JP2020026433A - Method for producing solid preparation - Google Patents

Abstract

To provide a method for producing a solid preparation, containing ibuprofen and a non-narcotic antitussive, and formed in a size suitable for ingestion, and with less trouble of poor appearances such as pestle attachment and sticking during tableting.SOLUTION: The present invention provides a method for producing a solid preparation, containing ibuprofen and a non-narcotic antitussive, having the steps of (i) agitating and granulating ibuprofen and/or a non-narcotic antitussive, and (ii) blending a silicate compound.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a solid preparation containing ibuprofen and a non-narcotic antitussive.

  Among the medicinal components of pharmaceutical preparations, many medicinal components adhere to the surface of a punch in the tableting step, and it is known that a formulation containing these medicinal components causes the sticking of a punch at the time of tableting. Punch adhesion refers to the attachment of a medicinal ingredient or tablet powder to the tablet surface of the punch during tableting, which results in the formation of irregularities on the tablet surface, from mild to loss of gloss on the tablet surface. In addition, since the appearance is poor even when the tablet is severe or the tablet surface is partially peeled off, there is a problem that the commercial value of the pharmaceutical preparation is reduced. In addition, sticking a medicinal ingredient to a punch leads to a decrease in the content of the ingredient, which causes not only a decrease in commercial value due to poor appearance, but also a decrease in quality as a pharmaceutical formulation and a decrease in productivity in the manufacturing process of the formulation. Becomes

  Ibuprofen is widely used as an antipyretic analgesic, and is used as a general cold remedy in combination with an antitussive and the like. In addition, ibuprofen is known as a drug causing punch sticking, and in tablets containing ibuprofen and an active ingredient such as an antitussive, poor appearance and a decrease in content due to sticking of punches, and a decrease in productivity in manufacturing are major problems. Become.

  By blending a large amount of additives in the solid preparation containing ibuprofen, the concentration of ibuprofen in the whole solid preparation is diluted, so that the problem of poor appearance such as sticking of a punch and sticking at the time of tableting can be solved. However, when a large amount of additives is blended, there is a problem that the tablet size becomes large and the ingestibility becomes poor.

  Patent Document 1 relates to a pharmaceutical composition containing ibuprofen, ambroxol hydrochloride and tranexamic acid. In Formulation Example 11, these three components include dextromethorphan hydrobromide hydrochloride which is a non-narcotic antitussive. Disclosed are tablets containing a blend of light anhydrous silicic acid and light anhydrous silicic acid. However, Patent Document 1 does not disclose stirring granulation of ibuprofen and dextromethorphan hydrobromide hydrate, and does not disclose or suggest any problem of poor appearance such as sticking of a punch or sticking during tableting. It has not been.

JP-A-2017-171626

  In the present invention, mainly due to ibuprofen, poor appearance such as sticking sticking and sticking, quality deterioration such as a decrease in content, and a decrease in productivity in the manufacturing process and the like are improved, and a formulation size that is excellent in ingestibility is further improved. An object of the present invention is to provide a method for producing a solid preparation containing ibuprofen and a non-narcotic antitussive.

As a result of intensive studies, the present inventor has found that in the process of producing a solid preparation containing ibuprofen and dextromethorphan hydrobromide hydrate, (i) stirring ibuprofen and / or dextromethorphan hydrobromide hydrate By granulating and (ii) adding a silicate compound as an additional component, a solid preparation having a size excellent in ingestibility can be obtained, and poor appearance such as sticking of a punch and sticking during tableting can be improved. As a result, the present invention has been completed.
That is, the present invention includes the following aspects.
[1] A method for producing a solid preparation containing ibuprofen and a non-narcotic antitussive,
(I) stirring and granulating ibuprofen and / or a non-narcotic antitussive;
(Ii) A method for producing a solid preparation, comprising a step of mixing a silicate compound.
[2] The production method according to [1], wherein the ibuprofen and the non-narcotic antitussive are stirred and granulated in the same group.
[3] The production method according to [1] or [2], wherein the non-narcotic antitussive is dextromethorphan or a salt thereof.
[4] The production method according to any one of [1] to [3], wherein silicon dioxide contained in the silicate compound is 10% or more.
[5] The method according to any one of [1] to [4], wherein the silicate compound is at least one selected from the group consisting of light silicic anhydride, magnesium metasilicate aluminate, calcium silicate, and hydrous silicon dioxide. Manufacturing method.

According to the present invention, in a solid preparation containing ibuprofen and a non-narcotic antitussive, poor appearance such as sticking at the time of punching and sticking at the time of tableting, a decrease in quality such as a decrease in ibuprofen content can be remarkably improved, Further, the productivity in the manufacturing process can be kept high.
Further, in consideration of compliance with medication, the solid preparation needs to have an appropriate size. However, according to the present invention, ibuprofen and / or a non-narcotic antitussive are stirred and granulated, and a silicate compound is added as an additive. By doing so, it is possible to obtain a solid preparation having a size excellent in ingestibility.

  The solid preparation containing ibuprofen and a non-narcotic antitussive of the present invention comprises (i) a step of granulating the ibuprofen and / or the non-narcotic antitussive with stirring, and (ii) a step of blending a silicate compound.

(Medicinal ingredients contained in the solid preparation of the present invention)
“Ibuprofen” in the present invention is ibuprofen based on the Japanese Pharmacopoeia, and can be produced by a known method or a commercially available one.
The dose of ibuprofen in the present invention may be appropriately determined depending on the age, symptoms, etc. of the user, and may be determined, for example, 50 to 600 mg once or twice or three times a day. It is preferred to administer.
The content of ibuprofen contained in the solid preparation of the present invention is not particularly limited, and may be appropriately determined based on the above-mentioned dose, and may be, for example, 1 to 60% by mass of the whole solid preparation, preferably 5% by mass. -50 mass%, more preferably 10-30 mass%.

"Non-narcotic antitussive" in the present invention means a non-narcotic central antitussive, for example, allocramide, isoaminyl, epradinone, oxerazine, clofedanol, clobutinol, cloperastine, dibnate, dimemorphan, tipepidine, dexext Lometorphan, noscapine, hydrocotarnine, pentoxiverine, benproperin and hominoben, and salts and hydrates thereof, and examples of such salts and hydrates include, for example, allocramide hydrochloride, cloperastine hydrochloride, cloperastinphen Disodium salt, dibnate sodium, dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenol phthalate, pentoxyberin citrate And their hydrates can be exemplified.
The mass ratio of ibuprofen to the non-narcotic antitussive contained in the solid preparation of the present invention is not particularly limited. For example, with respect to 1 part by mass of ibuprofen, the non-narcotic antitussive is, for example, 0.01 parts by mass. Or more, preferably 0.02 parts by mass or more, more preferably 0.02 to 2 parts by mass, and still more preferably 0.02 to 1.5 parts by mass.

In one embodiment of the invention, the non-narcotic antitussive is "dextromethorphan or a salt thereof".
In the present invention, "dextromethorphan or a salt thereof" refers to dextromethorphan and a pharmaceutically acceptable salt thereof, and a solvate of dextromethorphan and a pharmaceutically acceptable salt thereof with water or alcohol. Including. As dextromethorphan or a salt thereof, for example, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, and preferably dextromethorphan hydrobromide hydrate It is. These can be produced by a known method, or commercially available ones can be used.
The dose of dextromethorphan or a salt thereof in the pharmaceutical composition of the present invention may be appropriately determined depending on the age, symptoms, etc. of the user, for example, 0.1 to 270 mg per day. Preferably, 0.5 to 180 mg, more preferably 1 to 90 mg, is administered once or in two to three divided doses. Moreover, when dextromethorphan or a salt thereof is dextromethorphan hydrobromide hydrate, 6 to 60 mg, preferably 15 to 60 mg, as dextromethorphan hydrobromide hydrate per day, Preferably, 20 to 60 mg is administered. Furthermore, when dextromethorphan or a salt thereof is dextromethorphan phenolphthalin salt, 9 to 90 mg, preferably 22 to 90 mg, more preferably 30 to 90 mg of dextromethorphan phenolphthalin salt is administered per day. Is preferred.
The content of “dextromethorphan or a salt thereof” contained in the solid preparation of the present invention is not particularly limited, but is, for example, 0.1 to 5% by mass, preferably 0.5 to 3% by mass of the whole solid preparation. is there.

  The mass ratio of ibuprofen and dextromethorphan or a salt thereof contained in the solid preparation of the present invention is not particularly limited. For example, with respect to 1 part by mass of ibuprofen, dextromethorphan or a salt thereof is, for example, 0.01% by mass. Part or more, preferably 0.02 part by mass or more, more preferably 0.02 to 2 parts by mass, and still more preferably 0.02 to 1.5 parts by mass.

  In the `` solid preparation '' in the present invention, unless inhibiting the effects of the present invention, active ingredients other than ibuprofen and non-narcotic antitussives, for example, antipyretic analgesics other than ibuprofen, drugs for rhinitis, antihistamines, narcotic antitussives, An expectorant, a bronchodilator, a gastric mucosa protective agent, caffeine, vitamins, a hypnotic sedative, a sputum dissolving agent, an anti-inflammatory agent, an anticholinergic agent, a crude drug, a Chinese medicine formulation, and the like may be blended.

Antipyretic analgesics other than ibuprofen include, for example, aspirin (acetylsalicylic acid), aspirin aluminum, acetaminophen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, loxoprofen sodium and the like.
Examples of drugs for rhinitis include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloid, isopropamide iodide, dipotassium glycyrrhizinate and the like.
Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isotipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline teocrate, isotipendyl hydrochloride, dipheterol hydrochloride, phosphoric acid Dipheterol, triprolidine hydrochloride hydrate, tripelenamine hydrochloride, tondylamine hydrochloride, phenetazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebuhydroline napadisylate, carbinoxamine maleate, iproheptin hydrochloride, promethazine hydrochloride, carbinoxamine diphenyldisulfonate, alimazine tartrate Phenetazine, promethazine methylene disalici Salt, clemastine fumarate, mequitazine and the like can be exemplified.
Examples of the narcotic antitussive include codeine phosphate hydrate and dihydrocodeine phosphate.
Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, 1-menthol, ammonia and fennel, potassium cresol sulfonate, and the like.
As a bronchodilator, for example, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, 1-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprofylline, Theophylline, proxyphylline and the like can be exemplified.
Examples of gastric mucosa protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum / aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, water Aluminum oxide / magnesium carbonate mixed dry gel, co-precipitated product of aluminum hydroxide / sodium hydrogen carbonate, co-precipitated product of aluminum hydroxide / calcium carbonate / magnesium carbonate, co-precipitated product of magnesium hydroxide / potassium aluminum sulfate, Examples thereof include magnesium carbonate.
Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine, and the like.
Examples of the vitamins include vitamin B1 or a derivative thereof or a salt thereof, vitamin B2 or a derivative thereof or a salt thereof, vitamin C or a derivative thereof or a salt thereof, vitamin P (hesperidin) or a derivative thereof or a derivative thereof. And the like.
Examples of the hypnotic sedative include allylisopropylacetyl urea, bromvalerylurea and the like.
Examples of the sputum dissolving agent include lysozyme chloride, L-ethylcysteine hydrochloride, methylcysteine hydrochloride and the like.
Examples of the anti-inflammatory agent include lysozyme chloride, serapase, tranexamic acid, glycyrrhizic acid and salts thereof.
Examples of anticholinergic agents include belladonna total alkaloids, iodide isopropamide and the like.
Herbal medicines include ephedra, nantenjitsu, spruce, onji, licorice, fennel, shazenshi, shazensou, sexan, senega, bimo, fennel, oubak, uren, gejutsu, chamomile, keihi, gentian, gouhan, zuigan (including yutan), Examples thereof include shojin, ginger, citrus, clove, chimpanzee, sandalwood, giraffe, carrot, carrot and the like.
Examples of Kampo formulas include Neto, Neto-ka-kikyo, Keisatsu-to, Koso-san, Saiko-keisatsu-to, Sho-saiko-to, Sho-seiryu-to, Bakumondo-to, Hangesatsu-koboku-to, Mao-to and the like.

(Additive components contained in the solid preparation of the present invention)
The `` silicic acid compound '' in the present invention is not particularly limited as long as the above-mentioned effects of the present invention are produced. For example, known silicates listed in Japanese Pharmacopoeia, Pharmaceutical Excipient Standards, Quasi-drug Raw Material Standards And the like. The higher the content of silicon dioxide (SiO ₂ ) in the “silicate compound”, the better. Specifically, those containing 10% or more of silicon dioxide (SiO ₂ ) are preferable, and those containing 20% or more are more preferable.
Specific examples of such silicate compounds include light silicic anhydride, hydrous silicon dioxide, metal silicates (eg, aluminum silicate, calcium silicate, magnesium silicate), and metal metasilicates (eg, silicate Magnesium aluminate, magnesium metasilicate), and the like, preferably light anhydrous silicic acid, magnesium metasilicate aluminate, calcium silicate, or hydrous silicon dioxide.

The content of the “silicate compound” contained in the solid preparation of the present invention is not particularly limited, and may be determined by appropriately examining the content of ibuprofen and the non-narcotic antitussive, etc. Contains a silicate compound in an amount of 0.3 to 15% by mass, preferably 0.5 to 7% by mass of the whole solid preparation.
In the solid preparation of the present invention, the silicate compound may be one kind or two or more kinds.

The mass ratio of "ibuprofen" and "silicate compound" in the present invention is not particularly limited, but, for example, preferably contains 0.01 to 0.5 parts by mass of the silicate compound with respect to 1 part by mass of ibuprofen. , 0.03 to 0.3 parts by mass.
In the present invention, the mass ratio of the “non-narcotic antitussive” to the “silicic acid compound” is not particularly limited. For example, the silicate compound is added to 0.1 part by mass of the non-narcotic antitussive. It is preferably contained in an amount of 3 to 3 parts by mass, more preferably 0.2 to 2 parts by mass.

The solid preparation of the present invention may further contain, in addition to the silicate compound, a pharmaceutically acceptable carrier or additive commonly used in the field of preparation technology, as long as the effects of the present invention are not inhibited.
Carriers or additives include, for example, excipients, disintegrants, binders, fluidizers, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, flavors, and the like. These additives are used in conventional amounts in the technical field of formulation.

Examples of the excipient include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and perforated starch; lactose hydrate, purified sucrose, fructose, glucose, mannitol Sorbitol, erythritol, xylitol, trehalose, maltitol, sugars or sugar alcohols such as powdered aqueous maltose syrup, lactitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, calcium carbonate and the like.
Examples of the disintegrant include carmellose, carmellose calcium, carboxymethyl starch sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), Hydroxypropyl starch and the like are used, and preferred are croscarmellose sodium and L-HPC.
As the binder, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, gum arabic powder, methylcellulose, low-substituted hydroxypropylcellulose, hypromellose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan , Gum arabic, agar, gelatin, tragacanth, sodium alginate and the like are used, and preferred are hydroxypropylcellulose and hydroxypropylmethylcellulose.
Examples of the fluidizing agent include talc.
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like.
Examples of the coloring agent include yellow iron sesquioxide, iron sesquioxide, edible blue No. 1, edible blue No. 2, edible yellow No. 4, edible yellow No. 5, edible green No. 3, edible red No. 2, and edible red No. 3. Edible red No. 102, edible red No. 104, edible red No. 105, edible red No. 106, edible lake pigment, riboflavin, sodium riboflavin phosphate and the like.
Examples of the pH adjuster include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and salts thereof.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.
Examples of the stabilizer include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins.
Examples of the flavoring agent include ascorbic acid, citric acid, tartaric acid, malic acid, sucralose, stevia extract and the like.
Examples of the flavor include L-menthol, peppermint oil, lemon oil, vanillin and the like.
The above carriers or additives may be used as a mixture of two or more kinds as appropriate.

(Method for producing solid preparation in the present invention)
The method for producing the solid preparation of the present invention,
(I) stirring and granulating ibuprofen and / or a non-narcotic antitussive;
(Ii) a step of blending a silicate compound. As a result, poor appearance such as sticking of a punch and sticking at the time of tableting can be suppressed, and a decrease in quality such as a decrease in ibuprofen content can be remarkably improved. In addition, the productivity in the production process can be maintained at a high level, and a solid preparation can be produced in an appropriate size with excellent ingestibility.

  As the stirring granulation method in the above step (i), a known method can be used. For example, a granulation handbook (edited by Japan Powder Industry Technology Association, Ohmsha), prescription design of an oral administration preparation (Kyoto University Graduate School) Graduate School of Pharmaceutical Sciences, edited by Mitsuru Hashida, Pharmaceutical Industry Report, Powder compression molding technology (powder engineering, formulation and particle design subcommittee, edited by Nikkan Kogyo Shimbun), Handbook of formulation machine technology (second edition, formulation machine technology) A method described in a publication such as the 20th anniversary of the study group's 20th anniversary publishing editorial committee, Pharmaceutical Machinery Technology Study Group) can be used.

In the step of stirring and granulating ibuprofen and / or a non-narcotic antitussive in the present invention, a group containing one of ibuprofen and a non-narcotic antitussive is stirred and granulated, and the other group is ( The formulation may be granulated by a commonly used granulation method (other than agitated granulation), or both may be agitated and granulated, but it is preferable to agitate both ibuprofen and a non-narcotic antitussive. More preferred.
In addition, ibuprofen and non-narcotic antitussive may be stirred and granulated in the same group, or ibuprofen and non-narcotic antitussive may be stirred and granulated in a separate group. More preferred.
"Improving granulation in the same group" with ibuprofen and non-narcotic antitussive refers to agitating and granulating ibuprofen with the non-narcotic antitussive (in the same group) and ibuprofen as non-narcotic antitussive. "Stir granulation in a separate group" refers to stirring granulation of a group containing ibuprofen separately (in a single group) separately from a group containing a non-narcotic antitussive.
Here, to agitate and granulate ibuprofen with a non-narcotic antitussive, a part of the non-narcotic antitussive contained in the solid preparation is agitated and granulated with the same group as ibuprofen, and And stirring granulation in a group different from ibuprofen.
Examples of granulation methods other than stirring granulation include, for example, extrusion granulation, tumbling granulation, fluidized bed granulation, spray drying granulation, crushing granulation, and melt granulation. A method described in a publication such as a handbook can be used.

In the method for producing a solid preparation of the present invention, it is preferable that ibuprofen and the non-narcotic antitussive are stirred and granulated in the same group. In this case, the effect of the present invention can be further enhanced.
The step of stirring and granulating ibuprofen and the non-narcotic antitussive in the present invention in the same group, ibuprofen, non-narcotic antitussive, and, if necessary, additives such as excipients are charged into a stirring granulator, This includes adding a binder or the like (for example, spraying) and granulating. If necessary, the obtained granules may be dried, sized and the like by a method generally used for preparations.

  In the step of agitating and granulating ibuprofen and a non-narcotic antitussive in a separate group according to the present invention, the ibuprofen and, if necessary, additives such as excipients (not including a non-narcotic antitussive) are agitated and granulated. And adding (eg, spraying) a binder or the like to the mixture and granulating, adding a non-narcotic antitussive and, if necessary, an active ingredient other than ibuprofen, to an additive such as an excipient or a binder. And a step of granulating together. If necessary, the obtained granules may be dried, sized and the like by a method generally used for preparations.

Then, the method for producing the solid preparation of the present invention comprises: (ii) a silicate compound (preferably one selected from the group consisting of light anhydrous silicic acid, magnesium metasilicate magnesium aluminate, calcium silicate, and hydrous silicon dioxide) Including the above silicate compound). The silicic acid compound is added to the granules obtained from the step of (i) stirring and granulating ibuprofen and / or a non-narcotic antitussive, together with additives such as excipients and lubricants, if necessary. Mixing).
The method of compounding in the step (ii) is not particularly limited, but may be, for example, any of various mixers generally used in preparations (for example, a universal mixer, using a method described in a publication such as the above-mentioned granulation handbook). Tumbler mixer).

Examples of the solid preparation 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 and the like), capsules (soft capsules, hard capsules) And the like), granules, powders and pills, and preferably tablets.
When the solid preparation in the present invention is a tablet, the above-mentioned mixture (mixture) can be prepared by using a method described in a publication such as the above-mentioned granulation handbook, for example, by using various tableting machines generally used in preparations (for example, , A rotary tableting machine).
When the solid preparation according to the present invention is a capsule, the mixture (mixture) may be filled into a capsule to form a capsule.

In one embodiment of the present invention, the solid preparation comprises a first portion in which a silicic acid compound is blended in a stirred granule containing ibuprofen, and a second portion including a granulate granulated in a separate group from ibuprofen. Is a molded product (laminated tablet) obtained by stacking the above layers in a layer and compressing and forming (preferably, tableting). In the molded article, an intermediate layer may be provided using an inert additive (for example, an excipient) for the purpose of avoiding direct contact between the parts.
Further, in another embodiment of the present invention, the solid preparation is obtained by blending a silicate compound into a granulated product containing ibuprofen and a granulated product not containing ibuprofen, and compression-forming (preferably, tableting). The resulting molded product (single-layer tablet).

The solid preparation of the present invention may be coated by an ordinary method using a coating base that is usually blended. For example, tablets may be coated with a coating base to form film-coated tablets.
Examples of the coating base include water-soluble bases such as hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymer, macrogol, and water-insoluble bases such as ethylcellulose. , Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, acrylic acid copolymer, enteric base such as carboxyvinyl polymer, polyvinyl acetal diethylamino Acetate, aminoalkyl methacrylate copo Mer, gastric base such as polyvinyl acetate diethylamino acetate, 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 one type or two or more types.
Further, coating additives may be used in the coating. Examples of the coating additive include a light-blocking agent, a fluidizing agent, a coloring agent, a plasticizer, and the like.
Examples of the plasticizer include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, polysorbate and the like.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

[Example 1]
Ibuprofen (BASF), dextromethorphan hydrobromide hydrate (DSM), corn starch (Japan corn starch), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), crystalline cellulose (Asahi Kasei Chemicals), croscarmellose sodium ( Meijidai Kako) into a stirring granulator, granulate by injecting a hydroxypropylcellulose (HPC, Nippon Soda) solution, wet granulate with a granulator (power mill), and apply to a fluid bed dryer. After drying, the resultant was subjected to dry sizing using a sizing machine (power mill) to obtain sieved powder 1. The composition ratio of sized powder 1 is ibuprofen 42.3%, dextromethorphan hydrobromide hydrate 1.1%, corn starch 8.9%, powdered reduced maltose water candy 19.6%, crystalline cellulose 20.7%, croscarmellose sodium 3.5% , And HPC was 3.9%.
In addition, d-chlorpheniramine maleate (Kongo Chemical), dextromethorphan hydrobromide hydrate (DSM), L-carbocysteine (Myonaka Mining), anhydrous caffeine (BASF), pseudoephedrine hydrochloride (Alps Pharmaceutical), corn starch (Nippon corn starch), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), mannitol (Rocket Japan) in a fluidized bed granulator, HPC (Nippon Soda) After granulating and drying by spraying the solution, it was sized with a sizing machine (power mill) to obtain sieved powder 2. The composition ratio of the sized powder 2 is d-chlorpheniramine maleate 0.2%, dextromethorphan hydrobromide hydrate 2.3%, L-carbocysteine 47.6%, anhydrous caffeine 4.8%, pseudoephedrine hydrochloride 8.6% Corn starch 4.4%, crystalline cellulose 14.6%, powdered reduced maltose water candy 6.7%, mannitol 6.7%, HPC 4.1%.
The obtained sized powder 1: 90.9%, crystalline cellulose (Asahi Kasei Chemicals) 3.2%, light anhydrous silicic acid (Sylysia ^(R) 320, Fuji Silysia) 3.0%, croscarmellose sodium (Meijidai Kako) 2.6%, stearin The mixture was mixed at a composition of 0.3% of magnesium acid (Taihei Chemical Co., Ltd.) to obtain a mixed powder 1. The obtained sized powder 2: 87.6%, crystalline cellulose (Asahi Kasei Chemicals) 6.8%, pregelatinized starch (Asahi Kasei Chemicals) 5.0%, and magnesium stearate (Taihei Chemical Industry) 0.6% were mixed and mixed. Got two.
The obtained mixed powder 1 was tableted with a rotary tableting machine (AQU 2L, Kikusui Seisakusho) so that the mixed powder 1 became 195 mg per tablet and the mixed powder 2 became 300 mg per tablet. Obtained.
The obtained uncoated tablet was subjected to film coating by a conventional method to obtain a film-coated tablet.

[Example 2]
Ibuprofen (BASF), dextromethorphan hydrobromide hydrate (DSM), corn starch (Japan corn starch), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), crystalline cellulose (Asahi Kasei Chemicals), croscarmellose sodium ( Meijidai Kako) into a stirring granulator, granulate by injecting a hydroxypropylcellulose (HPC, Nippon Soda) solution, wet granulate with a granulator (power mill), and apply to a fluid bed dryer. After drying, the resultant was subjected to dry sizing using a sizing machine (power mill) to obtain sieved powder 1. The composition ratio of sized powder 1 is ibuprofen 42.3%, dextromethorphan hydrobromide hydrate 1.1%, corn starch 8.9%, powdered reduced maltose water candy 19.6%, crystalline cellulose 20.7%, croscarmellose sodium 3.5% , And HPC was 3.9%.
In addition, d-chlorpheniramine maleate (Kongo Chemical), dextromethorphan hydrobromide hydrate (DSM), L-carbocysteine (Myonaka Mining), anhydrous caffeine (BASF), pseudoephedrine hydrochloride (Alps Pharmaceutical), corn starch (Nippon corn starch), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), mannitol (Rocket Japan) in a fluidized bed granulator, HPC (Nippon Soda) After granulating and drying by spraying the solution, it was sized with a sizing machine (power mill) to obtain sieved powder 2. The composition ratio of the sized powder 2 is d-chlorpheniramine maleate 0.2%, dextromethorphan hydrobromide hydrate 2.3%, L-carbocysteine 47.6%, anhydrous caffeine 4.8%, pseudoephedrine hydrochloride 8.6% Corn starch 4.4%, crystalline cellulose 14.6%, powdered reduced maltose water candy 6.7%, mannitol 6.7%, HPC 4.1%.
The obtained sized powder 1: 35.8%, sized powder 2: 53.1%, crystalline cellulose (Asahi Kasei Chemicals) 5.4%, light anhydrous silicic acid (Sylysia ^(R) 320, Fuji Silysia) 1.2%, croscarmellose sodium ( A mixture of 1.0% of Meiji Chemical Co., pregelatinized starch (Asahi Kasei Chemicals) 3.0%, and magnesium stearate (Taihei Chemical Industry) 0.5% was obtained to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted with a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have an uncoated tablet weight of 330 mg to obtain uncoated tablets.
The obtained uncoated tablet was subjected to film coating by a conventional method to obtain a film-coated tablet.

[Example 3]
Ibuprofen (BASF), dextromethorphan hydrobromide hydrate (DSM), corn starch (Japan corn starch), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), crystalline cellulose (Asahi Kasei Chemicals), croscarmellose sodium ( Meijidai Kako) into a stirring granulator, granulate by injecting a hydroxypropylcellulose (HPC, Nippon Soda) solution, wet granulate with a granulator (power mill), and apply to a fluid bed dryer. After drying, the resultant was subjected to dry sizing using a sizing machine (power mill) to obtain sieved powder 1. The composition ratio of sized powder 1 is ibuprofen 42.3%, dextromethorphan hydrobromide hydrate 1.1%, corn starch 8.9%, powdered reduced maltose water candy 19.6%, crystalline cellulose 20.7%, croscarmellose sodium 3.5% , And HPC was 3.9%.
In addition, d-chlorpheniramine maleate (Kongo Chemical), dextromethorphan hydrobromide hydrate (DSM), L-carbocysteine (Myonaka Mining), anhydrous caffeine (BASF), pseudoephedrine hydrochloride (Alps Pharmaceutical), corn starch (Nippon corn starch), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), mannitol (Rocket Japan) in a fluidized bed granulator, HPC (Nippon Soda) After granulating and drying by spraying the solution, it was sized with a sizing machine (power mill) to obtain sieved powder 2. The composition ratio of the sized powder 2 is d-chlorpheniramine maleate 0.2%, dextromethorphan hydrobromide hydrate 2.3%, L-carbocysteine 47.6%, anhydrous caffeine 4.8%, pseudoephedrine hydrochloride 8.6% Corn starch 4.4%, crystalline cellulose 14.6%, powdered reduced maltose water candy 6.7%, mannitol 6.7%, HPC 4.1%.
The obtained sized powder 1: 35.3%, sized powder 2: 52.3%, crystalline cellulose (Asahi Kasei Chemicals) 5.2%, light silicic anhydride (Sylysia ^(R) 320, Fuji Silysia) 1.2%, magnesium metasilicate magnesium (Neusillin ^(R) UFL2, Fuji Chemical Industries) 1.5%, Croscarmellose sodium (Meiji Chemical) 1.0%, Pregelatinized starch (Asahi Kasei Chemicals) 3.0%, Magnesium stearate (Taihei Chemical) 0.5% Then, a mixed powder for tableting was obtained. The obtained mixed powder for tableting was tableted with a rotary tableting machine (AQU3, Kikusui Seisakusho) to a mass of uncoated tablet of 335 mg to obtain an uncoated tablet.
The obtained uncoated tablet was subjected to film coating by a conventional method to obtain a film-coated tablet.

[Example 4]
Ibuprofen (BASF), dextromethorphan hydrobromide hydrate (DSM), corn starch (Japan corn starch), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech), crystalline cellulose (Asahi Kasei Chemicals), croscarmellose sodium ( Meijidai Kako) into a stirring granulator, granulate by injecting a hydroxypropylcellulose (HPC, Nippon Soda) solution, wet granulate with a granulator (power mill), and apply to a fluid bed dryer. After drying, the resultant was subjected to dry sizing using a sizing machine (power mill) to obtain sieved powder 1. The composition ratio of sized powder 1 is ibuprofen 42.3%, dextromethorphan hydrobromide hydrate 4.5%, corn starch 2.7%, powdered reduced maltose water candy 22.0%, crystalline cellulose 21.1%, croscarmellose sodium 3.5% , And HPC was 3.9%.
Furthermore, d-chlorpheniramine maleate (Kongo Chemical), corn starch (Nippon corn starch), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Shoji Foodtech) were charged to a fluidized bed granulator, and HPC was added. (Nippon Soda) The solution was granulated and dried by spraying, and then sized using a sizing machine (power mill) to obtain sieved powder 2. The composition ratio of the sized powder 2 was d-chloropheniramine maleate 1.4%, corn starch 37.2%, crystalline cellulose 42.9%, powdered reduced maltose water candy 7.1%, and HPC 11.4%.
The obtained sized powder 1: 41.0%, sized powder 2: 45.2%, crystalline cellulose (Asahi Kasei Chemicals) 12.6%, light anhydrous silicic acid (Sylysia ^(R) 320, Fuji Silysia) 0.6%, magnesium stearate (Tahei) (Chemical industry) The mixture was mixed at a composition of 0.6% to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted with a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have an uncoated tablet mass of 162 mg to obtain uncoated tablets.
The obtained uncoated tablet was subjected to film coating by a conventional method to obtain a film-coated tablet.

[Comparative example]
After charging ibuprofen (BASF), corn starch (Nippon corn starch) and lactose hydrate (Megure) into a fluidized bed granulator, spraying a hydroxypropylcellulose (HPC, Nippon Soda) solution, granulating and drying The resulting mixture was sized using a sizing machine (power mill) to obtain a sieved powder 1. The composition ratio of the sized powder 1 was 60.0% of ibuprofen, 18.0% of corn starch, 20.0% of lactose hydrate, and 2.0% of HPC.
In addition, d-chlorpheniramine maleate (Kongo Chemical), dextromethorphan hydrobromide hydrate (DSM), corn starch (Nippon corn starch), crystalline cellulose (Asahi Kasei Chemicals), powdered reduced maltose water candy (Mitsubishi Corporation) Food Tech) was charged into a fluidized bed granulator, and granulated and dried by spraying an HPC (Nippon Soda) solution, and then sized with a sizing machine (Power Mill) to obtain sieved powder 2. . The composition ratio of the sized powder 2 is d-chlorpheniramine maleate 1.25%, dextromethorphan hydrobromide hydrate 12.5%, corn starch 32.5%, crystalline cellulose 37.5%, powdered reduced maltose water candy 6.25%, HPC was 10.0%.
The obtained sized powder 1: 40.4%, sized powder 2: 50.5%, crystalline cellulose (Asahi Kasei Chemicals) 7.6%, light anhydrous silicic acid (Sylysia ^(R) 320, Fuji Silysia) 1.0%, magnesium stearate (Tahei) (Chemical industry) 0.5% was mixed to obtain a mixed powder for tableting. The obtained mixed powder for tableting was tableted with a rotary tableting machine (AQU3, Kikusui Seisakusho) so as to have an uncoated tablet weight of 220 mg to obtain uncoated tablets.
The obtained uncoated tablet was subjected to film coating by a conventional method to obtain a film-coated tablet.

比較例では杵1本あたりの良品錠数が92錠と少なく、製造工程における著しい生産性の低下を確認した。その一方で、実施例1から実施例4では比較例の約11倍以上と高く、さらにいずれも外観不良の発生はなく生産性及び品質の改善が確認された。 [Test example]
Evaluation of sticking improvement Evaluation of the appearance of uncoated tablets during tableting in Examples and Comparative Examples was visually checked, and the presence or absence of appearance defects and the number of non-defective tablets per punch until appearance defects occurred on the tablet surface were calculated. (If there is no appearance defect, all products produced are described as good products). The results are shown in the table below. Here, the poor appearance refers to a tablet surface having sticky debris formed on the tablet surface.

In the comparative example, the number of good tablets per punch was as small as 92 tablets, and a remarkable decrease in productivity in the manufacturing process was confirmed. On the other hand, in Examples 1 to 4, it was as high as about 11 times or more that of the comparative example, and further, there was no appearance defect and improvement in productivity and quality was confirmed.

  In a solid preparation containing ibuprofen and a non-narcotic antitussive, (i) granulation of the ibuprofen and / or non-narcotic antitussive by stirring and (ii) addition of a silicic acid compound results in poor appearance such as sticking of a punch. In addition, quality reduction such as content reduction can be remarkably improved, and productivity in the production process can be maintained high. Such a solid preparation does not cause poor appearance, can ensure good quality and stability, and has an appropriate size with excellent ingestibility.

Claims (5)

A method for producing a solid preparation containing ibuprofen and a non-narcotic antitussive,
(I) stirring and granulating ibuprofen and / or a non-narcotic antitussive;
(Ii) A method for producing a solid preparation, comprising a step of mixing a silicate compound.   The method according to claim 1, wherein ibuprofen and the non-narcotic antitussive are stirred and granulated in the same group.   3. The method according to claim 1, wherein the non-narcotic antitussive is dextromethorphan or a salt thereof.   The method according to any one of claims 1 to 3, wherein silicon dioxide contained in the silicate compound is 10% or more.   The method according to any one of claims 1 to 4, wherein the silicic acid compound is at least one selected from the group consisting of light silicic anhydride, magnesium metasilicate aluminate, calcium silicate, and hydrous silicon dioxide.