Solid composition and method for producing the same

Abstract

To provide a solid composition having sufficient hardness and containing at least one selected from the group consisting of tipepidine and salts thereof. [Solution] A solid composition containing licorice and at least one selected from the group consisting of tipepidine and salts thereof.

Description

[Technical Field]

[0001] The present invention broadly relates to a solid composition containing at least one selected from the group consisting of tipepidine and salts thereof and licorice, and a method for producing the same. [Background technology]

[0002] Orally administered solid compositions such as tablets disintegrate in the digestive tract, and the active ingredients in the compositions are then absorbed into the body. From the viewpoints of transportability and wear resistance, it is extremely important in designing a formulation that the solid composition has a certain level of hardness or higher.

[0003] Since some active ingredients of pharmaceuticals reduce the hardness of solid compositions, techniques for improving the hardness of solid compositions have been investigated.

[0004] For example, Patent Document 1 discloses a composition that contains a disintegrant component and microfibrous cellulose, and thereby has excellent tablet hardness and disintegrability without containing any excipients.

[0005] Patent Document 2 discloses a method for improving the hardness of tablets and suppressing the delay in disintegration time by incorporating crystalline cellulose into granules obtained by wet granulating a mixture containing a main ingredient and compressing the granules. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2020 / 022053 [Patent Document 2] Japanese Patent Application Laid-Open No. 2005-047861 Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventors have found that the hardness of a solid composition containing at least one selected from the group consisting of tipepidine and salts thereof can be reduced. Therefore, an object of the present invention is to provide a solid composition containing at least one selected from the group consisting of tipepidine and salts thereof, which has sufficient hardness. [Means for solving the problem]

[0008] The present inventors have discovered that when licorice is added to at least one selected from the group consisting of tipepidine and its salts, the decrease in hardness caused by at least one selected from the group consisting of tipepidine and its salts is suppressed, and have completed the present invention.

[0009] That is, this embodiment includes the following aspects. [1] A solid composition comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice. [2] The solid composition according to [1], which contains a granulated product containing at least one selected from the group consisting of tipepidine and salts thereof and licorice. [3] The solid composition according to [1] or [2], further comprising acetaminophen. [4] The solid composition according to [2], wherein the granules further contain acetaminophen. [5] The solid composition according to any one of [1] to [4], wherein the solid composition has a hardness of 40 N or more. [6] A method for producing the solid composition according to any one of [1] to [5], comprising a step of mixing at least one selected from the group consisting of tipepidine and salts thereof with licorice. [7] The manufacturing method described in [6], further comprising a step of mixing acetaminophen. [8] forming a granulation product containing at least one selected from the group consisting of tipepidine and a salt thereof, and licorice; A step of compressing the granules into tablets; The manufacturing method according to [6], comprising: [9] The manufacturing method according to [8], wherein in the step of forming the granules, a granule containing at least one selected from the group consisting of tipepidine and salts thereof, licorice, and acetaminophen is formed. [Effects of the Invention]

[0010] According to the present invention, a solid composition having sufficient hardness and containing at least one selected from the group consisting of tipepidine and salts thereof can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, an embodiment of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not to be construed as being limited to the following embodiment. In the present embodiment, the composition may contain each component either alone or in combination of two or more. In this specification, the symbol "to" indicating a numerical range means "at least" or "at most", and includes both of the numerical values ​​at both ends.

[0012] (solid composition) In a first aspect, there is provided a solid composition comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice. The solid composition is in particular a solid pharmaceutical composition.

[0013] Each component contained in the solid composition according to this embodiment may be contained in the form of a pharmacologically acceptable salt, or may be contained as a complex with another component. That is, the solid composition according to this embodiment may contain salts of not only tipepidine but also acetaminophen and other components. "Pharmacologically acceptable salts" include, for example, salts with pharmaceutically acceptable bases or acids. Non-limiting specific examples of pharmacologically acceptable salts include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids. The pharmacologically acceptable salt may be a hydrated salt or an anhydrous salt.

[0014] In this embodiment, the solid composition contains licorice in addition to at least one selected from the group consisting of tipepidine and salts thereof, and therefore has sufficient hardness.

[0015] The hardness of the solid composition in this embodiment is determined by the "Tablet Hardness Measurement Method" in the Reference Information of the 18th Edition of the Japanese Pharmacopoeia. <g6-4-180>". More specifically, the hardness may be measured in the form of a tablet obtained by tableting with a 9φ, 10.8R punch at a pressure of 1,000 kgf in a tablet press. The volume of the tablet when measuring the hardness is not particularly limited, but may be 400 mg per tablet. More specifically, the hardness of the solid composition in this embodiment may be measured by the method described in the Examples.

[0016] The hardness of the solid composition measured as described above is preferably 40 N or more, more preferably 40 to 250 N, more preferably 50 N or more, even more preferably 50 to 200 N, even more preferably 55 to 150 N, even more preferably 60 to 120 N, and particularly preferably 65 to 100 N.

[0017] (At least one selected from the group consisting of tipepidine and salts thereof) As used herein, "tipepidine" refers to the compound having the CAS Registry Number 5169-78-8 and C 15 H 17 It is a compound represented by the chemical formula NS2 (molecular weight: 275.43 g / mol). The salt of tipepidine is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include tipepidine hibenzate and tipepidine citrate.

[0018] The amount of at least one selected from the group consisting of tipepidine and its salts is adjusted appropriately depending on the use of the solid composition, the required level of antitussive and expectorant effect, the required level of hardness, the symptoms, age, weight, sex, etc. of the subject to be administered. Note that the amount and content of at least one selected from the group consisting of tipepidine and its salts described below are the amounts and contents of tipepidine and tipepidine salts, respectively, but it is preferable that the total amount and content of tipepidine and tipepidine salts fall within the ranges of the amount and content described below.

[0019] The amount of at least one compound selected from the group consisting of tipepidine and its salts can be adjusted, for example, in the range of 8 mg to 120 mg, more preferably 16 mg to 72 mg, as the amount administered to an adult per day. In this embodiment, "adult" refers to men and women aged 15 years or older. However, the solid composition according to this embodiment is not limited to that for adults, but may also be that for children under 15 years of age. When administered to children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount administered to adults per day depending on the age group. The same applies to ingredients other than at least one compound selected from the group consisting of tipepidine and its salts.

[0020] The weight and dosage of the solid composition described above are the daily dosage (daily dose), but the same amount may be administered to a subject in a single dose or multiple times a day, for example, two or three times, preferably three divided doses. The same applies to components other than at least one selected from the group consisting of tipepidine and its salts. Furthermore, since each dosage is a total amount, the content of each component contained in the solid composition may vary depending on the single dose, the dosage form of the solid composition, etc.

[0021] In a specific embodiment, the solid composition is a tablet, and the dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient contained in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3, and the single dose is 2, 3, or 4 tablets, preferably 3 tablets.

[0022] (Daylily) As used herein, "licorice" can refer to those listed in the 18th edition of the Japanese Pharmacopoeia. Licorice includes, for example, those using water or 30% ethanol aqueous solution as an extraction solvent. Various extracts, such as licorice extract, licorice dried extract, licorice soft extract, and licorice liquid extract, are commercially available with various crude drug equivalent ratios depending on the type of extract. The amounts of licorice described herein are values ​​converted to crude drug equivalents unless otherwise specified. For example, licorice soft extract contains approximately 4 parts by mass of licorice in crude drug equivalent ratio per 1 part by mass of extraction solvent. In addition to these licorice extracts, powdered extracts (extract powders) of licorice extracted with water or 30% ethanol aqueous solution, licorice extracts, and licorice extract liquids may also be used as appropriate and are not particularly limited. However, a preferred extract is a dried licorice extract containing about 5 to about 9 parts by mass, for example, about 6 to about 8 parts by mass of licorice, calculated as an original herbal medicine, per 1 part by mass of extraction solvent.The extraction solvent is preferably water.

[0023] Licorice contains, as a main component, at least one selected from the group consisting of glycyrrhizic acid and its salts. As used herein, "glycyrrhizic acid" refers to glycyrrhizic acid having CAS Registry Number 1405-86-3 and C 42 H 62 O 16 (Molecular weight: 822.93 g / mol) The salt of glycyrrhizinic acid is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, dipotassium glycyrrhizinate, and monopotassium glycyrrhizinate.

[0024] Therefore, in the solid composition according to this embodiment, at least one selected from the group consisting of glycyrrhizinic acid and its salts may be blended in place of and / or in addition to licorice. Licorice may contain at least one selected from the group consisting of glycyrrhizinic acid and its salts in an amount of 2.0% or more based on the dried herbal product. Licorice powder may contain at least one selected from the group consisting of glycyrrhizinic acid and its salts in an amount of 2.0% or more based on the dried herbal product. Licorice extract may contain at least one selected from the group consisting of glycyrrhizinic acid and its salts in an amount of 3.6% or more based on the dried herbal product. Licorice crude extract may contain at least one selected from the group consisting of glycyrrhizinic acid and its salts in an amount of 4.8% or more based on the dried herbal product. In the solid composition according to this embodiment, the total content of glycyrrhizinic acid and its salts may be, for example, in the range of 0.01 to 0.1 times (e.g., 0.02 times, 0.036 times, 0.04 times, 0.048 times) the licorice content described below.

[0025] The extract can be obtained by conventional methods, such as extracting the active ingredients from the herbal medicine using an extraction solvent. The extraction solvent is often water, a hydrophilic solvent, or a mixture thereof. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; ethers such as dioxane and tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or in combination.

[0026] The amount of licorice to be added is adjusted as appropriate depending on the purpose of the solid composition, the required level of hardness, and the symptoms, age, weight, sex, etc. of the subject to be administered. The amount of licorice to be added is, for example, in the range of 100 mg to 5,000 mg, preferably 200 mg to 2,000 mg, more preferably 50 mg to 1,200 mg per day, calculated as the amount of the crude drug.

[0027] The content of licorice in the composition administered daily is 1% by mass to 70% by mass, preferably 5% by mass to 50% by mass, and more preferably 10% by mass to 30% by mass, calculated as the amount of the crude drug.

[0028] The mass ratio of the total amount of tipepidine and its salts to licorice contained in the composition administered daily, expressed as the ratio of the total amount of tipepidine and its salts to licorice converted to crude drug, is preferably 1:20 to 1:1, more preferably 1:15 to 1:2, and even more preferably 1:10 to 1:3. When licorice extract powder is used as the licorice, the mass ratio of the total amount of tipepidine and its salts to licorice extract powder is preferably 1:2 to 10:1, more preferably 1:1 to 5:1, and even more preferably 2:1 to 3:1.

[0029] From the viewpoint of further increasing the hardness of the solid composition according to this embodiment, it is preferable that licorice is contained in the same granule as at least one selected from the group consisting of tipepidine and its salts. That is, the solid composition according to this embodiment preferably contains a granule containing at least one selected from the group consisting of tipepidine and its salts and licorice, and preferably contains a granule obtained by granulating a mixed powder containing at least one selected from the group consisting of tipepidine and its salts and licorice. The solid composition according to this embodiment may be a tablet obtained by compressing the granules. However, the solid composition according to this embodiment may be a tablet produced by a direct compression method in which a mixed powder containing at least one selected from the group consisting of tipepidine and its salts and licorice is directly compressed, or may be a powder obtained by dissolving at least one selected from the group consisting of tipepidine and its salts and licorice in a solvent and then drying and evaporating the solvent, or a tablet produced by optionally granulating the powder and then compressing it. In such an embodiment, at least one selected from the group consisting of tipepidine and its salts and licorice are present in close proximity in the solid composition, and the effect of licorice in increasing the hardness of the solid composition containing at least one selected from the group consisting of tipepidine and its salts tends to be more effectively achieved.

[0030] (Acetaminophen) The solid composition according to this embodiment may further contain acetaminophen. The inclusion of acetaminophen tends to further improve the hardness of the solid composition. As used herein, "acetaminophen" refers to a compound with CAS Registry Number 103-90-2 and the chemical formula C8H9NO2. The salt of acetaminophen is not particularly limited as long as it is pharmacologically acceptable.

[0031] The amount of acetaminophen to be added is adjusted as appropriate depending on the purpose of the solid composition, the required level of hardness, and the symptoms, age, weight, sex, etc. of the subject to be administered. When acetaminophen is included, the amount to be added varies depending on the amount of at least one selected from the group consisting of tipepidine and salts thereof, but can be adjusted to within the range of 120 mg to 1200 mg, preferably 150 mg to 900 mg, and more preferably 180 mg to 600 mg per day.

[0032] The mass ratio of the total amount of tipepidine and its salts to acetaminophen contained in the composition administered daily is preferably 1:10 to 3:1, more preferably 1:5 to 2:1, and even more preferably 1:2 to 1:1, in terms of the ratio of the total amount of tipepidine and its salts to acetaminophen.

[0033] From the viewpoint of further increasing the hardness of the solid composition according to this embodiment, acetaminophen is preferably contained in the same granule as at least one selected from the group consisting of tipepidine and its salts, and is preferably contained in the same granule as at least one selected from the group consisting of tipepidine and its salts and licorice. That is, the solid composition according to this embodiment preferably contains a granule containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen, and preferably contains a granule obtained by granulating a mixed powder containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen. The solid composition according to this embodiment may be a tablet obtained by compressing the granules, which are the granules. From a similar viewpoint, the solid composition according to this embodiment may be a tablet produced by direct compression, in which a mixed powder containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen is directly compressed, or may be a powder obtained by dissolving at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen in a solvent and then distilling the solvent off to dryness, or a tablet produced by optionally granulating the powder and then compressing the powder into tablets. In such an embodiment, tipepidine and at least one selected from the group consisting of its salts, licorice, and acetaminophen are present in close proximity in the solid composition, which tends to further improve the hardness of the solid composition.

[0034] (Other ingredients) The solid composition according to this embodiment may contain ingredients other than those described above depending on its intended use. When the solid composition is intended to relieve cold symptoms, such as runny nose, stuffy nose, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine and meloxicam, the solid composition may contain active ingredients such as antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), or other pharmacologically acceptable ingredients.

[0035] Nonsteroidal anti-inflammatory drugs are broadly classified into non-selective COX-2 inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and selective COX-2 inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be incorporated into the composition as a nonsteroidal anti-inflammatory drug. Preferably, the nonsteroidal anti-inflammatory drug is a non-selective COX-2 inhibitor. The nonsteroidal anti-inflammatory drug may be in the form of a salt.

[0036] Other pharmacologically acceptable ingredients may be added, such as antihistamines, antipyretics, expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmin agents, which are typically added to general cold medicines, antipyretics, and rhinitis medicines.

[0037] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisilate, promethazine methylenedisalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, mequitazine, and the like.

[0038] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, isopropylantipyrine, etc.

[0039] Antitussive and expectorant drugs include noscapine, noscapine hydrochloride hydrate, dextromethorphan hydrobromide hydrate, bromhexine, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0040] Anti-inflammatory drugs include glycyrrhizinic acid and its derivatives and salts thereof (for example, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid, etc.

[0041] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0042] Vitamin preparations include vitamin B1 and its derivatives and salts thereof (e.g., benfotiamine), vitamin B2 and its derivatives and salts thereof (e.g., riboflavin), vitamin C and its derivatives and salts thereof (e.g., ascorbic acid), hesperidin and its derivatives and salts thereof, etc.

[0043] Anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scopolia extract, Scopolia root, and Scopolia root total alkaloid citrate.

[0044] If necessary, formulation additives may be added to the solid composition according to this embodiment. Examples of formulation additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, flavorings, aromas, coloring agents, bases, coating agents, sugar-coating agents, plasticizers, dispersants, antifoaming agents, fluidizing agents, and flavorings and fragrances. Formulation additives that can be used in conventionally known solid formulations may be used for the above purposes.

[0045] Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch-crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminum metasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0046] Examples of binders include gum arabic, powdered gum arabic, dried plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0047] Examples of disintegrants include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0048] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

[0049] Examples of glossing agents include carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0050] Examples of foaming agents include dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, and anhydrous citric acid.

[0051] Examples of moisture-proofing agents include ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid esters, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

[0052] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0053] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and dichloromethane. Iron, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, hydrated silicon dioxide, carmellose sodium, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, chondroitin. Sodium leucine sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glycerin monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0054] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. In the case of a solid composition containing acetaminophen, it is preferable not to add tocopherols as antioxidants or stabilizers.

[0055] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, and calcium hydrogen phosphate.

[0056] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin sodium hydrate, sucralose, stevia extract, purified stevia extract, refined sucrose, fructose, sucralose, maltitol, D-mannitol, and erythritol.

[0057] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Phellodendron extract, Coptis chinensis, Coptis chinensis powder, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, saccharin sodium hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, and sucrose. Examples include snowbell powder, sucralose, stevia extract, purified stevia extract, Swertia japonica, D-sorbitol, tannic acid, clove oil, tangerine tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, bittern powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, ryunou, ryunou powder, green tea powder, DL-malic acid, DL-sodium malate, lemon oil, and rose oil.

[0058] Examples of the cooling agent include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0059] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0060] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginkgo powder, spearmint oil, clove oil, turpentine, chili pepper powder, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0061] Examples of colorants include yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, ferric oxide, diaz azo yellow, Food Blue No. 1, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide-glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, and rose oil.

[0062] Bases include: gum arabic powder, pregelatinized starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerin, potato starch, Hydroxypropyl cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0063] Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, aqueous ethyl cellulose dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, a mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hypromellose. Hydroxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methylacrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0064] Examples of sugar-coating agents include gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, refined sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0065] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

[0066] Dispersants include aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, light anhydrous silicic acid, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, and low-substituted hydroxypropyl cellulose. , dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0067] Antifoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane-silicon dioxide mixtures, sucrose fatty acid esters, silicone antifoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0068] Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0069] Examples of flavoring agents and fragrances include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar flavor, spearmint oil, cherry flavor, clove oil, chili flavor, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter essence, vitabase, Himalayan cedar oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, ryunou, ryunou powder, lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0070] These components may be contained alone or in combination of two or more.

[0071] (Dosage form) The solid composition of this embodiment can be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as preparations for oral administration (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, powders, etc.), preparations for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition of this embodiment is preferably an oral solid composition.

[0072] The dosage form of the solid composition of this embodiment may be, for example, a tablet, a capsule, a pill, a granule, or a fine granule. These solid compositions may be coated with sugar coating, film coating, or the like by a known method, as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0073] The solid composition of this embodiment may be temporarily packaged in a bottle, PTP, pouch, stick, or SP package and then stored airtight. These may then be pillow-packaged, or stored in a box or the like. The material used for the pillow packaging is not particularly limited, and examples include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. If moisture absorption is a concern, a desiccant or the like may be stored simultaneously in the bottle packaging or pillow packaging.

[0074] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition of this embodiment may be contained in, for example, an airtight package. By forming the solid composition into a package, for example, convenience during use of the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0075] As for the packaging form of the solid preparation, the solid composition may be temporarily packaged and stored airtight in a bottle, PTP (Press-Through Package), pouch, stick, or SP (Strip Package) or the like. These may also be pillow-packaged, or may be stored in a box or the like. Furthermore, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant or the like may be stored in the packaging container, such as the bottle or pillow package, at the same time.

[0076] Materials used for SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as these resin films with aluminum foil attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0077] Furthermore, it is preferable that the material constituting the packaging container contains a material that is resistant to the effects of moisture. Examples of such packaging include packaging made of at least one of a moisture-proof material and a gas barrier material.

[0078] An example of a moisture-proof material is a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. When the solid composition is a tablet, PTP packaging (Al-Al packaging) with aluminum on both sides may be used as the moisture-proof material, taking into consideration the prevention of an increase in the moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0079] Any known gas barrier material may be used, for example, a laminate film having a functional barrier layer, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material.

[0080] Furthermore, the packaging container may be environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material.

[0081] (Manufacturing method) In a second aspect, there is provided a method for producing a solid composition, comprising the step of mixing at least one selected from the group consisting of tipepidine and salts thereof with licorice.

[0082] The method for producing the solid composition according to this embodiment may further include a step of mixing acetaminophen.

[0083] The solid composition can be produced using known techniques. The components are added at any step and finally brought into contact with each other. After contact, a solvent and a binder may be added to the mixture, followed by kneading, to produce a solid composition.

[0084] The resulting kneaded product can be further subjected to a drying process and a granulation process to produce granules (granulated material). In this case, granules (granulated material) containing each component may be prepared separately. Granulation may be performed by either a wet method or a dry method.

[0085] The obtained granules (granulated product) can be used as they are or can be mixed with additives and compressed into tablets to produce plain tablets, which can then be further film-coated.

[0086] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the "Tablets" section of the Japanese Pharmacopoeia's General Provisions for Preparations. Specifically, a mixed powder containing at least one selected from the group consisting of tipepidine and its salts, licorice, and optionally acetaminophen, is granulated to obtain a granule (granule), and then the obtained granule and optional extragranular components are compressed to produce a tablet. Alternatively, a mixed powder containing at least one selected from the group consisting of tipepidine and its salts to obtain first granules, a mixed powder containing licorice is granulated to obtain second granules, and these two types of granules and any extragranular components are compressed to produce a tablet. From the viewpoint of increasing the hardness of the solid composition, it is preferable to granulate a mixed powder containing at least one selected from the group consisting of tipepidine and its salts, and licorice to form a granulated product (granules), and to include both ingredients in the same granulated product, and it is even more preferable to include acetaminophen in the same granulated product.

[0087] When a solid formulation contains an extragranular component, a final component may be added to the granulated granules to form an extragranular component, and the mixture may be compressed to produce a tablet. Alternatively, the extragranular component may be in the form of granules. For example, granulated granules containing at least one selected from the group consisting of tipepidine and its salts and licorice may be produced as the first granules, and granulated granules containing other active ingredients may be produced as the second granules. In this case, the first granules containing at least one selected from the group consisting of tipepidine and its salts and licorice may be prepared separately from the second granules containing other active ingredients, and the solid formulation may be produced so that the ingredients in the first granules and the other active ingredients in the second granules are not substantially in contact with each other. The other active ingredients may be contained in either the first granules or the second granules, depending on the formulation.

[0088] The granules obtained in the above steps may be used as a granule formulation as they are.

[0089] In order to explain the present invention in more detail, examples are described below, but the present invention is not limited to these. [Example]

[0090] 1.Raw materials In this example, the following raw materials were used: The licorice extract powder described below has a crude drug equivalent ratio of 7:1, that is, it is a 7-fold concentrated crude drug. [Table 1]

[0091] 2. Granulation production Granules containing tipepidine hibenzate, licorice extract powder, or acetaminophen were prepared as follows. An appropriate amount of ethanol was added to each raw material, and the mixture was kneaded and granulated using a mortar and pestle. The granules were vacuum dried and then sieved through a 30-mesh sieve to produce granules. As shown in Tables 2 and 3, the co-granules of tipepidine hibenzate and licorice extract powder were prepared by blending the raw materials at a mass ratio of tipepidine hibenzate to licorice extract powder of 2:1 (2:7 when licorice is used as an original herbal drug). The co-granules of tipepidine hibenzate, licorice extract powder, and acetaminophen were prepared by blending the raw materials at a mass ratio of tipepidine hibenzate to licorice extract powder to acetaminophen of 1:1:1 (1:7:1 when licorice is used as an original herbal drug).

[0092] 3. Tablet manufacturing and hardness measurement Each raw material was weighed to a total of 2.5 g at the blending ratios shown in Tables 2 and 3, and then uniformly mixed in a bottle to prepare each tablet powder. The blending ratio of each component in Tables 2 and 3 is expressed in parts by mass. Each tablet powder was compressed using a 9φ, 10.8R punch in a hand press tableting machine (manufactured by Riken Seiki) at a pressure of 1,000 kgf to produce 400 mg tablets. Note that in Tables 2 and 3, the components labeled "granulated product" were granulated products obtained by the method described in "2. Production of Granulated Product." Specifically, for example, using Examples 1 and 2 listed in Table 2, Example 1 used 40 parts by mass of tipepidine hibenzate powder and 20 parts by mass of licorice extract powder, while Example 2 used 60 parts by mass of a co-granulated product containing tipepidine hibenzate and licorice extract powder in a mass ratio of 2:1. The hardness (unit: N) of each tablet was measured using a load cell type tablet hardness tester Tablet Tester 8M (manufactured by Pharmatron). The measured values ​​are shown in Tables 2 and 3.

[0093] [Table 2]

[0094] [Table 3]

[0095] As shown in Table 2, the solid compositions containing licorice and at least one selected from the group consisting of tipepidine and its salts had higher hardness than solid compositions not containing licorice. In addition, the solid compositions containing granules obtained by co-granulating licorice and at least one selected from the group consisting of tipepidine and its salts had particularly high hardness. Furthermore, as shown in Table 3, the solid compositions containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen had higher hardness than the solid compositions not containing licorice. Furthermore, the solid compositions obtained by co-granulating at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen had particularly high hardness.

[0096] Examples of solid preparations are shown below. In the following preparation examples, glycyrrhizic acid, the main component of licorice, is added instead of licorice, but licorice may be added instead of glycyrrhizic acid.

[0097] [Table 4]

[0098] [Table 5]

[0099] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible within the scope of the present invention.

Claims

1. A solid composition comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice.

2. The solid composition according to claim 1, comprising a granulated product containing licorice and at least one selected from the group consisting of tipepidine and salts thereof.

3. 10. The solid composition of claim 1, further comprising acetaminophen.

4. 3. The solid composition of claim 2, wherein the granulation further comprises acetaminophen.

5. The solid composition according to any one of claims 1 to 4, wherein the solid composition has a hardness of 40 N or more.

6. A method for producing the solid composition according to any one of claims 1 to 4, comprising a step of mixing at least one selected from the group consisting of tipepidine and salts thereof with licorice.

7. 7. The method of claim 6, further comprising the step of mixing acetaminophen.

8. forming a granulation product containing at least one selected from the group consisting of tipepidine and a salt thereof, and licorice; A step of compressing the granules into tablets; The method of claim 6, comprising:

9. The method according to claim 8, wherein in the step of forming a granule, a granule containing at least one selected from the group consisting of tipepidine and a salt thereof, licorice, and acetaminophen is formed.

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