JP2022104611A - Solid preparation - Google Patents

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

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

In the common cold treatment, a pharmaceutical preparation containing a plurality of medicinal ingredients is widely used. The common cold medicine contains many components such as antipyretic analgesics, antihistamines, antitussives, bronchodilators, anti-inflammatory drugs, caffeines, and vitamins. However, some medicinal ingredients of pharmaceutical preparations have reduced stability when combined with a specific medicinal ingredient, and the content of the medicinal ingredient decreases during storage. In pharmaceutical preparations, it is necessary to prevent a decrease in the content of medicinal ingredients from the viewpoint of safety, which is to exert a desired effect and prevent unexpected side effects.

Mequitazine is known as a phenothiazine-based antihistamine, and is an antiallergic drug based on an antihistamine action, and a drug used as an antihistamine component in a common cold treatment drug, a rhinitis drug, and the like. Mequitazine has been studied for use in combination with various drugs due to its pharmacological action, and may be used as a common cold treatment in combination with the vitamins ascorbic acid or a salt thereof.

Patent Document 1 discloses a solid preparation containing mequitazine and _one or more selected from acetaminophen, ephedrines and vitamin B1 as a solid preparation in which the content of mequitazine is prevented from decreasing. However, Patent Document 1 does not suggest a combination of mequitazine and ascorbic acid or a salt thereof, and a multi-layer tablet containing the combination.

Patent Document 2 discloses a tablet containing mequitazine and ascorbic acid or a salt thereof. However, Patent Document 2 does not describe or suggest that the content of mequitazine decreases during storage when mequitazine and ascorbic acid or a salt thereof are co-blended into a solid preparation, and a multi-layer tablet containing the combination thereof. Is not described either.

Japanese Unexamined Patent Publication No. 2000-169367 Japanese Unexamined Patent Publication No. 11-209305

The present inventors have found that co-blending mequitazine and ascorbic acid or a salt thereof in a solid preparation causes a problem that the content of mequitazine decreases during storage. Therefore, an object of the present invention is to provide a stable solid preparation in which a decrease in the content of mequitazine in the preparation is suppressed in a solid preparation in which mequitazine and ascorbic acid or a salt thereof are simultaneously blended.

As a result of diligent studies to solve the above problems, the present inventors have found that in a solid preparation containing mequitazine and ascorbic acid or a salt thereof, a layer containing mequitazine and not containing ascorbic acid or a salt thereof, and ascorbic acid or It has been found that a decrease in the content of mequitazine can be suppressed by making a solid preparation having a layer containing the salt and not containing mequitazine, and the present invention has been completed.
That is, the present invention includes the following aspects.
[1] A layer containing mequitazine and not containing ascorbic acid or a salt thereof.
With a layer containing ascorbic acid or a salt thereof and not containing mequitazine,
A solid formulation characterized by containing.
[2] The solid preparation according to [1], which is a two-layer tablet.
[3] The solid preparation according to [1] or [2], wherein the ascorbic acid or a salt thereof is calcium ascorbic acid.

According to the present invention, it is possible to provide a solid preparation in which mequitazine and ascorbic acid or a salt thereof are simultaneously blended and which can suppress a decrease in the content of mequitazine.

The "mequitazine" in the present invention is a mequitazine conforming to the Japanese Pharmacopoeia, and can be produced by a known method or a commercially available product can be used.
The content of mequitadin contained in the solid preparation in 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 0.05% of the total solid preparation. It is 0.5% by mass.

"Ascorbic acid or a salt thereof" in the present invention includes ascorbic acid and a pharmaceutically acceptable salt thereof. These can be produced by a known method, or commercially available products can be used.
Examples of the pharmaceutically acceptable salt 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 ascorbic acid, potassium ascorbic acid, calcium ascorbic acid, zinc ascorbic acid, magnesium ascorbic acid and the like, and calcium ascorbic acid is preferable. Further, in the present invention, ascorbic acid or a salt thereof may be one kind or two or more kinds.
The content of "ascorbic acid or a salt thereof" contained in the solid preparation in the present invention is not particularly limited, but is, for example, 1 to 80% by mass, preferably 7 to 70% by mass, as calcium ascorbic acid, based on the whole solid preparation. It is preferably 15 to 45% by mass.

The mass ratio of "mekitadine" and "ascorbic acid or a salt thereof" contained in the solid preparation in the present invention is not particularly limited, but 12.5 parts by mass or more of ascorbic acid or a salt thereof is used with respect to 1 part by mass of mekitadine. It is preferably 75 to 200 parts by mass, and more preferably 100 to 150 parts by mass.

The solid preparation in the present invention includes active ingredients other than mequitazine and ascorbic acid or salts thereof, for example, antipyretic analgesics, rhinitis drugs, antihistamines other than mequitazine, antitussives, sputum, and bronchi, as long as the effects of the present invention are not impaired. Dilators, gastromucosal protective agents, caffeines, vitamins other than ascorbic acid or its salts, hypnotic sedatives, sputum solubilizers, anti-inflammatory agents, anticholinergic agents, crude drugs, Chinese herbal prescriptions, etc. may be blended. ..

Examples of the antipyretic analgesic include aspirin (acetylsalicylic acid), aspirin aluminum, acetaminophen, ibuprofen, salicylamide, sodium salicylate, etenzamid, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, sodium loxoprofen and the like.
Examples of the drug for rhinitis include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, veradonna total alkaloid, isopropamide iodide, dipotassium glycyrrhizinate and the like.
Examples of antihistamines other than mekitadine include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isotipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyralineteocrate, diphenylpyralineteocrate, and phosphoric acid. Diphenhydramine, triprolysine hydrochloride hydrate, tryperenamine hydrochloride, tonsilamine hydrochloride, phenetazine hydrochloride, metodilazine hydrochloride, diphenyldisulfonic acid carbinoxamine, mebuhydrolin napadisylate, carbinoxamine maleate, iproheptin hydrochloride, promethazine hydrochloride, alimemazine tartrate, phenetazine tannate. An example is salt.
Examples of the narcotic antitussive agent include codeine phosphate hydrate and dihydrocodeine phosphate.
Non-pharmaceutical antitussives include, for example, allocramid, isoamynyl, epradinone, oxerazine, clofedanol, clobutinol, cloperastin, dibunato, dimemorphan, tipepidin, dextromethorphan, noscapin, hydrocotarnin, pentoxyberin, beneproperin and hominoben, as well as them. Salts and hydrates thereof include, for example, alloclamid hydrochloride, cloperastine hydrochloride, cloperastinfendizoate, dextromethorphan, dimemophorphan phosphate, tipepidin. Examples thereof include hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthaline salt, pentoxyberin quinate and hydrates thereof.
Examples of expectorants include potassium guayacol sulfonate, bromhexine hydrochloride, guaifenesin, tipepidin citrate, L-carbocisteine, ammonium chloride, l-menthol, ammonia / uikyosei, potassium cresol sulfonate and the like.
Examples of the bronchial dilator include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimetokinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline and diprophylline. , Theophylline, Proxophilin and the like can be exemplified.
Examples of the gastric mucosa protective agent include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum / aminoacetate, aluminum hydroxide gel, dry aluminum hydroxide gel, and water. Mixed dry gel of aluminum oxide / magnesium carbonate, 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 include magnesium carbonate.
Examples of caffeine include sodium benzoate caffeine, caffeine hydrate, anhydrous caffeine and the like.
Examples of vitamins other than ascorbic acid or salts thereof include vitamin _B1 or derivatives thereof or salts thereof, such as thiamine nitrate, vitamin B2 or derivatives thereof or salts thereof, such as riboflavin and vitamin P ₍ hesperidin). ) Or its derivatives or salts thereof.
Examples of the hypnotic sedative include allylisopropylacetylurea and bromvalerylurea.
Examples of the sputum solubilizer include lysozyme chloride, L-ethylcysteine hydrochloride, methylcysteine hydrochloride and the like.
Examples of the anti-inflammatory agent include lysozyme chloride, seraptase, glycyrrhizic acid and its salt, tranexamic acid and its salt, and the like.
Examples of the anticholinergic agent include belladonna total alkaloids and isopropamide iodide.
Examples of crude drugs include Maou, Nantenjitsu, Ohi, Onji, Kanzo, Kikyo, Shazenshi, Shazensou, Sexan, Senega, Baimo, Fennel, Oubaku, Coptis, Gajutsu, Kamitsure, Keihi, Gentiana, Goou, and Beast. ), Shajin, Atractylodes lanceolata, Coptis chinensis, Coptis chinensis, Chinpi, Byakujutsu, Jiryu, Chikusetsu carrot, Carrot, etc. can be exemplified.
Examples of the Chinese medicine prescription include kakkonto, kakkonto kakikyo, cinnamon hot water, kasosan, cinnamon bark hot water, shosaiko hot water, shoseiryuto, bakumondoto, hangekobokuto, and maoto. ..

In addition to the above-mentioned active ingredient, the solid preparation in the present invention may further contain a carrier or additive conventionally pharmaceutically acceptable in the field of preparation technology as long as the effect of the present invention is not impaired.
Examples of the carrier or additive include excipients, disintegrants, binders, fluidizers, lubricants, colorants, pH regulators, surfactants, stabilizers, flavoring agents, fragrances and the like. The amount of these carriers or additives used in the pharmaceutical technology field is used.

Examples of the excipient include starches such as corn starch, horse belly starch, wheatco starch, rice starch, partially pregelatinized starch, pregelatinized starch, and perforated starch; lactose hydrate, purified sucrose, fructose, glucose, and mannitol. , Sorbitol, erythritol, xylitol, trehalose, martitol, powdered reduced starch sugar water, sugars or sugar alcohols such as 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 cellulose sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl starch and the like. It is used, preferably croscarmellose sodium, L-HPC.
Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, gum arabic powder, methyl cellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, dextrin, partially pregelatinized starch, purulan, and arabic. Rubber, canten, gelatin, tragant, sodium alginate and the like are used, preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like.
As the fluidizing agent, for example, light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, talc and the like are used, and light anhydrous silicic acid and magnesium aluminometasilicate are preferable. Is.
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid ester and the like.
Coloring agents include, for example, 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, Riboflavin Phosphate Sodium, Titanium Oxide 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, cyclodextrins and the like.
Examples of the flavoring agent include ascorbic acid, citric acid, tartaric acid, malic acid, sucralose, stevia extract and the like.
Examples of the fragrance include L-menthol, peppermint oil, lemon oil, vanillin and the like.

The solid preparation in the present invention includes a layer containing mequitazine and not containing ascorbic acid or a salt thereof, and a layer containing ascorbic acid or a salt thereof but not containing mequitazine. In addition to the two layers, the solid preparation in the present invention may have a layer containing an active ingredient other than mequitazine and ascorbic acid or a salt thereof, if necessary, and may have a layer containing no active ingredient. May be good.

The layer containing mequitazine in the present invention may contain other active ingredients and additives in addition to mequitazine, as long as it does not contain ascorbic acid or a salt thereof. In layers containing mequitazine, mequitazine can be present in the form of powder or granulation. Therefore, the layer containing mequitazine in the present invention contains a powder of mequitazine, a mixture with mequitazine containing other active ingredients and / or additives as required, and other active ingredients and / or additives as needed. It may contain a granule of mequitazine, or a mixture with the granule, further comprising other active ingredients and / or additives as needed.

The layer containing ascorbic acid or a salt thereof in the present invention may contain other active ingredients and additives as necessary in addition to ascorbic acid or a salt thereof, as long as it does not contain mequitazine. In a layer containing ascorbic acid or a salt thereof, ascorbic acid or a salt thereof may be present in the form of a powder or granulation. Therefore, the layer containing ascorbic acid or a salt thereof in the present invention is a powder of ascorbic acid or a salt thereof, a mixture with ascorbic acid or a salt thereof containing, if necessary, other active ingredients and / or additives, if necessary. It may contain granules of ascorbic acid or a salt thereof containing other active ingredients and / or additives, or a mixture with said granules further containing other active ingredients and / or additives as needed.

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, etc.), capsules, granules, powders, and pills. Is mentioned, and is preferably a tablet. For example, when the solid preparation in the present invention is a tablet, the solid preparation is preferably a multi-layer tablet, and more preferably a double-layer tablet.

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

The solid preparation of the present invention can be prepared by a conventional method, for example, Granulation Handbook (edited by Japan Powder Industry Technology Association, Ohm Co., Ltd.), Formulation design of orally administered preparation (edited by Mitsuru Hashida, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Pharmaceutical Industry Time Report). ), Powder compression molding technology (powder engineering / formulation and particle design subcommittee edition, Nikkan Kogyo Shimbun), formulation machine technology handbook (2nd edition, formulation machine technology study group 20th anniversary publication editorial committee edition, It can be manufactured using the methods described in publications such as the Formulation Machinery Technology Study Group).

For example, a layer containing mequitazine and a layer containing ascorbic acid or a salt thereof are stacked in layers and directly tableted to produce a tablet. Alternatively, if necessary, mekitadin and ascorbic acid or a salt thereof are separately granulated to produce a granulated product together with additives and other active ingredients normally used in pharmaceutical preparations, and if necessary, the granulated product is further granulated. Layers containing each granulated product to which an additive is added and mixed are stacked in layers and tableted to produce a multi-layer tablet. The granulation method of the granulated product is not particularly limited, and known methods (extruded granulation, rolling granulation, stirring granulation, fluidized layer granulation, spray drying granulation, crushing granulation, melt granulation, etc.) can be used. You can use it.

The solid pharmaceutical product in the present invention may be coated by a conventional method with a coating base which is usually blended. For example, the tablet may be coated with a coating base to form a film-coated tablet.
Examples of the coating base include hydroxypropylmethyl cellulose (hypromerose), hydroxypropyl cellulose, methyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymer, water-soluble bases such as macrogol, and water-insoluble bases such as ethyl cellulose. , Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, acrylic acid copolymer, enteric bases such as carboxyvinyl polymer, polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer , Polyvinyl acetate, gastrosoluble bases such as diethylaminoacetate, gum arabic, purulan, carnauba wax, cellac, macrogol, glycerin fatty acid ester, magnesium stearate and the like.
Further, in the present invention, the coating base may be one kind or two or more kinds.
In addition, coating additives may be used for coating. Examples of the coating additive include a light-shielding agent, a fluidizing agent, a colorant, 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, but the present invention is not limited thereto.

(Example 1)
Each component was mixed and granulated according to the formulation shown in Category A of Table 1 below to obtain a first-layer granulated product and a second-layer granulated product, respectively. The obtained first-layer granules and second-layer granules were mixed with each component according to the formulation shown in Category B, respectively, to obtain a first-layer mixture and a second-layer mixture. The obtained first-layer mixture and second-layer mixture were put into a locking machine and locked in a laminate to obtain a two-layer tablet.
(Comparative Example 1)
Each component was mixed and granulated according to the formulation shown in Category A of Table 1 below. The obtained granulated product was mixed with each component according to the formulation shown in Category B. The obtained mixture was put into a tableting machine and locked to obtain a single-layer tablet.

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

As shown in Table 2, the single-layer tablet containing mequitazine and calcium ascorbate (Comparative Example 1) had a reduced residual rate of mequitazine after storage, but the double-layer tablet containing mequitazine and calcium ascorbate (Example 1). The residual rate of mequitazine remained high, and the storage stability of mequitazine was improved.

(Manufacturing example)
Each component was mixed and granulated according to the formulation shown in Category A of Table 3 below to obtain a first-layer granulated product and a second-layer granulated product, respectively. The obtained first-layer granules and second-layer granules were mixed with each component according to the formulation shown in Category B, respectively, to obtain a first-layer mixture and a second-layer mixture. The obtained first-layer mixture and second-layer mixture were put into a locking machine and locked in a laminate to obtain an uncoated tablet. The obtained uncoated tablets were coated according to the formulation shown in Category C to obtain coated tablets.

In a solid preparation containing mequitazine and ascorbic acid or a salt thereof, a solid preparation having a layer containing mequitazine and not containing ascorbic acid or a salt thereof and a layer containing mequitazine or a salt thereof and not containing mequitazine. Therefore, it is possible to suppress a decrease in the content of mequitazine, and it is possible to provide a solid preparation having good stability.

Claims (3)

With a layer containing mequitazine and not ascorbic acid or a salt thereof,
With a layer containing ascorbic acid or a salt thereof and not containing mequitazine,
A solid formulation characterized by containing. The solid preparation according to claim 1, which is a two-layer tablet. The solid preparation according to claim 1 or 2, wherein the ascorbic acid or a salt thereof is calcium ascorbic acid.