Solid composition and method for producing the same

Abstract

Providing a solid composition containing at least one selected from the group consisting of tipelpidine and its salts, which has sufficient hardness. 【Solution means】A solid composition containing at least one selected from the group consisting of tipelpidine and its salts and licorice.

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 its salts and licorice, and a method for producing the same.

Background Art

[0002] Solid compositions such as tablets for oral administration disintegrate in the digestive tract, and then the active ingredient in the composition is absorbed into the body. From the viewpoints of transportability and abrasion resistance, it is extremely important in the formulation design that the solid composition has a hardness of a certain level or more.

[0003] Since there are active ingredients of pharmaceuticals that lower the hardness of solid compositions, techniques for improving the hardness of solid compositions have been studied.

[0004] For example, Patent Document 1 discloses a composition having excellent tablet hardness and disintegrability without containing an excipient by containing a disintegrant component and microfibrous cellulose.

[0005] Patent Document 2 discloses a method for improving the hardness of a tablet and suppressing the delay of the disintegration time by blending crystalline cellulose in the granules obtained by tableting the granules obtained by wet granulating a mixture containing the main drug.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0007] The inventor has found that in a solid composition containing at least one selected from the group consisting of tipepidine and its salts, the hardness can decrease. 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 its salts and having sufficient hardness.

Means for Solving the Problems

[0008] The inventor has found that when glycyrrhiza is blended with 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 thus the present invention has been completed.

[0009] That is, the present embodiment includes the following aspects. [1] A solid composition containing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza. [2] The solid composition according to [1], containing a granulated product containing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza. [3] The solid composition according to [1] or [2], further containing acetaminophen. [4] The solid composition according to [2], wherein the granulated product further contains acetaminophen. [5] The solid composition according to any one of [1] to [4], wherein the hardness of the solid composition is 40 N or more. [6] A method for producing the solid composition according to any one of [1] to [5], including a step of mixing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza. [7] The production method according to [6], further including a step of further mixing acetaminophen. [8] The step of forming a granule containing at least one selected from the group consisting of tipepidine and its salts, and licorice; The step of tabletting the granule; The production method according to [6], comprising: [9] In the step of forming the granule, a granule containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen is formed, according to the production method of [8]. [Advantages of the Invention]

[0010] According to the present invention, a solid composition containing at least one selected from the group consisting of tipepidine and its salts and having sufficient hardness can be provided. [Modes for Carrying Out the Invention]

[0011] Hereinafter, embodiments of the present invention (hereinafter referred to as "the present embodiment") will be described, but the scope of the present invention is not construed as being limited to the following embodiments. In the present embodiment, the composition can contain each component alone or in combination of two or more. In this specification, "~" indicating a numerical range represents "above" and "below", and includes both end values.

[0012] (Solid Composition) In a first aspect, a solid composition containing at least one selected from the group consisting of tipepidine and its salts and licorice is provided. The solid composition is specifically a solid pharmaceutical composition.

[0013] Each component contained in the solid composition according to the present embodiment may be contained in the state of a pharmaceutically acceptable salt or may be contained as a complex with other components. That is, the solid composition according to the present embodiment may contain salts of each component, for example, not only tipepidine but also acetaminophen and other components. "Pharmaceutically acceptable salts" include, for example, salts with bases and acids acceptable as pharmaceuticals. Non-limiting specific examples of pharmaceutically 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 acid, 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, etc. The pharmaceutically acceptable salts may be hydrates or anhydrous salts.

[0014] In this embodiment, since the solid composition contains licorice in addition to at least one selected from the group consisting of tipepidine and its salts, it 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 Revised Japanese Pharmacopoeia" <g6-4-180>It is the hardness measured by the method described in 「」. More specifically, it may be the above hardness measured in the form of tablets obtained by tableting with a tableting machine at a pressure of 1,000 kgf using a 9φ, 10.8R punch. The volume of the tablets when measuring the hardness is not particularly limited, but may be 400 mg per tablet. More specifically, the hardness of the solid composition in the present embodiment may be the hardness 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, still more preferably 50 N or more, still more preferably 50 to 200 N, still more preferably 55 to 150 N, still 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 its salts) As used herein, "tipepidine" has a CAS registration number of 5169-78-8 and is a compound represented by the chemical formula of C 15 H 17 NS2 (molecular weight: 275.43 g / mol). The salts of tipepidine are not particularly limited as long as they are pharmacologically acceptable, and examples include tipepidine hibenzate and tipepidine citrate.

[0018] The blending amount of at least one selected from the group consisting of tipepidine and its salts is appropriately adjusted according to the use of the solid composition, the degree of the required antitussive and expectorant effects, the degree of the required hardness, the symptoms, age, body weight, gender, etc. of the subject to be administered. In addition, the following blending amounts and contents of at least one selected from the group consisting of tipepidine and its salts are the blending amounts and contents for each of tipepidine and its salts, but it is preferable that the total blending amount and content of tipepidine and its salts fall within the ranges of the blending amounts and contents described below.

[0019] The dosage of at least one 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 per day administered to adults. In this embodiment, "adult" means men and women aged 15 or older. However, the solid composition according to this embodiment is not limited to those for adults to take, and may be for children under 15 years old to take. When children take it, it can be used after reducing the amount taken by adults per day, such as 1 / 2 or 2 / 3, according to each age group. The same applies to components other than at least one selected from the group consisting of tipepidine and its salts.

[0020] The weight and dosage of the above solid composition are the dosage per day (one-day dose), but the same amount can be administered to the subject once or divided into multiple times a day, for example, 2 times or 3 times, preferably 3 times. The same applies to components other than at least one selected from the group consisting of tipepidine and its salts. Also, since each dosage is the total amount, the content of each component contained in the solid composition can vary depending on the single dose and the dosage form of the solid composition.

[0021] In a specific embodiment, the solid composition is a tablet, and the above dosage is the amount of the component contained in 3 tablets, 6 tablets or 9 tablets, preferably the amount of the component in 9 tablets. In this embodiment, the number of times of taking for an adult (15 years old or older) is 3 times, and the single dose is 2 tablets, 3 tablets or 4 tablets, preferably the single dose is 3 tablets.

[0022] (Licorice) As used herein, "Licorice Root" can be the one listed in the 18th Revised Japanese Pharmacopoeia. As Licorice Root, for example, there are those extracted with water, 30% aqueous ethanol solution, etc. as the extraction solvent. For example, depending on the type of extract such as Licorice Root extract, Licorice Root dry extract, Licorice Root soft extract, Licorice Root fluid extract, etc., various crude drug conversion ratios are sold. The description of the amount of Licorice Root in this specification is the value converted to crude drug unless otherwise specified. For example, Licorice Root soft extract contains about 4 parts by mass of Licorice Root in terms of crude drug conversion ratio per 1 part by mass of the extraction solvent. In addition to these Licorice Root extracts, extracts obtained by powdering extracts of Licorice Root extracted with water, 30% aqueous ethanol solution, etc. (extract powder), Licorice Root extracts, Licorice Root extracts, etc. may be appropriately used and are not particularly limited. However, an extract powder obtained by drying a Licorice Root dry extract containing about 5 to about 9 parts by mass, for example, about 6 to about 8 parts by mass of Licorice Root in terms of crude drug conversion ratio per 1 part by mass of the extraction solvent is preferred. The extraction solvent is preferably water.

[0023] In addition, Licorice Root contains at least one selected from the group consisting of glycyrrhizic acid and its salts as the main component. As used herein, "glycyrrhizic acid" has a CAS registration number of 1405-86-3 and is a compound represented by the chemical formula of C 42 H 62 O 16 (molecular weight: 822.93 g / mol). The salts of glycyrrhizic acid are not particularly limited as long as they are pharmacologically acceptable. Examples include trisodium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate.

[0024] Therefore, in the solid composition according to the present embodiment, at least one selected from the group consisting of glycyrrhizic acid and its salts may be blended instead of and / or in addition to licorice. Licorice may contain at least one selected from the group consisting of glycyrrhizic acid and its salts in an amount of 2.0% or more based on the dried crude drug in terms of conversion. Licorice powder may contain at least one selected from the group consisting of glycyrrhizic acid and its salts in an amount of 2.0% or more based on the dried crude drug in terms of conversion. Licorice extract may contain at least one selected from the group consisting of glycyrrhizic acid and its salts in an amount of 3.6% or more based on the dried crude drug in terms of conversion. Crude licorice extract may contain at least one selected from the group consisting of glycyrrhizic acid and its salts in an amount of 4.8% or more based on the dried crude drug in terms of conversion. In the solid composition according to the present embodiment, the total content of glycyrrhizic acid and its salts may be in the range of, for example, 0.01 to 0.1 times (for example, 0.02 times, 0.036 times, 0.04 times, 0.048 times) the content described later as the content of licorice.

[0025] The extraction component can be obtained by a conventional method, for example, by extracting the active ingredient from the crude drug with an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. Examples of the hydrophilic solvent include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, t-butanol; cellosolves such as methyl cellosolve, ethyl cellosolve; ketones such as acetone; ethers such as dioxane, tetrahydrofuran; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and the like. These hydrophilic solvents may be used alone or as a mixed solvent of two or more.

[0026] The dosage of Glycyrrhizae Radix et Rhizoma is appropriately adjusted according to the use of the solid composition, the required degree of hardness, the symptoms, age, body weight, sex, etc. of the subject to be administered. The dosage of Glycyrrhizae Radix et Rhizoma 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, in terms of the crude drug equivalent amount per day.

[0027] The content of Glycyrrhizae Radix et Rhizoma contained in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, more preferably 10% to 30% by mass, in terms of the crude drug equivalent amount.

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

[0029] From the viewpoint of further increasing the hardness of the solid composition according to the present embodiment, glycyrrhiza is preferably contained in the same granulated product as at least one selected from the group consisting of tipepidine and its salts. That is, the solid composition according to the present embodiment preferably contains a granulated product containing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza, and preferably contains a granulated product obtained by granulating a mixed powder containing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza. The solid composition according to the present embodiment may be a tablet obtained by tableting granules which are the granulated product. However, the solid composition according to the present embodiment may also be a tablet produced by a direct tableting method in which a mixed powder containing at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza is directly tableted, or a powder obtained by dissolving at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza in a solvent and drying and distilling off the solvent, and a tablet obtained by tableting the powder after optionally granulating it. In such an embodiment, at least one selected from the group consisting of tipepidine and its salts and glycyrrhiza will exist in a proximate state in the solid composition, and the effect of increasing the hardness of the solid composition containing at least one selected from the group consisting of tipepidine and its salts by glycyrrhiza tends to be more effectively exhibited.

[0030] (Acetaminophen) The solid composition according to the present embodiment may further contain acetaminophen. By further containing acetaminophen, the hardness of the solid composition tends to be further improved. As used herein, "acetaminophen" is a compound having a CAS registration number of 103-90-2 and represented by the chemical formula C8H9NO2. The salts of acetaminophen are not particularly limited as long as they are pharmacologically acceptable.

[0031] The dosage of acetaminophen is appropriately adjusted according to the use of the solid composition, the required degree of hardness, the symptoms, age, weight, gender, etc. of the subject to be administered. When acetaminophen is included, the dosage varies depending on the amount of at least one selected from the group consisting of tipepidine and its salts, etc., but as the amount per day, it can be adjusted in the range of 120 mg to 1200 mg, preferably 150 mg to 900 mg, more preferably 180 mg to 600 mg.

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

[0033] From the perspective of further increasing the hardness of the solid composition according to the present 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 the present 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 the present embodiment may be a tablet obtained by tableting granules which are the said granule. From the same perspective, the solid composition according to the present embodiment may also be a tablet produced by the direct tableting method of directly tableting a mixed powder containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen, or may be a tablet obtained by dissolving at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen in a solvent, drying and distilling off the solvent to obtain a powder, and tableting the powder after optionally granulating it. In such an embodiment, at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen will exist in a proximate state in the solid composition, and the hardness of the solid composition tends to be further improved.

[0034] (Other components) The solid composition according to the present embodiment may contain components other than the above components according to its use. When the solid composition is for the purpose of relieving various symptoms of a cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, muscle pain, etc., in addition to bromhexine and meloxicam, active ingredients such as analgesics and antipyretics, particularly non-steroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically acceptable components may be formulated.

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

[0036] As other pharmacologically acceptable components, antihistamines, antipyretics, antitussives and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, antiplasmin agents, etc. that are formulated in combination cold medicines, antipyretics and analgesics, rhinitis medicines, etc. may be additionally formulated.

[0037] For example, as antihistamines, isopentyl hydrochloride, diphenhydramine hydrochloride, tripelennamine hydrochloride, tonzylamine hydrochloride, phenetidine hydrochloride, methdilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyl disulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimemazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebumrine napadisilate, promethazine methylene disalicylate, carbinoxamine maleate, diphenhydramine phosphate, clemastine fumarate, mequitazine, etc. can be mentioned.

[0038] As antipyretics and analgesics other than non-steroidal anti-inflammatory drugs, for example, aspirin, ethenzamide, salsalate, salicylamide, lactylphenetidine, isopropylantipyrine, etc. can be mentioned.

[0039] Examples of antitussive and expectorant drugs include noscapine, noscapine hydrochloride hydrate, dextromethorphan hydrobromide hydrate, bromhexine, dihydrocodeine phosphate, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharinate, pseudoephedrine hydrochloride, ambroxol hydrochloride, L-carbocysteine, and the like.

[0040] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), tranexamic acid, and the like.

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

[0042] Examples of vitamin agents include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, and the like.

[0043] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyl dioxolane iodide, rhubarb extract, rhubarb root, total alkaloids of rhubarb root citrate, and the like.

[0044] For the solid composition according to this embodiment, pharmaceutical additives may be further added as needed. Examples of the pharmaceutical additives include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, glazing agents, foaming agents, moisture-proof agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, flavoring agents, coloring agents, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents and fragrances, etc. The pharmaceutical additives that can be used in conventionally known solid preparations can be used for the above purposes.

[0045] Examples of the excipients include glucose powder, gum arabic, powdered gum arabic, cacao butter, caramel, sodium carboxymethyl starch, hydrous silicon dioxide, anhydrous amorphous silicon dioxide, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose - sodium carboxymethyl cellulose, crystalline cellulose (fine particles), 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 sugar, spherical granulated refined sugar, gelatin, D - sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low - substituted hydroxypropyl cellulose, dextrin, corn starch, granulated corn starch, trehalose, silicon dioxide, lactose hydrate, granulated lactose, sucrose, potato starch, hydroxypropyl starch, pre - gelatinized starch, powdered sugar, powdered maltose, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D - mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0046] Examples of the binder include gum arabic, powdered gum arabic, 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, methyl cellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and the like.

[0047] Examples of the disintegrant include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, partially alpha - dextrinized starch, and the like.

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

[0049] Examples of the brightening agent include carnauba wax, white beeswax, purified shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, and the like.

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

[0051] Examples of the moisture-proof agent include ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylaminoacetate, magnesium aluminometasilicate, and the like.

[0052] Examples of the surfactant include sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit molasses, polyoxyethylene nonyl phenyl 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, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate, and the like.

[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, ferric chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cacao butter, carboxyvinyl polymer, calcium carmellose, hydrous silicon dioxide, sodium carmellose, anhydrous sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soy lecithin, gelatin, hydrolyzed gelatin, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, 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 acid glyceryl (7 E.O.) Polysorbate 20, Polysorbate 60, Polysorbate 80, Polyvinyl Alcohol (partially saponified), Macrogol 300, Macrogol 400, Macrogol 4000, Citric Anhydride, Sodium Citrate Anhydride, Sodium Hydrogen Phosphate Anhydride, Sodium Dihydrogen Phosphate Anhydride, Magnesium Aluminum Metasilicate, Methylcellulose, l-Menthol, Glyceryl 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. can be mentioned.

[0054] As antioxidants, for example, ascorbic acid, L-ascorbyl stearate, citric acid hydrate, soy lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbyl palmitate, sodium pyrosulfite, etc. can be mentioned. In the case of a solid composition containing acetaminophen, it is preferable not to blend tocopherols as antioxidants or stabilizers.

[0055] As fillers, for example, RSS No.1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide, calcium hydrogen phosphate, etc. can be mentioned.

[0056] As sweeteners, for example, aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, refined sugar, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. can be mentioned.

[0057] Examples of flavoring agents include, for example, sodium chloride, cinnamon powder, aconite extract, Chinese magnoliavine, Chinese magnoliavine powder, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, sansho powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, ginger powder, sucralose, stevia extract, purified stevia extract, assemblage, D-sorbitol, tannic acid, clove oil, chinpi chinchi, capsicum, capsicum powder, torreya powder, trehalose hydrate, bitter orange powder, umeboshi extract, fructooligosaccharide, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, borneol, borneol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, and the like.

[0058] Examples of cooling agents include, for example, star anise oil, d-camphor, dl-camphor, cinnamon oil, perilla water, perilla oil, l-menthol, and the like.

[0059] Examples of fragrances include, for example, 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, perilla oil, and the like.

[0060] Examples of aromatic agents include, for example, star anise powder, star anise oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, ginseng powder, spearmint oil, clove oil, turpentine oil, capsicum powder, pineapple powder fragrance 51357, pineapple powder fragrance 59492, perilla water, perilla oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, and the like.

[0061] Examples of the coloring agent include iron oxide yellow, yellow ferric oxide, orange essence, iron oxide brown, carbon black, caramel, β-carotene, gold leaf, iron oxide black, titanium oxide, ferric oxide, disazo 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 phosphate sodium, green tea powder, rose oil, and the like.

[0062] Examples of the base include gum arabic powder, α - starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, sodium carmellose, reduced maltose syrup, hydrous silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium 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, for example, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold foil, silver foil, triethyl citrate, glycerin, glycerin fatty acid ester, hardened 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 foil, precipitated calcium carbonate, thick glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 - titanium oxide - macrogol 400 mixture, hypromellose, fumaric acid - stearic acid - polyvinyl acetal diethylaminoacetate - 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 aluminometasilicate, methyl acrylate - methacrylic acid - methyl methacrylate copolymer, methyl cellulose, 2-methyl-5-vinylpyridine methyl acrylate - methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol - acrylic acid - methyl methacrylate copolymer, and the like.

[0064] Examples of sugar coating agents include gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, sodium carboxymethylcellulose, titanium oxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, 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 ester, D - sorbitol, medium - chain fatty acid triglyceride, 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, liquid paraffin, and the like.

[0066] Examples of the dispersant 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, soy lecithin, 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, sodium anhydrous citrate, magnesium aluminum metasilicate, methyl cellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, and the like.

[0067] Examples of the antifoaming agent include ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for oral use), dimethylpolysiloxane - silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, and the like.

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

[0069] As the fragrance agent and perfume, for example, Chinese chive powder, Chinese chive 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, torreya nut tincture, torreya nut oil, pine oil, peppermint oil, vanilla flavor, vanilla, bitter essence, vita base, Himalayan cedar oil, fruit flavor, flavor G1, hesperidin peppermint essence, bergamot oil, bergamot flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, borneol, borneol powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc. may be mentioned.

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

[0071] (Dosage form) The solid composition of the present embodiment can be made into dosage forms described in the General Rules of Pharmaceutical Forms of the Japanese Pharmacopoeia, Eighteenth Revision, etc., such as preparations for oral administration (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, soluble tablets, etc.), capsules, granules, and powders, etc.), preparations for application in the oral cavity (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition of the present embodiment is preferably an oral solid composition.

[0072] Examples of the dosage form of the solid composition of the present embodiment include tablets, capsules, pills, granules, and fine granules. These solid compositions may be coated with sugar coating, film coating, etc. by a known method as necessary. The dosage form of the solid composition is preferably a tablet. Specific examples of the tablet include plain tablets, film-coated tablets, and sugar-coated tablets.

[0073] The solid composition of this embodiment may be once packaged by bottle packaging, PTP packaging, pouch packaging, stick packaging, or SP packaging and stored in an airtight manner. Furthermore, they may be pillow-packaged, or they may be stored in a box or the like. The material used for pillow packaging is not particularly limited, and for example, resin films such as polypropylene films, polyethylene terephthalate films, and polyethylene films, or those obtained by attaching aluminum foil to these resin films can be used. In addition, when there are concerns about hygroscopicity, a desiccant or the like may be stored simultaneously inside the bottle packaging or inside the 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, for example, in an airtight package. By forming a package, for example, the convenience during the use of the solid composition can be improved. The package in this embodiment is specifically a pharmaceutical product.

[0075] As a packaging form of the solid preparation, the solid composition may be once packaged by bottle packaging, PTP packaging (Press Through Package), pouch packaging, stick packaging, SP packaging (Strip Package), or the like and stored in an airtight manner. Furthermore, they may be pillow-packaged, or they may be stored in a box or the like. Also, from the perspective of reducing the moisture absorption of the solid composition, a desiccant or the like may be stored simultaneously inside the packaging container such as inside the bottle packaging or inside the pillow packaging.

[0076] Examples of the materials used for SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include resin films such as polypropylene films, polyethylene terephthalate films, and polyethylene films, and those obtained by attaching aluminum foil to these resin films. Either a single-layer film or a multi-layer film (for example, a laminate film) may be used.

[0077] In addition, the material constituting the packaging container preferably includes a material that is less susceptible to the influence of moisture. Examples of such packaging include packaging formed by at least one of a moisture-proof material and a gas barrier material.

[0078] Examples of the moisture-proof material include, for example, a combined packaging of PTP (polypropylene) and a polyethylene aluminum pillow. Further, when the solid composition is a tablet, in consideration of suppressing an increase in the moisture value in the tablet, the storage stability of the tablet, the tablet stability after opening, etc., a PTP packaging (Al-Al packaging) using aluminum on both sides may be used as the moisture-proof material.

[0079] Known materials may be used as the gas barrier material. For example, it may be a laminated film having a functional barrier layer, and may be used in combination with or in addition to the above moisture-proof material while also serving the role of the above moisture-proof material.

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

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

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

[0083] The production of the solid composition can be carried out using known techniques. Each component is added in an arbitrary step and finally brought into contact with each other. A solvent or a binder may be added to the mixture after contact and kneaded, and the obtained kneaded product may be used as the solid composition.

[0084] The obtained kneaded product can also be subjected to a further drying step or granulation step to produce a granule (granulated product). In this case, the granule (granulated product) containing each component may be prepared separately. The granulation may be wet or dry.

[0085] The obtained granules (granulated product) as they are, or additives may be blended with the granules, and the mixture may be tabletted to produce a core tablet, or further film-coated.

[0086] For example, when the solid composition is a tablet, the tablet can be produced in accordance with the section "Tablets" in the General Rules for Preparations of the Japanese Pharmacopoeia. Specifically, at least one kind selected from the group consisting of tipepidine and its salts, and licorice, and optionally acetaminophen, are granulated to obtain a granulated product (granules), and then the obtained granulated product and optionally the excipients are tabletted to produce a tablet. Alternatively, at least one kind selected from the group consisting of tipepidine and its salts is granulated to obtain the first granules, and a mixture containing licorice is granulated to obtain the second granules, and the two kinds of granules and appropriately the excipients are tabletted to produce a tablet. From the viewpoint of increasing the hardness of the solid composition, it is preferable to granulate a mixture containing at least one kind selected from the group consisting of tipepidine and its salts, and licorice to form a granulated product (granules), and include both components in the same granulated product, and more preferably include acetaminophen in the same granulated product.

[0087] When the solid preparation contains excipients, the tablets may be produced by adding the after-powder components to the granulated granules so as to form the outside of the granulated granules, and tabletting these mixtures. Also, the excipients may be in the form of granules. For example, granulated granules containing at least one kind 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 kind selected from the group consisting of tipepidine and its salts, and licorice, and the second granules containing other active ingredients are provided separately, and the solid preparation may be produced so that the components in the first granules and the other active ingredients in the second granules do not substantially contact each other. The other active ingredients may be included in the first granules or the second granules so as to obtain an appropriate preparation.

[0088] Incidentally, the granules obtained in the above process may be used as they are as the granule agent.

[0089] To explain the present invention in more detail, examples are described below, but the present invention is not limited thereto.

Example

[0090] 1. Raw materials In this example, the following raw materials were used. Incidentally, the following licorice extract powder has a crude drug conversion ratio of 7:1, that is, the crude drug is concentrated 7 times.

Table 1

[0091] 2. Production of granulated product Granulated products containing tipepidine hibenzate, licorice extract powder, or acetaminophen were prepared as follows. An appropriate amount of ethanol was added to each raw material, and kneading granulation was performed using a mortar and pestle. After vacuum drying the granulated product, it was sieved through a 30-mesh sieve to prepare the granulated product. Incidentally, as shown in Tables 2 and 3, for the co-granulated product of tipepidine hibenzate and licorice extract powder, the raw materials were blended so that the mass ratio of tipepidine hibenzate: licorice extract powder was 2:1 (2:7 in terms of crude drug conversion for licorice). Also, for the co-granulated product of tipepidine hibenzate, licorice extract powder, and acetaminophen, the raw materials were blended so that the mass ratio of tipepidine hibenzate: licorice extract powder: acetaminophen was 1:1:1 (1:7:1 in terms of crude drug conversion for licorice).

[0092] 3. Production of tablets and measurement of hardness Each raw material was weighed so that the total would be 2.5 g according to the formulation ratios in Tables 2 and 3, and they were uniformly mixed in a bottle to prepare each tablet powder. The formulation ratios of each component in Tables 2 and 3 are expressed in parts by mass. Each tablet powder was tableted at a pressure of 1,000 kgf using a 9φ, 10.8R pestle and a hand press tableting machine (manufactured by Riken Seiki Co., Ltd.) to prepare tablets of 400 mg per tablet. In Tables 2 and 3, for the component marked as "granulated product", the granulated product obtained by the method described in "2. Manufacture of granulated product" was added. That is, specifically explained using Examples 1 and 2 described in Table 2, for example, in Example 1, 40 parts by mass of tipepidine hibenzate powder and 20 parts by mass of licorice extract powder were used, while in Example 2, 60 parts by mass of a co-granulated product containing tipepidine hibenzate and licorice extract powder in a mass ratio of 2:1 was used. For each tablet, the hardness (unit: N) of the tablet was measured using a load cell type tablet hardness tester Tablet Tester 8M (manufactured by Pharmatron). The measured values are described in Tables 2 and 3.

[0093]

Table 2

[0094]

Table 3

[0095] As shown in Table 2, the solid composition containing at least one selected from the group consisting of tipepidine and its salts and licorice had a higher hardness than the solid composition not containing licorice. Also, the solid composition containing the granulated product obtained by co-granulating at least one selected from the group consisting of tipepidine and its salts and licorice had a particularly high hardness. Also, as shown in Table 3, the solid composition containing at least one selected from the group consisting of tipepidine and its salts, licorice, and acetaminophen had a higher hardness than the solid composition not containing licorice. Further, the solid composition 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, which is 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] As described above, the preferred embodiments and examples of the present invention have been described, but the present invention is not limited thereto. Additions, omissions, substitutions, and other changes can be made without departing from the spirit of the present invention.

Claims

1. comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice; containing a granule comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice; a solid composition (however, excluding a solid composition containing loratadine or levocetirizine).

2. The solid composition according to claim 1, further comprising acetaminophen.

3. The solid composition according to claim 2, wherein the granule further comprises acetaminophen.

4. The solid composition according to any one of claims 1 to 3, wherein the hardness of the solid composition is 40 N or more.

5. A method for producing the solid composition according to any one of claims 1 to 3, comprising a step of mixing at least one selected from the group consisting of tipepidine and salts thereof, and licorice.

6. The production method according to claim 5, further comprising a step of further mixing acetaminophen.

7. forming a granule comprising at least one selected from the group consisting of tipepidine and salts thereof, and licorice; tableting the granule; The production method according to claim 5, comprising:

8. The production method according to claim 7, wherein in the step of forming the granule, a granule comprising at least one selected from the group consisting of tipepidine and salts thereof, licorice, and acetaminophen is formed.

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