Solid Dosage Forms

Abstract

To provide a solid preparation containing mequitazine and ascorbic acid or salts thereof.SOLUTION: A solid preparation has a layer containing mequitazine while not containing ascorbic acid or a salt thereof, and a layer containing ascorbic acid or a salt thereof while not containing mequitazine.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid preparation containing mequitazine and ascorbic acid or a salt thereof.

Background Art

[0002] In over-the-counter cold medicines, pharmaceutical preparations containing multiple medicinal components are widely used. Over-the-counter cold medicines contain, for example, many components such as antipyretics, antihistamines, antitussives, bronchodilators, anti-inflammatory agents, caffeine, and vitamins. However, among the medicinal components of pharmaceutical preparations, there are some whose stability decreases when combined with specific medicinal components, and whose content decreases during storage. From the perspective of safety in pharmaceutical preparations, which is to exert the desired effects and prevent unexpected side effects, it is necessary to prevent the decrease in the content of medicinal components.

[0003] Mequitazine is known as a phenothiazine antihistamine drug and is a drug used as an anti-allergy drug based on its antihistamine action and as an antihistamine component in over-the-counter cold medicines and nasal allergy medicines. Mequitazine has been studied for use in combination with various drugs based on its pharmacological action, and may be used in over-the-counter cold medicines in combination with ascorbic acid, which is a vitamin, or a salt thereof.

[0004] Patent Document 1 discloses a solid preparation for preventing the decrease in the content of mequitazine, which contains mequitazine and one or more selected from acetaminophen, ephedrines, and vitamin B1. However, Patent Document 1 does not describe or suggest the combination of mequitazine and ascorbic acid or a salt thereof, and a multilayer tablet containing such a combination.

[0005] Patent Document 2 discloses tablets containing mequitazine and ascorbic acid or a salt thereof. However, Patent Document 2 neither describes nor suggests that the content of mequitazine decreases during storage when mequitazine and ascorbic acid or a salt thereof are simultaneously incorporated into a solid dosage form, nor does it describe multilayer tablets containing this combination. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Japanese Patent Publication No. 2000-169367 [Patent Document 2] Japanese Patent Application Publication No. 11-209305 [Overview of the project] [Problems that the invention aims to solve]

[0007] The inventors have found that when mequitazine and ascorbic acid or a salt thereof are simultaneously incorporated into a solid dosage form, a problem arises in which the mequitazine content decreases during storage. Therefore, the present invention aims to provide a stable solid dosage form in which mequitazine and ascorbic acid or a salt thereof are simultaneously incorporated, thereby suppressing the decrease in the mequitazine content in the formulation. [Means for solving the problem]

[0008] As a result of diligent research to solve the above problems, the present inventors have found that by creating a solid formulation containing mequitazine and ascorbic acid or a salt thereof, which has a layer containing mequitazine but not ascorbic acid or a salt thereof, and a layer containing ascorbic acid or a salt thereof but not mequitazine, the decrease in mequitazine content can be suppressed, and thus the present invention has been completed. In other words, the present invention includes the following embodiments. [1] A layer containing mequitazine and not containing ascorbic acid or a salt thereof, A layer containing ascorbic acid or a salt thereof, and not containing mequitazine, A solid dosage form characterized by containing the following: [2] A two-layer tablet, the solid dosage form described in [1]. [3] The solid preparation according to [1] or [2], wherein the ascorbic acid or salt thereof is calcium ascorbate. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a solid formulation containing mequitazine and ascorbic acid or a salt thereof, which can suppress the decrease in the content of mequitazine. [Modes for carrying out the invention]

[0010] The "mequitazine" used in this invention is mequitazine in accordance with the Japanese Pharmacopoeia, and can be manufactured by known methods or commercially available mequitazine can be used. The content of mequitazine in the solid formulation in the present invention is not particularly limited, but for example, it is 0.01 to 10% by mass of the total solid formulation, preferably 0.02 to 2% by mass, and more preferably 0.05 to 0.5% by mass.

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

[0012] The mass ratio of "mequitazine" to "ascorbic acid or its salt" contained in the solid formulation 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 its salt per 1 part by mass of mequitazine.

[0013] The solid formulation of the present invention may contain active ingredients other than mequitazine and ascorbic acid or its salts, as long as they do not inhibit the effects of the present invention, such as antipyretic analgesics, rhinitis medications, antihistamines other than mequitazine, antitussives, expectorants, bronchodilators, gastric mucosal protectants, caffeines, vitamins other than ascorbic acid or its salts, hypnotics and sedatives, sputum dissolving agents, anti-inflammatory agents, anticholinergics, herbal medicines, and traditional Chinese medicine formulations.

[0014] Examples of antipyretic and analgesic drugs include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, ibuprofen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium. Examples of medications 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, alimazine tartrate, isotipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, diphenyldisulfonic acid carbinoxamine, mebhydroline napadisylate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimazine tartrate, phenetazine tannate, and clemastine fumarate. Examples of narcotic antitussives include codeine phosphate hydrate and dihydrocodeine phosphate. Examples of non-narcotic antitussives include alloclamide, isoaminyl, eprazinon, oxerazine, clofedanol, clobutinol, cloperastine, dibnate, dimemorphan, tipepidine, dextromethorphan, noscapine, hydrocotarnin, pentoxyverine, benproperine, and hominoben, as well as their salts and hydrates. Examples of their salts and hydrates include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibnate sodium, dimemorphan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthalein salt, pentoxyverine citrate, and their hydrates. 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-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methyl ephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosal protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitation products of aluminum hydroxide and sodium bicarbonate, coprecipitation products of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitation products of magnesium hydroxide and aluminum potassium sulfate, and magnesium carbonate. Examples of caffeine-containing substances include sodium benzoate caffeine, caffeine hydrate, and anhydrous caffeine. Examples of vitamins other than ascorbic acid or its salts include vitamin B1 or its derivatives or salts, such as thiamine nitrate; vitamin B2 or its derivatives or salts, such as riboflavin; and vitamin P (hesperidin) or its derivatives or salts. Examples of hypnotic sedatives include allyl isopropylacetylurea and bromovalerylurea. Examples of mucolytic agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, seraptase, glycyrrhizic acid and its salts, and tranexamic acid and its salts. Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide. Examples of crude drugs include Mao Wu, Nantenjitsu, Ouhi, Onji, Kanzou, Kikyou, Shazenshi, Shazensou, Sekisan, Senega, Baimo, Uikyou, Oubaku, Ouren, Gajutsu, Kamitsure, Keihi, Gentiana, Gouou, animal bile (including Yutan), Shazin, Shoukyou, Soushutsu, Chouji, Chinpi, Byakujutsu, Jiryuu, Chikusetsu Ninjin, and Ninjin. Examples of Kampo prescriptions include Kakkonto, Kakkonto plus Kikyou, Keihi-to, Kousosann, Saiko Keihi-to, Sho-saikoto, Shoseiryu-to, Baikamotsuto, Hanninbokuto, Maoto, etc.

[0015] In addition to the above active ingredients, the solid preparation in the present invention may further contain a pharmaceutically acceptable carrier or additive commonly used in the pharmaceutical technology field, as long as it does not inhibit the effects of the present invention. Examples of the carrier or additive include excipients, disintegrants, binders, fluidizing agents, lubricants, coloring agents, pH adjusters, surfactants, stabilizers, flavoring agents, fragrances, etc. These carriers or additives are used in amounts commonly used in the pharmaceutical technology field.

[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 sugar, 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, calcium carbonate, etc. Examples of disintegrants include carmellose, carmellose calcium, sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch, etc. Croscarmellose sodium and L-HPC are preferably used. Examples of binders used include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, acacia powder, methylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, acacia gum, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropylcellulose and hydroxypropylmethylcellulose being preferred. Examples of fluidizing agents include light anhydrous silicic acid, hydrated 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 colorants include yellow iron(III) oxide, iron(III) 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 pigment, riboflavin, sodium riboflavin phosphate, and titanium dioxide. Examples of pH adjusting agents include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and their salts. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (160) polyoxypropylene (30) glycol. 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 fragrances include L-menthol, peppermint oil, lemon oil, and vanillin.

[0017] The solid dosage form in the present invention comprises a layer containing mequitazine but not ascorbic acid or a salt thereof, and a layer containing ascorbic acid or a salt thereof but not mequitazine. In addition to these two layers, the solid dosage form in the present invention may optionally have a layer containing active ingredients other than mequitazine and ascorbic acid or a salt thereof, or a layer that does not contain active ingredients.

[0018] The mequitazine-containing layer in the present invention may contain other active ingredients and additives as needed, in addition to mequitazine, provided that it does not contain ascorbic acid or a salt thereof. In the mequitazine-containing layer, mequitazine may exist in the form of a powder or granules. Therefore, the mequitazine-containing layer in the present invention may include mequitazine powder, a mixture of mequitazine and other active ingredients and / or additives as needed, granules of mequitazine and other active ingredients and / or additives as needed, or a mixture of the granules and other active ingredients and / or additives as needed.

[0019] The layer containing ascorbic acid or a salt thereof in the present invention may contain other active ingredients and additives as needed, in addition to ascorbic acid or a salt thereof, provided that it does not contain mequitazine. In the layer containing ascorbic acid or a salt thereof, ascorbic acid or a salt thereof may exist in the form of a powder or granules. Therefore, the layer containing ascorbic acid or a salt thereof in the present invention may include powder of ascorbic acid or a salt thereof, a mixture of ascorbic acid or a salt thereof containing other active ingredients and / or additives as needed, granules of ascorbic acid or a salt thereof containing other active ingredients and / or additives as needed, or a mixture of the granules said to further contain other active ingredients and / or additives as needed.

[0020] Examples of solid formulations 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, granules, powders, and pills, with tablets being preferred. For example, if the solid formulation in the present invention is a tablet, it is preferably a multilayer tablet, and more preferably a two-layer tablet.

[0021] In the present invention, a multilayer tablet is a tablet formed from two or three or more layers having different compositions, and a two-layer tablet is a tablet formed from two layers having different compositions.

[0022] The solid dosage forms of the present invention can be manufactured using conventional methods, such as those described in publications like the Granulation Handbook (edited by the Japan Powder Technology Association, Ohmsha), Formulation Design for Orally Administered Formulations (edited by Professor Mitsuru Hashida, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Compression Molding Technology of Powders (edited by the Powder Engineering, Formulation and Particle Design Subcommittee, Nikkan Kogyo Shimbun), and the Handbook of Pharmaceutical Machinery Technology (2nd edition, edited by the Pharmaceutical Machinery Technology Research Association 20th Anniversary Publication Editorial Committee, Pharmaceutical Machinery Technology Research Association).

[0023] For example, a layer containing mequitazine and a layer containing ascorbic acid or a salt thereof are stacked in layers and compressed directly to produce tablets. Alternatively, granules are produced by separately granulating mequitazine and ascorbic acid or a salt thereof together with additives and other active ingredients commonly used in pharmaceutical preparations, and layers containing each of these granules, to which additional additives may be added as needed, are stacked in layers and compressed to produce multilayer tablets. The granulation method for the granules is not particularly limited, and known methods (extrusion granulation, rolling granulation, agitation granulation, fluidized bed granulation, spray drying granulation, crushing granulation, melt granulation, etc.) may be used.

[0024] The solid dosage form in this invention may be coated by a conventional method using a commonly formulated coating base. 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, copolividone, polyvinyl alcohol, polyvinyl alcohol copolymer, and macrogol; water-insoluble bases such as ethylcellulose; enteric-coated bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, acrylic acid copolymer, and carboxyvinyl polymer; gastric-soluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and polyvinyl acetate diethylaminoacetate; and gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. Furthermore, 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. Examples of coating additives include light-shielding agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate. [Examples]

[0025] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0026] (Example 1) The components were mixed and granulated according to the formulation shown in Category A of Table 1 below to obtain the first layer granules and the second layer granules, respectively. The obtained first layer granules and second layer granules were then mixed with the components according to the formulation shown in Category B to obtain the first layer mixture and the second layer mixture, respectively. The obtained first layer mixture and second layer mixture were fed into a tablet press and compressed into stacks to obtain two-layer tablets. (Comparative Example 1) Each component was mixed and granulated according to the formulation shown in Category A of Table 1 below. The resulting granules were then mixed with each component according to the formulation shown in Category B. The resulting mixture was fed into a tablet press and compressed to obtain single-layer tablets. [Table 1]

[0027] (Example test) The tablets obtained above were stored under accelerated conditions (40°C). The percentage of mequitazine remaining after 3 or 6 months of storage was measured. The results are shown in Table 2. [Table 2]

[0028] As shown in Table 2, the single-layer tablet containing mequitazine and calcium ascorbate (Comparative Example 1) showed a decrease in the remaining mequitazine content after storage. However, the double-layer tablet containing mequitazine and calcium ascorbate (Example 1) maintained a high remaining mequitazine content, indicating improved storage stability of mequitazine.

[0029] (Manufacturing example) The components were mixed and granulated according to the formulation shown in Category A of Table 3 below to obtain the first layer granules and the second layer granules, respectively. The obtained first layer granules and second layer granules were mixed with the components according to the formulation shown in Category B to obtain the first layer mixture and the second layer mixture, respectively. The obtained first layer mixture and second layer mixture were fed into a tablet press and compressed into stacked tablets to obtain uncoated tablets. The obtained uncoated tablets were coated according to the formulation shown in Category C to obtain coated tablets. [Table 3] [Industrial applicability]

[0030] In a solid dosage form containing mequitazine and ascorbic acid or a salt thereof, by having a layer containing mequitazine but not ascorbic acid or a salt thereof, and a layer containing ascorbic acid or a salt thereof but not mequitazine, the decrease in mequitazine content can be suppressed, and a solid dosage form with good stability can be provided.

Claims

1. A layer containing mequitazine and not containing ascorbic acid or its salts, A layer containing ascorbic acid or a salt thereof, and not containing mequitazine, A solid dosage form characterized by containing the following:

2. The solid preparation according to claim 1, which is a two-layer tablet.

3. The solid preparation according to claim 1 or 2, wherein the ascorbic acid or salt thereof is calcium ascorbate.

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