WO2022114240A1

WO2022114240A1 - Solid preparation containing ibuprofen

Info

Publication number: WO2022114240A1
Application number: PCT/JP2021/043984
Authority: WO
Inventors: Yoichi Onuki; Mia YOSHIDA; Rina SHIBOSAWA; Satoru Yoshimura
Original assignee: Ssp Co., Ltd.
Priority date: 2020-11-30
Filing date: 2021-11-30
Publication date: 2022-06-02
Also published as: JP2022087085A; CN116406260A; KR20230116831A

Abstract

The disclosure provides a solid preparation having excellent dissolution of ibuprofen and a good color tone. The 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. The disclosure also provides methods of making such a solid preparation.

Description

SOLID PREPARATION CONTAINING IBUPROFEN

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

Ibuprofen (chemical name:
2-(4-isobutylphenyl)propionic acid) is a drug which is widely known as one of
the Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., Patent Literature 1).
There is a problem of decreased dissolution when ibuprofen is formed into
a tablet.

In particular, when a poorly water
soluble drug, such as ibuprofen, is granulated together with a basic compound
and a disintegrating agent, it has been generally inferred that at the time of
disintegration, the granulated product itself disintegrates to disperse the
basic compound from the vicinity of the poorly water soluble drug, and thereby
an environment suitable for dissolution of the poorly water soluble drug is
lost.

Accordingly, as a tablet with improved dissolution of ibuprofen, proposed is a tablet obtained by preparing a granulated product containing magnesium hydroxide and magnesium oxide as basic compounds in addition to ibuprofen and sodium lauryl sulfate without blending a disintegrating agent, adding crospovidone (cross linked polyvinyl N-pyrrolidone, or PVP) and magnesium stearate to the resulting granulated product, and then performing tableting (Patent Literature 2).

[PTL 1] JP-A-2002-255802
[PTL 2] JP-A-2014-141518

However, according to the
examination by the present inventors, it was found that a granulated product
containing ibuprofen, which was prepared without blending a disintegrating
agent, has a dark color tone and is unlikely to be manufactured into a tablet
having a good color tone.

It was also observed that when the
granulated product containing ibuprofen, which was prepared without blending a
disintegrating agent, is mixed with low substituted hydroxypropylcellulose, and
formed into a tablet, not only the color tone becomes dark, but also the
dissolution would be rather suppressed.

It is an object of the present invention
to provide a solid preparation having excellent dissolution of ibuprofen and
having a good color tone.

Accordingly, the present inventors diligently studied and, as a result, found that a solid preparation comprising a granulated product containing one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium, together with ibuprofen, magnesium oxide, and sodium lauryl sulfate, surprisingly, has excellent dissolution of ibuprofen and a good color tone, to accomplish the present invention.

Thus, in certain embodiments, the
present invention provides the following <1> to <9>:
<1> A solid preparation comprising a granulated product comprising 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;
<2> The solid preparation according to <1>, wherein a dosage form is a granule, a fine granule, a powder, a tablet, a pill, a capsule, or a dry syrup;
<3> A solid preparation comprising an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product comprises 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;
<4> The solid preparation according to <3>, wherein a mass ratio of the additive layer (B) to the granulated product (A), (B)/(A), is from 0.001 to 1.5;
<5> The solid preparation according to <3> or <4>, wherein a dosage form is a tablet;
<6> The solid preparation according to any one of <1> to <5>, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, and crospovidone;
<7> The solid preparation according to any one of <1> to <6>, wherein a mass ratio of the ingredient (a3) to the ingredient (a1), (a3)/(a1), in the granulated product is from 0.0001 to 0.5;
<8> A method for manufacturing a tablet, comprising a tableting step of mixing a granulated product comprising the following ingredients (a1), (a2), (a3), and (a4) and an additive and tableting the resulting mixture:
(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; and
<9> The manufacturing method according to <8>, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, and crospovidone.

According to the manufacturing method of the present invention, a tablet having excellent dissolution of ibuprofen and a good color tone can be manufactured. The solid preparation of the present invention has excellent dissolution of ibuprofen and also a good color tone.

Detailed Description of Invention

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods, and materials are now described.

As used herein the term “good color tone” refers to a color tone that is acceptable for the commercial sale of ibuprofen without including an additional colorant in the preparation.

It is noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation.

Throughout
the description and claims of this specification, the words “comprise” and
“contain” and variations of the words, for example “comprising” and
“comprises,” mean “including but not limited to,” and are not intended to (and
do not) exclude other components.

As used
herein, the term “consisting of” excludes any element, step, or ingredient not
specified in the claim element.

Ranges: throughout this
disclosure, various aspects of the invention can be presented in a range
format. It should be understood that the description in range format is merely
for convenience and brevity and should not be construed as an inflexible
limitation on the scope of the invention. Accordingly, the description of
a range should be considered to have specifically disclosed all the possible
subranges as well as individual numerical values within that range. For
example, description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1
to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers
within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This
applies regardless of the breadth of the range.

(Solid preparation)
The solid preparation of the
present invention comprises a granulated product containing the above-mentioned
ingredients: (a1) ibuprofen or a salt thereof or a
solvate thereof; (a2) magnesium oxide: (a3) sodium lauryl sulfate; and (a4) one or more disintegrating agents. The
ingredients (a1) to (a4) contained in the granulated product are described
below.

(Ingredient (a1) - ibuprofen or a salt thereof or a solvate thereof)
Examples of ibuprofen or a salt thereof or a solvate thereof include ibuprofen; alkali metal salts of ibuprofen, such as ibuprofen sodium and ibuprofen potassium; and hydrates and alcohol adducts thereof.

The ibuprofen or a salt thereof or a solvate thereof is preferably in a powder form. The powder preferably has a mean particle size of from 5 to 75 μm and more preferably from 15 to 60 μm. The mean particle size of a powder can be measured by a laser diffraction method.

The ibuprofen or a salt thereof or a solvate thereof can be manufactured by a known method. Alternatively, a commercial product may be used.

The content of ibuprofen or a salt thereof or a solvate thereof in the granulated product is preferably from 5 to 70 mass%, more preferably from 15 to 55 mass%, further preferably from 25 to 50 mass%, and particularly preferably from 30 to 45 mass% based on the total mass of the granulated product from the viewpoint of the dissolution of ibuprofen, the manufacturability at the time of tableting, etc.

(Ingredient (a2) － magnesium oxide)
The magnesium oxide may be heavy magnesium oxide or may be light magnesium oxide. Although the particle size, the specific volume, etc., of the magnesium oxide are not particularly limited, the specific volume is preferably from 1 to 12 mL/g and more preferably from 2 to 10 mL/g.

The
magnesium oxide can be manufactured by a known method. Alternatively, a
commercial product may be used.

The
content of magnesium oxide in the granulated product is preferably from 5 to 30
mass%, more preferably from 7.5 to 27.5 mass%, further preferably from 12.5 to
25 mass%, and particularly preferably from 15 to 25 mass% based on the total
mass of the granulated product from the viewpoint of immediate effectiveness,
reduction in unpleasant taste, color tone, etc.

The
mass ratio of the ingredient (a2) to the ingredient (a1), (a2)/(a1), in the
granulated product is preferably from 0.3 to 0.7 from the viewpoint of
immediate effectiveness, reduction in unpleasant taste, color tone, etc.

(Ingredient (a3) － sodium lauryl sulfate)
Sodium lauryl sulfate is an anionic surfactant of formula: CH₃(CH₂)₁₁OS(=O)₂O^-Na⁺. The dissolution of ibuprofen is improved by adding sodium lauryl sulfate in the granulated product.

Sodium lauryl sulfate can be manufactured by a known method. Alternatively, a commercial product may be used.

The content of sodium lauryl sulfate in the granulated product is preferably from 0.005 to 12.5 mass%, more preferably from 0.01 to 10 mass%, further preferably from 0.05 to 7.5 mass%, further preferably from 0.1 to 5 mass%, and particularly preferably from 0.3 to 3 mass% based on the total mass of the granulated product from the viewpoint of the dissolution of ibuprofen, formability, granulation, etc.

When the content of sodium lauryl sulfate in the granulated product is 0.1 mass% or more or 0.3 mass% or more and 10 mass% or less, 5 mass% or less, or 3 mass% or less, the dissolution of ibuprofen is particularly improved.

The mass ratio of the ingredient (a3) to the ingredient (a1), (a3)/(a1), in the granulated product is preferably from 0.0001 to 0.5, more preferably from 0.0005 to 0.4, further preferably from 0.001 to 0.25, further preferably from 0.001 to 0.2, and particularly preferably from 0.01 to 0.1 from the viewpoint of the dissolution of ibuprofen, formability, granulation properties, etc.

When the mass ratio (a3)/(a1) is 0.01 or more and 0.2 or less or 0.1 or less, the dissolution of ibuprofen is particularly improved.

(Ingredient (a4) － on or more disintegrating agents)
The solid preparation of the present invention contains one or more disintegrating agents (a4) selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, carmellose calcium, crospovidone, and croscarmellose sodium in the granulated product. When the ingredient (a4) is added to the granulated product, not only the disintegration of the solid preparation and the dissolution of ibuprofen but also the color tone of the solid preparation is improved. As described in Patent Literature 2 (JP-A-2014-141518), it has been generally inferred that when a poorly water soluble drug such as ibuprofen is granulated together with a basic compound and a disintegrating agent, the granulated product itself disintegrates to disperse the basic compound from the vicinity of the poorly water soluble drug, and thereby an environment suitable for dissolution of the poorly water soluble drug is lost at the time of disintegration; in the present invention, nonetheless, entirely unexpectedly, the dissolution of ibuprofen is improved as described above.

As used herein, the term “low substituted hydroxypropylcellulose” refers to the low substituted hydroxypropylcellulose described in The Japanese Pharmacopoeia Seventeenth Edition, specifically, hydroxypropylcellulose with from 5.0% to 16.0% of a hydroxypropoxy group quantified when dried. The content of the hydroxypropoxy group is preferably from 6 to 13 mass% and particularly preferably from 7 to 11 mass%.

The low substituted hydroxypropylcellulose can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of commercial products of the low substituted hydroxypropylcellulose 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., L-HPC (LH32) manufactured by Shin-Etsu Chemical Co., Ltd., and L-HPC (NBD-020) manufactured by Shin-Etsu Chemical Co., Ltd.

As used herein, the term “sodium carboxymethyl starch” refers to the sodium starch glycolate described in The Japanese Pharmacopoeia Seventeenth Edition, specifically, a sodium salt of carboxymethyl ether of starch or a crosslinked product thereof, including from 2.8% to 4.2% or from 2.0% to 3.4% of sodium quantified when ethanol (99.5)/water mixture solution (8:2) insoluble matter is dried.

The sodium carboxymethyl starch can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of commercial products of the sodium carboxymethyl starch include Primojel (manufactured by DMV), EXPLOTAB (manufactured by Kimura Sangyo Co., Ltd.), and GLYCOLYS (manufactured by Roquette Japan KK).

The term “carmellose” refers to the carmellose described in The Japanese Pharmacopoeia Seventeenth Edition, specifically, partially O-carboxymethylated cellulose. The carmellose can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of commercial products of the carmellose include NS-300 (manufactured by Gotoku Chemical Co., Ltd.).

The term “carmellose calcium” refers to the carmellose calcium described in The Japanese Pharmacopoeia Seventeenth Edition, specifically, a calcium salt of multivalent carboxymethyl ether of cellulose. The carmellose calcium can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of commercial products of the carmellose calcium include E.C.G-505 (manufactured by Gotoku Chemical Co., Ltd.).

Crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone. The crospovidone is preferably crospovidone with from 11.0% to 12.8% of nitrogen quantified when dried, as described in The Japanese Pharmacopoeia Seventeenth Edition. The crospovidone usually has a mean particle size (D50%) of from 3 to 140 μm. Crospovidone may be crospovidone type A or crospovidone type B defined in The Japanese Pharmacopoeia Seventeenth Edition.

The crospovidone can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of the commercial products of crospovidone include Kollidon CL, Kollidon CL-F, and Kollidon CL-SF (the above manufactured by BASF Japan Ltd.), Polyplasdone (manufactured by ISP Japan Ltd.), and Crospovidone (manufactured by DSP GOKYO FOOD & CHEMICAL Co., Ltd.).

The term “croscarmellose sodium” refers to the croscarmellose sodium described in The Japanese Pharmacopoeia Seventeenth Edition, specifically, a sodium salt of a crosslinked product of multivalent carboxymethyl ether of cellulose. The croscarmellose sodium can be manufactured by a known method. Alternatively, a commercial product may be used. Examples of commercial products of the croscarmellose sodium include Primellose-300 (manufactured by DMV), Ac-Di-Sol (manufactured by DuPont de Nemours, Inc.), and Kiccolate (manufactured by Asahi Kasei Corporation).

As the ingredient (a4), from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, and the color tone of the solid preparation, low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, and crospovidone are preferred, low substituted hydroxypropylcellulose, sodium carboxymethyl starch, and crospovidone are more preferred, low substituted hydroxypropylcellulose and sodium carboxymethyl starch are further preferred, and low substituted hydroxypropylcellulose is particularly preferred.

The content of the ingredient (a4) in the granulated product is preferably from 3 to 55 mass%, more preferably from 10 to 50 mass%, further preferably from 15 to 45 mass%, and particularly preferably from 20 to 40 mass% based on the total mass of the granulated product from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, the color tone of the solid preparation, etc.

The mass ratio of the ingredient (a4) to the ingredient (a1), (a4)/(a1), in the granulated product is preferably from 0.05 to 2, more preferably from 0.1 to 1.5, further preferably from 0.3 to 1.2, and particularly preferably from 0.6 to 1 from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, the color tone of the solid preparation, etc.

When the mass ratio (a4)/(a1) is 0.3 or more or 0.6 or more, the dissolution of ibuprofen is particularly improved.

In certain embodiments of the invention, any combination of (a1), (a2), (a3), and (a4) may be used in any of the amounts provided. In other embodiments, the granulated product has at least ingredients (a1), (a2), (a3), (a4) as described above in any of the amounts for the ingredient identified in the Table below or any mass ratio identified in the Table below:

(Additional drugs in granulated product)
The granulated product may include a drug other than the ingredients (a1) and (a2), in addition to the ingredients (a1) to (a4).

Examples of the drug other than the ingredients (a1) and (a2) include one or more drugs selected from the group consisting of caffeines (a5) and sedative-hypnotics (a6) and further include a drug (hereinafter, also referred to as other drug) other than these ingredients (a1), (a2), (a5), and (a6).

(Ingredient (a5) － caffeines)
Examples of the caffeines include caffeine hydrate, anhydrous caffeine, and caffeine and sodium benzoate. One of them may be used alone, or a combination of two or more of them may be used.

The content of the caffeines in the granulated product is preferably from 0 to 25 mass%, more preferably from 0 to 20 mass%, further preferably from 0 to 17.5 mass%, and particularly preferably from 0 to 15 mass% based on the total mass of the granulated product.

(Ingredient (a6) － sedative hypnotic)
Examples of the sedative-hypnotic include allylisopropylacetylurea and bromovalerylurea. One of them may be used alone, or a combination of the two may be used.

The content of the sedative-hypnotic in the granulated product is preferably from 0 to 20 mass%, more preferably from 0 to 17.5 mass%, further preferably from 0 to 15 mass%, and particularly preferably from 0 to 12.5 mass% based on the total mass of the granulated product.

(Additional drugs that may be used in combination with ibuprofen)
Examples of the other drug include an anti-inflammatory agent other than the ingredient (a1), an antacid agent other than the ingredient (a2), an antitussive agent, an antihistamine agent, an antiallergic agent, an anticholinergic agent, vitamins, a muscle relaxant agent, and crude drugs. One of them may be used alone, or a combination of two or more of them may be used.

Examples of the anti-inflammatory agent other than the ingredient (a1) include glycyrrhizic acid and a salt thereof, tranexamic acid, glycyrrhetinic acid, sodium azulene sulfonate, aspirin, and salicylamide. One of them may be used alone, or a combination of two or more of them may be used.

The content of the anti-inflammatory agent other than the ingredient (a1) in the granulated product is usually from 0 to 30 mass%, preferably from 0 to 10 mass%, and more preferably from 0 to 0.1 mass% based on the total mass of the granulated product.

Examples of the antacid agent other than the ingredient (a2) include sodium hydrogen carbonate, precipitated calcium carbonate, calcium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-sodium hydrogen carbonate coprecipitation product, aluminum hydroxide-magnesium carbonate mixture dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitation product, magnesium hydroxide-aluminum potassium sulfate coprecipitation product, glycine, magnesium silicate, dihydroxyaluminum aminoacetate, and magnesium carbonate. One of them may be used alone, or a combination of two or more of them may be used.

The content of the antacid agent other than the ingredient (a2) in the granulated product is preferably from 0 to 5 mass%, more preferably from 0 to 1 mass%, further preferably from 0 to 0.1 mass%, further preferably from 0 to 0.01 mass%, and particularly preferably 0 mass% based on the total mass of the granulated product.

Examples of the antitussive agent include ambroxol hydrochloride, L-ethylcysteine hydrochloride, potassium guaiacolsulfonate, potassium cresolsulfonate, guaifenesin, bromhexine hydrochloride, L-carbocisteine, codeine phosphate hydrate, dihydrocodeine phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalinate, dimemorfan phosphate, noscapine, noscapine hydrochloride hydrate, dl-methylephedrine hydrochloride, and dl-methylephedrine saccharin salt. One of them may be used alone, or a combination of two or more of them may be used.

The content of the antitussive agent in the granulated product is usually from 0 to 30 mass%, preferably from 0 to 10 mass%, and particularly preferably from 0 to 0.1 mass% based on the total mass of the granulated product.

Examples of the antihistamine agent or the antiallergic agent include mequitazine, azelastine hydrochloride, fexofenadine hydrochloride, epinastine hydrochloride, loratadine, cetirizine hydrochloride, olopatadine hydrochloride, alimemazine tartrate, carbinoxamine maleate, clemastine fumarate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, and diphenhydramine hydrochloride. One of them may be used alone, or a combination of two or more of them may be used.

Examples of the anticholinergic agent include isopropamide iodide, scopolia extract, scopolia root, belladonna total alkaloid, scopolamine hydrobromide, butylscopolamine bromide, methylbenactyzium bromide, timepidium bromide, and pirenzepine. One of them may be used alone, or a combination of two or more of them may be used.

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

Examples of the muscle relaxant agent include methocarbamol, chlorzoxazone, pridinol mesylate, chlorphenesin carbamate, eperisone hydrochloride, afloqualone, and tizanidine hydrochloride. One of them may be used alone, or a combination of two or more of them may be used.

Examples of the crude drugs include ziryu (Oligochaeta), Cinnamon Bark (Cinnamomi Cortex), Glycyrrhiza (Glycyrrhizae Radix), Peony Root (Paeoniae Radix), Mountan Bark (Moutan Cortex), Citrus Unshiu Peel (Aurantii Nobilis Pericarpium), Ginger (Zingiberis Rhizoma), Zanthoxylum Fruit (Zanthoxyli Fructus), Platycodon Root (Platycodi Radix), Ephedra Herb (Ephedrae Herba), Apricot Kernel (Armeniacae Semen), Pinellia Tuber (Pinelliae Tuber), Plantago Seed (Plantago Seed), Senega (Senegaea Radix), Bupleurum Root (Bupleuri Radix), and Magnolia Flower (Magnolia Flos). One of them may be used alone, or a combination of two or more of them may be used.

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

(Additional pharmaceutical additive)
Furthermore, the granulated product may include a pharmaceutical additive other than the ingredients (a3) and (a4).

Examples of the pharmaceutical additive other than the ingredients (a3) and (a4) include surfactants other than the ingredient (a3), such as sucrose fatty acid ester and polyoxyethylene polyoxypropylene glycol; disintegrating agents other than the ingredient (a4), such as alginic acid, bentonite, and partly pregelatinized starch; excipients, such as corn starch, crystalline cellulose, lactose, lactose hydrate, saccharose, glucose, mannitol, sorbitol, and xylitol; and binders, such as gelatin, sodium alginate, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and carmellose sodium. One of them may be used alone, or a combination of two or more of them may be used. Furthermore, a solubilizing agent, a buffering agent, a preservative, and the like can be used as needed.

The total content of the pharmaceutical additives other than the ingredients (a3) and (a4) in the granulated product is usually from 0 to 40 mass%, preferably from 0 to 30 mass%, more preferably from 0 to 25 mass%, further preferably from 0 to 0.01 mass%, and particularly preferably 0 mass% based on the total mass of the granulated product.

The granulated product is preferably in a granular form. The mean particle size of the granulated product is usually from 100 to 1,000 μm and preferably from 150 to 710 μm. The mean particle size can be measured by a sieving method.

Examples of the dosage form of the solid preparation of the present invention include a granule, a fine granule, a powder, a tablet, a pill, a capsule, and a dry syrup. A granule, a tablet, and a capsule are preferred are, and a tablet is particularly preferred. The solid preparation of the present invention has excellent dissolution of ibuprofen even when the dosage form is a tablet.

Specifically, examples of the tablet include an uncoated tablet, a film-coated tablet, a sugar-coated tablet, an orally disintegrating tablet, and a chewable tablet. From the viewpoint of the disintegration of the tablet, the dissolution of ibuprofen, easy to take, etc., an uncoated tablet, a film-coated tablet, and an orally disintegrating tablet are preferred. In addition, the solid preparation of the present invention has a good color tone even when the dosage form is an uncoated tablet or an orally disintegrating tablet. In addition, the color tone is good even in a solid preparation of a non-coated type.

(Additive Layer)
Although the solid preparation of the present invention may consist of the granulated product or may comprise the granulated product and an ingredient (an additive layer and a film coating layer) other than the granulated product, preferred is a solid preparation comprising an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product contains the ingredients (a1) to (a4) (herein, this solid preparation may also be referred to as “solid preparation (α)”), and particularly preferred is a tablet comprising an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product contains the ingredients (a1) to (a4), from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, and the color tone of the solid preparation.

The granulated product included in the solid preparation (α) may be at least partially dispersed in the additive layer, and a plurality of particles of the granulated product in the additive layer may be in contact with each other, as long as at least a part of the granulated product is dispersed in the additive layer.

The solid preparation (α) includes an additive layer in addition to the granulated product. The additive layer is preferably in a solid state.

The additive layer preferably contains a lubricant (b1) from the viewpoint of the tableting properties, the filling properties, etc.

(Ingredient (b1) － lubricants in additive layer)
Examples of the lubricant include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, and glycerin fatty acid ester. One of them may be used alone, or a combination of two or more of them may be used.

The content of the ingredient (b1) in the additive layer is preferably from 0.5 to 100 mass%, more preferably from 0.75 to 95 mass%, further preferably from 1 to 90 mass%, and particularly preferably from 2 to 85 mass% based on the total mass of the additive layer from the viewpoint of the tableting properties, the filling properties, etc.

The additive layer preferably further contains one or more selected from the group consisting of a disintegrating agent (b2) and an excipient (b3), in addition to the above-mentioned ingredient (b1), from the viewpoint of the dissolution of ibuprofen, disintegration, fluidity, etc.

(Ingredient (b2) － disintegrating agents in additive layer)
Examples of the disintegrating agent include crospovidone, carmellose calcium, low substituted hydroxypropylcellulose, and sodium carboxymethyl starch, croscarmellose sodium. One of them may be used alone, or a combination of two or more of them may be used. Incidentally, examples of the crospovidone, the carmellose calcium, the low substituted hydroxypropylcellulose, the sodium carboxymethyl starch, and the croscarmellose sodium include those mentioned as the ingredient (a4).

Among these examples, from the viewpoint of the disintegration of the solid preparation and the dissolution of ibuprofen, crospovidone, sodium carboxymethyl starch, and croscarmellose sodium are preferred, and crospovidone is more preferred.

The content of the ingredient (b2) in the additive layer is preferably from 0 to 50 mass%, more preferably from 0 to 40 mass%, further preferably from 0 to 35 mass%, and particularly preferably from 0 to 30 mass% based on the total mass of the additive layer from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, the formability, the manufacturability at the time of tableting, etc.

The mass ratio of the ingredient (b2) in the additive layer to the ingredient (a1), (b2)/(a1), in the granulated product is preferably from 0 to 0.8, more preferably from 0.05 to 0.6, further preferably from 0.075 to 0.4, and particularly preferably from 0.1 to 0.2 from the viewpoint of the disintegration of the solid preparation and the dissolution of ibuprofen, etc.

The mass ratio of the ingredient (b2) in the additive layer to the ingredient (a4), (b2)/(a4), in the granulated product is preferably from 0 to 0.8, more preferably from 0.05 to 0.6, further preferably from 0.075 to 0.4, and particularly preferably from 0.1 to 0.3 from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, etc.

(Ingredient (b3) － excipients in the additive layer)
Examples of the excipient include corn starch, crystalline cellulose, lactose, lactose hydrate, saccharose, glucose, mannitol, sorbitol, and xylitol. One of them may be used alone, or a combination of two or more of them may be used. Among these excipients, crystalline cellulose, corn starch, and mannitol are preferred.

The content of the ingredient (b3) in the additive layer is preferably from 0 to 95 mass%, more preferably from 5 to 95 mass%, further preferably from 10 to 95 mass%, and particular preferably from 15 to 95 mass% based on the total mass of the additive layer from the viewpoint of the disintegration of the solid preparation, formability, etc.

(Ingredient (b4) in the additive layer － glidants)
The additive layer may further include a glidant (b4) in addition to the ingredients (b1) to (b3).
Examples of the glidant include light anhydrous silicic acid and hydrated silicon dioxide. One of them may be used alone, or a combination of two or more of them may be used.

The content of the ingredient (b4) in the additive layer is preferably from 0 to 15 mass%, more preferably from 0 to 10 mass%, further preferably from 0 to 7.5 mass%, and particularly preferably from 0 to 5 mass% based on the total mass of the additive layer.

(Additional pharmaceutical additives in additive layer)
Furthermore, the additive layer may include a pharmaceutical additive other than the ingredients (b1) to (b4).

Examples of the pharmaceutical additive other than the ingredients (b1) to (b4) include surfactants, such as sodium lauryl sulfate, sucrose fatty acid ester, and polyoxyethylene polyoxypropylene glycol. One of them may be used alone, or a combination of two or more of them may be used. Furthermore as needed, a solubilizing agent, a buffering agent, a preservative, a flavoring agent, a coloring matter, a sensitive sweetener, a corrigent, etc. can be used.

The total content of the pharmaceutical additive other than the ingredients (b1) to (b4) in the additive layer is usually from 0 to 30 mass%, preferably from 0 to 10 mass%, more preferably from 0 to 1 mass%, further preferably from 0 to 0.01 mass%, and particularly preferably 0 mass% based on the total mass of the additive layer.

The total content of the granulated product and the additive layer is preferably from 80 to 100 mass%, more preferably from 90 to 100 mass%, further preferably from 95 to 100 mass%, and particularly preferably from 99.9 to 100 mass% based on the total mass of the solid preparation (α). Preferably, the solid preparation of the present invention does not include phosphates, such as sodium dihydrogen phosphate, and clay minerals, such as smectite.

The mass ratio of the additive layer (B) to the granulated product (A), (B)/(A), in the solid preparation (α) is preferably from 0.001 to 1.5, more preferably from 0.005 to 1, further preferably from 0.0075 to 0.5, further preferably from 0.01 to 0.5, and particularly preferably from 0.1 to 0.3 from the viewpoint of the disintegration of the solid preparation, the dissolution of ibuprofen, the color tone of the solid preparation, formability, etc.

As the solid preparation (α), the additive layer is preferably the outermost layer. Also in such a case, the solid preparation of the present invention has a good color tone and can achieve both the dissolution of ibuprofen and a good color tone.

The solid preparation of the present invention is preferably for oral administration.

The dose of the solid preparation of the present invention is, as the dose of the ingredient (a1) in the free base of ibuprofen, preferably from 100 to 2,400 mg per day, more preferably from 120 to 1,200 mg per day, and particularly preferably from 390 to 1,200 mg per day. In addition, the dose is, as the dose of the ingredient (a1) in the free base of ibuprofen, preferably from 60 to 800 mg per dose, more preferably from 60 to 400 mg per dose, further preferably from 70 to 400 mg per dose, and particularly preferably from 130 to 400 mg per dose.

The solid preparation of the present invention has excellent dissolution of ibuprofen and also has a good color tone.

Accordingly, the solid preparation of the present invention can sufficiently show the anti-inflammatory and analgesic effects of ibuprofen and is significantly useful as, for example, an antipyretic analgesic, a general cold medicine, or a psychiatric drug.

(Method for manufacturing a tablet)
The solid preparation of the present invention can be manufactured by appropriately combining usual methods. When the dosage form is a tablet, the solid preparation may be manufactured by a method comprising a tableting step of mixing a granulated product containing the ingredients (a1), (a2), (a3), and (a4) and an additive and tableting the resulting mixture.

The granulated product can be obtained by a granulation step of granulating a composition (hereinafter, also referred to as composition X) containing the ingredients (a1) to (a4) and as needed, other ingredients (such as ingredients (a5) and (a6)) according to a known granulation method described in, for example, General Rules for Preparations of The Japanese Pharmacopoeia Seventeenth Edition. Incidentally, the order of blending the ingredients (a1) to (a4) into the composition X does not matter.

The composition X can be prepared by, for example, a procedure of mixing the ingredients (a1) to (a4) and as needed, other ingredients, or a procedure of mixing the ingredients (a1) to (a4) and as needed, other ingredients and kneading the resulting mixture with a solvent such as water or water-containing alcohol. Examples of the water-containing alcohol include a mixture solution of ethanol and/or isopropanol and water. The mixing and kneading are each preferably performed at from 20 to 1,200 rpm for from 0.5 to 10 minutes.

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

The additive is preferably in a solid form and more preferably in a powder form. The additive may include a pharmaceutical additive. Examples of the pharmaceutical additive are the same as those which may be included in the additive layer, and the pharmaceutical additive is preferably an additive including at least the ingredient (b1) and more preferably an additive including at least the ingredients (b1) to (b3).

Tableting in the tableting step may be performed according to a usual method using, for example, a rotary tableting machine or a single-shot tableting machine. The tableting pressure is usually from 3 to 15 kN. Prior to adding the additive, the granulated product may be dried and/or sized as needed.

Examples

The present invention will now be described in detail with Examples but is not limited to these Examples. The following examples are included to demonstrate embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

Examples 1 to 7 illustrate embodiments of the disclosure and Comparative Examples 1 to 6 are uncoated tablets.

(Manufacturing method)
Each ingredient was weighed according to each granule formulation shown in Table 1 and was put in a high speed stirring granulator (VG-10 model, manufactured by Powrex Corporation), followed by mixing for 3 minutes. Subsequently, an appropriate amount of purified water was added to the resulting mixture powder of the granule formulation ingredients, followed by kneading with a high speed stirring granulator (VG-10 model, manufactured by Powrex Corporation) for 3 minutes. The kneaded product was subjected to extrusion granulation with an extrusion granulator (Twin Dome Gran TDG-80A, manufactured by Dalton Co., Ltd.) to obtain wet granule A. Subsequently, the granule A was dried with a fluidized bed dryer (FLO-2, manufactured by Freund Corporation) to obtain dry granule B. Furthermore, sizing with a sizer (Comil QC-U10, manufactured by Powrex Corporation) was performed to obtain sized granule C.

The resulting granule C was mixed with the additives shown in Table 1 at the time of mixing, followed by tableting with a rotary tableting machine (VIRG 0512 model, manufactured by Kikusui Seisakusyo Ltd.) at a tableting pressure of 4.5 kN to obtain uncoated tablets of Examples 1 to 7 and Comparative Examples 1 to 6 (the mass per four tablets (daily dose): 1,000 mg).

(Measuring method and evaluation method)
(1) Ibuprofen dissolution
McIlvaine buffer was diluted with a purified water to obtain 900 mL of a liquid with pH 4.0, and one uncoated tablet of Example 1 was added to this liquid, followed by paddle rotating at 37°C at 50 rpm. After 15 minutes from the start of paddle rotating, the ibuprofen dissolution rate from the uncoated tablet of Example 1 was measured.

The dissolution amount of ibuprofen was measured by high performance liquid chromatography (HPLC), and the ibuprofen dissolution rate was calculated from the dissolution amount by the following expression (α):

(HPLC measurement condition)
Column: a stainless steel tube with an inner diameter of 3.0 mm and a length of 5 cm filled with 3 μm octadecyl silylated silica gel for liquid chromatography

Detector: ultraviolet absorptiometer (measurement wavelength: 210 nm)

Mobile phase: diluted phosphoric acid (1 → 1,000)/acetonitrile mixture solution

The dissolution rates of ibuprofen from the uncoated tablets of Examples 2 to 7 and Comparative Examples 1 to 6 were similarly measured.

The results are shown in Table 1. As shown in Table 1, a larger dissolution rate after 15 minutes means better dissolution of ibuprofen.
(2) Color tone

Each granule (sized granule C) and the uncoated tablet immediately after manufacturing were visually verified for the color tone of the surface and were evaluated by the following criteria. The results are shown in Table 1.

Evaluation criteria for color tone of granule:
-: no change in color from white to grayish white;
+: slight change in color from white to grayish white; and
++: change in color from white to grayish white.

Evaluation criteria for color tone of tablet:
-: no dark spots;
+: a few dark spots; and
++: a large number of dark spots.

The signs in Table 1 indicate the followings, respectively.
*1: ibuprofen 25, manufactured by BASF SE;
*2: heavy type, manufactured by Kyowa Chemical Industry Co., Ltd.
*3: Kolliphor SLS Fine, manufactured by BASF SE;
*4: L-HPC (LH31), manufactured by Shin-Etsu Chemical Co., Ltd.;
*5: Kollidon CL-F (crospovidone type A), manufactured by BASF SE;
*6: Primojel, manufactured by DFE Pharma GmbH & Co KG;
*7: NS-300, manufactured by Gotoku Chemical Co., Ltd.;
*8: Pharmatose 200M, manufactured by DFE Pharma GmbH & Co KG;
*9: VIVAPUR 105, manufactured by JRS Pharma Company;
*10: MICRO ACE P-3, manufactured by NIPPON TALC Co., Ltd.; and
*11: magnesium stearate (vegetable), manufactured by Taihei Chemical Industrial Co., Ltd.

(Preparation Examples 1 and 2: granule)
Each ingredient was weighed according to granule formulation shown in Table 2 and was put in a high speed stirring granulator (VG-25 model, manufactured by Powrex Corporation), followed by mixing for 3 minutes. Subsequently, purified water was added thereto, followed by kneading with a high speed stirring granulator (VG-25 model, manufactured by Powrex Corporation) for 3 minutes. The kneaded product was subjected to extrusion granulation with an extrusion granulator (TDG-80A model, manufactured by Dalton Co., Ltd.). Furthermore, the resulting extruded granules were put in and dried with a fluidized bed dryer (FLO-5 model, manufactured by Freund Corporation) and were then sized with a granulator (Comil QC-U10) to obtain granules of Preparation Example 1 and Preparation Example 2.

(Preparation Example 3: hard capsule)
Magnesium stearate (2.8 g) was added to the granule (910 g) obtained in Preparation Example 1, followed by mixing with a V type mixer (TCV-5 model, manufactured by Tokuju Corporation) to obtain a mixture powder (912.8 g). The mixture powder was filled in gelatin capsules to obtain hard capsules (capsule content mass: 326 mg corresponding to an ibuprofen content of 100 mg) of Preparation Example 3.

(Preparation Example 4: film-coated tablet)
Crystalline cellulose (297.6 g), crospovidone (38.4 g), light anhydrous silicic acid (9.6 g), and magnesium stearate (14.4 g) were each added to the granule (1,560 g) obtained in Preparation Example 1, followed by mixing with a V type mixer (TCV-10 model, manufactured by Tokuju Corporation) to obtain a tableting powder (1,920 g). Subsequently, tableting was performed with a rotary tableting machine (VIRG 0512 model, manufactured by Kikusui Seisakusyo Ltd.) to manufacture uncoated tablets having a diameter of 9.5 mm and a tablet mass of 400 mg (ibuprofen content: 100 mg).

Subsequently, hypromellose (120 g) and macrogol 6000 (20 g) were dissolved in purified water, and talc (10 g) and titanium oxide (10 g) were dispersed therein to prepare a film coating solution (2,000 g) having a solid concentration of 8%. Subsequently, the uncoated tablets (500 g) were put in a coater (HC-LABO model, manufactured by Freund Corporation), and the prepared film coating solution was sprayed to perform coating to obtain film-coated tablets (tablet mass: 412 mg, white) of Preparation Example 4.

(Preparation Example 5: orally disintegrating tablet)
Crystalline cellulose (425.6 g), corn starch (400 g), acesulfame potassium (28.8 g), aspartame (28.8 g), light anhydrous silicic acid (14.4 g), and magnesium stearate (14.4 g) were added to the granules (2,064 g) obtained in Preparation Example 2, followed by mixing with a V type mixer (TCV-10 model, manufactured by Tokuju Corporation) to obtain a tableting powder (2,976 g). Subsequently, tableting was performed with a rotary tableting machine (VIRG 0512 model, manufactured by Kikusui Seisakusyo Ltd.) to obtain orally disintegrating tablet having a diameter of 12 mm and a tablet mass of 620 mg (ibuprofen content: 150 mg).

(Illustrative Embodiments)
Provided here are illustrative embodiments of the disclosed technology. These embodiments are illustrative only and do not limit the scope of the present disclosure or of the claims attached.

Embodiment 1.
A solid preparation comprising a granulated product comprising 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, croscarmellose sodium, and combinations thereof.

Embodiment 2.
The solid preparation according to Embodiment 1, wherein a dosage form is a granule, a fine granule, a powder, a tablet, a pill, a capsule, or a dry syrup.

Embodiment 3.
A solid preparation comprising an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product comprises 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, croscarmellose sodium, and combinations thereof.

Embodiment 4.
The solid preparation according to Embodiment 3, wherein a mass ratio of the additive layer (B) to the granulated product (A), (B)/(A), is from 0.001 to 1.5.

Embodiment 5.
The solid preparation according to Embodiment 3 or 4, wherein the solid preparation is a tablet.

Embodiment 6.
The solid preparation according to any one of Embodiments 1 to 5, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, crospovidone, and combinations thereof.

Embodiment 7.
The solid preparation according to any one of Embodiments 1 to 6, wherein a mass ratio of the ingredient (a3) to the ingredient (a1), (a3)/(a1), in the granulated product is from 0.0001 to 0.5.

Embodiment 8.
The solid preparation according to any one of Embodiments 1-7, wherein the granulated product comprises from 5 to 70 mass% of (a1), from 5 to 30 mass% of (a2), from 0.005 to 12.5 mass% of (a3), and from 3 to 55 mass% of (a4) based on the total mass of the granulated product.

Embodiment 9.
The solid preparation according to any one of Embodiments 1-7, wherein the granulated product comprises from 30 to 45 mass% of (a1), from 15 to 25 mass% of (a2), from 0.3 to 3 mass% of (a3), from 20 to 40 mass% of (a4) based on the total mass of the granulated product.

Embodiment 10.
The solid preparation according to any one of Embodiments 1-9, wherein: (a) a mass ratio of (a2) to (a1), (a2)/(a1) in the granulated product is from 0.3 to 0.7; (b) a mass ratio of (a3)/(a1) in the granulated product is 0.01 or more; and (c) a mass ratio of (a4) to (a1), (a4)/(a1) in the granulated product is from 0.3 to 1.2.

Embodiment 11.
A method for manufacturing a tablet, comprising a tableting step of mixing a granulates product comprising following ingredients (a1), (a2), (a3), and (a4) and an additive and tableting a resulting mixture: (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, croscarmellose sodium, and a combination thereof.

Embodiment 12.
The manufacturing method according to Embodiment 11, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, crospovidone, and a combination thereof.

Embodiment 13.
The manufacturing method of clams 11 or 12, wherein the granulated product comprises from 5 to 70 mass% of (a1), from 5 to 30 mass% of (a2), from 0.005 to 12.5 mass% of (a3), and from 3 to 55 mass% of (a4) based on the total mass of the granulated product.

Embodiment 14.
The manufacturing method of embodiments 11 or 12, wherein the granulated product comprises from 30 to 45 mass% of (a1), from 15 to 25 mass% of (a2), from 0.3 to 3 mass% of (a3), from 20 to 40 mass% of (a4) based on the total mass of the granulated product.

While the invention has been described and illustrated herein by references to various specific materials, procedures, and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

A solid preparation comprising a granulated product comprising 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, croscarmellose sodium, and combinations thereof.
The solid preparation according to Claim 1, wherein a dosage form is a granule, a fine granule, a powder, a tablet, a pill, a capsule, or a dry syrup.
A solid preparation comprising an additive layer and a granulated product dispersed in the additive layer, wherein the granulated product comprises 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, croscarmellose sodium, and combinations thereof.
The solid preparation according to Claim 3, wherein a mass ratio of the additive layer (B) to the granulated product (A), (B)/(A), is from 0.001 to 1.5.
The solid preparation according to Claim 3 or 4, wherein the solid preparation is a tablet.
The solid preparation according to any one of Claims 1 to 5, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, crospovidone, and combinations thereof.
The solid preparation according to any one of Claims 1 to 6, wherein a mass ratio of the ingredient (a3) to the ingredient (a1), (a3)/(a1), in the granulated product is from 0.0001 to 0.5.
The solid preparation according to any one of Claims 1-7, wherein the granulated product comprises from 5 to 70 mass% of (a1), from 5 to 30 mass% of (a2), from 0.005 to 12.5 mass% of (a3), and from 3 to 55 mass% of (a4) based on the total mass of the granulated product.
The solid preparation according to any one of Claims 1-7, wherein the granulated product comprises from 30 to 45 mass% of (a1), from 15 to 25 mass% of (a2), from 0.3 to 3 mass% of (a3), from 20 to 40 mass% of (a4) based on the total mass of the granulated product.
The solid preparation according to any one of Claims 1-9, wherein:
(a) a mass ratio of (a2) to (a1), (a2)/(a1) in the granulated product is from 0.3 to 0.7;
(b) a mass ratio of (a3)/(a1) in the granulated product is 0.01 or more; and
(c) a mass ratio of (a4) to (a1), (a4)/(a1) in the granulated product is from 0.3 to 1.2.
A method for manufacturing a tablet, comprising a tableting step of mixing a granulates product comprising following ingredients (a1), (a2), (a3), and (a4) and an additive and tableting a resulting mixture:
(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, croscarmellose sodium, and a combination thereof.
The manufacturing method according to Claim 11, wherein the ingredient (a4) is one or more disintegrating agents selected from the group consisting of low substituted hydroxypropylcellulose, sodium carboxymethyl starch, carmellose, crospovidone, and a combination thereof.
The manufacturing method of clams 11 or 12, wherein the granulated product comprises from 5 to 70 mass% of (a1), from 5 to 30 mass% of (a2), from 0.005 to 12.5 mass% of (a3), and from 3 to 55 mass% of (a4) based on the total mass of the granulated product.
The manufacturing method of claims 11 or 12, wherein the granulated product comprises from 30 to 45 mass% of (a1), from 15 to 25 mass% of (a2), from 0.3 to 3 mass% of (a3), from 20 to 40 mass% of (a4) based on the total mass of the granulated product.