JP2019081757A - Method for producing solid preparation - Google Patents

Abstract

To provide a method for producing a solid preparation containing ibuprofen and other medicinal components, solving a poor appearance such as pestle attachment.SOLUTION: The present invention provides a method for producing a solid preparation containing two or more medicinal components including ibuprofen, having the steps of (i) agitating and granulating ibuprofen as a separate group from other medicinal components, and (ii) blending a fumarate or an ester thereof or a salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a solid preparation containing two or more medicinal ingredients containing ibuprofen.

Among the medicinal components of the pharmaceutical preparation, many medicinal components having adhesiveness on the surface of chewing at the time of tableting, it is known that, in a preparation in which those medicinal components are blended, vaginal adhesion occurs at the time of tableting.
Sticking on the tablet refers to sticking of a pharmaceutically effective ingredient and tableting powder on the tableting surface of the tablet during tableting, thereby causing appearance defects such as unevenness on the surface of the tablet. Such uncoated tablets remain uneven even when coated, and therefore, there is a problem of a reduction in the commercial value as a pharmaceutical preparation.
In addition, since the adhesion of a medicinal active ingredient to soot also leads to a decrease in the content of the ingredient, it causes problems not only in the reduction of the commercial value due to the appearance defect but also in the deterioration of the quality as a pharmaceutical preparation.

Ibuprofen is widely used as an antipyretic analgesic, and is also widely used as one component of general cold medicine in combination with various medicinal ingredients such as anti-inflammatory agents.
On the other hand, since ibuprofen is a low melting point substance, it is known that the melting point depression is caused by the combination with various active ingredients, which causes adhesion of soot and poor fluidity of granulated material.
Adhesion of wrinkles and poor fluidity of the granulated product are serious problems leading not only to a reduction in commercial value due to a poor appearance, and to a reduction in quality due to a reduction in content but also to a reduction in productivity in the manufacturing process of a preparation.

  As a technique for preventing adhesion of a ibuprofen-containing preparation, for example, Patent Document 1 discloses that in a pharmaceutical preparation containing ibuprofen, ibuprofen bulk powder is directly coated with a coating composition containing a plasticizer to form granules. There is disclosed a technique of mixing and adding the granules to tableted powder for tablet preparation.

JP 2007-169273

  In the present invention, the appearance is poor such as adhesion of wrinkles, the quality is deteriorated such as content reduction, etc. due to the combination of ibuprofen and various medicinal components by a simple and usually used method without using a special preparation. The purpose of the present invention is to provide a method for producing a solid preparation containing two or more pharmaceutically active ingredients including ibuprofen, in which the fluidity of the granulated material is reduced and the productivity is decreased in the production process associated therewith. Do.

As a result of intensive investigations, the present inventor (i) stir-granulates ibuprofen in a group separate from other medicinal components in the process of producing a solid preparation containing two or more medicinal components including ibuprofen, (ii) By mix | blending fumaric acid or its ester, or those salts, it discovers that the appearance defect, such as adhesion of an eyebrows, the fluidity defect of a granulated product, etc. are improved, and came to complete this invention.
That is, the present invention includes the following aspects.
[1] A method for producing a solid preparation containing two or more medicinal ingredients containing ibuprofen, which method comprises:
(I) stirring and granulating ibuprofen separately from other medicinal ingredients;
(Ii) A method for producing a solid preparation, comprising the step of blending fumaric acid or an ester thereof or a salt thereof.
[2] The method for producing a solid preparation according to [1], wherein the fumaric acid or ester thereof or a salt thereof is fumaric acid or stearyl sodium fumarate.
[3] The method for producing a solid preparation according to [1] or [2], wherein the other medicinal component is an anti-inflammatory agent.
[4] The method for producing a solid preparation according to [3], wherein the anti-inflammatory agent is one or more selected from the group consisting of lysozyme chloride, seraptase, tranexamic acid, and glycyrrhizinic acid or a salt thereof.
[5] The method for producing a solid preparation according to any one of [1] to [4], wherein the other medicinal component is ascorbic acid or a salt thereof.
[6] to [5], wherein the ascorbic acid or a salt thereof is at least one selected from the group consisting of ascorbic acid, sodium ascorbate, potassium ascorbate, calcium ascorbate, zinc ascorbate, and magnesium ascorbate The manufacturing method of the solid formulation as described.
[7] The method for producing a solid preparation according to [5] or [6], wherein the ascorbic acid or a salt thereof is granulated in a single group.

According to the present invention, in a solid preparation containing two or more pharmaceutically effective ingredients including ibuprofen, appearance defect such as adhesion of sputum, decrease in ibuprofen content, etc. Can be significantly improved, and productivity in the manufacturing process can be maintained high.
In addition, since ibuprofen is a low melting point substance, it is known that the melting point depression is caused by the combination with various pharmaceutically active ingredients, and it is known to cause adhesion of soot and poor fluidity of granulated products, according to the present invention. For example, ibuprofen can be granulated in a separate group from other active ingredients to alleviate contact between active ingredients in the preparation that causes such melting point depression.

It is the figure which showed the wrinkle adhesion generation | occurrence | production mechanism and example in the conventional solid preparation.

  The method for producing a solid preparation containing two or more medicinal ingredients containing ibuprofen according to the present invention comprises the steps of (i) stirring granulating ibuprofen separately from other medicinal ingredients and (ii) fumaric acid or an ester thereof Or including the step of blending their salts.

[Pharmaceutical ingredient contained in the solid preparation of the present invention]
"Ibuprofen" in the present invention is ibuprofen in accordance with the Japanese Pharmacopoeia, and can be produced by a known method or commercially available one.
The dose of ibuprofen in the present invention may be appropriately determined and determined in accordance with the age, symptoms and the like of the user, but for example, 50 to 600 mg per day may be divided into one or two or three times. It is preferred to administer.
Although the content of ibuprofen contained in the solid preparation in the present invention is not particularly limited, it may be appropriately determined based on the above dose, and it may be, for example, 1 to 60% by mass of the whole solid preparation, preferably 5 It is 50 to 50% by mass, more preferably 10 to 30% by mass.

  In the present invention, "other medicinal ingredients" mean all medicinal ingredients other than ibuprofen, for example, antipyretic analgesics other than ibuprofen, drugs for rhinitis, antihistamines, antitussives, noscapines, expectorants, bronchodilators, gastric mucosa Protective agents, caffeines, vitamins, hypnotic sedatives, antiseptics, anti-inflammatory agents, anticholinergic agents, herbal medicines, traditional Chinese medicine prescriptions, etc. may be mentioned.

As an antipyretic analgesic other than ibuprofen, for example, aspirin (acetylsalicylic acid), aspirin aluminum, acetaminophen, salicylamide, sodium salicylate, ethensamide, Sazapyrin, lactyl phenetidine, ketoprofen, isopropylantipyrine, loxoprofen sodium and the like can be exemplified.
As a rhinitis drug, for example, pseudoephedrine hydrochloride, chlorpheniramine maleate dl-chlorpheniramine maleate, d-chlorpheniramine maleate, veradonna total alkaloid, isopropamide iodide, dipotassium glycyrrhizinate and the like can be exemplified.
Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isothipendyl hydrochloride, promethazine methylene disalicylic acid salt, diphenylpyraline hydrochloride, diphenylpyraline theocurate, isothipendyl hydrochloride, diphetherol hydrochloride, phosphoric acid Difeterol, triprolidine hydrochloride hydrate, triperenamine hydrochloride, tongilamine hydrochloride, phenetazine hydrochloride, methozirazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydrolin napadisylate, carbinoxamine maleate, ipuroheptin hydrochloride, promethazine hydrochloride, alimemazine tartrate, phenetazine tannate mastaculin fatty acid Salt, mequitadine and the like can be exemplified.
As an antitussive, for example, codeine phosphate hydrate, dihydrocodeine phosphate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, aloclamide hydrochloride, cloperastine hydrochloride, cloperastine phendizo Examples thereof include acid salts, pentoxeverbdenate (carbetapentane citrate), tipepidine hibenzate, dibunato sodium, tipepidine citrate, dimemorphan phosphate and the like.
Examples of noscapins include, for example, noscapine, noscapine hydrochloride hydrate and the like.
As an expectorant, for example, potassium guaiacol sulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia, vicinal oil, potassium guaiacol sulfonate, guaifenesin, cresol sulfonate potassium Etc. can be illustrated.
Examples of bronchodilators include dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, 1-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprofilin, Theophylline, proxiphyrin, etc. can be exemplified.
As the gastric mucosa protective agent, for example, glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dry aluminum hydroxide gel, water Aluminum oxide / magnesium carbonate mixed dried gel, coprecipitated product of aluminum hydroxide / sodium bicarbonate, coprecipitated product of aluminum hydroxide / calcium carbonate / magnesium carbonate, coprecipitated product of magnesium hydroxide / aluminum potassium sulfate, Magnesium carbonate etc. can be illustrated.
Examples of caffeine include sodium caffeine benzoate, caffeine hydrate, anhydrous caffeine and the like.
As vitamins other than ascorbic acid or a salt thereof, for example, vitamin B1 or derivatives thereof or salts thereof, vitamin B2 or derivatives thereof or salts thereof, vitamin P (hesperidin) or derivatives thereof or salts thereof It can be illustrated.
Examples of hypnotic sedatives include allyl isopropyl acetyl urea, brom valeryl urea and the like.
Examples of the solubilizer include lysozyme chloride, L-ethylcysteine hydrochloride, methylcysteine hydrochloride and the like.
As an anti-inflammatory agent, glycyrrhizinic acid and its salts, tranexamic acid etc. can be illustrated, for example.
Examples of anticholinergic agents include, for example, veradonna total alkaloid, isopropamide iodide and the like.
Examples of herbal medicines include Maou, Nantenjitsu, Oohi, Onji, Persimmon, Kienshi, Persimmon, Persimmon, Sexan, Senega, Beimo, Neisseria, Oi Vac, Ooen, Gajutsu, Camomile, Keihi, Gentian, Gooiwa, Veterinary , Ginseng, ginseng, ginseng, clove, chimpi, birch, gill, ginseng, ginseng and the like.
Examples of Kampo prescriptions include root hot spring, root hot spring, Chinese steaming pot, kanji hot water, kaisosan, sweet pepper hot water, Sho-saiko hot water, small blue hot spring, mochi mon hot spring, semi-summer hot spring bath, mao hot spring, etc. .

In one embodiment of the present invention, the other medicinal ingredient is an "anti-inflammatory agent".
The "anti-inflammatory agent" in the present invention means a drug having anti-inflammatory activity, and is not particularly limited as long as it is an anti-inflammatory drug, for example, lysozyme chloride, seraptase, tranexamic acid, and glycyrrhizinic acid or a salt thereof Can be mentioned. In the present invention, the anti-inflammatory agent may be of one type or two or more types.
As the "anti-inflammatory agent" in the present invention, preferably glycyrrhizinic acid or a salt thereof, more preferably glycyrrhizinic acid.
The "glycyrrhizinic acid or a salt thereof" in the present invention includes glycyrrhizinic acid and a pharmaceutically acceptable salt thereof. These can be manufactured by a well-known method, and can use a commercially available thing.
The dosage of “glycyrrhizin acid or a salt thereof” in the present invention may be appropriately determined and determined in accordance with the age, symptoms, etc. of the recipient, and may be, for example, 20 to 200 mg once a day as glycyrrhizin acid. Alternatively, it is preferable to administer in two or three divided doses.
The pharmaceutically acceptable salts include, for example, salts of alkali metals such as sodium and potassium and salts of alkaline earth metals such as calcium and magnesium. In the present invention, glycyrrhizinic acid or a salt thereof may be used alone or in combination of two or more.
The content of “glycyrrhizinic acid or a salt thereof” contained in the solid preparation of the present invention is not particularly limited, and, for example, 0.1 to 10.0% by mass, preferably 0.5 to 5.0% by mass of the whole solid preparation. It is mass%, more preferably 1.0 to 3.0 mass%.

In one embodiment of the present invention, the other medicinal ingredient is "ascorbic acid or a salt thereof".
The "ascorbic acid or a salt thereof" in the present invention includes ascorbic acid and a pharmaceutically acceptable salt thereof. These can be manufactured by a well-known method, and can use a commercially available thing.
The pharmaceutically acceptable salts include, for example, salts of alkali metals such as sodium and potassium and salts of alkaline earth metals such as calcium and magnesium.
Specific examples of the above "ascorbic acid or a salt thereof" include ascorbic acid, sodium ascorbate, potassium ascorbate, calcium ascorbate, zinc ascorbate, magnesium ascorbate and the like, with preference given to calcium ascorbate. In the present invention, ascorbic acid or a salt thereof may be used alone or in combination of two or more.
The dose of "ascorbic acid or a salt thereof" in the present invention may be appropriately determined and determined in accordance with the age, symptoms, etc. of the user, but for example, 50 to 2000 mg per day as ascorbic acid. It is preferable to administer once or in two or three times.
The content of "ascorbic acid or a salt thereof" contained in the solid preparation in the present invention is not particularly limited, but for example, 1 to 80% by mass, preferably 7 to 70% by mass of the whole solid preparation as ascorbic acid Is 15 to 45% by mass.

[Additional components contained in the solid preparation of the present invention]
The "fumaric acid or ester thereof or a salt thereof" in the present invention is not particularly limited as long as the effects of the present invention described above occur, and fumaric acid listed in Japanese Pharmacopoeia, pharmaceutical additive standard, quasi-drug raw material standard, etc. And acids or esters thereof or salts thereof.
For example, fumaric acid, dimethyl fumarate, diethyl fumarate, dibutyl fumarate, dioctyl fumarate, monosodium fumarate, sodium fumarate, ferrous fumarate, sodium stearyl fumarate and the like can be mentioned, with preference given to fumarate Or sodium stearyl fumarate, more preferably sodium stearyl fumarate.
The content of “fumaric acid or an ester or a salt thereof” contained in the solid preparation of the present invention is not particularly limited, and may be appropriately determined and determined according to the contents of ibuprofen and other medicinally active ingredients. The solid preparation of the present invention comprises fumaric acid or an ester thereof or a salt thereof in an amount of 0.1 to 20.0% by mass, preferably 0.5 to 10.0% by mass, more preferably 1. It contains 5 to 8.5% by mass, more preferably 1.8 to 5.0% by mass.

  The mass ratio of ibuprofen contained in the solid preparation in the present invention and fumaric acid or an ester thereof or a salt thereof is not particularly limited as long as the effects of the present invention described above occur, for example, 1 part by mass of ibuprofen It is preferable to include 0.05 to 0.50 parts by mass of the acid or its ester or a salt thereof, and more preferable to include 0.10 to 0.20 parts by mass.

In addition to the above components, the solid preparation of the present invention may further contain a pharmaceutically acceptable carrier or additive conventionally used in the pharmaceutical technical field as long as the effects of the present invention are not impaired.
Carriers or additives include, for example, excipients, disintegrants, binders, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, perfumes and the like. These additives are used in conventional amounts in the formulation art.

As the excipient, for example, starches such as corn starch, potato starch, wheat co-starch, rice starch, partially pregelatinized starch, pregelatinized starch, perforated starch and the like; lactose hydrate, sucrose, fructose, glucose, mannitol And sorbitol, erythritol, xylitol, trehalose, maltitol, sugars such as powdered reduced maltose starch syrup, lactitol or sugar alcohols; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, calcium carbonate and the like.
As the disintegrant, for example, carmellose, carmellose calcium, carboxymethyl starch sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch and the like Preferably, croscarmellose sodium or L-HPC is used.
As the binder, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), polyvinyl pyrrolidone, copolyvidone, gum arabic powder, methyl cellulose, low substituted hydroxypropyl cellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, arabic Gum, agar, gelatin, tragacanth, sodium alginate and the like are used, preferably hydroxypropyl cellulose and hydroxypropyl methylcellulose.
As the fluidizing agent, for example, light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, talc etc. are used, preferably light anhydrous silicic acid, magnesium aluminometasilicate It is.
As the lubricant, for example, stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like can be mentioned.
Examples of coloring agents include yellow ferric oxide, ferric oxide, food blue 1, food blue 2, food yellow 4, food yellow 5, food green 3, food red 2, food red 3 Food red 102, food red 104, food red 105, food red 106, food lake pigment, riboflavin, riboflavin phosphate ester sodium and the like.
Examples of pH adjusters include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids and salts thereof.
As the surfactant, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol and the like can be mentioned.
As the stabilizer, for example, tocopherol, tetrasodium edetate, nicotinamide, cyclodextrins and the like can be mentioned.
Examples of the acidulant include ascorbic acid, citric acid, tartaric acid, malic acid and the like.
Examples of the flavor include L-menthol, peppermint oil, lemon oil, vanillin and the like.
The above-described carriers or additives may be used as a mixture of two or more.

[Method for producing solid preparation of the present invention]
The method for producing a solid preparation of the present invention comprises the step of (i) stirring and granulating ibuprofen in a separate group from the other medicinal ingredients.
Here, “stir-granulate in a separate group with another pharmaceutically active ingredient” means to stir-granulate (in a single group) a group containing ibuprofen separately from the group containing the other medicinal ingredient.
Since this can alleviate the contact between ibuprofen and the other pharmacologically active ingredients, it is possible to suppress the melting point depression.
As the stirring granulation method in the above-mentioned process, known methods can be used. For example, granulation handbook (Japan Powder Industry Technology Association, edited by Ohm Co., Ltd.), prescription design of orally administered preparation (Kyoto University Graduate School of Pharmaceutical Sciences) Professor Futoshi Hashida, Pharmaceutical Industry Pharmaceutical Co., Ltd.), Powder compression molding technology (Particle Engineering · Formulation and Particle Design Committee, Nikkan Kogyo Shimbun), Pharmaceutical Machinery Technology Handbook (2nd Edition, Pharmaceutical Machinery Technology Research Association established) Methods described in publications such as the 20th anniversary publication editorial committee, Pharmaceutical Machinery Technology Research Committee) can be used.

  In the above stirring granulation step, for example, ibuprofen and, if necessary, additives such as excipients (without any other medicinal ingredients) are charged into a stirring granulator, and a binder etc. is added thereto (for example, spraying) And granulating. If necessary, the obtained granulated product may be dried, sized, etc. by a method generally used for preparation.

In the present invention, the other pharmaceutically active ingredient may be contained in the solid preparation separately from the ibuprofen-containing granulated product, but the granulated product containing the component (a fibrillated from a group different from ibuprofen) It is preferable to include them as grains.
Accordingly, the method for producing a solid preparation of the present invention may include the step of granulating other medicinal ingredients.
As the granulation method of other medicinal ingredients, for example, known methods such as extrusion granulation, rolling granulation, stirring granulation, fluidized bed granulation, spray drying granulation, crushing granulation, melt granulation and the like are used For example, methods described in publications such as the above-mentioned granulation handbook can be used. If necessary, the obtained granulated product may be dried, sized, etc. by a method generally used for preparation.

  In one embodiment of the present invention, the other pharmacologically active ingredient is ascorbic acid or a salt thereof (eg calcium ascorbate), and the ascorbic acid or a salt thereof is produced by the other known method using the above-mentioned known method. The active ingredient (eg, glycyrrhizinic acid) and ibuprofen are granulated in separate single groups. For example, in the method for producing a solid preparation containing ibuprofen, calcium ascorbate, and glycyrrhizinic acid as a pharmaceutically active ingredient, it is desirable to granulate as separate single groups (divided into three groups).

Furthermore, the method for producing a solid preparation of the present invention includes the step of (ii) combining fumaric acid or an ester thereof or a salt thereof (preferably fumaric acid or stearyl sodium fumarate). Fumaric acid or stearyl sodium fumarate is optionally added to the above ibuprofen-containing granulated product and other medicinal ingredients (preferably, the component-containing granulated product) together with other additives commonly used in medicines. (Mixed).
The blending method in the above step is not particularly limited, but various mixing machines (for example, universal mixers, tumbler mixers) generally used for the preparation can be prepared using methods described in publications such as the above-mentioned granulation handbook etc. Etc.).
In one embodiment of the present invention, the effect of suppressing adhesion of soot by blending a fluidizing agent such as light anhydrous silicic acid or magnesium metasilicate aluminosilicate with the above (ii) fumaric acid or stearyl sodium fumarate. Can be further strengthened.

Granulate the above (i) ibuprofen in a separate group from other pharmaceutically active ingredients (eg, in the case of two or more other pharmaceutically active ingredients including calcium ascorbate, ibuprofen, calcium ascorbate, three groups of other pharmaceutically active ingredients) There is concern that the size of the solid preparation may be increased by the step of (granulation) separately, but it can be improved by the above-mentioned (ii) fumaric acid or stearyl fumarate sodium blend (optimization of additives).
That is, (ii) by adding fumaric acid or stearyl sodium fumarate, in addition to the improvement effect of appearance defects such as sputum adhesion, while maintaining high content of medicinal active ingredients such as ibuprofen, from the viewpoint of good doseability. Solid preparations can be produced in the desired size.

Examples of solid preparations in the present invention include tablets (including uncoated tablets, coated tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc.), capsules (soft capsules, hard capsules) And the like), granules, powders, pills, etc., preferably tablets.
When the solid preparation in the present invention is a tablet, using the method described in the above-mentioned publication such as the granulation handbook, for example, the above-mentioned granulated product together with an additive which is usually used for pharmaceutical products as needed. The tablet can be formed into tablets by using various tableting machines (for example, a rotary tableting machine and the like) generally used for preparations.
In addition, when the solid preparation in the present invention is a capsule, it may be filled in a capsule together with the above-mentioned granulated product and, if necessary, an additive that is usually used for medicine, to make a capsule.

The solid preparation in the present invention may be coated by a conventional method using a coating base usually formulated. For example, tablets may be coated with a coating base to give a film-coated tablet.
The coating base includes, for example, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymer, water-soluble base such as macrogol, water-insoluble base such as ethyl cellulose , Hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer, acrylic acid copolymer, enteric base such as carboxy vinyl polymer, polyvinyl acetal diethyl amino acetate, amino alkyl methacrylate copolymer , Such as polyvinyl acetate diethylamino acetate Soluble base, gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerol fatty acid ester, magnesium stearate, and the like.
In the present invention, the coating base may be of one type or two or more types.
In addition, coating additives may be used in the coating. As a coating additive, a light-shielding agent, a fluidizer, a coloring agent, a plasticizer etc. are mentioned, for example.
As a plasticizer, copolyvidone, polyethylene glycol, triethyl citrate, castor oil, polysorbate etc. are mentioned, for example.

  EXAMPLES The present invention will be described in more detail by way of the following Examples and Test Examples, but the present invention is not limited thereto.

Example 1
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was 42.6% ibuprofen, 20.8% crystalline cellulose, 19.8% powdered reduced maltose starch syrup, 9.5% corn starch, 3.5% croscarmellose sodium, and 3.9% HPC.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 11.8%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 4.0%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
The obtained sieved powder 1: 846 g, the sieved powder 2: 858.6 g, the sieved powder 3: 526.5 g, low substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.) 126.9 g, sodium stearyl fumarate (Nihon Seikagaku Kogyo Co., Ltd.) 48 g and 24 g of magnesium aluminometasilicate (Fuji Chemical Industry) were mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

Example 2
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was 42.6% ibuprofen, 20.8% crystalline cellulose, 19.8% powdered reduced maltose starch syrup, 9.5% corn starch, 3.5% croscarmellose sodium, and 3.9% HPC.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 11.8%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 4.0%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
The obtained sieved powder 1: 846 g, the sieved powder 2: 858.6 g, the sieved powder 3: 526.5 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 150.9 g, sodium stearyl fumarate (Nihon Seikagaku Kogyo Co., Ltd.) 48 g were mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

[Example 3]
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was ibuprofen 44.0%, crystalline cellulose 19.9%, powdered reduced maltose starch syrup 18.9%, corn starch 9.4%, croscarmellose sodium 4.0%, HPC 3.7%.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 12.6%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 3.1%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
Obtained particle size 1: 818 g, particle size 2: 858.5 g, particle size 3: 526.5 g, croscarmellose sodium 120 g, sodium stearyl fumarate (Nihon Seikagaku Kogyo) 48 g, crystalline cellulose 47 g, light anhydrous 12 g of silicic acid (Nippon Aerosil) was mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

Comparative Example 1
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was 42.6% ibuprofen, 20.8% crystalline cellulose, 19.8% powdered reduced maltose starch syrup, 9.5% corn starch, 3.5% croscarmellose sodium, and 3.9% HPC.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 11.8%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 4.0%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
The obtained sieved powder 1: 846 g, the sieved powder 2: 858.6 g, the sieved powder 3: 526.5 g, croscarmellose sodium 120 g, 54 g of magnesium aluminometasilicate (Fuji Chemical Industries), magnesium stearate (Taipei Chemical Industrial) 17 g of crystalline cellulose and 7.9 g of crystalline cellulose were mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

Comparative Example 2
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was 42.6% ibuprofen, 20.8% crystalline cellulose, 19.8% powdered reduced maltose starch syrup, 9.5% corn starch, 3.5% croscarmellose sodium, and 3.9% HPC.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 11.8%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 4.0%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
Obtained sized powder 1: 846 g, sized powder 2: 858.6 g, sized powder 3: 526.5 g, croscarmellose sodium 120 g, light anhydrous silicic acid (Nippon Aerosil) 36 g, crystalline cellulose 30.9 g, magnesium stearate (Daitai Chemical Industry Co., Ltd.) 12 g was mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

Comparative Example 3
Acetaminophen (Mallinckrodt), Ibuprofen (BASF), d-Chlorpheniramine Maleate (Gumo Chemical), Glycyrrhizinic Acid (Alp Pharmaceutical Co., Ltd.), Dihydrocodeine Phosphate (Takeda Pharmaceutical Co., Ltd.), dl-Methylephedrine Hydrochloride ( Alps Chemical Industries, Anhydrous caffeine (BASF), Hesperidin (Alps Chemical Industry), powdered reduced maltose starch syrup, corn starch, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) in a fluid-bed granulator, HPC solution After granulating and drying, the mixture was sieved with a particle sizer (power mill) to obtain particle size 1.
The composition ratio of the sized powder 1 is acetaminophen 11.5%, ibuprofen 23.1%, d-chlorpheniramine maleate 0.2%, glycyrrhizinic acid 2.5%, dihydrocodeine phosphate 1.5%, dl-methylephedrine hydrochloride 3.8% Anhydrous caffeine 4.8%, hesperidin 5.8%, powdered reduced maltose starch syrup 17.5%, corn starch 17.5%, low substituted hydroxypropyl cellulose 8.8%, HPC 2.9%.
In addition, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and after granulation and drying by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 2.
The compositional ratio of the sized powder 2 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
The obtained sized powder 1: 1559.3 g, sized powder 2: 526.5 g, crystalline cellulose 174.2 g, croscarmellose sodium 120 g, sodium stearyl fumarate (Nippon Seikagaku Kogyo Co., Ltd.) 48 g, and mixed powder for tableting I got The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

Comparative Example 4
Ibuprofen (BASF), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation Foodtech), corn starch (Japan corn starch), croscarmellose sodium (Meidai Koko) are charged into a stirring granulator, hydroxypropyl The solution is granulated by pouring a solution of cellulose (HPC, Nippon Soda), wet-typed with a power mill, and dried with a fluid bed dryer, and then dry-typed with a power mill. The particles were sized to obtain a sized powder 1.
The compositional ratio of sized powder 1 was 42.6% ibuprofen, 20.8% crystalline cellulose, 19.8% powdered reduced maltose starch syrup, 9.5% corn starch, 3.5% croscarmellose sodium, and 3.9% HPC.
In addition, acetaminophen (Mallinckrodt), d-chlorpheniramine maleate (Kongo Chemical), glycyrrhizinic acid (Alp Pharmaceutical Co., Ltd.), dihydrocodeine phosphate (Takeda Pharmaceutical Co., Ltd.), dl-methylephedrine hydrochloride (Alp Pharmaceutical Co., Ltd.) ), Anhydrous caffeine (BASF), hesperidin (Alps Chemical Industries), powdered reduced maltose starch syrup, corn starch, crystalline cellulose, croscarmellose sodium in a fluid bed granulator and spraying it with HPC solution After granulation and drying, the mixture was sized by a particle sizer (power mill) to obtain sized particles 2.
Composition ratio of sized powder 2: acetaminophen 21.0%, d-chlorpheniramine maleate 0.4%, glycyrrhizinic acid 4.5%, dihydrocodeine phosphate 2.8%, dl-methyl ephedrine hydrochloride 7.0%, anhydrous caffeine Hesperidin 10.5%, powdered reduced maltose starch syrup 16.8%, corn starch 11.8%, crystalline cellulose 8.4%, croscarmellose sodium 4.2%, HPC 4.0%.
Furthermore, after calcium ascorbate (CSPC Weisheng) and corn starch are charged into a fluid bed granulator, and granulated and dried by spraying a solution of tartaric acid (Showa Kako) and hydroxypropyl methylcellulose (HPMC, Shin-Etsu Chemical Co., Ltd.) The mixture was sized with a particle sizer (power mill) to obtain particle size 3.
The compositional ratio of the sized powder 3 was calcium ascorbate 95.0%, corn starch 2.1%, tartaric acid 0.1%, HPMC 2.8%.
The obtained sized powder 1: 846 g, sized powder 2: 858.6 g, sized powder 3: 526.5 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.) 150.9 g, crystalline cellulose 31 g, magnesium stearate (Taipei Chemical Industrial) 17 g was mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted using a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have a weight of uncoated tablet of 405 mg to obtain a cored tablet.
The uncoated tablets thus obtained were subjected to film coating by a conventional method to give film-coated tablets.

[Test example]
Tables 1 and 2 show the results of confirming the presence or absence of adhesion of chewing in the tableting operation in Examples 1 to 3 and Comparative Examples 1 to 4.
In each of Examples 1 to 3, although adhesion of wrinkles did not occur 120 minutes after the start of tableting (Table 1), adhesion of wrinkles occurred in Comparative Examples 1 to 4 (Table 2). In particular, in Comparative Example 3, 杵 adhesion occurred 20 minutes after the start of tableting in Comparative Example 4 10 minutes after the start of tableting (Table 2).

  In a solid preparation containing two or more active pharmaceutical ingredients containing ibuprofen, (i) stir-granulate ibuprofen in a group separate from the other active pharmaceutical ingredients, and (ii) combine fumaric acid or an ester thereof or a salt thereof As a result, appearance defects such as adhesion of wrinkles, quality deterioration such as content reduction, and flow defects of granulated products can be significantly improved, and productivity in the manufacturing process can be maintained high. Such a solid preparation does not cause appearance defects, and can secure good quality and stability.

Claims (7)

A method for producing a solid preparation containing two or more medicinal ingredients containing ibuprofen, comprising:
(I) stirring and granulating ibuprofen separately from other medicinal ingredients;
(Ii) A method for producing a solid preparation, comprising the step of blending fumaric acid or an ester thereof or a salt thereof.   The method for producing a solid preparation according to claim 1, wherein fumaric acid or an ester thereof or a salt thereof is fumaric acid or stearyl sodium fumarate.   The method for producing a solid preparation according to claim 1 or 2, wherein the other active ingredient is an anti-inflammatory agent.   The method for producing a solid preparation according to claim 3, wherein the anti-inflammatory agent is one or more selected from the group consisting of lysozyme chloride, seraptase, tranexamic acid, and glycyrrhizinic acid or a salt thereof.   The method for producing a solid preparation according to any one of claims 1 to 4, wherein the other active ingredient is ascorbic acid or a salt thereof.   The solid according to claim 5, wherein the ascorbic acid or a salt thereof is at least one selected from the group consisting of ascorbic acid, sodium ascorbate, potassium ascorbate, calcium ascorbate, zinc ascorbate, and magnesium ascorbate. Method of manufacturing a preparation.   The method for producing a solid preparation according to claim 5 or 6, wherein ascorbic acid or a salt thereof is granulated in a single group.