ ) ₁₁ OS (= O) ₂ O ^{—Na +} . Inclusion of sodium lauryl sulfate in the granules improves the elution of ibuprofen.
Sodium lauryl sulfate can be produced by a known method, and a commercially available product can also be used.

The content of sodium lauryl sulfate in the granulated product is preferably 0.005 to 12.5% by mass with respect to the total mass of the granulated product from the viewpoint of elution property, moldability, granulation property and the like of ibprofen. It is more preferably 0.01 to 10% by mass, further preferably 0.05 to 7.5% by mass, still more preferably 0.1 to 5% by mass, and particularly preferably 0.3 to 3% by mass.
Ibuprofen when the content of sodium lauryl sulfate in the granulated product is 0.1% by mass or more or 0.3% by mass or more and 10% by mass or less, 5% by mass or less or 3% by mass or less. Dissolution is particularly improved.

The mass ratio of the component (a3) to the component (a1) in the granulated product [(a3) / (a1)] is 0. 0001 to 0.5 is preferable, 0.0005 to 0.4 is more preferable, 0.001 to 0.25 is further preferable, 0.001 to 0.2 is further preferable, and 0.01 to 0.1 is particularly preferable. preferable.
When the content mass ratio [(a3) / (a1)] is 0.01 or more and 0.2 or less or 0.1 or less, the elution of ibuprofen is particularly improved.

(Component (a4))
In the solid preparation of the present invention, one or more disintegrants selected from (a4) low-degree-of-substitution hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, crospovidone and croscarmellose sodium are added to the granules. It contains. By incorporating the component (a4) into the granulated product, not only the disintegration property of the solid preparation and the elution of ibuprofen but also the color tone of the solid preparation is improved. As described in Patent Document 2 (Japanese Unexamined Patent Publication No. 2014-141518), when a sparingly soluble drug such as ibuprofen is collectively granulated together with a basic compound and a disintegrant, granulation occurs at the time of disintegration. Although it was generally thought that the substance itself would collapse and the basic compound would be dispersed from the vicinity of the poorly soluble drug, and thus the environment suitable for elution of the poorly soluble drug would be lost, in the present invention, it is completely Surprisingly, the elution of ibuprofen was improved as described above.

In the present specification, the low-degree-of-substitution hydroxypropyl cellulose means the low-degree-of-substitution hydroxypropyl cellulose described in the 17th revised Japanese Pharmacopoeia. Specifically, it refers to hydroxypropyl cellulose in which hydroxypropoxy groups are quantified by 5.0 to 16.0% when dried. The content of the hydroxypropoxy group is preferably 6 to 13% by mass, particularly preferably 7 to 11% by mass.
Hydroxypropyl cellulose having a low degree of substitution can be produced by a known method, and a commercially available product can also be used. Commercially available products of low-substituted hydroxypropyl cellulose include L-HPC (LH31) manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC (LH21) manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC (LH11) manufactured by Shin-Etsu Chemical Co., Ltd., and Shin-Etsu Chemical Co., Ltd. Examples thereof include L-HPC manufactured by Kogyo Co., Ltd. (LH32) and L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. (NBD-020).

Further, in the present specification, carboxymethyl starch sodium means carboxymethyl starch sodium described in the 17th revised Japanese Pharmacopoeia. Specifically, it is a sodium salt of carboxymethyl ether of starch or a crosslinked product thereof, and when the insoluble matter of ethanol (99.5) / water mixture (8: 2) is dried, sodium is 2.8 to 4 .2% or 2.0-3.4% quantified.
Sodium carboxymethyl starch can be produced by a known method, and a commercially available product can also be used. Examples of commercially available products of carboxymethyl starch sodium include Primojel (manufactured by DMV), Explotab (manufactured by Kimura Sangyo Co., Ltd.), GLYCOLYS (manufactured by Rocket Japan) and the like.

In addition, carmellose refers to carmellose described in the 17th revised Japanese Pharmacopoeia. Specifically, it refers to cellulose that is partially O-carboxymethylated. Carmellose can be produced by a known method, and a commercially available product can also be used. Examples of commercially available carmellose include NS-300 (manufactured by Gotoku Yakuhin Co., Ltd.).

In addition, carmellose calcium means carmellose calcium described in the 17th revised Japanese Pharmacopoeia. Specifically, it refers to a calcium salt of a polyvalent carboxymethyl ether of cellulose. Carmellose calcium can be produced by a known method, and a commercially available product can also be used. As a commercial product of carmellose calcium, E.I. C. G-505 (manufactured by Gotoku Yakuhin Co., Ltd.) and the like can be mentioned.

In addition, crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone. As the crospovidone, as described in the 17th revised Japanese Pharmacopoeia, crospovidone in which nitrogen is quantified by 11.0 to 12.8% when dried is preferable. The average particle size (D50%) of crospovidone is usually 3 to 140 μm. Further, the crosspovidone may be a type A crosspovidone specified in the 17th revised Japanese Pharmacopoeia or a type B crosspovidone.
Crospovidone can be produced by a known method, and a commercially available product can also be used. Commercially available products of Cross Povidon include Corridon CL, Corridon CL-F, Corridon CL-SF (above, manufactured by BASF Japan), Polyplusdon (manufactured by ISP Japan), and Cross Povidon (manufactured by DSP Gokyo Food & Chemicals). ) Etc. can be mentioned.

In addition, croscarmellose sodium means croscarmellose sodium described in the 17th revised Japanese Pharmacopoeia. Specifically, it refers to a sodium salt of a crosslinked product of polyvalent carboxymethyl ether of cellulose. Croscarmellose sodium can be produced by a known method, and a commercially available product can also be used. Examples of commercially available products of croscarmellose sodium include Primellose-300 (manufactured by DMV), Ac-Di-Sol (manufactured by DuPont), and Kiccolate (manufactured by Asahi Kasei).

Among the components (a4), low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, carmellose, and crospovidone are preferable, and low-substituted hydroxypropyl cellulose is preferable from the viewpoint of disintegration of the solid preparation, elution of ibprofen, and color tone of the solid preparation. Cellulose, carboxymethyl starch sodium and crospovidone are more preferable, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium are even more preferable, and low-substituted hydroxypropyl cellulose is particularly preferable.

The content of the component (a4) in the granulated product is preferably 3 to 55% by mass with respect to the total mass of the granulated product from the viewpoint of the disintegration property of the solid product, the elution of ibprofen, the color tone of the solid product and the like. , More preferably 10 to 50% by mass, still more preferably 15 to 45% by mass, and particularly preferably 20 to 40% by mass.

The mass ratio of the component (a4) to the component (a1) in the granulated product [(a4) / (a1)] is from the viewpoint of disintegration of the solid preparation, elution of ibprofen, color tone of the solid preparation, and the like. Therefore, 0.05 to 2 is preferable, 0.1 to 1.5 is more preferable, 0.3 to 1.2 is further preferable, and 0.6 to 1 is particularly preferable.
When the content mass ratio [(a4) / (a1)] is 0.3 or more or 0.6 or more, the elution of ibuprofen is particularly improved.

The granulated product may contain a drug other than the components (a1) and (a2) in addition to the above components (a1) to (a4).
Drugs other than the components (a1) and (a2) include one or more drugs selected from (a5) caffeines and (a6) hypnotic sedatives, as well as these components (a1), (a2), and (a5). ) And drugs other than (a6) (hereinafter, also referred to as other drugs).

(Component (a5))
Examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine and the like. One of these may be used alone or two or more thereof may be used in combination.
The content of caffeine in the granulated product is preferably 0 to 25% by mass, more preferably 0 to 20% by mass, still more preferably 0 to 17.5% by mass, based on the total mass of the granulated product. Particularly preferably, it is 0 to 15% by mass.

(Component (a6))
Examples of the hypnotic sedative include allylisopropylacetylurea, bromovalerylurea and the like. One of these may be used alone or two of them may be used in combination.
The content of the hypnotic sedative in the granulated product is preferably 0 to 20% by mass, more preferably 0 to 17.5% by mass, still more preferably 0 to 15% by mass, based on the total mass of the granulated product. Particularly preferably, it is 0 to 12.5% by mass.

Examples of other drugs include anti-inflammatory agents other than the component (a1), antacids other than the component (a2), antitussive expectorants, antihistamines, antiallergic agents, anticholinergic agents, vitamins, muscle relaxants, and crude drugs. Kind and the like. One of these may be used alone or two or more thereof may be used in combination.

Examples of the anti-inflammatory agent other than the component (a1) include glycyrrhizinic acid and salts thereof, tranexamic acid, glycyrrhetinic acid, sodium azulene sulfonate, aspirin, salicylamide and the like. One of these may be used alone or two or more thereof may be used in combination.
The content of the anti-inflammatory agent other than the component (a1) in the granulated product is usually 0 to 30% by mass, preferably 0 to 10% by mass, and more preferably 0 to 0% by mass with respect to the total mass of the granulated product. It is 1% by mass.

Examples of the antioxidant other than the component (a2) include sodium hydrogen carbonate, precipitated calcium carbonate, calcium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum hydroxide gel, and dry hydroxide. Aluminum gel, aluminum hydroxide / sodium hydrogen carbonate co-precipitated product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate co-precipitated product, magnesium hydroxide / aluminum potassium sulfate co-precipitated product Products, glycine, magnesium silicate, dihydroxyaluminum aminoacetate, magnesium carbonate and the like can be mentioned. One of these may be used alone or two or more thereof may be used in combination.
The content of the antioxidant other than the component (a2) in the granulated product is preferably 0 to 5% by mass, more preferably 0 to 1% by mass, and further preferably 0 to 0 to the total mass of the granulated product. It is 0.1% by mass, more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass.

Examples of antitussive sputum salts include ambroxol hydrochloride, L-ethylcysteine hydrochloride, potassium guayacol sulfonate, potassium cresol sulfonate, guayphenesin, bromhexin hydrochloride, L-carbocysteine, codeine phosphate hydrate, and dihydrocodein phosphorus. Acidate, Tipepidine Citrate, Tipepidine hibenzate, Dextrometorphan Hydrobromide Hydrate, Dextromethorphan Phenolphthaline Salt, Dimemorphan Phosphate, Noscapine, Noscapine Hydrochloride Hydrate, dl-Methylefedrin Hydrochloride, Examples thereof include dl-methyleffedrin saccharin salt. One of these may be used alone or two or more thereof may be used in combination.
The content of the antitussive expectorant in the granulated product is usually 0 to 30% by mass, preferably 0 to 10% by mass, and particularly preferably 0 to 0.1% by mass, based on the total mass of the granulated product.

Examples of antihistamines and antiallergic agents include mequitazine, azelastin hydrochloride, hexofenazine hydrochloride, epinastine hydrochloride, loratazine, cetirizine hydrochloride, olopatazine hydrochloride, alimemazine tartrate, carbinoxamine maleate, and clemastin fumarate. Examples thereof include salts, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, diphenhydramine hydrochloride and the like. One of these may be used alone or two or more thereof may be used in combination.

Examples of the anticholinergic drug include isopropamide iodide, scopolia extract, scopolia root, belladonna total alkaloid, scopolamine hydrobromide, butylscopolamine bromide, methylbenactidium bromide, timepidium bromide, pirenzepine and the like. One of these may be used alone or two or more thereof may be used in combination.

Examples of vitamins include vitamin B1, vitamin B1 derivative, vitamin B2, vitamin B2 derivative, vitamin C, vitamin C derivative, hesperidin, hesperidin derivative, and salts thereof. One of these may be used alone or two or more thereof may be used in combination.

Examples of the muscle relaxant include methocarbamol, chlorzoxazone, prizinol mesylate, chlorphenesin carbamic acid ester, emerison hydrochloride, afroqualon, tizanidine hydrochloride and the like. One of these may be used alone or two or more thereof may be used in combination.

Examples of crude drugs include liquorice, peony, licorice, peony, buttonpi, chimpi, ginger, sansho, kikyo, maou, apricot kernel, hange, peony, senega, psycho, and cinnamon. One of these may be used alone or two or more thereof may be used in combination.

The total content of the other drugs in the granulated product is usually 0 to 50% by mass, preferably 0 to 10% by mass, more preferably 0 to 1% by mass, still more preferably 0 to 1% by mass, based on the total mass of the granulated product. It is 0 to 0.01% by mass, particularly preferably 0% by mass.

Further, the granulated product may contain a pharmaceutical additive other than the components (a3) to (a4).
Examples of pharmaceutical additives other than the components (a3) to (a4) include surfactants other than the component (a3) such as sucrose fatty acid ester and polyoxyethylene polyoxypropylene glycol; alginate, bentonite, and partially pregelatinized starch. Disintegrants other than the component (a4) such as: corn starch, crystalline cellulose, lactose, lactose hydrate, sucrose, glucose, mannitol, sorbitol, xylitol and other excipients; gelatin, sodium alginate, hydroxypropylmethylcellulose, polyvinylpyrrolidone. , Binders such as sodium carmellose and the like. One of these may be used alone or two or more thereof may be used in combination. Further, a lysis aid, a buffer, a preservative and the like can be used as needed.

The total content of the pharmaceutical additives other than the components (a3) to (a4) in the granulated product is usually 0 to 40% by mass, preferably 0 to 30% by mass, more preferably with respect to the total mass of the granulated product. Is 0 to 25% by mass, more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass.

The granulated product is preferably in the form of granules. The average particle size of the granulated product is usually 100 to 1000 μm, preferably 150 to 710 μm. The average particle size can be measured by a sieving method.

Examples of the dosage form of the solid preparation of the present invention include granules, fine granules, powders, tablets, pills, capsules, dry syrups and the like, but granules, tablets and capsules are preferable, and tablets are particularly preferable. .. The solid preparation of the present invention has excellent elution of ibuprofen even when the dosage form is a tablet.
Specific examples of the tablets include uncoated tablets, film-coated tablets, sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc. from the viewpoint of tablet disintegration, ibuprofen elution, and easy-to-dose. , Uncoated tablets, film-coated tablets, orally disintegrating tablets are preferable. Further, even when the dosage form is an uncoated tablet or an orally disintegrating tablet, the solid preparation of the present invention has a good color tone. In addition, the color tone is good even in the case of a non-coated type solid preparation.

Further, the solid preparation of the present invention may be composed of the above-mentioned granules or may contain components other than the above-mentioned granules and the granules (additive layer and film coating layer), but the disintegration property of the solid preparation. From the viewpoint of the elution of ibprofen and the color tone of the solid pharmaceutical product, the additive layer and the granules dispersed in the additive layer are included, and the granules contain the components (a1) to (a4). A solid preparation (hereinafter, this solid preparation is also referred to as “solid preparation (α)”) is preferable, and the granulated product contains an additive layer and a granulated product dispersed in the additive layer. Tablets containing the components (a1) to (a4) are particularly preferable.
It is only necessary that at least a part of the granulated product contained in the solid preparation (α) is dispersed in the additive layer, and as long as at least a part of the granulated product is dispersed in the additive layer, it is added. A plurality of granules in the agent layer may be in contact with each other.

The solid pharmaceutical product (α) contains an additive layer separately from the above-mentioned granulated product. The additive layer is preferably solid.
As the additive layer, one containing (b1) a lubricant is preferable from the viewpoint of tableting property, filling property and the like.

(Component (b1))
Examples of the lubricant include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerin fatty acid ester and the like. One of these may be used alone or two or more thereof may be used in combination.

The content of the component (b1) in the additive layer is preferably 0.5 to 100% by mass, more preferably 0.75, based on the total mass of the additive layer from the viewpoint of tableting property, filling property and the like. It is ~ 95% by mass, more preferably 1 to 90% by mass, and particularly preferably 2 to 85% by mass.

As the additive layer, in addition to the above component (b1), one or more selected from (b2) disintegrant and (b3) excipient may be used from the viewpoint of elution, disintegration, fluidity, etc. of ibuprofen. Those containing are preferable.

(Component (b2))
Examples of the disintegrant include crospovidone, carmellose calcium, low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and the like. One of these may be used alone or two or more thereof may be used in combination. Examples of crospovidone, carmellose calcium, low-degree-of-substitution hydroxypropyl cellulose, carboxymethyl starch sodium, and croscarmellose sodium include those listed as the component (a4).
Among these, crospovidone, carboxymethyl starch sodium, and croscarmellose sodium are preferable, and crospovidone is more preferable, from the viewpoint of disintegration of the solid preparation and elution of ibuprofen.

The content of the component (b2) in the additive layer is preferably the total mass of the additive layer from the viewpoints of disintegration of the solid preparation, elution of ibuprofen, moldability, manufacturability at the time of tableting and the like. It is 0 to 50% by mass, more preferably 0 to 40% by mass, still more preferably 0 to 35% by mass, and particularly preferably 0 to 30% by mass.

The mass ratio of the component (b2) in the additive layer to the component (a1) in the granulated product [(b2) / (a1)] is from the viewpoint of disintegration of the solid preparation, elution of ibprofen, and the like. Therefore, 0 to 0.8 is preferable, 0.05 to 0.6 is more preferable, 0.075 to 0.4 is further preferable, and 0.1 to 0.2 is particularly preferable.

The mass ratio of the component (b2) in the additive layer to the component (a4) in the granulated product [(b2) / (a4)] is from the viewpoint of disintegration of the solid preparation, elution of ibprofen, and the like. Therefore, 0 to 0.8 is preferable, 0.05 to 0.6 is more preferable, 0.075 to 0.4 is further preferable, and 0.1 to 0.3 is particularly preferable.

(Component (b3))
Examples of the excipient include corn starch, crystalline cellulose, lactose, lactose hydrate, sucrose, glucose, mannitol, sorbitol, xylitol and the like. One of these may be used alone or two or more thereof may be used in combination.
Of these, crystalline cellulose, corn starch and mannitol are preferred.

The content of the component (b3) in the additive layer is preferably 0 to 95% by mass, more preferably 5 to 95% with respect to the total mass of the additive layer from the viewpoint of disintegration property, moldability and the like of the solid preparation. It is by mass, more preferably 10 to 95% by mass, and particularly preferably 15 to 95% by mass.

The additive layer may further contain (b4) a fluidizing agent in addition to the above components (b1) to (b3).
(Component (b4))
Examples of the fluidizing agent include light anhydrous silicic acid and hydrous silicon dioxide. One of these may be used alone or two or more thereof may be used in combination.
The content of the component (b4) in the additive layer is preferably 0 to 15% by mass, more preferably 0 to 10% by mass, still more preferably 0 to 7.5% by mass, based on the total mass of the additive layer. Particularly preferably, it is 0 to 5% by mass.

Further, the additive layer may contain pharmaceutical additives other than the components (b1) to (b4).
Examples of the pharmaceutical additive other than the components (b1) to (b4) include surfactants such as sodium lauryl sulfate, sucrose fatty acid ester, and polyoxyethylene polyoxypropylene glycol. One of these may be used alone or two or more thereof may be used in combination. Further, if necessary, lysis aids, buffers, preservatives, flavors, pigments, high-sensitivity sweeteners, flavoring agents and the like can be used.

The total content of the pharmaceutical additives other than the components (b1) to (b4) in the additive layer is usually 0 to 30% by mass, preferably 0 to 10% by mass, more preferably with respect to the total mass of the additive layer. Is 0 to 1% by mass, more preferably 0 to 0.01% by mass, and particularly preferably 0% by mass.

The total content of the granulated product and the additive layer is preferably 80 to 100% by mass, more preferably 90 to 100% by mass, and further preferably 95 with respect to the total mass of the solid preparation (α). It is about 100% by mass, particularly preferably 99.9 to 100% by mass. The solid preparation of the present invention preferably does not contain phosphoric acids such as disodium hydrogen phosphate and clay minerals such as smectite.

The mass ratio of the additive layer (B) to the granulated product (A) in the solid preparation (α) [(B) / (A)] is the disintegration of the solid preparation, the elution of ibprofen, and the solid preparation. From the viewpoint of color tone, moldability and the like, 0.001 to 1.5 is preferable, 0.005 to 1 is more preferable, 0.0075 to 0.5 is further preferable, 0.01 to 0.5 is further preferable. 0.1 to 0.3 is particularly preferable.

Further, as the solid preparation (α), one having an additive layer as the outermost layer is preferable. Even in such a case, the solid preparation of the present invention has a good color tone, and can achieve both the elution of ibuprofen and a good color tone.
In addition, the solid preparation of the present invention is preferably for oral use.

The dose of the solid preparation of the present invention is preferably 100 to 2400 mg per day in terms of the free form of ibuprofen, and more preferably 120 to 1200 mg per day. An amount that can be taken at 390 to 1200 mg per day is particularly preferable. In addition, the amount of the component (a1) in the free form of ibuprofen is preferably 60 to 800 mg at a time, more preferably 60 to 400 mg at a time, and 70 to 400 mg at a time. The amount is more preferable, and the amount that can be taken at 130 to 400 mg at a time is particularly preferable.

The solid preparation of the present invention has excellent elution of ibuprofen and a good color tone.
Therefore, the solid preparation of the present invention can sufficiently exert the anti-inflammatory analgesic effect of ibuprofen, and is extremely useful as an antipyretic analgesic, a common cold drug, a neuropsychiatric drug and the like.

<Tablet manufacturing method>
The solid preparation of the present invention can be produced by appropriately combining conventional methods, but when the dosage form is a tablet, the above-mentioned components (a1), (a2), (a3) and (a4) are used. It may be produced by a method including a tableting step of mixing the contained granules and the additive and tableting the obtained mixture.

The above granulated product shall be prepared according to the known granulation method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation, etc., and the components (a1) to (a4) and other components (components (a5) to 5) as necessary. It can be obtained by a granulation step of granulating a composition containing (a6) and the like (hereinafter, also referred to as composition X). The order of blending the components (a1) to (a4) into the composition X does not matter.

The composition X can be obtained, for example, by mixing the components (a1) to (a4) and other components as needed, or by mixing the components (a1) to (a4) and other components as needed. The resulting mixture can be prepared by kneading with a solvent such as water or hydrous alcohol. Examples of the hydrous alcohol include ethanol and / or a mixed solution of isopropanol and water. Mixing and kneading are preferably carried out at 20 to 1200 rpm for 0.5 to 10 minutes, respectively.

The granulation in the granulation step may be performed by a wet granulation method or a dry granulation method. Specific examples thereof include extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, and crushing granulation. Among these, extrusion granulation and stirring granulation are preferable.

Further, as the additive, a solid state is preferable, and a powder state is more preferable. Additives may include pharmaceutical additives. The pharmaceutical additive is the same as that may be contained in the above-mentioned additive layer, preferably an additive containing at least the component (b1), and more preferably an additive containing at least the components (b1) to (b3). Is.
The locking in the locking step may be performed according to a conventional method using a rotary locking machine, a single-shot locking machine, or the like. The tableting pressure is usually 3 to 15 kN. Further, prior to the addition of the additive, the granulated product may be dried and / or granulated as necessary.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

[Examples 1 to 7 and Comparative Examples 1 to 6 uncoated tablets]
(Production method)
Each component was weighed according to each granule formulation shown in Table 1, put into a high-speed stirring granulator (VG-10 type, manufactured by Paulec), and mixed for 3 minutes. Subsequently, an appropriate amount of purified water was added to the mixed powder of the obtained granule formulation components, and the mixture was kneaded with a high-speed stirring granulator (VG-10 type, manufactured by Paulec) for 3 minutes. The kneaded product was extruded and granulated with an extrusion granulator (Twindome Gran TDG-80A, manufactured by Dalton) to obtain wet granules A. Subsequently, it was dried in a fluidized bed dryer (FLO-2, manufactured by Freund Sangyo Co., Ltd.) to obtain dried granules B. Further, the granules C were obtained by sizing with a sizing machine (Komil QC-U10, manufactured by Paulec).
Additives at the time of mixing shown in Table 1 were added to the obtained granules C and mixed, and the granules were tableted with a rotary tableting machine (VIRG0512 type, manufactured by Kikusui Seisakusho Co., Ltd.) at a tableting pressure of 4.5 kN. The uncoated tablets (mass 1000 mg per 4 tablets (daily dose)) of 1 to 7 and Comparative Examples 1 to 6 were obtained.

(Measurement method and evaluation method)
(1) Ibuprofen-eluting McIlvaine buffer was diluted with purified water to obtain 900 mL of a solution having a pH of 4.0, and one uncoated tablet of Example 1 was added to this solution and stirred at 37 ° C. at 50 rpm. .. After 15 minutes had passed from the start of stirring, the ibuprofen elution rate of the uncoated tablet of Example 1 was measured.
The ibuprofen elution rate was measured by a high performance liquid chromatography (HPLC) method, and was calculated from the elution amount of ibuprofen according to the following formula (α).
Ibuprofen elution rate (% by mass) = {(ibuprofen elution amount (mg)) / (initial ibuprofen content (mg))} × 100 ・ ・ ・ (α)
<HPLC measurement conditions>
Column: A stainless steel tube with an inner diameter of 3.0 mm and a length of 5 cm filled with 3 μm of octadecylsilylated silica gel for liquid chromatography. Detector: Ultraviolet absorptiometer (measurement wavelength: 210 nm)
Mobile phase: Diluted phosphoric acid (1 → 1000) / acetonitrile mixed solution In addition, the elution rate of ibuprofen was measured in the same manner for the uncoated tablets of Examples 2 to 7 and Comparative Examples 1 to 6.
The results are shown in Table 1. It can be said that the larger the elution rate after 15 minutes, the better the elution property of ibuprofen.

(2) Color tone The surface color tone of each granule (granule C that has been sized) and the uncoated tablet immediately after production was visually confirmed and evaluated according to the following criteria. The results are shown in Table 1.
(Evaluation criteria for granule color tone)
-: No discoloration from white to grayish white +: Slight discoloration from white to grayish white ++: Discoloration from white to grayish white (evaluation criteria for tablet color tone)
-: No black spots +: There are a few black spots ++: Many black spots

The symbols in Table 1 indicate the following.
* 1: BASF's ibuprofen 25
* 2: Heavy type manufactured by Kyowa Chemical Industry Co., Ltd. * 3: Corifol SLS Fine manufactured by BASF * 4: L-HPC (LH31) manufactured by Shin-Etsu Chemical Industry Co., Ltd.
* 5: BASF Corridon CL-F (Cross Povidon Type A)
* 6: Primojel manufactured by DFE Pharma
* 7: NS-300 manufactured by Gotoku Yakuhin Co., Ltd.
* 8: Pharmatose 200M manufactured by DFE Pharma
* 9: VIVAPUR105 manufactured by JRS Pharma
* 10: Micro Ace P-3 manufactured by Nippon Talc
* 11: Magnesium stearate manufactured by Taihei Kagaku Co., Ltd. (vegetable)

[Pharmaceutical Example 1-2: Granules]
Each component weighed according to the granule formulation shown in Table 2 was put into a high-speed stirring granulator (VG-25 type, manufactured by Paulec) and mixed for 3 minutes. Subsequently, purified water was added, and the mixture was kneaded with a high-speed stirring granulator (VG-25 type, manufactured by Paulec) for 3 minutes. The kneaded product was extruded and granulated using an extrusion granulator (TDG-80 type, manufactured by Dalton). Further, the obtained extruded granules are put into a fluidized bed dryer (FLO-5 type, manufactured by Freund Sangyo Co., Ltd.) and dried, and then granulated by a granulator (Comil QC-U10). , The granules of Pharmaceutical Example 1 and Pharmaceutical Example 2 were obtained.

[Pharmaceutical Example 3 Hard Capsule]
2.8 g of magnesium stearate is added to 910 g of the granules obtained in Formulation Example 1, and this is mixed with a V-type mixer (TCV-5 type, manufactured by Tokuju Kosakusho Co., Ltd.) to add 912.8 g of the mixed powder. Obtained. This was filled in a gelatin capsule to obtain a hard capsule of Pharmaceutical Example 3 (capsule content substance amount 326 mg corresponding to ibuprofen content 100 mg).

[Formation Example 4 Film-coated tablet]
To 1560 g of the granules obtained in Formulation Example 1, 297.6 g of crystalline cellulose, 38.4 g of crospovidone, 9.6 g of light anhydrous silicic acid, and 14.4 g of magnesium stearate were added, respectively, and a V-type mixer (TCV-) was added. Type 10, manufactured by Tokuju Kosakusho Co., Ltd.) was mixed to obtain 1920 g of tableted powder. Next, tableting was performed with a rotary tableting machine (VIRG0512 type, manufactured by Kikusui Seisakusho Co., Ltd.) to produce uncoated tablets having a diameter of 9.5 mm and a tablet mass of 400 mg (ibuprofen content 100 mg).
Next, 120 g of hypromellose and 20 g of macrogol 6000 were dissolved in purified water, and then 10 g of talc and 10 g of titanium oxide were dispersed to prepare 2000 g of a film coating solution having a solid content concentration of 8%. Next, 500 g of the uncoated tablet was put into a coating machine (HC-LABO type, manufactured by Freund Sangyo Co., Ltd.), and the prepared film coating liquid was sprayed to coat the film. Got

[Pharmaceutical example 5 Orally disintegrating tablet]
To 2064 g of the granules obtained in Preparation Example 2, 425.6 g of crystalline cellulose, 400 g of corn starch, 28.8 g of acesulfame potassium, 28.8 g of aspartame, 14.4 g of light anhydrous silicic acid and 14.4 g of magnesium stearate were added. , V-type mixer (TCV-10 type, manufactured by Tokuju Kosakusho Co., Ltd.) was used for mixing to obtain 2976 g of starch. Next, tableting was performed with a rotary tableting machine (VIRG0512 type, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain an orally disintegrating tablet having a diameter of 12 mm and a tablet mass of 620 mg (ibuprofen content 150 mg).

Claims (9)

A solid preparation containing a granulated product containing the following components (a1), (a2), (a3) and (a4).
(A1) Ibuprofen or a salt thereof or a solvate thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low degree of substitution Hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone and croscarmé One or more disintegrants selected from loin sodium The solid preparation according to claim 1, wherein the dosage form is a granule, a fine granule, a powder, a tablet, a pill, a capsule or a dry syrup. A solid containing an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product contains the following components (a1), (a2), (a3) and (a4). pharmaceutical formulation.
(A1) Ibuprofen or a salt thereof or a solvate thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low degree of substitution Hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone and croscarmé One or more disintegrants selected from loin sodium (A) The solid preparation according to claim 3, wherein the content mass ratio [(B) / (A)] of the (B) additive layer to the granulated product is 0.001 to 1.5. The solid preparation according to claim 3 or 4, wherein the dosage form is a tablet. The solid preparation according to any one of claims 1 to 5, wherein the component (a4) is one or more disintegrants selected from low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose and crospovidone. The item according to any one of claims 1 to 6, wherein the content mass ratio [(a3) / (a1)] of the component (a3) to the component (a1) in the granulated product is 0.0001 to 0.5. The solid formulation described. Production of tablets comprising a tableting step of mixing an additive with a granulated product containing the following components (a1), (a2), (a3) and (a4) and tableting the obtained mixture. Method.
(A1) Ibuprofen or a salt thereof or a solvate thereof (a2) Magnesium oxide (a3) Sodium lauryl sulfate (a4) Low degree of substitution Hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone and croscarmé One or more disintegrants selected from loin sodium The production method according to claim 8, wherein the component (a4) is one or more disintegrants selected from low-degree-of-substitution hydroxypropyl cellulose, sodium carboxymethyl starch, carmellose and crospovidone.