JP7780242B2 - Granules containing fexofenadine hydrochloride - Google Patents

Description

The present invention relates to a granule containing fexofenadine hydrochloride and ephedrines, and a solid formulation containing the same.

Fexofenadine hydrochloride, chemically known as 2-(4-{(1RS)-1-Hydroxy-4-[4-(hydroxydiphenylmethylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic acid monohydrochloride, not only has histamine H1 receptor antagonistic activity, but also inhibits the release of various chemical mediators, the release of inflammatory cytokines, and eosinophil migration. Due to these effects, formulations containing fexofenadine hydrochloride have already been put to practical use as a treatment for various allergic diseases, including allergic rhinitis, urticaria, and itching associated with skin diseases such as eczema, dermatitis, pruritus, and atopic dermatitis.

A technology has been proposed that aims to improve the stability of fexofenadine by granulating particles containing fexofenadine and a binder to prepare them into tablets, and by selecting the appropriate binder (Patent Document 1).

JP 2013-119540 A

There is a need to develop solid formulations containing granules with good granulation properties.

The present invention was developed based on the poor granulation properties of fexofenadine hydrochloride, which makes granulation difficult. As a result of extensive research, the inventors unexpectedly discovered that by creating a composition containing fexofenadine hydrochloride and one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts, granulation properties are improved and an excellent solid formulation can be produced, leading to the completion of the present invention.

That is, the present invention provides:
[1]
A granule containing (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts;
[2]
A solid formulation comprising a granule containing (A) fexofenadine hydrochloride and (B) 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) ephedrine 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]
Item 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 ephedrine (B) is methylephedrine hydrochloride and is contained in an amount of 60 to 100 mg per day;
[8]
Item 7. The solid formulation according to any one of Items 2 to 6, wherein the ephedrine (B) is pseudoephedrine hydrochloride and is contained in an amount of 60 to 300 mg per day;
[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 method for producing a solid formulation, comprising blending (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts, followed by granulation; and

The present invention makes it possible to obtain granules with good granulation properties and solid preparations obtained from them.

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 formulation containing the granule.

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

[(A) Fexofenadine Hydrochloride]
Fexofenadine ((RS)-2-[4-[1-hydroxy-4-[4-(hydroxy-diphenyl-methyl)-1-piperidyl]butyl]phenyl]-2-methyl-propionic acid) hydrochloride (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.

Fexofenadine may be either the R- or S-isomer, and either optically resolved or racemic may be used.

The dose (administration amount) of component (A) in the solid formulation 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.). While not limited, from the perspective of more significantly demonstrating the effects of the present invention, the typical 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.

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.

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

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

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

[(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., α action and β action, and is known to have bronchodilatory action and central antitussive action. Methylephedrine hydrochloride is commercially available or can be produced according to known methods.

Methylephedrine may be either the R- or S-isomer, and either optically resolved or racemic may be used.

The dosage (administration amount) of component (B-1) in the solid formulation 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 perspective of more significantly exhibiting the effects of the present invention, when component (B-1) is included, the daily oral dosage can typically 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, 72 mg per day is most preferred. This amount can also be contained in a single solid formulation.

When component (B-1) is included, the total content of component (B-1) in the solid formulation of the present invention is not limited, but from the perspective 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 formulation. The content of component (B-1) can be 20% by mass or less, preferably 15% by mass or less, and more preferably 12% by mass or less, based on the total amount of the solid formulation.

When component (B-1) is included, the total content of component (B-1) can be 0.1 to 20% by mass, preferably 1 to 15% by mass, more preferably 5 to 12% by mass, and even more preferably 8 to 12% by mass, based on the total mass of the solid formulation.

[(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., α action and β action, and is known to have bronchodilatory and central antitussive effects. Pseudoephedrine hydrochloride is commercially available or can be produced according to known methods.

Pseudoephedrine may be either the R- or S-isomer, and either optically resolved or racemic may be used.

The dosage (administration amount) of component (B-2) in the solid formulation 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 perspective of more significantly exhibiting the effects of the present invention, when component (B-2) is included, the daily oral dosage can typically be, for example, about 20 to about 400 mg of pseudoephedrine hydrochloride, 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.

When the solid formulation of the present invention contains the component (B-22), 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 formulation. The content of the component (B-2) can be 30% by mass or less, preferably 15% by mass or less, and more preferably 12% by mass or less, based on the total amount of the solid formulation.

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

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

The total content of component (B) in the solid formulation of the present invention is not limited, but from the perspective of more significantly exhibiting the effects of the present invention, for example, the content of each single (B) component (B-1) or (B-2) based on the total weight of the solid formulation 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. The total content of component (B) in the solid formulation of the present invention is not limited, but from the perspective of more significantly exhibiting the effects of the present invention, for example, the content of each single (B) component (B-1) or (B-2) based on the total weight of the solid formulation can be 12% by mass or less, and from the perspective of more significantly exhibiting the effects of the present invention, the content 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 ranges.

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

From the perspective 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 the weight ratio of component (A)/component (B-1), is within the range of 1.3 to 1.9. Preferably, the weight ratio of component (A)/component (B-1) is within the range of 1.3 to 1.8, more preferably within the range of 1.3 to 1.7, and most preferably 5/3.

From the perspective 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 1.0.

The solid formulation of the present invention can usually be administered 1 to 6 times a day, preferably 1 to 3 times a day, and most preferably twice a day. Therefore, a solid formulation of the present invention for single administration preferably contains an amount calculated by dividing the above-mentioned daily dose by the number of daily administrations. Furthermore, since the granulated product of the present invention also has a sustained effect, a high level of efficacy is maintained even when administered once or twice a day.

The granulated product and solid formulation of the present invention may further contain optional ingredients other than component (A) and component (B). One or more of these optional ingredients may be used in appropriate combination. A representative example of such optional ingredients is (C) an anticholinergic ingredient, such as a tropane alkaloid or a derivative thereof. Furthermore, it is preferable that the granulated product and solid formulation of the present invention 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.

[(C) Anticholinergic component]
In the present invention, the anticholinergic component can be exemplified by alkaloids having a tropane skeleton or derivatives thereof.Specific examples include tropane alkaloids (atropine, scopolamine, hyoscyamine, etc.) and their derivatives (for example, quaternary ammonium derivatives such as methylatropine, methylscopolamine, butylscopolamine, etc.), and components containing these alkaloids (Datura extract, total alkaloids of belladonna, belladonna cone, belladonna extract, total alkaloids of Scopolum cone, Scopolum cone, Scopolum extract, isopropamide iodide, methylscopolamine or its salt, butylscopolamine or its salt, etc.).These may also be in the form of pharmaceutically acceptable salts or solvates.Among these, total alkaloids of belladonna are particularly preferred, from the viewpoint of being able to have a better effect on the tableting properties of the solid preparation of the present invention.

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

One or more anticholinergic ingredients can be used in combination.

When an anticholinergic ingredient is contained in the solid formulation of the present invention, the anticholinergic ingredient can typically be administered to an adult in an amount of 0.1 to 100 mg of active ingredient per day. 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.

When an anticholinergic component is contained in the solid formulation of the present invention, the total content of the anticholinergic component, based on the total weight of the solid formulation, can be, for example, 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 in the case of total belladonna alkaloids. In some cases, it can be adjusted to approximately 0.02 to 0.06% by mass. In the case of Scopolia extract, belladonna extract, and Datura extract, it can be 0.1 to 40% by mass. In the case of isopropamide iodide, it can be 0.01 to 4% by mass.

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

[(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. The pharmaceutical uses of these components (D) may be 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.

When the granulated product of the present invention contains (D) a binder, 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 (A) fexofenadine hydrochloride, from the perspective of sufficiently enhancing the efficacy of (A) fexofenadine hydrochloride against allergic diseases, more significantly exhibiting the effects of the present invention, such as improved granulation properties, and from the perspective of cost-effectiveness. Because the granulated product of the present invention has improved granulation properties, it has good granulation properties even with a small amount of binder.

The granules of the present invention may contain other physiologically active ingredients in addition to fexofenadine hydrochloride and ephedrines, if desired.
Examples of such physiologically active ingredients include (1) sympathomimetic ingredients (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, 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, aspirin aluminum, 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-ibuthiamine, bis-bentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, Vitamin C [e.g., ascorbic acid, erythorbic acid, or derivatives thereof, etc.], vitamin D [e.g., ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrocholecalciferol, dihydrocholecalciferol, hydroxy ... rotachisterol, 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.], and (9) mucosal protecting components (e.g., aluminum-based mucosal protecting agents such as aminoacetic acid, dried aluminum hydroxide gel, and dihydroxyaluminum-aminoacetate salts; magnesium-based mucosal protecting agents such as magnesium aluminum metasilicate, aluminum silicate, hydrotalcite, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation products of aluminum hydroxide and sodium bicarbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation products of aluminum hydroxide, calcium carbonate and magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium silicate, and co-precipitation products of magnesium hydroxide and aluminum potassium sulfate).
These physiologically active ingredients may be in the free form or in the form of a salt.

Solid formulations containing the granules of the present invention are preferably orally administered compositions. Examples of dosage forms include 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 formulations containing granules containing fexofenadine hydrochloride and methylephedrine hydrochloride or pseudoephedrine hydrochloride are preferred from the standpoint of further demonstrating the effects of the present invention and versatility. Solid formulations prepared via granulation include granules, tablets, troches, hard capsules, and dry syrups. Of these, tablets or granules prepared via granulation are particularly preferred.

When the solid preparation containing the granules of the present invention is a tablet, granule, or capsule, from the viewpoint of the effects of the present invention and convenience of administration, the content of fexofenadine hydrochloride relative to the total weight of the solid preparation is typically 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.

When the solid preparation containing the granules of the present invention is a tablet, granule, or capsule, the content of ephedrines relative to the total weight of the solid preparation is typically 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 achieving the effects of the present invention. When a herbal medicine or herbal extract is used as the ephedrine, the content of the herbal medicine or herbal extract containing ephedrines relative to the total weight of the solid preparation is preferably 15 to 50% by mass.

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% to 90% by mass, more preferably 0.5 to 50% by mass, even more preferably 1 to 30% by mass, and most preferably 10 to 20% by mass, from the viewpoint of more significantly achieving the effects of the present invention.

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

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 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, and preservatives. In any case, these compositions may also contain antioxidants, sweeteners, acidulants, colorants, fragrances, and flavoring agents, as appropriate.

Solid formulations containing the granules of the present invention can be obtained by preparing fexofenadine hydrochloride, ephedrines, and optionally other physiologically active ingredients and additives using conventional methods, depending on the dosage form.

In addition, solid preparations containing the granules of the present invention are 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 allergen alleviates nasal allergy symptoms such as sneezing and runny nose.

The solid formulation containing the granules of the present invention is preferably obtained by simultaneously granulating fexofenadine hydrochloride and ephedrines, and the two ingredients are contained in a single formulation.

[Solid dosage form manufacturing method]
The solid preparation of the present invention can be produced by any known method as long as it includes 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.

Here, the granulation method can be an appropriate combination of extrusion granulation, pulverization granulation, dry compaction granulation, fluidized bed granulation, tumbling granulation, high-speed stirring granulation, etc.

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

When the solid formulation of the present invention is a capsule, a method can be used in which the granules obtained by granulation are filled into capsules.

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

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 (D) binder, and the ratio of these components are the same as in the solid formulation.

[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 in an SP package or a PTP package, or a form in which multiple doses (e.g., a large number of 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 a large number of tablets are packed together in a package is advantageous in terms of cost. In particular, a form in which a large number of 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.

[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, "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 refers to a smaller proportion of fine particles in the total weight and an increased median diameter D50 value compared to granulation of fexofenadine hydrochloride 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 amounts of (B) ephedrines, (A) fexofenadine hydrochloride, (C) anticholinergic component and (D) binder, which are optional ingredients, and the ratio of these ingredients are the same as in the case of the granulated product or solid preparation.

[Tablet form]
Here, 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, although not limited thereto, the weight per tablet is preferably 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.

The tablets preferably have a diameter of 3.0 to 12.0 mm and a thickness of 2.0 to 7.0 mm. Tablet thickness and diameter can be measured using a general-purpose caliper or similar. There are no particular limitations on their hardness as long as they can achieve the effects of the present invention, but from the perspective of achieving good dissolution, a hardness of approximately 40 to 200 N is preferred. The hardness values used in the present invention are values measured using a hardness tester (PTB311E, manufactured by Pharma Test).

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

Example 1
Based on the formulation 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 microcrystalline cellulose was loaded into a fluidized bed granulator. Under conditions of an intake air temperature setting of 75°C and an air volume of 20 to 50 ^m3 /h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed onto the mixture, which was then dried to obtain granules. Ten grams of the resulting granules were classified using six sieves with mesh sizes of 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 the cumulative distribution curve, was calculated according to a standard method.

Example 2
Based on the formulation 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 microcrystalline cellulose was loaded into a fluidized bed granulator. Under conditions of an intake air temperature setting of 75°C and an air volume of 20 to 50 ^m3 /h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed onto the mixture, which was then dried to obtain granules. Ten grams of the resulting granules were classified using six sieves with mesh sizes of 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 the cumulative distribution curve, was calculated according to a standard method.

Example 3
Based on the formulation 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 microcrystalline cellulose was loaded into a fluidized bed granulator. Under conditions of an intake air temperature setting of 75°C and an air volume of 20 to 50 ^m3 /h, 360 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed onto the mixture, which was then dried to obtain granules. Ten grams of the resulting granules were classified using six sieves with mesh sizes of 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 the cumulative distribution curve, was calculated according to a standard method.

Example 4
Based on the formulation 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 microcrystalline cellulose was loaded into a fluidized bed granulator. Under conditions of an intake air temperature setting of 75°C and an air volume of 20 to 50 ^m3 /h, 300 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed onto the mixture, which was then dried to obtain granules. Ten grams of the resulting granules were classified using six sieves with mesh sizes of 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 the cumulative distribution curve, was calculated according to a conventional method.

Comparative Example 1
Based on the formulation 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 charged into a fluidized bed granulator. 600 g of a 5% aqueous solution of polyvinylpyrrolidone was sprayed onto the mixture under conditions of an intake air temperature setting of 75°C and an air volume of 20 to 50 ^m3 /h, and the mixture was dried to obtain granules. The weight proportion of fine powder of 75 μm or less and the median diameter D50 were determined in the same manner as in Example 1.

The results of an investigation into improving granulation properties (reducing the proportion of fine powder and increasing the median diameter D50) for Examples 1 to 4 and Comparative Example 1 are shown in Table 1.

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 was 12.8%, 0.5%, 2.0%, and 3.0%, respectively. This shows that by blending ephedrine with fexofenadine hydrochloride, the amount of fine powder was reduced to more than half. It was also clear from the results 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.

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

(Formulation example)
Based on Formulation 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 Formulation 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 Formulation 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.

Based on prescription example 5, granules were prepared by dry granulation and then compressed into 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 into 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 into tablets of 400 mg each, with six tablets to be taken per day.

Based on prescription example 9, 0.36 g of granules were prepared per packet, with two packets taken per day. The same amount of granules was then filled into hard capsules, with two capsules taken per day. Based on prescription examples 10 and 11, 0.30 g of granules were prepared per packet, with four packets taken per day. The same amount of granules was then filled into hard capsules, with four capsules taken per day. Based on prescription example 12, 0.40 g of granules were prepared per packet, with six packets taken per day. The same amount of granules was then filled into hard capsules, with six capsules taken per day.

Claims (12)

(A) fexofenadine hydrochloride;
(B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts; and a water-soluble cellulose-based polymer, a starch, a water-soluble vinyl-based polymer, or a sugar;
A granulated product obtained by wet granulation, containing the above and having a weight ratio of fine powder of 75 μm or less of 12.8% or less (excluding (1) granulated products containing caffeine). (A) fexofenadine hydrochloride;
(B) one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts; and a water-soluble cellulose-based polymer, a starch, a water-soluble vinyl-based polymer, or a sugar;
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). (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) 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 . A solid preparation comprising the granules according to claim 1 or 2 . 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. The solid formulation according to claim 3, wherein (A) fexofenadine hydrochloride is contained in an amount of 60 to 120 mg per day. The solid preparation according to any one of claims 3 to 6, further comprising a lubricant. 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. 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. The solid formulation according to any one of claims 4 to 9, which is in the form of a tablet, granule, or capsule. one or more ephedrines selected from the group consisting of methylephedrine salts and pseudoephedrine salts;
A method for improving the granulation properties of fexofenadine hydrochloride by wet granulation in the presence of an anticholinergic component; and a water-soluble cellulose polymer, a starch, a water-soluble vinyl polymer , or a sugar (excluding the case where the wet granulation is carried out in the presence of caffeine ). (A) fexofenadine hydrochloride,
(B) one or more ephedrines selected from the group consisting of salts of methylephedrine and salts of pseudoephedrine;
an anticholinergic component; and a water-soluble cellulose polymer, a starch, a water-soluble vinyl polymer, or a sugar;
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) when the solid preparation contains, 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.