solid dosage forms

Abstract

To provide a solid preparation containing mequitazine and ascorbic acid or salts thereof, and a method for producing the same.SOLUTION: A solid preparation contains (A) mequitazine, and (B) ascorbic acid or a salt thereof. The component (A) and the component (B) are separate granules, or only one of the component (A) and the component (B) is granules and the other is not included in the granules.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid preparation containing mequitazine and ascorbic acid or a salt thereof, and a method for producing the same. [Background technology]

[0002] Pharmaceutical preparations containing multiple medicinal ingredients are widely used in comprehensive cold medicines. Comprehensive cold medicines contain many ingredients, such as antipyretics, analgesics, antihistamines, antitussives, bronchodilators, anti-inflammatory drugs, caffeines, and vitamins. However, some medicinal ingredients in pharmaceutical preparations become less stable when combined with specific medicinal ingredients, resulting in a decrease in their content during storage. From the perspective of safety, i.e., to ensure the desired effects and prevent unexpected side effects, it is necessary to prevent a decrease in the content of the medicinal ingredients in pharmaceutical preparations.

[0003] Mequitazine is known as a phenothiazine antihistamine, and is used in antiallergic drugs based on its antihistamine action, and as an antihistamine component in cold medicines, rhinitis medicines, etc. Due to its pharmacological action, mequitazine has been investigated for use in combination with various drugs, and it is sometimes used in cold medicines in combination with the vitamin ascorbic acid or its salts.

[0004] Patent Document 1 discloses a solid preparation containing mequitazine and one or more selected from acetaminophen, ephedrines, and vitamin B1s as a solid preparation that prevents a decrease in the mequitazine content. However, Patent Document 1 does not describe or suggest a combination of mequitazine and ascorbic acid or a salt thereof, or the preparation of such a combination by separately granulating them.

[0005] Patent Document 2 discloses a tablet containing mequitazine and ascorbic acid or a salt thereof. However, Patent Document 2 neither describes nor suggests that the mequitazine content decreases during storage when mequitazine and ascorbic acid or a salt thereof are simultaneously blended in a solid preparation, nor does it describe the preparation of such a combination by separately granulating them. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2000-169367 [Patent Document 2] Japanese Patent Application Publication No. 11-209305 Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have found that when mequitazine and ascorbic acid or a salt thereof are simultaneously incorporated into a solid preparation, the mequitazine content decreases during storage. Therefore, an object of the present invention is to provide a stable solid preparation in which mequitazine and ascorbic acid or a salt thereof are simultaneously incorporated, and in which the decrease in the mequitazine content in the preparation is suppressed. [Means for solving the problem]

[0008] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that in a solid preparation containing mequitazine and ascorbic acid or a salt thereof, a decrease in the mequitazine content can be suppressed by grouping mequitazine and ascorbic acid or a salt thereof and producing the solid preparation, and have thus completed the present invention. That is, the present invention includes the following aspects. [1] A solid preparation containing (A) mequitazine and (B) ascorbic acid or a salt thereof, The (A) component and the (B) component are separate granules, or A solid preparation characterized in that only one of component (A) and component (B) is a granulated product, and the other component is not contained within the granulated product. [2] The solid formulation according to [1], which is a multilayer tablet. [3] The solid formulation according to [1] or [2], wherein the ascorbic acid or a salt thereof is calcium ascorbate. [4] A method for producing a solid formulation containing (A) mequitazine and (B) ascorbic acid or a salt thereof, comprising: The (A) component and the (B) component are granulated separately, or A method for producing a solid formulation by granulating only one of the components (A) and (B) and then adding the other component. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a solid preparation containing mequitazine and ascorbic acid or a salt thereof at the same time, which can suppress a decrease in the mequitazine content. DETAILED DESCRIPTION OF THE INVENTION

[0010] The "mequitazine" in the present invention is mequitazine that complies with the Japanese Pharmacopoeia, and can be produced by known methods, or commercially available products can be used. The content of mequitazine contained in the solid preparation of the present invention is not particularly limited, but is, for example, 0.01 to 10% by mass, preferably 0.02 to 2% by mass, and more preferably 0.05 to 0.5% by mass of the entire solid preparation.

[0011] In the present invention, "ascorbic acid or a salt thereof" includes ascorbic acid and its pharmaceutically acceptable salts. These can be produced by known methods, or commercially available products can be used. Examples of the pharmaceutically acceptable salts include salts of alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium. Specific examples of the above-mentioned "ascorbic acid or a salt thereof" include ascorbic acid, sodium ascorbate, potassium ascorbate, calcium ascorbate, zinc ascorbate, magnesium ascorbate, etc., and calcium ascorbate is preferred. In the present invention, the ascorbic acid or a salt thereof may be one type or two or more types. The content of "ascorbic acid or a salt thereof" contained in the solid preparation of the present invention is not particularly limited, but is, for example, 1 to 80% by mass, preferably 7 to 70% by mass, and more preferably 15 to 45% by mass, of the total solid preparation in terms of calcium ascorbate.

[0012] The mass ratio of "mequitazine" to "ascorbic acid or a salt thereof" contained in the solid preparation of the present invention is not particularly limited, but is 12.5 parts by mass or more, preferably 75 to 200 parts by mass, and more preferably 100 to 150 parts by mass of ascorbic acid or a salt thereof per part by mass of mequitazine.

[0013] The solid preparation of the present invention may contain active ingredients other than mequitazine and ascorbic acid or a salt thereof, such as antipyretics and analgesics, drugs for rhinitis, antihistamines other than mequitazine, antitussives, expectorants, bronchodilators, gastric mucosa protecting agents, caffeines, vitamins other than ascorbic acid or a salt thereof, hypnotics and sedatives, phlegm dissolving agents, anti-inflammatory agents, anticholinergic agents, herbal medicines, and Chinese herbal prescriptions, as long as the effects of the present invention are not impaired.

[0014] Examples of antipyretic analgesics include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, ibuprofen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium. Examples of drugs for rhinitis include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, and dipotassium glycyrrhizinate. Examples of antihistamines other than mequitazine include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isothipendyl hydrochloride, promethazine methylenedisalicylate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, thondylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydroline napadisilate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimemazine tartrate, fenethazine tannate, and clemastine fumarate. Examples of narcotic antitussives include codeine phosphate hydrate, dihydrocodeine phosphate, etc. Examples of non-narcotic antitussives include alloclamide, isoaminil, eprazinone, oxeladin, clofedanol, clobutinol, cloperastine, dibunate, dimemorfan, tipepidine, dextromethorphan, noscapine, hydrocotalnin, pentoxyverine, benproperine, and fominoben, as well as salts and hydrates thereof. Examples of salts and hydrates thereof include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, pentoxyverine citrate, and hydrates thereof. Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia-fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. 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, aluminum hydroxide-magnesium carbonate mixed dried gel, co-precipitation product of aluminum hydroxide-sodium bicarbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, co-precipitation product of magnesium hydroxide-aluminum potassium sulfate, and magnesium carbonate. Examples of caffeine compounds include sodium caffeine benzoate, caffeine hydrate, and anhydrous caffeine. Examples of vitamins other than ascorbic acid or its salts include vitamin B1 or its derivatives or salts thereof, such as thiamine nitrate, vitamin B2 or its derivatives or salts thereof, such as riboflavin, vitamin P (hesperidin) or its derivatives or salts thereof, and the like. Examples of hypnotics and sedatives include allylisopropylacetylurea and bromvalerylurea. Examples of sputum dissolving agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizinic acid and its salts, and tranexamic acid and its salts. Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide. Examples of herbal medicines include ephedra, nandina, scutellaria, onji, licorice, bellflower, scutellaria, scutellaria, scutellaria, sekisan, senega, fritillary, fennel, Phellodendron bark, coptis, zedoary, chamomile, cinnamon bark, gentian, bezoar, animal gall (including yuutan), shanghai, ginger, atractylodes, clove, tangerine peel, atractylodes rhizome, jiru, ginseng, and ginseng. Examples of Chinese herbal medicine prescriptions include Kakkonto, Kakkonto-ka-kikyo, Keipito, Kososan, Saiko-keipito, Sho-saikoto, Sho-seiryuto, Bakumondo-to, Hange-koboku-to, and Mao-to.

[0015] In addition to the above-mentioned active ingredient, the solid preparation of the present invention may further contain pharmaceutically acceptable carriers or additives conventionally used in the technical field of formulations, as long as they do not impair the effects of the present invention. Examples of carriers or additives include excipients, disintegrants, binders, fluidizing agents, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, etc. These carriers or additives are used in amounts conventionally used in the technical field of formulation.

[0016] Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, refined sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, and calcium carbonate. Examples of disintegrants that can be used include carmellose, carmellose calcium, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and hydroxypropyl starch, and preferred are croscarmellose sodium and L-HPC. Examples of binders that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, powdered gum arabic, methylcellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropyl cellulose and hydroxypropyl methylcellulose being preferred. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, and talc, with light anhydrous silicic acid and magnesium aluminometasilicate being preferred. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and sucrose fatty acid esters. Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake color, riboflavin, riboflavin sodium phosphate, and titanium oxide. Examples of pH adjusters include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and salts thereof. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of flavoring agents include ascorbic acid, citric acid, tartaric acid, malic acid, sucralose, and stevia extract. Examples of flavoring agents include L-menthol, mint oil, lemon oil, and vanillin.

[0017] In the solid preparation of the present invention containing (A) mequitazine and (B) ascorbic acid or a salt thereof, (A) mequitazine and (B) ascorbic acid or a salt thereof are separate granules, or only one of (A) mequitazine and (B) ascorbic acid or a salt thereof is a granule, and the other component is not contained within the granule.

[0018] Therefore, in the solid preparation of the present invention, mequitazine and ascorbic acid or a salt thereof are not contained in the same granule. When only mequitazine is granulated, ascorbic acid or a salt thereof is not contained in the mequitazine granule, and ascorbic acid or a salt thereof is contained in the solid preparation as a non-granule. On the other hand, when only ascorbic acid or a salt thereof is granulated, mequitazine is not contained in the granule of ascorbic acid or a salt thereof, and mequitazine is contained in the solid preparation as a non-granule.

[0019] The mequitazine granules of the present invention may contain other active ingredients and additives in addition to mequitazine as needed, as long as they do not contain ascorbic acid or a salt thereof. Furthermore, in the solid preparation of the present invention, the mequitazine granules can be formulated by mixing with other active ingredients and additives as needed.

[0020] The granules of ascorbic acid or a salt thereof of the present invention may contain other active ingredients and additives in addition to ascorbic acid or a salt thereof, as needed, so long as they do not contain mequitazine. Furthermore, in the solid preparation of the present invention, the granules of ascorbic acid or a salt thereof may be mixed with other active ingredients and additives as needed to form a preparation.

[0021] Examples of the solid preparation of the present invention include tablets (including plain tablets, coated tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc.), capsules, granules, powders, and pills, with tablets being preferred. For example, when the solid preparation of the present invention is a tablet, the solid preparation is preferably a multi-layer tablet, more preferably a bi-layer tablet.

[0022] In the present invention, a multilayer tablet is a tablet formed from two or more layers having different compositions, and a bilayer tablet is a tablet formed from two layers having different compositions.

[0023] In the method for producing a solid preparation containing (A) mequitazine and (B) ascorbic acid or a salt thereof of the present invention, (A) mequitazine and (B) ascorbic acid or a salt thereof are separately granulated, or Only one of the ingredients (A) mequitazine and (B) ascorbic acid or a salt thereof is granulated, and then the other ingredient is added.

[0024] Therefore, in the method for producing a solid preparation of the present invention, when mequitazine and ascorbic acid or a salt thereof are granulated separately, each is granulated and then formulated. Alternatively, when only mequitazine is granulated, ascorbic acid or a salt thereof is added after granulation to produce a solid preparation. Furthermore, when only ascorbic acid or a salt thereof is granulated, ascorbic acid or a salt thereof is added after granulation to produce a solid preparation.

[0025] The solid preparation of the present invention can be manufactured using conventional methods, for example, methods described in publications such as Granulation Handbook (edited by the Japan Powder Industry and Engineering Association, Ohmsha), Formulation Design of Orally Administered Preparations (edited by Hashida Mitsuru, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Powder Compression Molding Technology (edited by the Powder Engineering, Formulation and Particle Design Committee, Nikkan Kogyo Shimbun), and Pharmaceutical Machinery Technology Handbook (2nd edition, edited by the Editorial Committee for the Publication Commemorating the 20th Anniversary of the Establishment of the Pharmaceutical Machinery Technology Research Association, Pharmaceutical Machinery Technology Research Association).

[0026] The granulation method is not particularly limited, and known methods (extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray-drying granulation, crushing granulation, melt granulation, etc.) may be used. If necessary, the obtained granules may be dried, sized, etc. by methods commonly used in pharmaceutical preparations.

[0027] For example, when the solid preparation of the present invention is a tablet, mequitazine and ascorbic acid or a salt thereof can be granulated separately, and the mequitazine granules and the ascorbic acid or a salt thereof granules can be compressed into tablets, if necessary, together with further additives, using a method described in publications such as the above-mentioned Granulation Handbook, for example, using various tablet presses commonly used for formulations (e.g., rotary tablet presses, etc.). Alternatively, mequitazine alone can be granulated, and the mequitazine granules and ascorbic acid or a salt thereof can be compressed, if necessary, together with further additives, to form tablets. Alternatively, ascorbic acid or a salt thereof alone can be granulated, and the ascorbic acid or a salt thereof granules and mequitazine can be compressed, if necessary, together with further additives, to form tablets.

[0028] In particular, when the solid preparation of the present invention is a multilayer tablet, mequitazine and ascorbic acid or a salt thereof can be granulated separately, and the mequitazine granules, the ascorbic acid or a salt thereof granules, and optionally further additives can be layered together and compressed to produce a multilayer tablet. Alternatively, mequitazine alone can be granulated, and the mequitazine granules, ascorbic acid or a salt thereof, and optionally further additives can be layered together and compressed to produce a multilayer tablet. Alternatively, ascorbic acid or a salt thereof alone can be granulated, and the ascorbic acid or a salt thereof granules, mequitazine, and optionally further additives can be layered together and compressed to produce a multilayer tablet.

[0029] When the solid preparation of the present invention is a capsule, mequitazine and ascorbic acid or a salt thereof can be granulated separately, and the mequitazine granules, the ascorbic acid or a salt thereof granules, and any other additives can be filled into a capsule to produce the capsule. Alternatively, mequitazine alone can be granulated, and the mequitazine granules, ascorbic acid or a salt thereof, and any other additives can be filled into a capsule to produce the capsule. Furthermore, ascorbic acid or a salt thereof alone can be granulated, and the ascorbic acid or a salt thereof granules, mequitazine, and any other additives can be filled into a capsule to produce the capsule.

[0030] The solid preparation of the present invention may be coated by a conventional method using a coating base that is commonly used. For example, a tablet may be coated with a coating base to form a film-coated tablet. Examples of coating bases include water-soluble bases such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, and macrogol; water-insoluble bases such as ethyl cellulose; enteric bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, acrylic acid copolymers, and carboxyvinyl polymers; gastrosoluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, and polyvinyl acetate diethylaminoacetate; gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. In the present invention, the coating base may be one type or two or more types. Furthermore, coating additives may be used in the coating, such as light blocking agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate. [Example]

[0031] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0032] Example 1 The components were mixed and granulated according to the recipe shown in Section A of Table 1 below, to obtain a first-layer granule and a second-layer granule, respectively. The obtained first-layer granule and second-layer granule were mixed with the components according to the recipe shown in Section B, to obtain a first-layer mixture and a second-layer mixture, respectively. The obtained first-layer mixture and second-layer mixture were fed into a tablet press and compressed into layers to obtain bilayer tablets. Example 2 The components were mixed and granulated according to the recipe shown in Section A of Table 1 below, to obtain Group 1 granules and Group 2 granules, respectively. The obtained Group 1 granules and Group 2 granules were mixed with the components according to the recipe shown in Section B. The obtained mixtures were fed into a tablet press and compressed to obtain tablets. (Comparative Example 1) The ingredients were mixed and granulated according to the recipe shown in Section A of Table 1 below. The resulting granules were mixed with the ingredients according to the recipe shown in Section B. The resulting mixture was placed in a tablet press and compressed to obtain single-layer tablets. [Table 1]

[0033] (Test example) The tablets obtained above were stored under accelerated conditions (40°C). The remaining percentage (%) of mequitazine after storage for 3 or 6 months was measured. The results are shown in Table 2. [Table 2]

[0034] As shown in Table 2, when mequitazine and calcium ascorbate were granulated in the same group to form a single-layer tablet (Comparative Example 1), the residual rate of mequitazine decreased after storage. On the other hand, when mequitazine and calcium ascorbate were granulated in a double-layer tablet (Example 1) or when mequitazine and calcium ascorbate were granulated in separate groups (Example 2), the residual rate of mequitazine remained high, and the storage stability of mequitazine was improved.

[0035] (Manufacturing example) The ingredients were mixed and granulated according to the recipe shown in Section A of Table 3 below, to obtain first-layer granules and second-layer granules, respectively. The obtained first-layer granules and second-layer granules were mixed with the ingredients according to the recipe shown in Section B, to obtain first-layer mixtures and second-layer mixtures, respectively. The obtained first-layer mixtures and second-layer mixtures were placed in a tablet press and compressed into layers to obtain uncoated tablets. The obtained uncoated tablets were coated according to the recipe shown in Section C to obtain coated tablets. [Table 3] [Industrial Applicability]

[0036] In a solid preparation containing mequitazine and ascorbic acid or a salt thereof, the mequitazine and ascorbic acid or a salt thereof are in the form of separate granules, or only one of the components, mequitazine and ascorbic acid or a salt thereof, is in the form of a granule, and the other component is not contained in the granule, thereby making it possible to suppress a decrease in the mequitazine content and provide a solid preparation with good stability.

Claims

1. A solid preparation containing (A) mequitazine and (B) ascorbic acid or a salt thereof, The component (A) and the component (B) are separate granules, or A solid preparation characterized in that only one of the components (A) and (B) is a granulated product, and the other component is not contained within the granulated product.

2. 2. The solid formulation according to claim 1, which is a multi-layer tablet.

3. 3. The solid formulation according to claim 1, wherein the ascorbic acid or a salt thereof is calcium ascorbate.

4. A method for producing a solid formulation containing (A) mequitazine and (B) ascorbic acid or a salt thereof, comprising the steps of: Component (A) and component (B) are granulated separately, or A method for producing a solid preparation, comprising granulating only one of the components (A) and (B) and then adding the other component.

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