Solid composition and method for producing same

Abstract

The invention relates to a solid composition and a method of making the same. The present invention addresses the problem of providing a solid composition which has sufficient hardness and contains acetaminophen. [Solution] A solid composition containing acetaminophen, glycine, and licorice.

Description

TECHNICAL FIELD

[0001] The present application relates to a solid composition containing acetaminophen, glycine and licorice, a method for producing the same, and the like. BACKGROUND

[0002] A solid composition such as a tablet administered orally disintegrates in the digestive tract, and then the effective ingredient in the composition is absorbed into the body. From the viewpoint of transportability and wear resistance, it is extremely important for the solid composition to have a hardness of one digit or more in the design of the preparation.

[0003] Since there are ingredients in the effective ingredient of a pharmaceutical product that decrease the hardness of a solid composition, techniques for improving the hardness of a solid composition have been studied.

[0004] For example, Patent Literature 1 discloses a composition that has excellent tablet hardness and disintegration even without excipients by containing a disintegrant ingredient and a microfibrous cellulose.

[0005] Patent Literature 2 discloses a method in which crystalline cellulose is incorporated in a granule (the granule is obtained by wet granulation of a mixture containing a main drug) in a tablet obtained by tableting the granule, thereby improving the hardness of the tablet and suppressing the delay of the disintegration time.

[0006] Patent Literature 3 discloses a solid preparation containing: acetaminophen; glycine; and at least one selected from the group consisting of caffeine, ethenzamide, ibuprofen, allyl isopropyl acetylurea, and bromoisovaleryl urea. Patent Literature 3 discloses that the solid preparation has sufficient hardness.

[0007] PRIOR ART DOCUMENTS

[0008] PATENT LITERATURE

[0009] Patent Literature 1: International Publication No. 2020 / 022053

[0010] Patent Literature 2: Japanese Patent Application Publication No. 2005-047861

[0011] Patent Literature 3: Japanese Patent Application Publication No. 2024-050466 SUMMARY

[0012] PROBLEMS TO BE SOLVED BY THE INVENTION

[0013] However, as for a solid composition containing acetaminophen, there is still room for improvement from the viewpoint of the decrease in hardness. An object of the present application is to provide a solid composition containing acetaminophen that has sufficient hardness.

[0014] Methods for solving problems

[0015] The inventors of this application discovered that a solid composition containing acetaminophen, glycine, and licorice has sufficiently high hardness, thereby completing this invention.

[0016] That is, this implementation includes the following methods.

[0017] [1] A solid composition comprising acetaminophen, glycine and licorice.

[0018] [2] The solid composition as described in [1] contains a granule comprising acetaminophen, glycine and licorice.

[0019] [3] The solid composition as described in [1] or [2], wherein the hardness of the aforementioned solid composition is 40 N or more.

[0020] [4] A method for manufacturing any one of the solid compositions described in [1] to [3], comprising the step of mixing acetaminophen, glycine and licorice.

[0021] [5] The method for manufacturing a solid composition as described in [4] includes:

[0022] The process of forming granules containing acetaminophen, glycine, and licorice; and

[0023] The process of compressing the aforementioned granules into tablets.

[0024] The effects of the invention

[0025] According to the present invention, it is possible to provide a solid composition containing acetaminophen with sufficient hardness. Detailed Implementation

[0026] Hereinafter, embodiments of the present invention (hereinafter referred to as "this embodiment") will be described, but the scope of the present invention is not to be construed as limited to the following embodiments. In this embodiment, the composition may contain each component individually or in combination of two or more components. In this specification, "~" indicating a numerical range means above or below, and the values ​​at both ends are inclusive.

[0027] (Solid composition)

[0028] In the first approach, a solid composition is provided comprising acetaminophen, glycine, and licorice.

[0029] Solid compositions specifically refer to solid pharmaceutical compositions.

[0030] The components included in the solid composition according to this embodiment may be contained in the form of pharmacologically permissible salts or as complexes with other components. "Pharmacologically permissible salts" may include, for example, salts that are pharmaceutically permissible and form with alkalis or acids.

[0031] Specific examples of pharmacologically permissible salts, without limitation, 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-bromobenzenesulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide, or alkali metal hydroxides or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids. Pharmacologically permissible salts can be either hydrated or anhydrous.

[0032] In this embodiment, the solid composition contains glycine and licorice in addition to acetaminophen, thus having sufficient hardness.

[0033] The hardness of the solid composition in this embodiment is the hardness measured using the method described in the "Tablet Hardness Test Method <G6-4-180>" of the 18th edition of the Japanese Pharmacopoeia. More specifically, it can be measured according to the method used... The hardness described above was measured by examining the morphology of tablets obtained by compressing a 10.8R tablet using a tablet press at a pressure of 1,000 kgf. The tablet volume used for hardness measurement is not particularly limited and can be set to 300 mg per tablet. More specifically, the hardness of the solid composition in this embodiment can be the hardness measured using the method described in the examples.

[0034] The hardness of the solid composition measured in the above manner is preferably 40 N or more, more preferably 40 to 200 N, even more preferably 45 to 150 N, even more preferably 50 to 140 N, even more preferably 60 to 130 N, and particularly preferably 70 to 120 N.

[0035] The solid composition in this embodiment tends to have excellent wear resistance and / or sheet thickness.

[0036] The abrasion degree of the solid composition in this embodiment is the abrasion degree measured using the method described in the "Test Method for Abrasion Degree of Tablets <G6-5-150>" of the 18th edition of the Japanese Pharmacopoeia. More specifically, it can be measured according to the method used... The abrasion degree described above was measured by examining the morphology of tablets obtained by compressing a 10.8R tablet using a tablet press at a pressure of 1,000 kgf. The tablet volume used for abrasion degree measurement is not particularly limited and can be set to 300 mg per tablet. More specifically, the abrasion degree of the solid composition in this embodiment can be the hardness measured using the method described in the examples.

[0037] The wear rate of the solid composition measured in the above manner is preferably 0.40% or less, more preferably 0.30% or less, and even more preferably 0.20% or less. The lower limit of the above wear rate is not particularly limited; for example, the wear rate can be 0% or more.

[0038] The tablet thickness of the solid composition in this embodiment varies depending on the tablet volume and compression conditions. For example, according to the use The morphological thickness of tablets of 300 mg each obtained by pressing a 10.8R tablet with a pressure of 1,000 kgf using a tablet press can be less than 5.0 mm, or 2.0 to 5.0 mm, or 3.0 to 4.5 mm.

[0039] (acetaminophen)

[0040] In this specification, "acetaminophen" is the compound with CAS Registry Number 103-90-2 and the chemical formula C8H9NO2. There are no particular limitations on the salts of acetaminophen, provided they are pharmacologically permissible.

[0041] The dosage of acetaminophen can be adjusted appropriately according to the intended use of the solid composition, the desired degree of antitussive and expectorant effect, the required hardness, the symptoms, age, weight, and gender of the recipient.

[0042] Regarding the dosage of acetaminophen, for example, the daily dose for adults can be adjusted within the range of 120 mg to 1200 mg, preferably 150 mg to 900 mg, and more preferably 180 mg to 600 mg. In this embodiment, "adult" refers to men and women aged 15 years and older. However, the solid composition involved in this embodiment is not limited to adult use, but can also be used for children under 15 years of age. When children take it, the dosage can be reduced to 1 / 2, 2 / 3, or the adult daily dose, depending on their age. The same applies to ingredients other than acetaminophen.

[0043] The weight and dosage of the solid composition described above are daily dosages (1-day doses). This dosage can be administered to the subject once, or it can be administered to the subject multiple times a day (e.g., 2 or 3 times, preferably 3 times). The same applies to ingredients other than acetaminophen. Furthermore, each dosage is a total amount; therefore, the content of each ingredient in the solid composition can vary depending on the single dosage, the dosage form of the solid composition, etc.

[0044] In a specific embodiment, the solid composition is a tablet, and the above-mentioned dosage is the amount of ingredients contained in 3, 6, or 9 tablets, preferably the amount of ingredients contained in 9 tablets. In this embodiment, the dosage for adults (15 years and older) is 3 times, and the dosage for a single dose is 2, 3, or 4 tablets, preferably 3 tablets.

[0045] (glycine)

[0046] In this specification, "glycine" is the compound with CAS Registry Number 56-40-6 and the chemical formula C2H5NO2. There are no particular limitations on the salts of glycine, provided they are pharmacologically permissible.

[0047] The amount of glycine varies depending on the amount of acetaminophen, and as a daily dose, it can be adjusted within the range of 10 mg to 1000 mg, preferably 30 mg to 950 mg, more preferably 100 mg to 900 mg, and even more preferably 180 mg to 900 mg.

[0048] The mass ratio of acetaminophen to glycine in the composition administered within one day is preferably 4:1 to 1:3, more preferably 3:1 to 1:2, and even more preferably 2:1 to 1:1.

[0049] (Licorice)

[0050] When used in this specification, "licorice" may be any substance described in the 18th edition of the Japanese Pharmacopoeia. As licorice, for example, there are products obtained using water, 30% aqueous ethanol, etc., as extraction solvents. For example, depending on the type of extract, such as licorice extract, dried licorice extract, soft licorice extract, or fluid licorice extract, various products are sold with a conversion ratio to the original drug. Unless otherwise specified, the amounts of licorice mentioned in this specification are values ​​converted to the original drug. For example, regarding soft licorice extract, approximately 4 parts by mass of licorice are contained relative to 1 part by mass of the extraction solvent, calculated using the original drug conversion ratio. In addition to these licorice extracts, substances obtained by pulverizing extracts obtained from licorice extracted with water, 30% aqueous ethanol, etc., into powder (extract powder), as well as licorice extracts, licorice extract solutions, etc., may also be used appropriately, without particular limitation. However, the preferred extract powder is prepared by drying a dried licorice extract containing approximately 5 to 9 parts by mass, for example, 6 to 8 parts by mass, of licorice relative to 1 part by mass of the extracting solvent, calculated using a conversion ratio based on the raw herb. Water is the preferred extracting solvent.

[0051] It should be noted that licorice contains at least one component selected from the group consisting of glycyrrhizic acid and its salts. In the context of this specification, "glycyrrhizic acid" is defined as CAS Registry No. 1405-86-3, and is produced by C... 42 H 62 O 16 The chemical formula of the compound is 822.93 g / mol. There are no particular limitations on salts of glycyrrhizic acid, provided they are pharmacologically permissible; examples include trisodium glycyrrhizate, disodium glycyrrhizate, diammonium glycyrrhizate, monoammonium glycyrrhizate, dipotassium glycyrrhizate, and monopotassium glycyrrhizate.

[0052] Therefore, in the solid composition according to this embodiment, licorice can be substituted, and / or at least one of the group consisting of glycyrrhizic acid and its salts can be added in addition to licorice. Licorice may contain at least 2.0% or more of the group consisting of glycyrrhizic acid and its salts relative to the dried weight of the converted crude drug. Licorice powder may contain at least 2.0% or more of the group consisting of glycyrrhizic acid and its salts relative to the dried weight of the converted crude drug. Licorice extract may contain at least 3.6% or more of the group consisting of glycyrrhizic acid and its salts. Crude licorice extract may contain at least 4.8% or more of the group consisting of glycyrrhizic acid and its salts. In the solid composition according to this embodiment, the total content of glycyrrhizic acid and its salts may be set within, for example, 0.01 to 0.1 times (e.g., 0.02 times, 0.036 times, 0.04 times, 0.048 times) of the content of licorice described below.

[0053] The active ingredients can be extracted from the aforementioned crude drugs using conventional methods, such as extraction solvents. Common extraction solvents include, for example, water, hydrophilic solvents, or mixtures thereof. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, and tert-butanol; cellolytic agents such as methyl and ethyl cellolytic agents; 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 can be used alone or as a mixture of two or more solvents.

[0054] The dosage of licorice can be appropriately adjusted according to the intended use of the solid composition, the required hardness, the symptoms, age, weight, and sex of the recipient. For example, the dosage of licorice, converted from raw herb, is in the range of 100 mg to 5,000 mg per day, preferably in the range of 200 mg to 2,000 mg, and more preferably in the range of 50 mg to 1,200 mg.

[0055] The composition administered within one day contains licorice in a content of 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass, based on the amount of raw herb.

[0056] The mass ratio of acetaminophen to licorice in the composition administered within one day, expressed as acetaminophen to licorice (converted to its raw form), is preferably 1:10 to 2:1, more preferably 1:7 to 2:1, and even more preferably 1:7 to 1:1. When using licorice extract powder as licorice, the mass ratio of acetaminophen to licorice extract powder is preferably 1:2 to 10:1, more preferably 1:2 to 7:1, and even more preferably 1:1 to 7:1.

[0057] From the viewpoint of further improving the hardness of the solid composition according to this embodiment, licorice is preferably included in the same granule as acetaminophen and / or glycine. That is, the solid composition according to this embodiment preferably contains granules containing acetaminophen and / or glycine and licorice, and preferably contains granules obtained by granulating a mixed powder containing acetaminophen and / or glycine and licorice. From the same viewpoint, licorice is preferably included in the same granule as acetaminophen and glycine. That is, the solid composition according to this embodiment preferably contains granules containing acetaminophen, glycine and licorice, and preferably contains granules obtained by granulating a mixed powder containing acetaminophen, glycine and licorice. The solid composition according to this embodiment can be a tablet obtained by compressing the granules that are its granules.

[0058] However, the solid composition involved in this embodiment can be a tablet manufactured by direct compression using a method of directly compressing a mixed powder containing acetaminophen, glycine and licorice, or a powder obtained by dissolving acetaminophen, glycine and licorice in a solvent and drying and distilling off the solvent, or optionally a tablet made by granulating the powder and then compressing it.

[0059] In such an embodiment, acetaminophen, glycine, and licorice exist in a similar state in the solid composition, which tends to further increase the hardness of the solid composition.

[0060] (Other ingredients)

[0061] The solid composition described in this embodiment may contain other components besides those mentioned above, depending on its intended use. In cases where the purpose is to relieve various symptoms of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, and muscle pain, in addition to bromhexine and meloxicam, antipyretic analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), and other pharmacologically permissible components may be added.

[0062] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into: non-selective COX-2 inhibitors such as ibuprofen, diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprazin, tiprofenicol, naproxen, lornoxicam, ampicillin, piroxicam, nabumetone, indomethacin, sulindac, mofuzolic acid, and mefenamic acid; and selective COX-2 inhibitors such as meloxicam, etodoxacin, and celecoxib. Meloxicillin can be incorporated into compositions as an NSAID. Non-selective COX-2 inhibitors are preferred. NSAIDs can be in salt form.

[0063] As other pharmacologically permissible ingredients, it can be added in combination with compound cold medicines, antipyretic analgesics, rhinitis medicines, etc., as well as antihistamines, antipyretic analgesics, antitussives and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, antifibrinolytics, etc.

[0064] For example, antihistamines include isoxependyne hydrochloride, difeterol hydrochloride, trapyrimidine diamine hydrochloride, fenethazine hydrochloride, methaqualone hydrochloride, racemic chlorpheniramine maleate, d-chlorpheniramine maleate, carbixamine diphenyl disulfonic acid, diphenylpyraline hydrochloride, diphenylpyraline teoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, methaqualone naphthalene disulfonic acid, methylene disalicylic acid promethazine, carbixamine maleate, difeterol phosphate, chlormastine fumarate, and mequinatazine.

[0065] Antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include, for example, aspirin, ethylsalicylate, salicylates, salicylamide, lactylphenethylamine, and isopropylantipyrine.

[0066] Examples of antitussive and expectorant drugs include noscarbene, noscarbene hydrochloride hydrate, teperidine hydrochloride, dextromethorphan hydrobromide hydrate, bromhexine, codeine dihydrophosphate, racemic methylephedrine hydrochloride, racemic methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carboxycysteine.

[0067] As anti-inflammatory drugs, glycyrrhizic acid and its derivatives and their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.), tranexamic acid, etc. can be cited.

[0068] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0069] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., phenylphosphine), 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, etc.

[0070] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isoproiodine, diphenylpiperidine methyldioxolane iodide, hyoscyamine extract, hyoscyamine root, and total hyoscyamine root alkaloids citrate.

[0071] For the solid composition involved in this embodiment, formulation additives may be further added as needed. Examples of pharmaceutically permissible carriers include excipients, binders, disintegrants, disintegration aids, gloss enhancers, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromas, colorants, matrices, coating agents, sugar coatings, plasticizers, dispersants, defoamers, flow agents, and flavoring agents / fragrances. For the purposes described above, conventionally known formulation additives usable in solid dosage forms may be used.

[0072] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, 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, purified white sugar, purified white sugar spheres. Granular components, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially α-substituted starch, powdered sugar, powdered sugar, 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.

[0073] Examples of adhesives include gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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, etc.

[0074] Examples of disintegrants include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, croscarmellose sodium, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially α-substituted starch.

[0075] Examples of disintegration aids include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, light anhydrous silica, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0076] Examples of gloss enhancers include carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, and beeswax.

[0077] Examples of foaming agents include dried sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0078] 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, purified shellac, purified 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 aluminum metasilicate.

[0079] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate, polyoxyethylene cetyl ether, polyoxyethylene dehydrated sorbitol monolaurate, polyoxyethylene sorbitol beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) diol, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene (120) polyoxypropylene (40) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, monooleic acid dehydrated sorbitol ester, glyceryl monostearate, monostearate dehydrated sorbitol ester, monolauric acid dehydrated sorbitol ester, and sodium dodecyl sulfate.

[0080] Examples of stabilizers include, for example, 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, hexadecylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymers, and carboxymethyl cellulose. Calcium, hydrated silicon dioxide, sodium carboxymethyl cellulose, dried sodium carbonate, glycerol, fatty acid glycerides, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamic acid, L-lysine, light anhydrous silica, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, dehydrated sorbitol fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, bicarbonate Sodium, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearate, 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 glyceride (7E). O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminum metasilicate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical 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.

[0081] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, ascorbic acid palmitate, and sodium metabisulfite. In the case of a solid composition containing acetaminophen, it is preferable to omit tocopherols as antioxidants or stabilizers.

[0082] Examples of fillers include RSS No.1 raw rubber, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0083] Examples of sweeteners include aspartame, acesulfame potassium, gancha, gancha powder, reduced malt syrup, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0084] Examples of flavoring agents include, for example, sodium chloride, phellodendron bark powder, cherry bark extract, coptis root, coptis root powder, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citrate hydrate, sodium citrate hydrate, L-glutamic acid, monosodium glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Sichuan pepper powder, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, and ginger. Powder, sucralose, stevia extract, purified stevia extract, angelica, D-sorbitol, tannic acid, clove oil, tangerine peel tincture, chili pepper, chili powder, spruce powder, trehalose hydrate, bitterwood powder, plum extract, fructooligosaccharides, 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, etc.

[0085] Examples of cooling agents include, for example, fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0086] Examples of flavorings include orange flavoring, guarana extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach essence, fruit flavoring, mint, melon powder flavoring, L-menthol, and peppermint oil.

[0087] Examples of aromatic agents include, for example, anise powder, anise oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili powder, pineapple powder spice 51357, pineapple powder spice 59492, peppermint water, peppermint oil, vanilla powder spice 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0088] Examples of coloring agents include yellow iron oxide, yellow ferric oxide, orange flavoring, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium dioxide, ferric oxide, diazo yellow, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, ferric oxide / glycerol suspension, sodium copper chlorophyllin, copper chlorophyllin, phenol red, malachite green, methylene blue, pharmaceutical charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc.

[0089] Examples of matrices include gum arabic powder, α-starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymers, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced malt syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycerol, fatty acid glycerides, light anhydrous silicate, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium dioxide, tartaric acid, sucrose fatty acid esters, 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 glycerol, potato starch, and hydroxypropyl cellulose. Ingredients include: hydroxypropyl methylcellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitol monostearate, squalene monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium dodecyl sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0090] Examples of coating agents include, for instance, ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers E, aminoalkyl methacrylate copolymers RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersions, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, fatty acid glycerides, hydrogenated oil, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methylcellulose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2 Mixture 910, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, methyl 2-methyl-5-vinylpyridine acrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, dehydrated sorbitol monostearate, dehydrated sorbitol monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0091] Examples of sugar coating agents include gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyoxyethylene stearate 40, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0092] Examples of plasticizers include triethyl citrate, glycerol, fatty acid glycerides, D-sorbitol, medium-chain fatty acid triglycerides, glyceryl triacetate, concentrated glycerol, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, and liquid paraffin.

[0093] Examples of dispersants include aminoalkyl methacrylate polymers (RS), gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, fatty acid glycerides, magnesium silicate, light alumina, light anhydrous silicate, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and 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, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glyceryl monooleate, dehydrated sorbitol monooleate, aluminum monostearate, glyceryl monostearate, dehydrated sorbitol monostearate, dehydrated sorbitol monopalmitate, dehydrated sorbitol monolaurate, sodium lauryl sulfate, etc.

[0094] Examples of defoaming agents include ethanol, glycerol fatty acid esters, dimethyl polysiloxane (for internal use), a mixture of dimethyl polysiloxane and silica, sucrose fatty acid esters, silicone defoamers, silicone oil, dehydrated sorbitol fatty acid esters, and polysorbate 80.

[0095] Examples of fluidizing agents include hydrated silica, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, calcium phosphate, talc, magnesium aluminum metasilicate, and granulated dicalcium phosphate.

[0096] Examples of flavoring agents and fragrances include, for example, anise powder, anise oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, lemongrass oil, sugar flavoring, spearmint oil, cherry flavoring, clove oil, chili flavoring, spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavoring, vanillin, bittering essence, vitamin base, Himalayan cedar oil, fruit flavoring, G1 flavoring, hesperidin peppermint extract, bergamot oil, bergamot flavoring, d-borneol, dl-borneol, matcha, mixed flavorings, peppermint flavoring, dl-menthol, l-menthol, eucalyptus oil, lavender oil, borneol, borneol powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0097] These ingredients may be a single ingredient or two or more.

[0098] (Dosage Form)

[0099] The solid composition of this embodiment can be formulated into dosage forms such as those described in the 18th edition of the Japanese Pharmacopoeia, including oral administration formulations (tablets (including intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, and powders), and oral formulations (including oral tablets, lozenges, sublingual tablets, oral lozenges, adhesive tablets, and gels). The solid composition of this embodiment is preferably an oral solid composition.

[0100] Examples of dosage forms for the solid compositions of this embodiment include tablets, capsules, pills, granules, and fine granules. These solid compositions can be coated using known methods, such as sugar coating or film coating, as needed. Tablets are preferred as the dosage form of the solid composition. Specific examples of tablets include plain tablets, film-coated tablets, and sugar-coated tablets.

[0101] The solid composition of this embodiment can be temporarily packaged and airtightly stored in bottles, PTP packages, bags, strips, or SP packages. It can also be further packaged in pillow-like containers or stored in boxes. There are no particular limitations on the materials used in pillow-like packaging; for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, or materials made by attaching aluminum foil to these resin films, can be used. It should be noted that, if there are concerns about moisture absorption, desiccants or similar substances can be stored simultaneously inside the bottle packaging or the pillow-like packaging.

[0102] The solid composition of this embodiment can be contained within a packaging container to form a package. For example, the solid composition of this embodiment can be contained in an airtight package. By forming a package, for example, the convenience of using the solid composition can be improved. Specifically, the package in this embodiment is a pharmaceutical product.

[0103] As packaging forms for solid dosage forms, solid compositions can be temporarily packaged and airtightly preserved using bottles, PTP (Press Through Package), pouches, strips, and SP (Strip Package). They can also be further packaged in pillow-like containers or stored in boxes. Furthermore, from the viewpoint of reducing moisture absorption by the solid composition, desiccants can be stored simultaneously within the bottle or pillow-like packaging container.

[0104] Materials used in SP packaging, PTP packaging, strip packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, and materials made by attaching aluminum foil to these resin films. Any of single-layer films and multi-layer films (e.g., laminated films) can be used.

[0105] Furthermore, the materials constituting the packaging container preferably include materials that are not easily affected by moisture. Examples of such packaging include packaging formed from at least one of moisture-proof materials and gas-barrier materials.

[0106] As a moisture-proof material, a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging can be cited as an example. Furthermore, when the solid composition is a tablet, considering factors such as inhibiting the rise in moisture content of the tablet, tablet storage stability, and tablet stability after opening, PTP packaging (Al-Al packaging) using aluminum on both sides can be used as a moisture-proof material.

[0107] As a gas barrier material, known materials can be used, such as laminates with functional barrier layers, or materials that also function as moisture-proof materials, or materials that are used together with moisture-proof materials.

[0108] In addition, packaging containers can be made in an environmentally conscious way. For example, environmentally friendly raw materials such as recycled plastics, biomass plastics, and biodegradable plastics can be used in part or all of the packaging materials.

[0109] (Manufacturing method)

[0110] In a second approach, a method for manufacturing a solid composition is provided, which includes a step of mixing acetaminophen, glycine and licorice.

[0111] The solid composition can be manufactured using known techniques. The components are added in any step, eventually coming into contact with each other. Solvents and binders can be added to the mixture after contact and kneaded, resulting in a kneaded compound as the solid composition.

[0112] The obtained kneaded mixture can also be further dried and granulated to produce granules. In this case, granules containing each component can be prepared separately. Granulation can be wet or dry.

[0113] The resulting granules can be used directly, or additives can be added to the granules and compressed into tablets to produce uncoated tablets, or they can be further coated with a film.

[0114] For example, when the solid composition is a tablet, it can be manufactured according to the "Tablets" section of the General Rules for Preparations in the Japanese Pharmacopoeia. Specifically, tablets can be manufactured by granulating a mixed powder containing acetaminophen and / or glycine and licorice to obtain granules (granules), and then compressing the obtained granules and optional extragranule components into tablets. Alternatively, a mixed powder containing at least one of acetaminophen, glycine, and licorice can be granulated to obtain a first granule, and a mixed powder containing at least one of acetaminophen, glycine, and licorice can be granulated to obtain a second granule, and these two granules and appropriate extragranule components can be compressed into tablets, thereby manufacturing a tablet. In this case, acetaminophen, glycine, and licorice are preferably included in either the first granule or the second granule. From the viewpoint of improving the hardness of the solid composition, it is preferable to granulate a mixed powder containing acetaminophen, glycine, and licorice to form granules (granules), so that these components are contained in the same granule.

[0115] When a solid dosage form contains extragranular ingredients, the subsequent ingredients can be added to the granulated granules in a manner that forms the exterior of the granules, and the mixture is compressed into tablets, thereby manufacturing tablets. Alternatively, the extragranular ingredients can be formed into granules. For example, granules containing acetaminophen, glycine, and licorice can be manufactured as the first granule, and granules containing other active ingredients can be manufactured as the second granule. In this case, the first granule containing acetaminophen, glycine, and licorice, and the second granule containing other active ingredients can be separately manufactured, such that the ingredients in the first granule and the other active ingredients in the second granule are not substantially in contact. The other active ingredients can be included in the first granule or in the second granule in a manner that yields a suitable formulation.

[0116] It should be noted that the granules obtained from the above process can be used directly as granules.

[0117] To illustrate the invention in more detail, embodiments are described below, but the invention is not limited to these.

[0118] Example

[0119] 1. Raw materials

[0120] In this embodiment, the following raw materials are used. It should be noted that the licorice extract powder described below is obtained by converting the raw herb to a 7:1 ratio, that is, by concentrating the raw herb 7 times.

[0121] In addition, due to its large particle size, glycine is crushed using an agate pestle and mortar, and then sieved through a 100-mesh sieve before use.

[0122] [Table 1]

[0123] Raw material Trade name Manufacturer Glycine Glycine Fuji Photo Film and Ohtsu Pharmaceutical Co. Glycyrrhiza extract powder Glycyrrhiza extract powder-A Nippon Powder Medicine Co. Acetaminophen Acetaminophen Yamamoto Chemical Industry Co. Lactose Lactose hydrate Armor Pharma Crystalline cellulose Ceolus UF-702 Asahi Kasei Co. Corn starch Corn starch Matsutani Chemical Industry Co. D-mannitol D-mannitol Bussan Food Science Co., Ltd. Magnesium stearate Magnesium stearate Taihei Chemical Industry Co.

[0124] 2. Manufacturing of granules

[0125] Granulations containing glycine, licorice extract powder, or acetaminophen are prepared as follows: Add appropriate amounts of ethanol to each raw material, mix and granulate using a mortar and pestle, vacuum dry the granules, and then sieve them through a 30-mesh sieve. It should be noted that, as shown in Table 2, for the co-granulation of acetaminophen, glycine, and licorice extract powder, the raw materials are combined in a mass ratio of acetaminophen:glycine:licorice extract powder of 1:1:1 (or 1:1:7 when converting licorice to its raw form).

[0126] 3. Tablet manufacturing and physical property determination

[0127] Weigh each raw material according to the proportions in Table 2 to make a total of 2.5g, mix them evenly in the bottle, and prepare each tablet powder. The proportions of each component in Table 2 are expressed in parts by weight. For each tablet powder, use... A 10.8R tablet was compressed using a manual tablet press (Riken Seiki) at a pressure of 1,000 kgf to produce 300 mg tablets per tablet. It should be noted that in Table 2, the components labeled "granules" are granules obtained using the method described in "2. Manufacturing of Granules". Specifically, when using Examples 1 and 3 described in Table 2, Example 1 used 20 parts by weight of acetaminophen powder, 20 parts by weight of glycine powder, and 20 parts by weight of licorice extract powder; in contrast, Example 3 used 60 parts by weight of a co-granule containing acetaminophen, glycine, and licorice extract powder in a mass ratio of 1:1:1.

[0128] For each tablet, the hardness was measured using a load-sensor type tablet hardness tester, Tablet Tester 8M (manufactured by Pharmatron). Next, for five tablets of each of Examples 1-3, the abrasion degree (percentage of mass reduction relative to the initial mass) after 100 rotations was calculated using an abrasion tester (manufactured by PHARMA TEST). Additionally, the thickness of each tablet of Examples 1-3 was measured using vernier calipers. The measured values ​​are recorded in Table 2.

[0129] [Table 2]

[0130]

[0131] As shown in Table 2, the solid compositions containing acetaminophen, glycine, and licorice exhibit sufficiently high hardness. The solid compositions containing granules formed by co-granulating acetaminophen, glycine, and licorice exhibit particularly high hardness.

[0132] In addition, solid compositions containing acetaminophen, glycine and licorice have excellent abrasion resistance and flake thickness, and solid compositions containing granules formed by co-granulation of acetaminophen, glycine and licorice have particularly excellent abrasion resistance and flake thickness.

[0133] The preferred embodiments and examples of the present invention have been described above, but the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration can be made without departing from the spirit of the present invention.

Claims

1. A solid composition comprising acetaminophen, glycine and licorice.

2. The solid composition according to claim 1, which contains a granulate comprising acetaminophen, glycine and licorice.

3. The solid state composition of claim 1, wherein, The hardness of the solid composition is 40 N or more.

4. A method for producing the solid composition according to any one of claims 1 to 3, which comprises a step of mixing acetaminophen, glycine and licorice.

5. The method for producing the solid composition according to claim 4, which comprises: a step of forming a granulate comprising acetaminophen, glycine and licorice; and a step of tableting the granulate. ​

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