JP7657571B2 - Pharmaceutical Compositions - Google Patents

Description

The present invention relates to a pharmaceutical composition containing ibuprofen.

Ibuprofen is a type of nonsteroidal anti-inflammatory drug (NSAID) classified as a propionic acid derivative, which inhibits cyclooxygenase (COX) to suppress the production of prostaglandins and exerts an antipyretic and analgesic effect. Ibuprofen is widely distributed not only as an ethical drug, but also as an active ingredient in general medicines such as cold remedies.

In addition to ibuprofen, other drugs known to be used as active ingredients in general cold medicines include, for example, the antihistamine diphenhydramine and the expectorant guaifenesin.
US Patent No. 5,999,633 discloses a bilayer tablet or caplet containing ibuprofen in a first layer and diphenhydramine or a salt thereof in a second layer for use in painful sleep disorders. This formulation was developed to eliminate the negative interactions between ibuprofen and diphenhydramine.

Patent Document 2 discloses a combination preparation containing a first comprehensive cold medicine containing an antihistamine and a second comprehensive cold medicine containing another antihistamine with a different rate of hypnotic effect, as a preparation aimed at improving the usefulness of comprehensive cold medicines from the viewpoint of QOL by effectively utilizing the hypnotic effect of antihistamines such as diphenhydramine while highlighting the effect of caffeine. In addition, as a preparation for the same purpose, Patent Document 3 discloses a combination preparation containing a first comprehensive cold medicine containing an antihistamine in a first dose and a second comprehensive cold medicine containing the antihistamine in a second dose different from the first dose. These documents disclose that the preparation may further contain ibuprofen, guaifenesin, etc.

Special table 2004-521104 Patent Publication 2007-302578 JP2008-100924

All of the above documents indicate that multiple active ingredients may be blended in a pharmaceutical product such as a general cold remedy, but there is no mention or suggestion whatsoever of the problem that the simultaneous blending of (a) ibuprofen, (b) diphenhydramine or a salt thereof, and (c) guaifenesin may cause wetting and/or dissolution due to an interaction between these drugs, resulting in a loss of appearance quality.
An object of the present invention is to provide a pharmaceutical composition which inhibits wetting and/or dissolution due to interactions when the above three components (a) to (c) are simultaneously blended, thereby inhibiting deterioration of appearance quality.

As a result of intensive research, the present inventors have found that the above problems can be solved by adding tranexamic acid or a salt thereof in addition to the above three components (a) to (c), and have thus completed the present invention.
That is, the present invention includes the following aspects.
[1] A pharmaceutical composition comprising ibuprofen, diphenhydramine or a salt thereof, guaifenesin, and tranexamic acid or a salt thereof.
[2] The pharmaceutical composition according to [1], wherein the diphenhydramine or a salt thereof is diphenhydramine hydrochloride.
[3] The pharmaceutical composition according to [1] or [2], wherein the tranexamic acid or a salt thereof is tranexamic acid.
[4] The pharmaceutical composition according to any one of [1] to [3], which is used for treating colds.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein the pharmaceutical composition is in the form of a tablet, a capsule, a granule, a powder or a pill.

According to the present invention, in a pharmaceutical composition containing (a) ibuprofen, (b) diphenhydramine or a salt thereof, and (c) guaifenesin, the addition of tranexamic acid or a salt thereof suppresses wetting and/or dissolution due to the interaction between these drugs, and suppresses deterioration of appearance quality. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition containing the above three components (a) to (c) and suppressing deterioration of appearance quality.

The pharmaceutical composition of the present invention is characterized by containing ibuprofen, diphenhydramine or a salt thereof, guaifenesin, and tranexamic acid or a salt thereof.

In the present invention, the "ibuprofen" can be produced by a known method, or a commercially available product can be used. For example, ibuprofen according to the Japanese Pharmacopoeia can be used.
The dosage of ibuprofen in the present invention may be appropriately determined depending on the age, symptoms, etc. of the recipient, but it is preferable to administer, for example, 50 to 600 mg per day in one dose or in two or three divided doses.
The content of ibuprofen contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, and is, for example, 1 to 60% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass of the entire pharmaceutical composition.

In the present invention, "diphenhydramine or a salt thereof" includes diphenhydramine and its pharma- ceutically acceptable salts, and solvates of diphenhydramine and its pharma- ceutically acceptable salts with water, alcohol, or the like. Examples of diphenhydramine or a salt thereof include diphenhydramine, diphenhydramine hydrochloride, diphenhydramine citrate, diphenhydramine salicylate, diphenhydramine tannate, diphenhydramine lauryl sulfate, and the like, and diphenhydramine hydrochloride is preferred. These can be produced by known methods, or commercially available products can be used. For example, diphenhydramine or a salt thereof according to the Japanese Pharmacopoeia can be used.
The dosage of diphenhydramine or a salt thereof in the present invention may be appropriately determined depending on the age, symptoms, etc. of the recipient. For example, in the case of diphenhydramine hydrochloride, it is preferable to administer 12.5 mg to 100 mg, preferably 25 mg to 75 mg, once or in 2 or 3 divided doses per day.
The content of "diphenhydramine or a salt thereof" contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, and is, for example, 0.1 to 20% by mass, preferably 0.5 to 10% by mass of the entire pharmaceutical composition.

The "guaifenesin" in the present invention can be produced by a known method, or a commercially available product can be used. For example, guaifenesin according to the Japanese Pharmacopoeia can be used.
The dosage of guaifenesin in the present invention may be appropriately determined depending on the age, symptoms, etc. of the recipient, but it is preferable to administer, for example, 20 to 600 mg per day in one dose or in two or three divided doses.
The content of guaifenesin contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately determined based on the above-mentioned dosage, and is, for example, 1 to 60% by mass, preferably 2.5 to 50% by mass, and more preferably 5 to 30% by mass of the total pharmaceutical composition.

In the present invention, "tranexamic acid or a salt thereof" includes tranexamic acid and its pharma- ceutically acceptable salts, as well as solvates of tranexamic acid and its pharma- ceutical acceptable salts with water, alcohol, or the like. Examples of tranexamic acid or a salt thereof include tranexamic acid, mineral acid salts such as hydrochloride, nitrate, and sulfate of tranexamic acid, organic acid salts such as methanesulfonate, alkali metal salts and alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt, and the like, and tranexamic acid is preferred. These can be produced by known methods, or commercially available products can be used. For example, tranexamic acid or a salt thereof according to the Japanese Pharmacopoeia can be used.
The dosage of tranexamic acid or a salt thereof in the present invention may be appropriately determined depending on the age, symptoms, etc. of the recipient. For example, in the case of tranexamic acid, it is preferable to administer 50 to 2000 mg per day in one dose or in two or three divided doses.
The content of tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited and may be determined appropriately based on the above-mentioned dosage, and is, for example, 1 to 80% by mass, preferably 5 to 60% by mass, and more preferably 10 to 40% by mass of the entire pharmaceutical composition.

The mass ratio of ibuprofen and diphenhydramine or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of diphenhydramine or a salt thereof per 1 part by mass of ibuprofen is 0.01 parts by mass or more, preferably 0.02 parts by mass or more, and the upper limit is 2 parts by mass or less, preferably 1.5 parts by mass or less.

The mass ratio of ibuprofen to guaifenesin contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of guaifenesin per 1 part by mass of ibuprofen is 0.1 parts by mass or more, preferably 0.5 parts by mass or more, and the upper limit is 10 parts by mass or less, preferably 5 parts by mass or less.

The mass ratio of ibuprofen and tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of tranexamic acid or a salt thereof per 1 part by mass of ibuprofen is 0.1 parts by mass or more, preferably 0.5 parts by mass or more, and the upper limit is 10 parts by mass or less, preferably 5 parts by mass or less.

The mass ratio of diphenhydramine or a salt thereof and tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of the amount of tranexamic acid or a salt thereof per 1 part by mass of diphenhydramine or a salt thereof is, for example, 1 part by mass or more, preferably 5 parts by mass or more, and the upper limit is 100 parts by mass or less, preferably 20 parts by mass or less.

The mass ratio of guaifenesin and tranexamic acid or a salt thereof contained in the pharmaceutical composition of the present invention is not particularly limited, but for example, the lower limit of tranexamic acid or a salt thereof per 1 part by mass of guaifenesin is 0.1 parts by mass or more, preferably 0.5 parts by mass or more, and the upper limit is 10 parts by mass or less, preferably 5 parts by mass or less.

The mass ratio of the combination of ibuprofen, diphenhydramine or a salt thereof, and guaifenesin contained in the pharmaceutical composition of the present invention to tranexamic acid or a salt thereof is not particularly limited, but for example, the lower limit of tranexamic acid or a salt thereof per 1 part by mass of the above combination is, for example, 0.05 parts by mass or more, preferably 0.1 parts by mass or more, and the upper limit is 10 parts by mass or less, preferably 5 parts by mass or less.

The issue of the present invention is that when (a) ibuprofen, (b) diphenhydramine or a salt thereof, and (c) guaifenesin are simultaneously blended, the wetting and/or dissolution and the resulting deterioration in appearance quality are believed to occur due to physical contact between the components (a) to (c). Therefore, the pharmaceutical composition of the present invention particularly includes a pharmaceutical composition in which the components (a) to (c) are not physically separated and are contained in a state in which they can come into contact with each other. Examples of such pharmaceutical compositions include tablets obtained by mixing and granulating these components in the same group and compressing them into tablets, or tablets obtained by granulating these components in separate groups, mixing the granulated powders, and compressing them into tablets.

The pharmaceutical composition of the present invention may contain active ingredients other than the above-mentioned active ingredients, such as antipyretics, analgesics, rhinitis medications, antihistamines, antitussives, expectorants, bronchodilators, gastric mucosa protectants, vitamins, hypnotics and sedatives, phlegm dissolving agents, anti-inflammatory agents, anticholinergic agents, herbal medicines, and Chinese herbal prescriptions, so long as they do not inhibit the effects of the present invention.

Examples of antipyretic analgesics include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, salicylamide, sodium salicylate, ethenzamide, sazapirin, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium.
Medication for rhinitis includes pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, dipotassium glycyrrhizinate, and the like.
Examples of antihistamines include alimemazine tartrate, isothipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, isothipendyl hydrochloride, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydroline napadisilate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, carbinoxamine diphenyldisulfonate, alimemazine tartrate, fenethazine tannate, promethazine methylene disalicylate, clemastine fumarate, and mequitazine.
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, hydrocotalnine, 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, tipepidine citrate, L-carbocysteine, ammonium chloride, 1-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, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide and sodium bicarbonate, co-precipitation product of aluminum hydroxide, calcium carbonate and magnesium carbonate, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, and magnesium carbonate.
Examples of vitamins include vitamin _B1 or a derivative or a salt thereof, vitamin _B2 or a derivative or a salt thereof, vitamin C or a derivative or a salt thereof, vitamin P (hesperidin) or a derivative or a salt thereof, and the like.
Examples of hypnotic 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, and glycyrrhizinic acid and its salts.
Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide.
Examples of medicinal herbs include Ephedra, Nandina, Coptis Root, Onji, Licorice, Platycodon, Spiraea Root, Spiraea Root, Scutellaria, Senega, Fritillaria, Fennel, Phellodendron Bark, Coptis Rhizome, Zedoary, Chamomile, Cinnamon Bark, Gentiana Root, Bezoar, Animal Gall (including Yutang), Shajin, Ginger, Sophora Root, Clove, Tangerine Peel, Atractylodes Root, Jiru, Chikusetsuginjin, and Carrot.
Examples of Chinese herbal prescriptions include Neto, Neto-ka-kikyo, Keipi-to, Koso-san, Saiko-keipi-to, Sho-saiko-to, Sho-sei-ryu-to, Bakumondo-to, Hange-kouboku-to, and Mao-to.

The pharmaceutical composition of the present invention preferably does not contain caffeine. Examples of caffeine include caffeine, caffeine hydrate, anhydrous caffeine, and pharma- ceutical acceptable salts of caffeine (e.g., sodium caffeine benzoate).

The pharmaceutical composition of the present invention may be in the form of a formulation prepared together with the above-mentioned active ingredient and a pharma- ceutical acceptable carrier or additive conventionally used in the technical field of formulation.
Examples of the carrier or additive include excipients, disintegrants, binders, flow agents, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavorings, fragrances, etc. These additives are used in amounts conventionally used in the technical field of formulations.

Examples of excipients include starches such as corn starch, potato starch, wheat cornstarch, 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, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and hydroxypropyl starch. Preferred are croscarmellose sodium and L-HPC.
Examples of binders that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol, powdered acacia, methylcellulose, low-substituted hydroxypropyl cellulose, hypromellose, sodium carmellose, dextrin, partially pregelatinized starch, pullulan, gum acacia, agar, gelatin, tragacanth, and sodium alginate, and preferred are hydroxypropyl cellulose and hydroxypropyl methylcellulose.
Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium aluminometasilicate, kaolin, and talc.
Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, 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, edible 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.
Surfactants 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 flavoring agents include ascorbic acid, citric acid, tartaric acid, malic acid, sucralose, and stevia extract.
Examples of the flavoring include L-menthol, peppermint oil, lemon oil, vanillin, and the like.
The above-mentioned carriers or additives may be used alone or in a suitable mixture of two or more kinds.

The pharmaceutical composition of the present invention can be formulated using general methods described in publications such as Granulation Handbook (edited by the Japan Powder Industry and Technology Association, Ohmsha), Formulation Design for Oral Dosage Formulations (edited by Hashida Mitsuru, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Times), Powder Compression Molding Technology (edited by 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 Pharmaceutical Machinery Technology Research Society, Pharmaceutical Machinery Technology Research Society), and there are no special limitations.

For example, when the pharmaceutical composition of the present invention is formulated into tablets, the active ingredient and conventional pharma- ceutically acceptable carriers or additives are mixed and granulated, and then the mixture is compressed into tablets using various tablet presses (e.g., rotary tablet presses, etc.) that are commonly used in pharmaceutical formulations. When the pharmaceutical composition of the present invention is formulated into capsules, the active ingredient and conventional pharma-ceutically acceptable carriers or additives are mixed and granulated, and then the granulated mixture is filled into capsules to form capsules.

The pharmaceutical composition of the present invention may take various formulation forms, but is preferably in the form of a solid formulation. Examples of solid formulations 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 (including soft capsules, hard capsules, etc.), granules, powders, and pills, and preferably tablets.

The solid preparation may be coated with a coating base that is usually blended in a conventional manner. 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, carboxymethyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid copolymers, acrylic acid copolymers, and carboxyvinyl polymers; gastric bases such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymers, and polyvinyl acetate diethylamino acetate; 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, flow agents, colorants, and plasticizers.
Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, polysorbate, and the like.

The present invention also provides a method for suppressing deterioration of the appearance of a pharmaceutical composition containing (a) ibuprofen, (b) diphenhydramine or a salt thereof, and (c) guaifenesin, characterized in that the method comprises blending tranexamic acid or a salt thereof. Each requirement of the method (each component, its amount used, its proportion used, etc.) is as described for the pharmaceutical composition of the present invention.

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

(Examples 1-2 and Comparative Examples 1-2)
The main ingredients shown in Table 1 were weighed out in predetermined amounts, granulated in a mortar using a small amount of purified water, and then dried to obtain granules.

(Test Example)
The granules obtained above (Examples 1 and 2 and Comparative Examples 1 and 2) were placed in a glass bottle, sealed, and stored for one week at 60° C. The properties of the granules after storage were compared with those immediately after the start of storage and evaluated.

As shown in Table 2, it was confirmed that the granulated state was maintained in the tranexamic acid-containing group even after storage at 60° C. for 1 week (Examples 1 and 2). On the other hand, in the tranexamic acid-free group, wetting and melting of the granulated state were observed, making it difficult to maintain the granulated state (Comparative Examples 1 and 2).
From the above, it was revealed that tranexamic acid or a salt thereof has the effect of suppressing the interaction between ibuprofen, diphenhydramine or a salt thereof, and guaifenesin.

(Production Examples 1 to 5)
The components were mixed according to the recipe and compounding ratio shown in Section A of Table 3 below, and compressed to obtain plain tablets. The obtained plain tablets were coated according to the recipe shown in Section B to obtain a coating agent.

According to the present invention, it is possible to provide a pharmaceutical composition in which the wetting and/or dissolution caused by the interaction between (a) ibuprofen, (b) diphenhydramine or a salt thereof, and (c) guaifenesin is suppressed by tranexamic acid or a salt thereof, thereby suppressing deterioration of the appearance quality.

Claims (3)

A pharmaceutical composition comprising ibuprofen, diphenhydramine hydrochloride, and guaifenesin, as well as tranexamic acid . The pharmaceutical composition according to claim 1 , which is used for treating colds. 3. The pharmaceutical composition according to claim 1 or 2 , wherein the pharmaceutical composition is in the form of a tablet, a capsule, a granule, a powder or a pill.