JP2019147797A - Granule containing fexofenadine hydrochloride - Google Patents

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

  The present invention relates to a granulated product containing fexofenadine hydrochloride and ephedrine and a solid preparation containing the same.

  Fexofenadine hydrochloride, chemical name 2- (4-{(1RS) -1-Hydroxy-4- [4- (hydroxydiphenylmethyl) piperidin-1-yl] butyl} phenyl) -2-methylpropanoic acid monohydrochloride 1 In addition to receptor antagonistic action, it has various chemical mediator release inhibitory actions, inflammatory cytokine release inhibitory actions, and eosinophil migration inhibitory action. Because of this action, formulations containing fexofenadine hydrochloride are allergic rhinitis, hives, and pruritus associated with skin diseases such as eczema / dermatitis, cutaneous pruritus, atopic dermatitis, It has already been put into practical use as a therapeutic agent for various allergic diseases.

  A technique for improving the stability of fexofenadine by granulating particles containing fexofenadine and a binder and selecting the binder is proposed (Patent Literature). 1).

JP 2013-119540 A

  There is a demand for the development of a solid preparation containing a granulated product having good granulation properties.

  The present invention is based on the fact that the granulation property of fexofenadine hydrochloride is poor and the granulation is difficult, and as a result of diligent investigation, it was surprising that fexofenadine hydrochloride and methyl It has been found that granulation improves by making a composition containing one or more ephedrines selected from the group consisting of a salt of ephedrine and a salt of pseudoephedrine, and an excellent solid preparation can be produced, The present invention has been completed.

That is, the present invention
[1]
A granulated product containing (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine;
[2]
A solid preparation comprising a granulated product containing (A) fexofenadine hydrochloride, and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine;
[3]
(A) The solid formulation of claim | item 2 which contains the said (B) ephedrine in the ratio of 0.5-2.0 mass parts with respect to 1 mass part of fexofenadine hydrochloride;
[4]
(A) The solid preparation according to Item 2 or 3, which contains 60 to 120 mg of fexofenadine hydrochloride as a daily dose;
[5]
Furthermore, the solid formulation of any one of claim | item 2 -4 containing an anticholinergic component;
[6]
Furthermore, solid preparation of any one of claim | item 2-5 containing a lubricant agent;
[7]
Item 7. The solid preparation 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 preparation 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 preparation 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 granulation of fexofenadine hydrochloride with one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine;
[11]
(A) fexofenadine hydrochloride, and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine, and granulated. Manufacturing method; etc. are provided.

  According to the present invention, a granulated product having good granulation properties and a solid preparation obtained therefrom can be obtained.

  The present invention provides a granulated product containing (A) fexofenadine hydrochloride, and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine, and the granulated product The present invention relates to a solid preparation containing a product.

  The fixed preparation of the present invention contains a granulated product, and in the granulated product of the present invention, (B) ephedrines have enhanced the effect on allergic diseases possessed by (A) fexofenadine hydrochloride. At the same time, the granulating property of fexofenadine hydrochloride having poor granulating property by itself can be improved.

[(A) Fexofenadine hydrochloride]
Fexofenadine ((RS) -2- [4- [1-hydroxy-4- [4- (hydroxy-diphenyl-methyl) -1-piperidyl] butyl] phenyl] -2-methyl- used in the present invention Propionic acid) hydrochloride (sometimes referred to herein as component (A)) is a compound known as a second generation antihistamine. Fexofenadine hydrochloride can be obtained as a commercial product or can be produced by a known production method.

  Fexofenadine may be either R-form or S-form, and optically separated or racemic form may be used.

  The dose (dosage) of component (A) in the solid preparation of the present invention is the amount of component (B), the type and amount of other components, and the condition of the user (weight, age, sex, symptoms, physical condition, etc.) However, from the viewpoint of exerting the effects of the present invention more remarkably, the oral dose per day is usually about 10 to about fexofenadine hydrochloride. 240 mg, more preferably from about 10 to about 200 mg, more preferably from about 20 to about 160 mg, even more preferably from about 30 to about 140 mg, particularly preferably from about 60 to about 120 mg. Can do. Or most preferably, it is 120 mg per day.

Content of (A) component in the solid formulation of this invention can be suitably set so that it may become said dose. Although not limited, from the viewpoint of more prominently exerting the effects of the present invention, for example, it can be 1% by mass or more, preferably 3% by mass or more, more preferably 5% by mass based on the total amount of the solid preparation. % Or more, still more preferably 10% by mass or more, 90% by mass or less, preferably 60% by mass or less, more preferably 50% by mass or less. it can.
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, based on the total amount of the solid preparation. Preferably it can be 10-50 mass%.

[(B) Ephedrines]
In the present specification, ephedrine refers to at least one selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine.

  In the present invention, the salt of methylephedrine or the salt of pseudoephedrine is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids, organic acids, inorganic bases, organic bases, and the like. For example, sulfate, hydrochloride, tartrate, maleate, fumarate, diphenyldisulfonate, theocrate, salicylate, tannate, besylate, napadisylate, phosphate, etc. Is mentioned. In the present invention, hydrochloride is preferable, and methylephedrine hydrochloride or pseudoephedrine hydrochloride is particularly preferable as ephedrines.

  Although the total content of the component (B) in the solid preparation of the present invention is not limited, it is preferably 1 to 20% by mass of the total amount of the solid preparation. The effect of the present invention and the component (B) relative to the component (A) are not particularly limited, and the component (B) is preferably 0.1 to 10 parts by mass relative to 1 part by mass of the component (A). And 0.5 to 2 parts by mass are particularly preferable.

[(B-1) methylephedrine hydrochloride]
As used in the present invention, methylephedrine ((1RS, 2SR) -2-dimethylamino-1-phenylpropan-1-ol) hydrochloride (sometimes referred to simply as component (B) in this specification) is It is a known compound that has a mechanism of action similar to that of ephedrine, that is, an α action and a β action, and is known to have a bronchodilating action and a central antitussive action. Methylephedrine hydrochloride can be obtained as a commercial product or can be produced according to a known method.

  Methylephedrine may be either R-form or S-form, and optically separated or racemic form may be used.

  The dose (dosage) of component (B-1) in the solid preparation of the present invention is the amount of component (A), the type and amount of other components, and the user's condition (weight, age, sex, symptoms, physical condition) Etc.) can be appropriately set according to the present invention, and is not limited. However, from the viewpoint of exhibiting the effects of the present invention more remarkably, when the component (B-1) is included, the oral dose per day is usually The methyl ephedrine hydrochloride can be about 10 to about 200 mg, 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. be able to. Or most preferably, it is 72 mg per day. This can be contained in one solid preparation.

  The total content of the component (B-1) in the solid preparation of the present invention is not limited when the component (B-1) is included, but from the viewpoint of more prominently exerting the effects of the present invention, for example, , Based on the total amount of the solid preparation, it can be 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 8% by mass or more, In some cases, it may be 10% by mass or more. (B-1) A component can be 20 mass% or less on the basis of the total amount of a solid formulation, Preferably it is 15 mass% or less, More preferably, it is 12 weight% or less.

  When the component (B-1) is included, the total content of the component (B-1) can be 0.1 to 20% by mass based on the total amount of the solid preparation. It can be made into 15 mass%, More preferably, it is 5-12 mass%, More preferably, it can be 8-12 mass%.

[(B-2) pseudoephedrine hydrochloride]
Pseudoephedrine ((1S, 2S) -2- (methylamino) -1-phenyl-1-propanol) hydrochloride (sometimes referred to as (B) component in the present specification) used in the present invention is: It is a known compound that has an action mechanism similar to that of ephedrine, that is, an α action and a β action, and is known to have a bronchodilator action and a central antitussive action. Pseudoephedrine hydrochloride can be obtained as a commercial product or can be produced according to a known method.

  The pseudoephedrine may be either R-form or S-form, and optically separated or racemic form may be used.

  The dose (dosage) of component (B-2) in the solid preparation of the present invention is the amount of component (A), the type and amount of other components, and the condition of the user (weight, age, sex, symptoms, physical condition) Etc.) can be appropriately set according to the present invention, and is not limited. However, from the viewpoint of exerting the effects of the present invention more remarkably, when the component (B-2) is included, the oral dose per day is usually For example, pseudoephedrine hydrochloride can be about 20 to about 400 mg, more preferably about 60 to about 300 mg, even more preferably about 100 to about 280 mg, particularly preferably about 120 to about 240 mg. can do.

  The total content of the component (B-2) in the solid preparation of the present invention is not limited when the component (B-22) is included, but from the viewpoint of more prominently exerting the effects of the present invention, for example, , Based on the total amount of the solid preparation, it can be 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 8% by mass or more, In some cases, it may be 10% by mass or more. (B-2) A component can be 30 mass% or less on the basis of the total amount of a solid formulation, Preferably it is 15 mass% or less, More preferably, it is 12 weight% or less.

  When (B-2) component is contained, the total content of (B-2) component can be 0.1-30 mass% on the basis of the total amount of a solid formulation, for example, Preferably 5-12 mass%, More preferably, it can be 8-12 mass%.

  The solid preparation of the present invention only needs to contain either one of the component (B-1) or the component (B-2), and in some cases, both the component (B-1) and the component (B-2) May be contained. The solid preparation of the present invention preferably contains either (B-1) component or (B-2) component.

  Although the total content of the component (B) of the solid preparation of the present invention is not limited, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, based on the total amount of the solid preparation, (B-1) or (B-2) Each component (B) can be 0.1% by mass or more, preferably 1% by mass or more, more preferably 5% by mass or more, and even more preferably 8% by mass or more. In some cases, it may be 10% by mass or more. Although the total content of the component (B) in the solid preparation of the present invention is not limited, from the viewpoint of exhibiting the effects of the present invention more remarkably, for example, based on the total amount of the solid preparation, (B-1) or (B-2) Each single (B) component is 12% by mass or less, and preferably 11.5% by mass or less from the viewpoint of exhibiting the effects of the present invention more remarkably, More preferably, it can be 11 mass% or less. However, since the component (B) is preferably each of the components (B-1) or (B-2), the total amount of the component (B) is preferably those values. .

  The total content of component (B) is, for example, 0.1 to 12% by mass for each single component (B) based on the total amount of the solid preparation (B-1) or (B-2). Preferably 12 to 12% by weight, more preferably 5 to 12% by weight, even more preferably 7 to 12% by weight, and most preferably 8 to 12% by weight. It can be 11 mass%.

  From the standpoint of achieving the effect of the present invention, the blending ratio of the total content of the component (A) and the total content of the component (B-1) is a weight ratio represented by the component (A) / (B-1). In this case, it is within the range of 1.3 to 1.9. Preferably, the weight ratio represented by component (A) / component (B-1) is in the range of 1.3 to 1.8, more preferably in the range of 1.3 to 1.7. Most preferably, it is 5/3.

  From the standpoint of achieving the effect of the present invention, the blending ratio of the total content of the component (A) and the total content of the component (B-2) is the weight ratio indicated by the component (A) / (B-2). In this case, it is in the range of 0.5 to 1.0. Preferably, the weight ratio represented by (A) component / (B-2) component is 0.5 or 1.

  The solid preparation of the present invention can be administered usually 1 to 6 times a day, preferably 1 to 3 times a day, and most preferably 2 times a day. Therefore, the solid preparation of the present invention for a single administration preferably contains an amount obtained by dividing the above-mentioned daily dose by the number of administrations per day. In addition, since the granulated material of this invention also has the sustainability of an effect, even if it is once or twice a day administration, a high effect will be continued.

  The granulated product and solid preparation of the present invention may further contain any component other than the component (A) and the component (B). Such optional components can be used alone or in combination of two or more thereof. A typical example of such an optional component is preferably (C) an anticholinergic component such as a tropane alkaloid or a derivative thereof. Furthermore, it is preferable that the granulated product and solid preparation of the present invention do not contain caffeine. Caffeine may volatilize, precipitate as crystals, and grow. That is, a crystal called a whisker (whisker crystal) may be formed to deteriorate the quality of the product.

[(C) Anticholinergic component]
In the present invention, the anticholinergic component is exemplified by alkaloids having a tropane skeleton or derivatives thereof. Specifically, tropane alkaloids (atropine, scopolamine, hyoscyamine and the like) and derivatives thereof (for example, quaternary ammonium derivatives such as methylatropine, methyl scopolamine and butyl scopolamine) and components containing these alkaloids (datsura extract, belladonna Total alkaloid, belladon nacon, belladonna extract, rotcon total alkaloid, rotcon, funnel extract, isopropamide iodide, methyl scopolamine or a salt thereof, butyl scopolamine or a salt thereof, and the like. These may be in the form of a pharmaceutically acceptable salt or solvate. Among these, the belladonna total alkaloid is particularly preferable from the viewpoint that it can have a better influence on the tableting property of the solid preparation of the present invention.

  Here, preferable specific examples of the salt include bromide salts (for example, butyl scopolamine bromide), hydrobromides (for example, scopolamine hydrobromide hydrate), citrates (for example, rotocon total And alkaloid citrate). Examples of solvates include hydrates.

  As an anticholinergic component, one or a combination of two or more can be used.

  When the anticholinergic component is contained in the solid preparation of the present invention, the anticholinergic component can be usually administered in an amount of 0.1 to 100 mg as an active ingredient amount per day for an adult. For example, in the case of total belladonna alkaloids, 0.01 to 1 mg, preferably 0.4 to 0.6 mg, 1 to 100 mg in the funnel extract, belladonna extract and duck extract, and 0.1 to 10 mg in the case of isopropamide iodide. Can be orally administered once to several times a day.

  When the anticholinergic component is contained in the solid preparation of the present invention, the total content of the anticholinergic component is, for example, 0.02 to 0.1 in the case of belladonna total alkaloid, based on the total amount of the solid preparation. It can be made into the mass%, Preferably it is 0.03-0.1 mass%, More preferably, it can be 0.03-0.06 mass%. Depending on the case, it can also adjust to about 0.02-0.06 mass%. In the case of funnel extract, belladonna extract, and duck extract, it can be 0.1 to 40% by mass. In the case of isopropamide iodide, it can be 0.01-4 mass%.

  From the viewpoint of achieving the effect of the present invention, the blending ratio of the component (A) and the component (C) is 1 part by mass of the component (A), and 0.001 part by mass to 0.00. The amount is preferably 005 parts by mass.

[(D) binder]
The granulated product of the present invention preferably further contains the following (D) binder from the viewpoint of more remarkably exhibiting the effect of the present invention that granulates well. The (D) binder that can be included in the granulated product of the present invention is not limited, and may be a poorly water-soluble binder (crystalline cellulose, low-substituted hydroxypropylcellulose), but a water-soluble binder is preferable. In particular, when the granulated product of the present invention is a composition that has undergone a granulation process, a water-soluble binder is preferred. The water-soluble binder that can be contained in the granulated product of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically or physiologically acceptable. Any of molecules, starches, water-soluble vinyl polymers, polyethers, and saccharides may be used. Specific examples of the polysaccharide include gum arabic, agar, gum tragacanth, sodium alginate, carrageenan, xanthan gum, guar gum, dextran, pullulan, pectin, chitosan, hemirose and the like. Specific examples of the protein include gelatin and purified gelatin. Specific examples of the water-soluble cellulose polymer include carmellose or a salt thereof, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and hydroxyethylcellulose. Specific examples of starches include starch (wheat starch, corn starch, potato starch, etc.), pregelatinized starch, dextrin, cyclodextrin, carboxymethyl starch, hydroxypropyl starch, hydroxyethyl starch, partially pregelatinized starch and the like. It is done. Specific examples of the water-soluble vinyl polymer include polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, and copolydon. Examples of the acrylic polymer include sodium polyacrylate. Specific examples of polyethers include macrogol. Specific examples of the saccharide include sucrose syrup, fructose, sugar alcohols (eg, xylitol, sorbitol), glucose and the like. The use of these components (D) on the formulation may be other than the binder. Among the above binders, cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose; starches such as potato starch, corn starch and pregelatinized starch; and vinyl polymers comprising polyvinylpyrrolidone, polyvinyl alcohol and the like A more preferable water-soluble polymer binder (also referred to herein as a water-soluble binder) is preferred, and hydroxypropylcellulose and polyvinylpyrrolidone are more preferred.

  When the granulated product of the present invention contains (D) a binder, the present invention includes (A) a viewpoint of sufficiently enhancing the effect of fexofenadine hydrochloride on allergic diseases and a viewpoint of improving granulation. From the viewpoint of producing the effect of the above, and from the viewpoint of cost effectiveness, (D) the binder is preferably 0.03 to 2.0 parts by mass with respect to 1 part by mass of (A) fexofenadine hydrochloride. More preferably, it contains 0.05-1.7 mass parts, More preferably, it contains 0.08-1.5 mass parts. Since the granulated product of the present invention has improved granulation properties, the granulation properties are good even with a small amount of binder.

If desired, the granulated product of the present invention may contain other physiologically active ingredients in addition to fexofenadine hydrochloride and ephedrines.
Examples of such physiologically active components include (1) sympathomimetic components (eg phenylephrine (phenylphenylamine, ephedrine, ethylephrine, methoxamine, middolin, methoxyphenamine, etc.),
(2) Anti-inflammatory enzymes (eg lysozyme, serrapeptase, bromelain, pronase)
(3) herbal medicines and herbal medicine-derived components (for example, shrimp, carrot, mao, keihi, kei-gai, saishin, shin-i, nantenjitsu, parrot, beak, zenko, kyoto, shazenshi, gooh, gadju, peony, sojutsu, gentian, fennel , Onji, Awaku, Auren, Chikutsujinjin, Chimpi, Clove, Senega, Shazenso, Shajin, etc.)
(4) Xanthine derivatives (for example, theophylline, aminophylline, theobromine, diprofeline, proxyphylline, pentoxyphylline, etc.),
(5) antipyretic analgesic components (for example, aspirin, aspirin aluminum, acetaminophen, etenzamide, sazapyrine, salicylamide, sodium salicylate, lactylphenetidine, ibuprofen, ketoprofen, etc.)
(6) Antitussive components (for example, achloramide, cloperastine, pentoxyberine (carbettapentane), tipepidine, dibutate, dextromethorphan, codeine, dihydrocodeine, noscapine, etc.)
(7) expectorants (for example, potassium guaiacol sulfonate, guaifenesin, etc.),
(8) vitamins (for example, vitamins A [for example, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, etc.), vitamins B [for example, thiamine, thiamine disulfide, discetiamine, octothiamine, chicotiamine, bisive Thiamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folate, tetrahydrofolate, dihydrofolate, nicotine Acid, nicotinamide, nicotinyl alcohol, pantothenic acid, panthenol, biotin, choline, inositol, etc.], vitamin C [eg ascorb Acid, erythorbic acid, or derivatives thereof], vitamin Ds [eg ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, dihydrotaxosterol, etc.], vitamin E [eg tocopherol and Derivatives thereof, ubiquinone derivatives, etc.], other vitamins [eg, hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, etc.], and (9) mucosal protective components (eg, aminoacetic acid) , Dry aluminum hydroxide gel, aluminum-based mucosal protective agent such as dihydroxyaluminum / aminoacetate; magnesium metasilicate magnesium aluminate, aluminum silicate, hydrotalcite, magnesium aluminate hydroxide, hydroxide Luminium gel, coprecipitation product of aluminum hydroxide / sodium bicarbonate, aluminum hydroxide / magnesium carbonate mixed dry gel, coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide , Magnesium-based mucosal protective agents such as coprecipitation products of magnesium silicate, magnesium hydroxide and potassium aluminum sulfate).
These physiologically active ingredients may be free forms or salts.

  The solid preparation containing the granulated product of the present invention is preferably an oral administration composition. The dosage form includes tablets (including plain tablets, intraoral quick disintegrating tablets, chewable tablets, effervescent tablets, jelly-like drops, drops, film-coated tablets, dragees, caplets, pills, etc.) Examples thereof include solid preparations such as agents, granules, pills, dry syrups, powders (including fine granules), and capsules (including hard capsules and soft capsules). Among these, a solid preparation containing a granulated product containing fexofenadine hydrochloride and methylephedrine hydrochloride or pseudoephedrine hydrochloride is preferable from the viewpoint of further exerting the effects of the present invention and versatility. Solid preparations prepared through granulation include granules, tablets, troches, hard capsules, dry syrups and the like. Among these, tablets or granules prepared through granulation are particularly preferable.

  When the solid preparation containing the granulated product of the present invention is a tablet, granule, or capsule, the content of fexofenadine hydrochloride relative to the total amount of the solid preparation from the viewpoint of the effect of the present invention and convenience of administration Is usually 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 granulated product of the present invention is a tablet, granule, or capsule, the content of ephedrine relative to the total amount of the solid preparation is usually from the viewpoint of more prominently achieving the effects of the present invention. It is 0.03-57.0 mass%, Preferably it is 0.5-30 mass%, More preferably, it is 1-20 mass%. When using a crude drug or a Chinese medicine extract as ephedrines, content of the crude drug or a Chinese medicine extract containing the ephedrines with respect to the total amount of a solid agent becomes like this. Preferably it is 15-50 mass%.

  When the solid preparation containing the granulated product of the present invention is a tablet, granule, or capsule, the solid content of the (D) binder with respect to the total amount of the solid agent from the viewpoint of exhibiting the effects of the present invention more remarkably. The content is preferably 0.5 to 90% by mass, more preferably 0.5 to 50% by mass, further preferably 1 to 30% by mass, and most preferably 10 to 20% by mass.

  Although (D) binder here is not limited, It is preferable that it is a water-soluble binder. The granulated product of the present invention exhibits the effects of the present invention remarkably by containing an appropriate amount of a water-soluble binder with respect to the total mass of the granulated product and composition.

  The granulated product of the present invention may contain an appropriate additive depending on the dosage form. Examples of such additives include solid preparations (eg, tablets, capsules, powders), excipients (eg, sucrose, lactose, mannitol, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (For example, sucrose fatty acid ester, magnesium stearate, talc, etc.), disintegrant (for example, low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium, etc.), foaming agent (for example, sodium bicarbonate, etc.), flow Examples thereof include agents such as sodium aluminate metasilicate and light anhydrous silicic acid. The use of these additives in the preparation may be other than those described above. Moreover, oily bases (for example, vegetable oils such as olive oil, corn oil, soybean oil, sesame oil, cottonseed oil; medium chain fatty acid triglycerides, etc.), aqueous bases (for example, Macrogol 400, water), gel bases (for example, carboxyvinyl) Polymers, gums, etc.), surfactants (eg, polysorbate 80, hydrogenated castor oil, glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agents (eg, white beeswax, various surfactants, soybean lecithin, etc.) , Dispersants, emulsifiers, stabilizers, buffers, solubilizers, pH adjusters, preservatives (preservatives), and the like. In any case, an antioxidant, a sweetener, a sour agent, a colorant, a fragrance, a flavoring agent, and the like may be appropriately added to these compositions.

  The solid preparation containing the granulated product of the present invention is prepared by a conventional method of fexofenadine hydrochloride and ephedrine, and other physiologically active ingredients and additives used as required depending on the dosage form. Can be obtained.

  In addition, the solid preparation containing the granulated product of the present invention has symptoms such as allergic rhinitis (perennial allergic rhinitis and seasonal allergic rhinitis (hay fever) caused by allergens such as mites, house dust, and pollen. Nasal inflammation, etc.) or urticaria, and pruritus associated with skin diseases such as eczema / dermatitis, cutaneous pruritus, and atopic dermatitis. The granulated product of the present invention is particularly useful for reducing allergic symptoms in patients with allergic rhinitis. In particular, by containing (A) fexofenadine hydrochloride and (B) ephedrines, nasal allergic symptoms such as sneezing and runny nose are alleviated.

  The solid preparation containing the granulated product of the present invention is preferably obtained by granulating fexofenadine hydrochloride and ephedrine at the same time, and the two components are preferably included in one preparation.

[Method for producing solid preparation]
The solid preparation of the present invention can be produced by any known method as long as it undergoes a granulation step. If necessary, a sterilization step can be included. The preparation can also be produced by mixing each component according to or in accordance with the 17th revised Japanese Pharmacopoeia General Rules.

  Here, as the granulation method, an extrusion granulation method, a pulverization granulation method, a dry compaction granulation method, a fluidized bed granulation method, a rolling granulation method, a high-speed stirring granulation method, or the like may be used in an appropriate combination. Can do.

  When the solid preparation of the present invention is a tablet, for example, it can be prepared by combining a granulation method and a tableting method. For example, an indirect compression method such as a wet granule tableting method or a dry granule tableting method can be used. The solid preparation of the present invention may be a sugar-coated tablet or a film-coated tablet with a coating. Furthermore, the solid preparation of the present invention may be a monolayer tablet or a laminated tablet such as a bilayer tablet. In the present invention, the solid preparation may be a monolayer tablet prepared by a wet granulation tablet method.

  When the solid preparation of the present invention is a capsule, a method of filling a granule obtained by granulation into a capsule can be used.

  The solid preparation of the present invention may be a sugar-coated tablet or a film-coated tablet with a coating. Furthermore, the solid preparation of the present invention may be a monolayer tablet or a laminated tablet such as a bilayer tablet. In the present invention, the solid preparation may be a monolayer tablet prepared by a wet granulation tablet method.

  Also in the production method of the present invention, (B) the amount of ephedrines, (A) the amount of fexofenadine hydrochloride, (C) the amount of the anticholinergic component, (D) the amount of the binder, and those The component ratio is the same as in the case of the solid preparation.

[Packaging]
The solid preparation of the present invention can be provided in any packaging form. For example, the packaging form may be one tablet, one capsule, one package, or a single package for each dose, such as SP packaging or PTP packaging, or any container (for example, Fill multiple doses (for example, multiple tablets) together in a glass or plastic bottle container, or a pouch-type packaging container made of a film of synthetic resin or aluminum foil. However, it may take a form that is repeatedly opened and continuously used for each dose. The latter form in which a large number of tablets are packed together and filled into a package is advantageous in terms of cost. In particular, a form in which a large number of tablets and capsules are packed together in a pouch-type packaging container (such as a zipper-type pouch-type packaging container) having an outlet that can be opened and closed by a zipper or the like can be advantageously used.

[Method for improving the granulating properties of fexofenadine hydrochloride]
The present invention also relates to a method for improving the granulation property of (A) fexofenadine hydrochloride by one or more ephedrines selected from the group consisting of (B) a salt of methylephedrine and a salt of pseudoephedrine. . For example, by allowing the granulated product of the present invention to coexist with (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine and (A) fexofenadine hydrochloride, Good granulation property can be imparted to the granulated product. Here, “improving granulation” and “providing good granulation” can be used in the same meaning, and (A) than granulation of fexofenadine hydrochloride alone, Say good. For example, it means that the proportion of fine particles in the whole is reduced and the value of the median diameter D50 is increased compared to the case where granulation is performed with fexofenadine hydrochloride alone. Although there is no particular limitation, it can be said that the smaller the proportion of the weight of the fine particles in the total weight, the better, but it is preferably at least 20% or less of the total. Also in this method, the amount of (B) ephedrine, (A) the amount of fexofenadine hydrochloride, (C) the anticholinergic component, (D) the amount of the binder, and the ratio of these components are This is the same as in the case of granules or solid preparations.

[Tablet form]
Here, the form of the tablet is not particularly limited, and as described above, uncoated tablet, intraoral quick disintegrating tablet, intraoral quick dissolving tablet, chewable tablet, effervescent tablet, troche, drop agent, film-coated tablet, sugar-coated tablet , Caplets, pills and the like. According to the present invention, a solid preparation with good tableting properties can be obtained without adding a large amount of a binder or the like. can do. Although these are not limited, for example, the weight per tablet is preferably 30 to 800 mg, more preferably 100 to 800 mg, further preferably 300 to 800 mg, and 300 to 600 mg. Even more preferably, it is most preferably 300-500 mg. The measurement can be performed using a general-purpose balance.

  The tablet preferably has a tablet diameter of 3.0 to 12.0 mm and a tablet thickness of 2.0 to 7.0 mm. The tablet thickness and the tablet diameter can be measured using a general purpose caliper or the like. The hardness is not particularly limited as long as the effect of the present invention can be obtained, but is preferably about 40 to 200 N from the viewpoint of achieving good elution. The hardness of the present invention is a value measured using a hardness meter (PTB311E, manufactured by Pharma Test).

  Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Example 1
Based on the recipe shown in Table 1, a fluidized bed granulator was charged with 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. did. 360 g of 5% polyvinylpyrrolidone aqueous solution was sprayed there under conditions of an intake air temperature setting of 75 ° C. and an air volume of 20 to 50 m ³ / h, and dried to obtain granules. 10 g of the obtained granule was classified using a sieve having six different mesh sizes of 500, 355, 250, 150, 106, and 75 μm, and the weight remaining on the sieve was measured. From each weight, the ratio of the weight of the fine powder amount of 75 μm or less to the whole was calculated. Further, a median diameter D50, which is a diameter corresponding to a 50% cumulative value of these cumulative distribution curves, was calculated based on a conventional method.

Example 2
Based on the recipe shown in Table 1, a fluidized bed granulator was charged with 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. 360 g of 5% polyvinylpyrrolidone aqueous solution was sprayed there under conditions of an intake air temperature setting of 75 ° C. and an air volume of 20 to 50 m ³ / h, and dried to obtain granules. 10 g of the obtained granule was classified using a sieve having six different mesh sizes of 500, 355, 250, 150, 106, and 75 μm, and the weight remaining on the sieve was measured. From each weight, the ratio of the weight of the fine powder amount of 75 μm or less to the whole was calculated. Further, a median diameter D50, which is a diameter corresponding to a 50% cumulative value of these cumulative distribution curves, was calculated based on a conventional method.

Example 3
Based on the recipe shown in Table 1, a fluidized bed granulator was charged with 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. 360 g of 5% polyvinylpyrrolidone aqueous solution was sprayed there under conditions of an intake air temperature setting of 75 ° C. and an air volume of 20 to 50 m ³ / h, and dried to obtain granules. 10 g of the obtained granule was classified using a sieve having six different mesh sizes of 500, 355, 250, 150, 106, and 75 μm, and the weight remaining on the sieve was measured. From each weight, the ratio of the weight of the fine powder amount of 75 μm or less to the whole was calculated. Further, a median diameter D50, which is a diameter corresponding to a 50% cumulative value of these cumulative distribution curves, was calculated based on a conventional method.

Example 4
Based on the recipe shown in Table 1, the fluidized bed granulator was charged with 120 g of fexofenadine hydrochloride, 240 g of pseudoephedrine hydrochloride, 0.4 g of belladonna total alkaloid, 270 g of lactose hydrate, 90 g of partially pregelatinized starch, 80 g of crystalline cellulose. Of the mixture. Thereto, 300 g of a 5% polyvinylpyrrolidone aqueous solution was sprayed under conditions of an intake air temperature setting of 75 ° C. and an air volume of 20 to 50 m ³ / h, and dried to obtain granules. 10 g of the obtained granule was classified using a sieve having six different mesh sizes of 500, 355, 250, 150, 106, and 75 μm, and the weight remaining on the sieve was measured. From each weight, the ratio of the weight of the fine powder amount of 75 μm or less to the whole was calculated. Further, a median diameter D50, which is a diameter corresponding to a 50% cumulative value of these cumulative distribution curves, was calculated based on a conventional method.

Comparative Example 1
Based on the recipe shown in Table 1, a fluidized bed granulator was charged with a mixture of 144 g of fexofenadine hydrochloride, 324 g of lactose hydrate, 108 g of partially pregelatinized starch, and 96 g of crystalline cellulose. Thereto was sprayed 600 g of 5% polyvinylpyrrolidone aqueous solution under the conditions of an intake air temperature setting of 75 ° C. and an air volume of 20 to 50 m ³ / h, and dried to obtain granules. In the same manner as in Example 1, the weight ratio of the fine powder amount of 75 μm or less and the median diameter D50 were determined.

  Table 1 shows the results of investigations on granulation improvement (reduction of the fine powder amount ratio, increase of the median diameter D50) of Examples 1 to 4 and Comparative Example 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% of the total, 0.5%, 2.0%, and 3.0%. That is, it turns out that the amount of fine powder has decreased to half or less by mix | blending ephedrine with fexofenadine hydrochloride. It was obvious that the granules prepared in Comparative Example 1 were more scattered to the surroundings and attached to the device than the granules prepared in Example 1.

  In Comparative Example 1, the 3 diameter D50 is 108.6 μm, whereas in Examples 1 to 4, the median diameter D50 is 184.8 μm, 259.4 μm, 229.8 μm, and 218.3 μm, respectively. . From this, it was shown that the median diameter of the granule obtained by granulation with fexofenadine hydrochloride and ephedrine is increased, and that there is an effect of increasing the particle diameter.

(Formulation example)
Based on Formulation Example 1, granules were prepared by wet granulation, and then tableted to prepare 360 mg tablets, which were taken as 2 tablets per day. Based on Formulation Examples 2-3, wet granulation was performed to prepare granules, and then tableting was performed to prepare 300 mg tablets, which were taken as 4 tablets per day. Based on Formulation Example 4, granules were prepared by wet granulation and then tableted to prepare 400 mg tablets, which were taken 6 tablets per day.

  Based on Formulation Example 5, dry granulation was performed to prepare granules, and tableting was performed to prepare 360 mg tablets, which were taken 2 tablets per day. Based on Formulation Examples 6 to 7, after dry granulation to prepare granules, tableting was performed to prepare 300 mg tablets, and 4 tablets per day were taken. Based on Formulation Example 8, dry granulation was performed to prepare granules, followed by tableting to prepare 400 mg tablets, which were taken 6 tablets per day.

  Based on Formulation Example 9, 0.36 g of granules per sachet were prepared and used for 2 sachets per day. In addition, the same amount of this granule was filled into a hard capsule to take 2 capsules per day. Based on Formulation Examples 10 to 11, 0.30 g of granules per package were prepared and used for 4 packages per day. In addition, the same amount of the granule was filled into a hard capsule to take 4 capsules per day. Based on Formulation Example 12, 0.40 g of granules per sachet were prepared and used for 6 sachets per day. In addition, the same amount of the granules were filled into hard capsules to take 6 capsules per day.

Claims (11)

A granulated product containing (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine. A solid preparation comprising a granulated product comprising (A) fexofenadine hydrochloride and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine. (A) The solid formulation of Claim 2 which contains the said (B) ephedrine in the ratio of 0.5-2.0 mass parts with respect to 1 mass part of fexofenadine hydrochloride. (A) The solid formulation of Claim 2 or 3 which contains 60-120 mg of fexofenadine hydrochloride as a dosage per day.   Furthermore, the solid formulation of any one of Claims 2-4 containing an anticholinergic component.   Furthermore, the solid formulation of any one of Claims 2-5 containing a lubricant.   The solid preparation according to any one of claims 2 to 6, wherein the (B) ephedrine is methylephedrine hydrochloride, and contains 60 to 100 mg as a daily dose.   The solid preparation according to any one of claims 2 to 6, wherein the (B) ephedrine is pseudoephedrine hydrochloride and contains 60 to 300 mg as a daily dose.   The solid preparation according to any one of claims 2 to 8, which is in the form of a tablet, granule, or capsule.   A method for improving the granulating property of fexofenadine hydrochloride by one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine. (A) fexofenadine hydrochloride, and (B) one or more ephedrines selected from the group consisting of a salt of methylephedrine and a salt of pseudoephedrine, and granulated. Production method.