Granules containing fexofenadine hydrochloride

Abstract

To provide a granule having excellent granulation properties.SOLUTION: A granule is prepared that contains a fexofenadine hydrochloride salt, and at least one ephedrine selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine. There is also provided a method for improving the granulation properties of fexofenadine hydrochloride by means of at least one ephedrine selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine. The present invention further provides a method for producing a solid preparation that includes blending fexofenadine hydrochloride with an ephedrine to granulate them.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a granule containing fexofenadine hydrochloride and an ephedrine analogue, and a solid preparation containing the same. [Background technology]

[0002] Fexofenadine hydrochloride, chemically known as 2-(4-{(1RS)-1-Hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic acid monohydrochloride, not only antagonizes histamine H1 receptors but also inhibits the release of various chemical mediators, the release of inflammatory cytokines, and eosinophil migration. Because of these effects, formulations containing fexofenadine hydrochloride have already been used to treat various allergic diseases, including allergic rhinitis, urticaria, and itching associated with skin diseases such as eczema, dermatitis, pruritus, and atopic dermatitis.

[0003] A technique has been proposed that aims to improve the stability of fexofenadine by granulating particles containing fexofenadine and a binder to prepare tablets, and by selecting the binder (Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Laid-Open No. 2013-119540 Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need for the development of a solid preparation containing a granulated product having good granulation properties. [Means for solving the problem]

[0006] The present invention was developed based on the poor granulation properties of fexofenadine hydrochloride, which makes granulation difficult. As a result of extensive investigations, the inventors unexpectedly found that by preparing a composition containing fexofenadine hydrochloride and one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts, the granulation properties are improved and an excellent solid preparation can be produced, which led to the completion of the present invention.

[0007] That is, the present invention provides: [1] (A) fexofenadine hydrochloride, and (B) a granulated product containing one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts; [2] (A) fexofenadine hydrochloride, and (B) a solid preparation containing a granule containing one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts; [3] Item 3. The solid formulation according to Item 2, comprising 0.5 to 2.0 parts by mass of (B) ephedrines per 1 part by mass of (A) fexofenadine hydrochloride; [4] (A) The solid formulation according to item 2 or 3, which contains 60 to 120 mg of fexofenadine hydrochloride per day; [5] The solid formulation according to any one of Items 2 to 4, further comprising an anticholinergic component; [6] Item 6. The solid formulation according to any one of Items 2 to 5, further comprising a lubricant; [7] Item 7. The solid formulation according to any one of Items 2 to 6, wherein the (B) ephedrine is methylephedrine hydrochloride and contains 60 to 100 mg as a daily dose; [8] Item 7. The solid formulation according to any one of Items 2 to 6, wherein the (B) ephedrine is pseudoephedrine hydrochloride and contains 60 to 300 mg as a daily dose; [9] Item 9. The solid formulation according to any one of Items 2 to 8, which is in the form of a tablet, granule, or capsule;

[10] A method for improving the granulation properties of fexofenadine hydrochloride by using one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts;

[11] (A) fexofenadine hydrochloride, and (B) A method for producing a solid preparation, which comprises blending one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts, and granulating the mixture; and [Effects of the Invention]

[0008] According to the present invention, it is possible to obtain a granulated product having good granulation properties and a solid preparation obtained therefrom. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to a granule containing (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts, and a solid preparation containing the granule.

[0010] The fixed formulation of the present invention contains a granulated product, and in the granulated product of the present invention, (B) ephedrine enhances the effect of (A) fexofenadine hydrochloride on allergic diseases, and at the same time, can also improve the granulation properties of fexofenadine hydrochloride, which has poor granulation properties when used alone.

[0011] [(A) Fexofenadine hydrochloride] The hydrochloride salt of fexofenadine ((RS)-2-[4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidyl]butyl]phenyl]-2-methylpropionic acid) (sometimes referred to as component (A) in this specification) used in the present invention is a compound known as a second-generation antihistamine. Fexofenadine hydrochloride is commercially available or can be produced by known production methods.

[0012] Fexofenadine may be either the R-form or the S-form, and either an optically resolved form or a racemic form may be used.

[0013] The dose (administration amount) of component (A) in the solid preparation of the present invention can be appropriately determined depending on the amount of component (B), the types and amounts of other components, and the condition of the recipient (body weight, age, sex, symptoms, physical condition, etc.), and is not limited thereto. From the viewpoint of more significantly exhibiting the effects of the present invention, the usual daily oral dose of fexofenadine hydrochloride is preferably about 10 to about 240 mg, more preferably about 10 to about 200 mg, even more preferably about 20 to about 160 mg, even more preferably about 30 to about 140 mg, and particularly preferably about 60 to about 120 mg. Alternatively, a daily dose of 120 mg is most preferred.

[0014] The content of component (A) in the solid preparation of the present invention can be appropriately set so as to achieve the above-mentioned dosage. Although not limited thereto, from the viewpoint of more significantly exhibiting the effects of the present invention, it can be, for example, 1% by mass or more, preferably 3% by mass or more, more preferably 5% by mass or more, and even more preferably 10% by mass or more, based on the total amount of the solid preparation, and can be 90% by mass or less, preferably 60% by mass or less, and more preferably 50% by mass or less. The total content of component (A) can be, for example, 1 to 90% by mass, preferably 3 to 60% by mass, more preferably 5 to 60% by mass, and even more preferably 10 to 50% by mass, based on the total amount of the solid preparation.

[0015] [(B) Ephedrines] In this specification, ephedrines refer to at least one selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine.

[0016] In the present invention, the salt of methylephedrine or pseudoephedrine is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples of the salt include salts with inorganic acids, organic acids, inorganic bases, organic bases, etc., such as sulfate, hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, teoclate, salicylate, tannate, besylate, napadisylate, phosphate, etc. In the present invention, hydrochloride is preferred, and as the ephedrine, methylephedrine hydrochloride or pseudoephedrine hydrochloride is particularly preferred.

[0017] The total content of component (B) in the solid preparation of the present invention is not particularly limited, but is preferably 1 to 20% by mass of the total amount of the solid preparation. The effects of the present invention and the ratio of component (B) to component (A) are not particularly limited, but the amount of component (B) is preferably 0.1 to 10 parts by mass, and particularly preferably 0.5 to 2 parts by mass, per part by mass of component (A).

[0018] [(B-1) Methylephedrine hydrochloride] Methylephedrine ((1RS,2SR)-2-dimethylamino-1-phenylpropan-1-ol) hydrochloride (sometimes simply referred to as component (B) in this specification) used in the present invention is a known compound that has a mechanism of action similar to that of ephedrine, i.e., alpha action and beta action, and is known to have bronchodilatory and central antitussive effects. Methylephedrine hydrochloride is commercially available or can be produced according to known methods.

[0019] Methylephedrine may be either the R- or S-isomer, and either an optically resolved form or a racemic form may be used.

[0020] The dosage (administration amount) of component (B-1) in the solid preparation of the present invention can be appropriately determined depending on the amount of component (A), the types and amounts of other components, and the condition of the recipient (body weight, age, sex, symptoms, physical condition, etc.), and is not limited thereto. However, from the viewpoint of more significantly exhibiting the effects of the present invention, when component (B-1) is included, the daily oral dosage can generally be about 10 to about 200 mg of methylephedrine hydrochloride, more preferably about 22 to about 160 mg, even more preferably about 30 to about 140 mg, and particularly preferably about 60 to about 100 mg. Alternatively, the most preferred amount is 72 mg per day. This amount can also be contained in a single solid preparation.

[0021] When the solid preparation of the present invention contains the component (B-1), the total content of the component (B-1) is not limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, it can be, for example, 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 8% by mass or more, and in some cases 10% by mass or more, based on the total amount of the solid preparation. The content of the component (B-1) can be 20% by mass or less, preferably 15% by mass or less, more preferably 12% by mass or less, based on the total amount of the solid preparation.

[0022] When the component (B-1) is contained, the total content of the component (B-1) can be 0.1 to 20 mass %, preferably 1 to 15 mass %, more preferably 5 to 12 mass %, and even more preferably 8 to 12 mass %, based on the total amount of the solid preparation.

[0023] [(B-2) Pseudoephedrine hydrochloride] Pseudoephedrine ((1S,2S)-2-(methylamino)-1-phenyl-1-propanol) hydrochloride (sometimes referred to as component (B) in this specification) used in the present invention is a known compound that has a mechanism of action similar to that of ephedrine, i.e., alpha action and beta action, and is known to have bronchodilatory and central antitussive effects. Pseudoephedrine hydrochloride is commercially available or can be produced according to known methods.

[0024] Pseudoephedrine may be either the R-form or the S-form, and either an optically resolved form or a racemic form may be used.

[0025] The dose (administration amount) of component (B-2) in the solid preparation of the present invention can be appropriately determined depending on the amount of component (A), the types and amounts of other components, and the condition of the recipient (body weight, age, sex, symptoms, physical condition, etc.), and is not limited thereto. However, from the viewpoint of more significantly exhibiting the effects of the present invention, when component (B-2) is contained, the daily oral dose can usually be, for example, about 20 to about 400 mg, more preferably about 60 to about 300 mg, even more preferably about 100 to about 280 mg, and particularly preferably about 120 to about 240 mg, of pseudoephedrine hydrochloride.

[0026] When the solid preparation of the present invention contains the component (B-2), the total content of the component (B-2) is not limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, it can be, for example, 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 8% by mass or more, and in some cases 10% by mass or more, based on the total amount of the solid preparation. The content of the component (B-2) can be 30% by mass or less, preferably 15% by mass or less, more preferably 12% by mass or less, based on the total amount of the solid preparation.

[0027] When the (B-2) component is included, the total content of the (B-2) component can be, for example, 0.1 to 30 mass %, preferably 5 to 12 mass %, and more preferably 8 to 12 mass %, based on the total amount of the solid preparation.

[0028] The solid preparation of the present invention may contain either the component (B-1) or the component (B-2), and may optionally contain both the component (B-1) and the component (B-2). The solid preparation of the present invention preferably contains either the component (B-1) or the component (B-2).

[0029] The total content of component (B) in the solid formulation of the present invention is not limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, for example, it can be 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, even more preferably 8% by mass or more, and in some cases 10% by mass or more, based on the total amount of the solid formulation, for each single (B) component (B-1) or (B-2). The total content of component (B) in the solid formulation of the present invention is not limited, but from the viewpoint of more significantly exhibiting the effects of the present invention, it can be 12% by mass or less, based on the total amount of the solid formulation, for example, for each single (B) component (B-1) or (B-2). From the viewpoint of more significantly exhibiting the effects of the present invention, it can be preferably 11.5% by mass or less, more preferably 11% by mass or less. However, since component (B-1) or (B-2) is preferably used alone as component (B), it is preferable that the total amount of component (B) also be within these values.

[0030] The total content of the component (B) can be, for example, 0.1 to 12 mass% for each single component (B) (B-1) or (B-2) based on the total amount of the solid preparation, preferably 1 to 12 mass%, more preferably 5 to 12 mass%, even more preferably 7 to 12 mass%, and most preferably 8 to 12 mass%, and in some cases 10 to 11 mass%.

[0031] From the viewpoint of achieving the effects of the present invention, the blending ratio of the total content of component (A) to the total content of component (B-1), expressed as a weight ratio of component (A) / component (B-1), is in the range of 1.3 to 1.9. Preferably, the weight ratio of component (A) / component (B-1) is in the range of 1.3 to 1.8, more preferably 1.3 to 1.7, and most preferably 5 / 3.

[0032] From the viewpoint of achieving the effects of the present invention, the blending ratio of the total content of component (A) to the total content of component (B-2), expressed as a weight ratio of component (A) / component (B-2), is within the range of 0.5 to 1.0. Preferably, the weight ratio of component (A) / component (B-2) is 0.5 or 1.

[0033] The solid preparation of the present invention can usually be administered 1 to 6 times a day, preferably 1 to 3 times a day, and most preferably 2 times a day. Therefore, a solid preparation of the present invention for single administration preferably contains an amount obtained by dividing the above-mentioned daily dose by the number of times of administration per day. Furthermore, since the granulated product of the present invention also has a sustained effect, a high effect is maintained even when administered 1 to 2 times a day.

[0034] The granulated product and solid preparation of the present invention may further contain optional components other than component (A) and component (B). One or more of these optional components may be appropriately combined. A representative example of such optional components is preferably an anticholinergic component (C), such as a tropane alkaloid or a derivative thereof. Furthermore, the granulated product and solid preparation of the present invention preferably do not contain caffeine. Caffeine may volatilize and precipitate as crystals, which may grow. This may result in the formation of crystals known as whiskers, which may impair the quality of the product.

[0035] [(C) Anticholinergic component] In the present invention, the anticholinergic component is exemplified by alkaloids having a tropane skeleton or derivatives thereof. Specific examples include tropane alkaloids (atropine, scopolamine, hyoscyamine, etc.) and their derivatives (e.g., quaternary ammonium derivatives such as methylatropine, methylscopolamine, and butylscopolamine), as well as components containing these alkaloids (e.g., Datura extract, total alkaloids of belladonna, belladonna cone, belladonna extract, total alkaloids of Scopolum cone, Scopolum cone, Scopolum extract, isopropamide iodide, methylscopolamine or a salt thereof, and butylscopolamine or a salt thereof). These may be in the form of pharmaceutically acceptable salts or solvates. Among these, total alkaloids of belladonna are particularly preferred from the viewpoint of their ability to favorably affect the tableting properties of the solid formulation of the present invention.

[0036] Specific examples of suitable salts include bromide salts (e.g., butylscopolamine bromide), hydrobromide salts (e.g., scopolamine hydrobromide hydrate), citrate salts (e.g., Scopolamine total alkaloid citrate), etc. Examples of solvates include hydrates.

[0037] As the anticholinergic component, one type or a combination of two or more types can be used.

[0038] When the solid preparation of the present invention contains an anticholinergic component, the anticholinergic component can usually be administered to an adult in an amount of 0.1 to 100 mg per day as an active ingredient. For example, in the case of belladonna total alkaloids, 0.01 to 1 mg, preferably 0.4 to 0.6 mg; in the case of Scopolia extract, belladonna extract, or Datura extract, 1 to 100 mg; and in the case of isopropamide iodide, 0.1 to 10 mg can be orally administered once or several times a day.

[0039] When an anticholinergic component is contained in the solid preparation of the present invention, the total content of the anticholinergic component, for example, in the case of total belladonna alkaloids, can be 0.02 to 0.1% by mass, preferably 0.03 to 0.1% by mass, and more preferably 0.03 to 0.06% by mass, based on the total mass of the solid preparation. In some cases, it can be adjusted to about 0.02 to 0.06% by mass. In the case of Scopolia extract, belladonna extract, or Datura extract, the content can be 0.1 to 40% by mass. In the case of isopropamide iodide, the content can be 0.01 to 4% by mass.

[0040] From the viewpoint of achieving the effects of the present invention, the blending ratio of the component (A) to the anticholinergic component (C) is preferably 0.001 to 0.005 parts by mass of the anticholinergic component (C) per 1 part by mass of the component (A).

[0041] [(D) Binder] In order to more significantly achieve the effect of the present invention, namely, good granulation, the granules of the present invention preferably further contain a binder (D) as described below. The binder (D) that can be contained in the granules of the present invention is not limited and can be a poorly water-soluble binder (such as crystalline cellulose or low-substituted hydroxypropyl cellulose), but a water-soluble binder is preferred. In particular, when the granules of the present invention are compositions that have undergone a granulation process, a water-soluble binder is preferred. The water-soluble binder that can be contained in the granules of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically, or physiologically acceptable, and may be any of polysaccharides, proteins, water-soluble cellulose-based polymers, starches, water-soluble vinyl-based polymers, polyethers, and sugars. Specific examples of polysaccharides include gum arabic, agar, tragacanth gum, sodium alginate, carrageenan, xanthan gum, guar gum, dextran, pullulan, pectin, chitosan, and hemilose. Specific examples of proteins include gelatin and purified gelatin. Specific examples of water-soluble cellulose polymers include carmellose or its salts, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, and hydroxyethyl cellulose. Specific examples of starches include starch (wheat starch, corn starch, potato starch, etc.), pregelatinized starch, dextrin, cyclodextrin, carboxymethyl starch, hydroxypropyl starch, hydroxyethyl starch, and partially pregelatinized starch. Specific examples of water-soluble vinyl polymers include polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, and copolydone. Specific examples of acrylic polymers include sodium polyacrylate. Specific examples of polyethers include macrogol. Specific examples of sugars include sucrose syrup, fructose, sugar alcohols (e.g., xylitol and sorbitol), and glucose. These components (D) may be used in formulations other than as binders.Among the above binders, water-soluble polymer binders (also referred to as water-soluble binders in this specification) selected from cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and methyl cellulose; starches such as potato starch, corn starch, and pregelatinized starch; and vinyl-based polymers such as polyvinylpyrrolidone and polyvinyl alcohol are preferred, with hydroxypropyl cellulose and polyvinylpyrrolidone being more preferred.

[0042] When the granules of the present invention contain a binder (D), the binder is preferably contained in an amount of 0.03 to 2.0 parts by mass, more preferably 0.05 to 1.7 parts by mass, and even more preferably 0.08 to 1.5 parts by mass per part by mass of fexofenadine hydrochloride (A), from the viewpoints of sufficiently enhancing the effect of fexofenadine hydrochloride (A) on allergic diseases, improving granulation properties, and otherwise more significantly exhibiting the effects of the present invention, as well as from the viewpoint of cost-effectiveness. The granules of the present invention have improved granulation properties, so they have good granulation properties even with a small amount of binder.

[0043] The granules of the present invention may contain other physiologically active ingredients in addition to fexofenadine hydrochloride and ephedrines, if desired. Such physiologically active ingredients include, for example, (1) Sympathomimetic components (e.g., phenylephrine, phenylpropanolamine, ephedrine, etilefrine, methoxamine, midodrine, methoxyphenamine, etc.), (2) Anti-inflammatory enzymes (e.g., lysozyme, serrapeptase, bromelain, pronase, etc.) (3) Herbal medicines and ingredients derived from herbal medicines (e.g., ginger, ginseng, ephedra, cinnamon bark, kaempferia, rhododendron, rhododendron bark, rhododendron, nandina fruit, angelica tree, angelica tree, bellflower, rhododendron bark, bezoar, zedoary, atractylodes, sophora rhizome, gentian, fennel, onion root, Phellodendron bark, coptis, ginseng root, tangerine peel, clove, senega, rhododendron, rhododendron, etc.), (4) Xanthine derivatives (e.g., theophylline, aminophylline, theobromine, diprofeiline, proxyphylline, pentoxifylline, etc.), (5) Antipyretic and analgesic ingredients (e.g., aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylic amide, sodium salicylate, lactylphenetidine, ibuprofen, ketoprofen, etc.), (6) Antitussive ingredients (e.g., achloramide, cloperastine, pentoxyverine (carbetapentane), tipepidine, dibunate, dextromethorphan, codeine, dihydrocodeine, noscapine, etc.), (7) Expectorants (e.g., potassium guaiacolsulfonate, guaifenesin, etc.), (8) Vitamins (e.g., vitamin A [e.g., retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.], vitamin B [e.g., thiamine, thiamine disulfide, dicethiamine, octotiamine, shikotiamine, bis-ibutiamine, bis-bentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinic acid amino], Vitamin C [e.g., ascorbic acid, erythorbic acid, or derivatives thereof, etc.], vitamin D [e.g., ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotachysterol, etc.], vitamin E [e.g., tocopherol and its derivatives, ubiquinone derivatives, etc.], other vitamins [e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, etc.], etc.], (9) Mucosal protective ingredients (for example, aluminum-based mucosal protective agents such as aminoacetic acid, dried aluminum hydroxide gel, and dihydroxyaluminum aminoacetate; magnesium-based mucosal protective agents such as magnesium aluminometasilicate, aluminum silicate, hydrotalcite, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, calcium carbonate, and magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, and co-precipitation product of magnesium hydroxide and aluminum potassium sulfate). These physiologically active ingredients may be in the free form or in the form of a salt.

[0044] The solid preparation containing the granules of the present invention is preferably an orally administered composition. Examples of dosage forms include solid preparations such as tablets (including plain tablets, orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, jelly-like drops, drops, film-coated tablets, sugar-coated tablets, caplets, and pills), troches, granules, pills, dry syrups, powders (including fine granules), and capsules (including hard capsules and soft capsules). Among these, solid preparations containing granules containing fexofenadine hydrochloride and methylephedrine hydrochloride or pseudoephedrine hydrochloride are preferred from the viewpoints of further demonstrating the effects of the present invention and versatility. Solid preparations prepared via granulation include granules, tablets, troches, hard capsules, and dry syrups. Of these, tablets or granules prepared via granulation are particularly preferred.

[0045] When the solid preparation containing the granules of the present invention is in the form of tablets, granules, or capsules, from the viewpoints of the effects of the present invention and convenience of administration, the content of fexofenadine hydrochloride relative to the total amount of the solid preparation is generally 2.5 to 35% by mass, preferably 10 to 25% by mass, preferably 13 to 20% by mass, and more preferably 13 to 18% by mass.

[0046] When the solid preparation containing the granules of the present invention is in the form of tablets, granules, or capsules, the content of ephedrines relative to the total amount of the solid preparation is usually 0.03 to 57.0% by mass, preferably 0.5 to 30% by mass, and more preferably 1 to 20% by mass, from the viewpoint of more significantly exhibiting the effects of the present invention. When a crude drug or a Chinese herbal extract is used as the ephedrine, the content of the crude drug or Chinese herbal extract containing ephedrines relative to the total amount of the solid preparation is preferably 15 to 50% by mass.

[0047] When the solid preparation containing the granules of the present invention is a tablet, granule, or capsule, the solid content of the binder (D) relative to the total amount of the solid preparation is preferably 0.5% by mass to 90% by mass, more preferably 0.5% by mass to 50% by mass, even more preferably 1% by mass to 30% by mass, and most preferably 10% by mass to 20% by mass, from the viewpoint of more significantly exhibiting the effects of the present invention.

[0048] The binder (D) here is not limited, but is preferably a water-soluble binder. The granules of the present invention exhibit the effects of the present invention remarkably by containing an appropriate amount of water-soluble binder relative to the total mass of the granulated material and composition.

[0049] The granules of the present invention may also contain appropriate additives depending on the dosage form. In the case of solid preparations (e.g., tablets, capsules, powders, etc.), such additives include excipients (e.g., sucrose, lactose, mannitol, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., sucrose fatty acid esters, magnesium stearate, talc, etc.), disintegrants (e.g., low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, etc.), effervescent agents (e.g., sodium bicarbonate, etc.), and fluidizers (e.g., sodium aluminometasilicate, light anhydrous silicic acid, etc.). The pharmaceutical uses of these additives may also be other than those described above. Other examples include oily bases (e.g., vegetable oils such as olive oil, corn oil, soybean oil, sesame oil, and cottonseed oil; medium-chain fatty acid triglycerides, etc.), aqueous bases (e.g., macrogol 400, water), gel bases (e.g., carboxyvinyl polymers, gums, etc.), surfactants (e.g., polysorbate 80, hydrogenated castor oil, glycerin fatty acid esters, sorbitan sesquioleate, etc.), suspending agents (e.g., white beeswax, various surfactants, soy lecithin, etc.), dispersants, emulsifiers, stabilizers, buffers, solubilizers, pH adjusters, preservatives, etc. In any case, antioxidants, sweeteners, acidulants, colorants, fragrances, and taste-imparting agents may also be added to these compositions as appropriate.

[0050] The solid preparation containing the granule of the present invention can be prepared by a conventional method from fexofenadine hydrochloride, ephedrines, and other physiologically active ingredients and additives, if desired, depending on the dosage form.

[0051] Furthermore, a solid preparation containing the granules of the present invention is highly effective against symptoms such as allergic rhinitis (including perennial allergic rhinitis and seasonal allergic rhinitis (such as rhinitis symptoms associated with hay fever)) caused by allergens such as dust mites, house dust, and pollen, as well as urticaria, and itching associated with skin diseases such as eczema, dermatitis, pruritus, and atopic dermatitis. The granules of the present invention are particularly useful for alleviating allergic symptoms in patients with allergic rhinitis. In particular, the inclusion of (A) fexofenadine hydrochloride and (B) an ephedrine analogue alleviates nasal allergic symptoms such as sneezing and runny nose.

[0052] The solid preparation containing the granule of the present invention is preferably obtained by simultaneously granulating fexofenadine hydrochloride and ephedrines, and the two ingredients are contained in one preparation.

[0053] [Solid dosage form manufacturing method] The solid preparation of the present invention can be produced by any known method, provided that it has undergone a granulation step. If necessary, a sterilization step can be included. The preparation can also be produced by mixing the components in accordance with or in accordance with the General Provisions of the Japanese Pharmacopoeia, 17th Edition.

[0054] Here, the granulation method may be an appropriate combination of extrusion granulation, pulverization granulation, dry compaction granulation, fluidized bed granulation, tumbling granulation, high speed stirring granulation, and the like.

[0055] When the solid preparation of the present invention is a tablet, it can be prepared, for example, by combining a granulation method with a tableting method. For example, an indirect compression method, such as a wet granulation tableting method or a dry granulation tableting method, can also be used. The solid preparation of the present invention can also be a coated sugar-coated tablet or a film-coated tablet. Furthermore, the solid preparation of the present invention can be a single-layer tablet or a layered tablet such as a double-layer tablet. In the present invention, the solid preparation can also be a single-layer tablet prepared by a wet granulation tableting method.

[0056] When the solid preparation of the present invention is a capsule, a method of filling the granules obtained by granulation into capsules can be used.

[0057] The solid preparation of the present invention may be a sugar-coated tablet or a film-coated tablet. Furthermore, the solid preparation of the present invention may be a single-layer tablet or a layered tablet such as a double-layer tablet. In the present invention, the solid preparation may also be a single-layer tablet prepared by wet granulation tableting.

[0058] In the manufacturing method of the present invention, the amount of (B) ephedrine, the amount of (A) fexofenadine hydrochloride, the amount of optional components (C) anticholinergic component, and the amount of optional component (D) binder, and the ratio of these components are the same as in the case of a solid preparation.

[0059] [Packaging] The solid preparation of the present invention can be provided in any packaging form. For example, the packaging form may be a form in which one tablet, one capsule, one packet, or one dose is individually packaged, such as SP packaging or PTP packaging, or a form in which multiple doses (e.g., many tablets) are packed together in any container (e.g., a glass or plastic bottle, or a pouch-type packaging container made of a film laminated with synthetic resin or aluminum foil, etc.) and repeatedly opened after each dose for continuous use. The latter form in which many tablets are packed together in a package is advantageous in terms of cost. In particular, a form in which many tablets or capsules are packed together in a pouch-type packaging container (e.g., a zipper-type pouch-type packaging container) having a dispensing opening that can be freely opened or closed by a zipper or the like can be advantageously used.

[0060] [Method for improving granulation properties of fexofenadine hydrochloride] The present invention also relates to a method for improving the granulation properties of (A) fexofenadine hydrochloride by using (B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts. For example, by adding (B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts and (A) fexofenadine hydrochloride to the granulated product of the present invention, good granulation properties can be imparted to the granulated product. Here, the terms "improving granulation properties" and "imparting good granulation properties" have the same meaning and refer to better granulation properties than those obtained with (A) fexofenadine hydrochloride alone. For example, this means that the proportion of fine particles in the total weight is smaller and the median diameter D50 is increased compared to when fexofenadine hydrochloride is granulated alone. Although not particularly limited, the smaller the proportion of fine particles in the total weight, the better, but it is preferable that the proportion is at least 20% of the total weight. In this method, the amount of (B) ephedrine, the amount of (A) fexofenadine hydrochloride, the amount of optional components (C) anticholinergic component, and (D) binder, and the ratio of these components are the same as in the case of the granulated product or solid preparation.

[0061] [Tablet form] The form of the tablet is not particularly limited, and as described above, it may be plain tablet, orally rapidly disintegrating tablet, orally rapidly dissolving tablet, chewable tablet, effervescent tablet, troche, drop, film-coated tablet, sugar-coated tablet, caplet, pill, etc. According to the present invention, a solid preparation with good tableting properties can be obtained without adding a large amount of binder, etc., and therefore, solid preparations of various sizes can be prepared as needed in an amount that does not interfere with administration. For example, the weight per tablet is preferably, but not limited to, 30 to 800 mg, more preferably 100 to 800 mg, even more preferably 300 to 800 mg, even more preferably 300 to 600 mg, and most preferably 300 to 500 mg. Measurement can be performed using a general-purpose balance.

[0062] The tablet preferably has a diameter of 3.0 to 12.0 mm and a thickness of 2.0 to 7.0 mm. The thickness and diameter can be measured using a general-purpose caliper or the like. The hardness is not particularly limited as long as the effects of the present invention can be achieved, but from the viewpoint of achieving good dissolution, a hardness of about 40 to 200 N is preferred. The hardness in the present invention is a value measured using a hardness tester (PTB311E, manufactured by Pharma Test Co., Ltd.). [Example]

[0063] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

[0064] Example 1 Based on the prescription shown in Table 1, a mixture of 144 g of fexofenadine hydrochloride, 86.4 g of methylephedrine hydrochloride, 324 g of lactose hydrate, 108 g of partially pregelatinized starch, and 96 g of crystalline cellulose was placed in a fluidized bed granulator. The intake air temperature was set to 75°C, and the air volume was set to 20 to 50 m. 3 Under conditions of 1000 / h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed and dried to obtain granules. 10 g of the resulting granules were classified using six sieves with different mesh sizes: 500, 355, 250, 150, 106, and 75 μm, and the weight of the granules remaining on the sieves was measured. From each weight, the weight percentage of fine powder of 75 μm or less was calculated. Furthermore, the median diameter D50, which is the diameter corresponding to the 50% cumulative value of these cumulative distribution curves, was calculated using a standard method.

[0065] Example 2 Based on the prescription shown in Table 1, a mixture of 144 g of fexofenadine hydrochloride, 144 g of pseudoephedrine hydrochloride, 324 g of lactose hydrate, 108 g of partially pregelatinized starch, and 96 g of crystalline cellulose was placed in a fluidized bed granulator. The intake air temperature was set to 75°C, and the air volume was set to 20 to 50 m. 3Under conditions of 1000 / h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed and dried to obtain granules. 10 g of the resulting granules were classified using six sieves with different mesh sizes: 500, 355, 250, 150, 106, and 75 μm, and the weight of the granules remaining on the sieves was measured. From each weight, the weight percentage of fine powder of 75 μm or less was calculated. Furthermore, the median diameter D50, which is the diameter corresponding to the 50% cumulative value of these cumulative distribution curves, was calculated using a standard method.

[0066] Example 3 Based on the prescription shown in Table 1, a mixture of 120 g of fexofenadine hydrochloride, 240 g of pseudoephedrine hydrochloride, 270 g of lactose hydrate, 90 g of partially pregelatinized starch, and 80 g of crystalline cellulose was placed in a fluidized bed granulator. The intake air temperature was set to 75°C, and the air volume was set to 20 to 50 m. 3 Under conditions of 1000 / h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed and dried to obtain granules. 10 g of the resulting granules were classified using six sieves with different mesh sizes: 500, 355, 250, 150, 106, and 75 μm, and the weight of the granules remaining on the sieves was measured. From each weight, the weight percentage of fine powder of 75 μm or less was calculated. Furthermore, the median diameter D50, which is the diameter corresponding to the 50% cumulative value of these cumulative distribution curves, was calculated using a standard method.

[0067] Example 4 Based on the prescription shown in Table 1, a mixture of 120 g of fexofenadine hydrochloride, 240 g of pseudoephedrine hydrochloride, 0.4 g of total belladonna alkaloids, 270 g of lactose hydrate, 90 g of partially pregelatinized starch, and 80 g of crystalline cellulose was placed in a fluidized bed granulator. The intake air temperature was set to 75°C, and the air volume was set to 20 to 50 m. 3 Under conditions of 1000 / h, 300 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed and then dried to obtain granules. 10 g of the resulting granules were classified using six sieves with different mesh sizes: 500, 355, 250, 150, 106, and 75 μm, and the weight of the granules remaining on the sieves was measured. From each weight, the weight percentage of fine powder of 75 μm or less was calculated. Furthermore, the median diameter D50, which is the diameter corresponding to the 50% cumulative value of these cumulative distribution curves, was calculated using a standard method.

[0068] Comparative Example 1 Based on the prescription shown in Table 1, a mixture of 144 g of fexofenadine hydrochloride, 324 g of lactose hydrate, 108 g of partially pregelatinized starch, and 96 g of microcrystalline cellulose was placed in a fluidized bed granulator. The intake air temperature was set to 75°C and the air volume was 20 to 50 m 3 / h, and then dried to obtain granules. The weight percentage of fine powder of 75 μm or less and the median diameter D50 were determined in the same manner as in Example 1.

[0069] Table 1 shows the results of the investigation into the improvement of granulation properties (reduction in the proportion of fine powder, increase in median diameter D50) in Examples 1 to 4 and Comparative Example 1.

[0070] [Table 1]

[0071] In Comparative Example 1, the amount of powder (fine powder) of 75 μm or less accounted for 31.3% of the total, whereas in Examples 1 to 4, the amount of powder of 75 μm or less accounted for 12.8%, 0.5%, 2.0%, and 3.0%, respectively, of the total. This indicates that by blending ephedrine with fexofenadine hydrochloride, the amount of fine powder was reduced to less than half. It was also clear that the granules prepared in Comparative Example 1 were more likely to scatter to the surrounding area and adhere to equipment than the granules prepared in Example 1.

[0072] Furthermore, the median diameter D50 was 108.6 μm in Comparative Example 1, whereas the median diameter D50 was 184.8 μm, 259.4 μm, 229.8 μm, and 218.3 μm in Examples 1 to 4. This indicates that the median diameter of the granules obtained by granulating fexofenadine hydrochloride and ephedrines together was larger, and that there was an effect of increasing the particle size.

[0073] (Formulation example) Based on Prescription Example 1, granules were prepared by wet granulation and then compressed to prepare tablets of 360 mg each, with two tablets to be taken per day. Based on Prescription Examples 2 and 3, granules were prepared by wet granulation and then compressed to prepare tablets of 300 mg each, with four tablets to be taken per day. Based on Prescription Example 4, granules were prepared by wet granulation and then compressed to prepare tablets of 400 mg each, with six tablets to be taken per day.

[0074] [Table 2]

[0075] Based on Prescription Example 5, granules were prepared by dry granulation and then compressed to prepare tablets of 360 mg each, with two tablets to be taken per day. Based on Prescription Examples 6 and 7, granules were prepared by dry granulation and then compressed to prepare tablets of 300 mg each, with four tablets to be taken per day. Based on Prescription Example 8, granules were prepared by dry granulation and then compressed to prepare tablets of 400 mg each, with six tablets to be taken per day.

[0076] [Table 3]

[0077] Based on Prescription Example 9, 0.36 g of granules were prepared per packet, and two packets were taken per day. The same amount of granules was filled into hard capsules, and two capsules were taken per day. Based on Prescription Examples 10 and 11, 0.30 g of granules were prepared per packet, and four packets were taken per day. The same amount of granules was filled into hard capsules, and four capsules were taken per day. Based on Prescription Example 12, 0.40 g of granules were prepared per packet, and six packets were taken per day. The same amount of granules was filled into hard capsules, and six capsules were taken per day.

[0078] [Table 4]

Claims

1. (A) fexofenadine hydrochloride; (B) one or more ephedrines selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine; and Water-soluble cellulose polymers, starches, water-soluble vinyl polymers or sugars; and a granulated product obtained by wet granulation, in which the weight ratio of fine powder of 75 μm or less is 12.8% or less (however, (1) granulated products containing caffeine are excluded).

2. (A) fexofenadine hydrochloride; (B) one or more ephedrines selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine; and Water-soluble cellulose polymers, starches, water-soluble vinyl polymers or sugars; and a granulated product obtained by wet granulation, the granulated product having a median diameter D50 of 184.8 μm or more (excluding granulated products containing (1) caffeine).

3. (A) fexofenadine hydrochloride, (B) one or more ephedrines selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine; anticholinergic components; and Water-soluble cellulose polymers, starches, water-soluble vinyl polymers or sugars; A solid preparation comprising a granule obtained by wet granulation comprising: The solid formulation is a tablet, a granule, or a capsule. (However, the following cases (1) and (2) are excluded.) (1) When the granules contain caffeine; and (2) In the case where the solid preparation is a preparation containing, in addition to the granules, sustained-release granules having a sustained-release coating containing an acrylic water-insoluble polymer, a cellulose water-insoluble polymer, a glycerin fatty acid ester, and talc on the surface of core particles containing at least two or more drugs with different solubilities in water.

4. A solid preparation comprising the granules according to claim 1 or 2.

5. 5. The solid formulation according to claim 3, wherein the ephedrine (B) is contained in an amount of 0.5 to 2.0 parts by mass per part by mass of fexofenadine hydrochloride (A).

6. 6. The solid formulation according to claim 3, wherein (A) fexofenadine hydrochloride is contained in an amount of 60 to 120 mg per day.

7. The solid preparation according to any one of claims 3 to 6, further comprising a lubricant.

8. 8. The solid preparation according to claim 3, wherein the ephedrine (B) is methylephedrine hydrochloride and is contained in an amount of 60 to 100 mg per day.

9. 8. The solid preparation according to claim 3, wherein the ephedrine (B) is pseudoephedrine hydrochloride and is contained in an amount of 60 to 300 mg per day.

10. The solid preparation according to any one of claims 4 to 9, which is in the form of a tablet, granule, or capsule.

11. one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts; anticholinergic components; and Water-soluble cellulose polymers, starches, water-soluble vinyl polymers or sugars A method for improving the granulation properties of fexofenadine hydrochloride by wet granulation in the presence of (However, this does not include cases where the wet granulation is carried out in the presence of caffeine.)

12. (A) fexofenadine hydrochloride, (B) one or more ephedrines selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine; anticholinergic components; and Water-soluble cellulose polymers, starches, water-soluble vinyl polymers or sugars; and wet granulating the mixture, the solid formulation is a tablet, granule, or capsule; Producing a granulate by wet granulation; and A step of preparing a solid formulation in the form of tablets, granules, or capsules from the granulated product. A manufacturing method including (However, the following cases (1) and (2) are excluded.) (1) When the granules contain caffeine; and (2) In the case where the solid preparation is a preparation containing, in addition to the granules, sustained-release granules having a sustained-release coating containing an acrylic water-insoluble polymer, a cellulose water-insoluble polymer, a glycerin fatty acid ester, and talc on the surface of core particles containing at least two or more drugs with different solubilities in water.

Images