solid components

Abstract

To provide a solid composition containing ibuprofen in which changes in properties are suppressed. [Solution] The following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of tranexamic acid and its salts Solid compositions containing (excluding solid compositions containing levocetirizine or loratadine). ).

Description

[Technical Field]

[0001] The present invention broadly relates to a small amount selected from the group consisting of ibuprofen, tipepidine, and its salts. At least one of the following, and at least one selected from the group consisting of tranexamic acid and its salts. This relates to a solid composition containing , [Background technology]

[0002] Ibuprofen is widely used as a nonsteroidal anti-inflammatory drug (NSAID). However, Furthermore, solid compositions containing ibuprofen may discolor, melt, separate, or solidify depending on the addition of other ingredients. Because changes in properties such as chemicalization, wetting, and aggregation can occur over time, it is possible to suppress these changes in properties. He has been killed.

[0003] For example, Patent Document 1 contains ibuprofen, diphenhydramine, and dextromethorphan. A pharmaceutical composition containing ruphan and tranexamic acid is disclosed.

[0004] Patent Document 2 contains ibuprofen, dextromethorphan, and guaifenesin, Furthermore, a pharmaceutical composition containing tranexamic acid is disclosed.

[0005] Patent Document 3 contains ibuprofen, levocetirizine, carbocysteine, and ambro. Xol, tranexamic acid, glycyrrhizic acid, tipepidine, dextromethorphan, A small number of substances selected from the group consisting of bromhexine, dimemorphan, and methyl ephedrine A pharmaceutical composition containing at least one of the following is disclosed.

[0006] Patent Document 4 contains ibuprofen, loratadine, carbocysteine, and ambroxo , bromhexine, tranexamic acid, glycyrrhizic acid, tipepidine, and dextrin A solid composition containing at least one selected from the group consisting of lomethylphan is disclosed. It is being done. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2021-075528 [Patent Document 2] Japanese Patent Publication No. 2021-075530 [Patent Document 3] Japanese Patent Publication No. 2022-008041 [Patent Document 4] Japanese Patent Publication No. 2020-158487 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Solid compositions containing ibuprofen still have room for improvement in terms of changes in properties over time. The present invention provides a solid composition containing ibuprofen in which changes in properties are suppressed. The purpose is to do so. [Means for solving the problem]

[0009] The present inventors selected ibuprofen from the group consisting of tipepidine and its salts. We found that when at least one of these is added, the properties change significantly. Furthermore, The change in state is due to the inclusion of at least one substance selected from the group consisting of tranexamic acid and its salts. We discovered that this can be suppressed by doing so, and thus completed the present invention.

[0010] In other words, this embodiment includes the following aspects. [1] A solid composition comprising the following components: (A) Ibuprofen, (B) at least one selected from the group consisting of tipepidine and its salts, and (C) at least one selected from the group consisting of tranexamic acid and its salts (however, excluding solid compositions containing levocetirizine or loratadine. ). [2] The solid composition according to [1], wherein the mass ratio of the total amount of component (A) to component (B) is 1:1 to 16:1 ((A):(B)). [3] The solid composition according to [1] or [2], comprising crystals composed of ibuprofen and tranexamic acid. [4] The solid composition according to [3], wherein the molar ratio of ibuprofen to tranexamic acid in the crystals is 1:1. [5] An inhibitor for suppressing changes in the properties of a solid composition comprising (I) ibuprofen and (II) at least one selected from the group consisting of tipepidine and its salts, comprising at least one selected from the group consisting of tranexamic acid and its salts. [Effects of the Invention]

[0011] According to the present invention, a solid composition containing ibuprofen with suppressed property changes can be provided. [Brief Description of the Drawings]

[0012] [Figure 1] Figure 1 shows the results of differential scanning calorimetry (DSC) of crystals composed of ibuprofen and tranexamic acid obtained in Example 3. [Modes for Carrying Out the Invention]

[0013] ​​​​​​The following describes embodiments of the present invention (hereinafter referred to as "this embodiment"), but The scope of the invention is not limited to the following embodiments. In this embodiment, the composition is Each component may be included individually or in combination of two or more. The "~" symbol, which indicates a numerical range, represents "greater than or equal to" or "less than or equal to," and includes both numbers at either end.

[0014] (solid composition) In the first embodiment, the following components: (A) Ibuprofen, (B) At least one selected from the group consisting of tipepidine and its salts, (C) At least one selected from the group consisting of tranexamic acid and its salts Solid compositions containing (excluding solid compositions containing levocetirizine or loratadine). ) It will be provided. The solid composition is specifically a solid pharmaceutical composition.

[0015] Each component contained in the solid composition according to this embodiment is included in a pharmaceutically acceptable salt state. It may be present on its own, or it may be included as a complex with other components. That is, in this embodiment The solid composition in question contains not only components (B) to (C), but also component (A) and other components. It may also contain salts of each component. "Pharmacologically acceptable salts" means, for example, salts that are permitted as medicine. It contains salts with bases and acids. Non-specific examples of pharmacologically acceptable salts include inorganic acids (hydrochloric acid, hydrobromic acid, iodide). Addition salts of hydrogen acids, sulfuric acid, phosphoric acid, etc., organic acids (p-toluenesulfonic acid, methanesulfone Acids, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoate Addition salts of acetic acid (such as acetic acid), inorganic bases (ammonium hydroxide or alkali or alkali) Examples include addition salts of earth metal hydroxides, carbonates, bicarbonates, etc., and addition salts of amino acids. Pharmacologically acceptable salts may be hydrated or anhydrous.

[0016] In this embodiment, ibuprofen, and tipepidine and its salts are selected from the group. Because it contains at least one selected component, as well as component (C) above, the properties of the solid composition change. In particular, changes in properties over time are suppressed.

[0017] In this specification, "change in properties" means at least aggregation, solidification, discoloration, moisture absorption, separation, and This refers to changes in properties and / or state, including liquefaction. Therefore, the solid components of this embodiment The resulting product is characterized by the suppression of any of the following processes that occur over time: aggregation, discoloration, moisture absorption, separation, and liquefaction. It is acceptable. Furthermore, "the change in properties is suppressed" means that the change in properties is unlikely to occur. However, compared to a solid composition that does not contain the above component (C), for example, the change in properties is suppressed. It's okay if it's not allowed.

[0018] The solid composition of this embodiment may have its properties suppressed under high-temperature conditions. High-temperature conditions are, for example, For example, the temperature can be 30-100°C or 40-90°C.

[0019] The period during which changes in properties are suppressed in the solid composition of this embodiment is not particularly limited, but for example... For example, if it is 12 hours or more, 18 hours or more, 24 hours or more, 1 week or more, or 2 weeks or more That's fine.

[0020] In addition, in the solid composition of this embodiment, "a solid containing levocetirizine or loratadine" "Composition" is excluded.

[0021] Here, "levocetirizine" refers to the chemical formula C 21 H25 This compound is represented as ClN2O3. Levocetirizine is the R-enantifoliate, which is the more biologically active optical isomer of cetirizine. This is an optically resolved specimen of Omar only, with a CAS registry number of 130018-77-8. Furthermore, in this embodiment, solid compositions containing a salt of levocetirizine are also excluded. It is done. The salt of levocetirizine is not particularly limited as long as it is a pharmacologically acceptable salt. For example, salts of inorganic acids such as hydrochloride, hydrobromide, and phosphate, and acetates and oxalates, Malonate, succinate, fumarate, maleate, lactate, malate, citrate Examples include organic acid salts such as tartrates and carbonates, with hydrochloride being particularly important.

[0022] Here, "loratadine" refers to the chemical formula C 22 H 23 It is a compound represented as ClN2O2, C The AS registration number is 79794-75-5.

[0023] Furthermore, in the solid composition of this embodiment, Japanese Patent Publication No. 2022-008041 and Japanese Patent Publication No. The solid compositions disclosed in Japanese Patent Publication No. 2020-158487 are excluded. The solid composition disclosed in Publication No. 22-008041 contains ibuprofen and levocetirizine. Or, even if it contains a salt thereof, the decrease in the content of levocetirizine or its salt over time is suppressed. The pharmaceutical composition, a solid composition disclosed in Japanese Patent Publication No. 2020-158487, is ibuprofen. Even when containing loratadine and rophene, the decrease in loratadine content over time is suppressed in the solid composition. The solid composition of this embodiment is ibuprofen, tipepidine, and its salt By incorporating at least one substance selected from the group consisting of the above, changes in properties that may occur can be suppressed. This is a solid composition containing ibuprofen.

[0024] (A) Ibuprofen As used herein, "ibuprofen" refers to CAS Registry Number 15687-27 -1, C 13 H 18 It is a compound represented by the chemical formula O2 (molecular weight: 206.29g). ( / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, and antipyretic drugs. The ibuprofen salt is not particularly limited, as long as it is pharmacologically acceptable.

[0025] The amount of ibuprofen included depends on the intended use of ibuprofen in the solid composition and the amount administered. The dosage is adjusted as appropriate depending on the elephant's symptoms, age, weight, sex, etc. For example, ibuprofen is non-sodium. When formulated as a teroid anti-inflammatory drug, the daily dose of ibuprofen administered to adults is equivalent to... The amount is, for example, 30 mg to 2000 mg, preferably 100 mg to 1000 mg, more Preferably, the dose can be adjusted in the range of 200 mg to 600 mg. In this embodiment, "adult" This refers to men and women aged 15 and over. However, the solid composition according to this embodiment is intended for adult consumption. It is not limited to those intended for this purpose, and may also be used by children under 15 years of age. When administered to children, the dosage should be 1 / 2 or 2 / 3 of the adult daily dose, depending on the age group. It can be used in reduced amounts, etc. The same applies to ingredients other than ibuprofen.

[0026] The above dosage is an example, and the ibuprofen content per solid composition administered daily is as follows: The amount is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass, more preferably The mass is approximately 10% to 30%.

[0027] In one embodiment, the ibuprofen content in the composition administered daily is 1 The mass is 70% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass. ru.

[0028] The weight and dosage of the above solid composition are the daily dose (daily amount), but the same amount The substance can be administered to the target in one dose, or multiple times a day, for example, two or three times, preferably in three separate doses. It may be administered. The same applies to ingredients other than ibuprofen. Also, the total amount of each dose Since it is a quantity, the content of each component contained in the solid composition varies depending on the single dose and the dosage form of the solid composition. It can fluctuate.

[0029] In certain embodiments, the solid composition is a tablet, and the above dosage is 3 tablets, 6 tablets, or This is the amount of the ingredient contained in 9 tablets, preferably the amount of the ingredient in 9 tablets. For adults (15 years and older), the single dose is three times a day, with each dose consisting of 2 tablets, 3 tablets, or The dosage is 4 tablets, preferably 3 tablets per dose.

[0030] The amounts of ibuprofen described herein are based on tranexamic acid and crystals. This concerns the total amount of ibuprofen that has crystallized and ibuprofen that has not crystallized. That's fine.

[0031] In one embodiment, the solid composition is tranexamic acid and crystallized ibuprofen. It contains tranexamic acid and non-crystallized ibuprofen.

[0032] In one embodiment, ibuprofen contained in the solid composition is 90% by mass or more. For example, 90% by mass, 91% by mass, 92% by mass, 93% by mass, 94% by mass, 95% by mass, 9 6% by mass, 97% by mass, 98% by mass, 99% by mass, or 100% by mass are crystallized.

[0033] In one embodiment, tranexamic acid contained in the solid composition and non-crystallized ibuprofen are used. The rophene content is, for example, 10% by mass or less, or 8% by mass, relative to the total amount of ibuprofen. The content is 5% by mass or less, 3% by mass or less, 1% by mass or less, or 0.1% by mass or less.

[0034] (B) At least one selected from the group consisting of tipepidine and its salts As used herein, "tipepidine" is the CAS registry number 5169-78-8 Yes, C 15 H 17 This compound is represented by the chemical formula NS2 (molecular weight: 275.43 g / molecular weight). The salt of tipepidine is not particularly limited as long as it is pharmacologically acceptable, but tipepidine Examples include hibenzate and tipepidine citrate. Furthermore, the following tipepidine and The amount and content of at least one selected from the group consisting of those salts is tipepidine and tipep The proportions and content of each of the pidine salts are as follows: tipepidine and tipepidine salts It is preferable that the total amount and content of the compound be within the range of the amounts and content described below.

[0035] The amount of at least one component selected from the group consisting of component (B) tipepidine and its salts The use of the solid composition, the required degree of cough suppressant and expectorant effect, the required degree of stability, and the application of the solid composition. The dosage will be adjusted as appropriate according to the symptoms, age, weight, gender, etc. of the person receiving the treatment.

[0036] The amount of at least one compound selected from the group consisting of tipepidine and its salts is ibuprofen. It may vary depending on the amount of fen or the like. For example, the mass ratio ((A):(B)) of the total amount of component (A ) and component (B) in the solid composition according to the present embodiment is in the solid composition administered per day , preferably 1:1 to 16:1, more preferably 1:1 to 14:1, and still more preferably 1:1 to 10:1. When at least one selected from the group consisting of tipepidine and its salts is included within the above range with respect to ibuprofen, the solid composition tends to suppress changes in properties.

[0037] The blending amount of at least one selected from the group consisting of tipepidine and its salts is, for example, as the amount per day, for example, 5 mg to 140 mg, and more preferably 16 mg to 100 mg can be adjusted within the range.

[0038] (C) At least one selected from the group consisting of tranexamic acid and its salts As used herein, "tranexamic acid" has a CAS registration number of 1197-18- 8 and is a compound represented by the chemical formula C8H 15 NO2 (molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient such as an anti-inflammatory drug. The salt of tranexamic acid is not particularly limited as long as it is pharmacologically acceptable. In addition, the blending amount and content of at least one selected from the group consisting of the following tranexamic acid and its salts are the blending amount and content for each of tranexamic acid and the salt of tranexamic acid, but the total blending amount and content of tranexamic acid and the salt of tranexamic acid are preferably within the range of the blending amount and content described below.

[0039] The blending amount of at least one selected from the group consisting of tranexamic acid and its salts is the composition In products, at least one use selected from the group consisting of tranexamic acid and its salts It is adjusted as appropriate. At least one selected from the group consisting of tranexamic acid and its salts. One type is intended to improve the properties of ibuprofen, or to alter its other characteristics. When combined, depending on the amount of ibuprofen, etc., from the group consisting of tranexamic acid and its salts The amount of at least one ingredient selected will vary, but for example, the daily amount may be 10 mg. ~3000mg, preferably 100mg~1500mg, more preferably 400mg~7 The range is 50 mg.

[0040] Selected from the group consisting of tranexamic acid and its salts contained in a composition administered daily. The content of at least one of the ingredients is 1% to 70% by mass, preferably 5% to 50% by mass, more preferably The mass is 10-30%.

[0041] Selected from the group consisting of tranexamic acid and its salts contained in a composition administered daily. At least one of these is, for example, 0.5 to 3.5 parts by mass per 1 part by mass of ibuprofen. parts by mass, preferably 0.6 to 3.0 parts by mass, more preferably 0.7 to 2.2 parts by mass It is a measure of parts.

[0042] A minimum of the following selected from the group consisting of tranexamic acid and its salts as described herein. The description regarding the quantity of one type refers to crystallized tranexamic acid and uncrystallized tranexamic acid. The total amount may be at least one selected from the group consisting of xamic acid and its salts.

[0043] In one embodiment, the solid composition is ibuprofen and crystalline tranexamic acid. and at least one selected from the group consisting of uncrystallized tranexamic acid and its salts. This includes.

[0044] In one embodiment, ibuprofen contained in the solid composition and non-crystallized tranexamic acid The content of at least one selected from the group consisting of xamic acid and its salts is tranexamic acid. For example, 0-50% by mass, 1-40% by mass, 2-30% by mass relative to the total amount of acid and its salts. or may be 2 to 20% by mass. It crystallizes with ibuprofen contained in the solid composition. The content of at least one selected from the group consisting of tranexamic acid and its salts is, With respect to the total amount of tranexamic acid and its salts, within the above range, for example, 8% by mass or less, 5% by mass The following amounts may be 3% by mass or less, 1% by mass or less, or 0.1% by mass or less.

[0045] If ibuprofen and tranexamic acid exist as crystals in the composition, then... Furthermore, ibuprofen and tranexamic acid may exist in a 1:1 molar ratio. In the crystal, ibuprofen and tranexamic acid form a crystalline unit cell of four molecules each. It's fine to do it.

[0046] In the crystal, the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid Between the ibuprofen carboxylic acid group and the tranexamic acid amino group, a hydrogen bond exists. It is acceptable for it to be formed.

[0047] The crystal exhibits an endothermic peak around 180°C in differential scanning calorimetry (DSC). It is acceptable to leave it as is. "Around 180°C" means, for example, a range of 180°C ± 20°C, and 180 The temperature may be within the range of ℃ ± 10℃. Furthermore, in the DSC of the crystal, ibuprofen is particularly The characteristic heat of fusion peak around 75°C may disappear.

[0048] The crystal has, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674. The crystal may have the X-ray diffraction pattern shown in Figure 2 of the same publication. In the X-ray diffraction pattern, there are seven main peaks (2θ = 6.3, 8.4, 16.2, It may have angles of 18.5, 19.1, 21.1, and 25.6 ± 0.5°.

[0049] A crystal composed of ibuprofen and tranexamic acid is, for example, described in Japanese Patent Publication No. 2022-70674. It can be manufactured by the method described in the publication. The following are two manufacturing methods.

[0050] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) To produce ibuprofen in a fluid form by adding a solvent or heating, (2) Mix the obtained fluid ibuprofen and tranexamic acid, 3) A method comprising producing crystals from the obtained mixture.

[0051] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Obtain tranexamic acid in a fluid form, (2) the obtained fluid form Ranexamic acid and ibuprofen, or fluidity obtained by adding or heating a solvent. (3) Mixing the fluid ibuprofen with the mixture, and (4) Producing crystals from the resulting mixture. A method that includes doing so.

[0052] (Other ingredients) The solid composition according to this embodiment may contain components other than those described above, depending on its intended use. Good. The solid composition relieves various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, and cough. It is used to relieve symptoms such as phlegm, chills, fever, headache, joint pain, and muscle pain. In addition to bromhexine, meloxicam, and acetaminophen, antipyretic analgesics, especially, Other active ingredients such as nonsteroidal anti-inflammatory drugs (NSAIDs) other than buprofen, and other Pharmacologically acceptable ingredients may be included.

[0053] Nonsteroidal anti-inflammatory drugs include diclofenac, loxoprofen, zaltoprofen, Pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam Ampiroxicam, Piroxicam, Nabumetone, Indomethacin, Sulindac, Mofe COX-2 nonselective inhibitors such as Zolac and mefenamic acid, and meloxicam, etodolac, ce They are broadly classified into COX-2 selective inhibitors such as recoxib. Meloxicam is a nonsteroidal anti-steroid. It may be incorporated into the composition as an anti-inflammatory agent. Nonsteroidal anti-inflammatory drugs are COX-2 nonselective. It is preferable that the agent be an inhibitor. Nonsteroidal anti-inflammatory drugs may also be in the form of a salt.

[0054] Other pharmacologically acceptable ingredients include those found in combination cold medicines, antipyretic analgesics, and rhinitis medications. Antihistamines, antipyretics and analgesics, cough suppressants and expectorants, anti-inflammatory drugs, central nervous system stimulants, vitamins The drug may also be formulated with other agents such as anticholinergics and antiplasmins.

[0055] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, and triphosphate hydrochloride. Perenamin, tondiamine hydrochloride, phenetazine hydrochloride, methidilazine hydrochloride, dl-chlor Pheniramine maleate, d-chlorpheniramine maleate, diphenyl disulfone Carbinoxamine phosphate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, Diphenhydramine hydrochloride, diphenhydramine salicylate, alimethazine tartrate, Diphenhydramine iodine, triprolidine hydrochloride hydrate, mebhydrolysine napadisylate N, promethazine methylene disalicylate, carbinoxamine maleate, diphosphate Examples include terol, clemastine fumarate, and mequitazine.

[0056] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin and acetamine. Nophen, ethenzamide, sazapyrine, salicylamide, lactylphenethidine, isop Examples include ropilantipyrine. Acetaminophen is included in the composition as an antipyretic and analgesic. They may be combined.

[0057] Examples of cough and expectorant medications include noscapine hydrochloride and dextromethorphan hydrobromide hydrate. , bromhexine, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl - Methyl ephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol salt Examples include salts and L-carbocysteine.

[0058] Anti-inflammatory drugs include glycyrrhizic acid and its derivatives and their salts (for example, glycyrrhizic acid and its derivatives and salts). Examples include dipotassium lysyrrhizinate and monoammonium glycyrrhizinate.

[0059] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0060] Vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., Benf Othiamine, vitamin B2 and its derivatives and their salts (e.g., riboflavin) Vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin Examples include ions and their derivatives, as well as salts thereof.

[0061] Anticholinergic agents include scopolamine hydrobromide, datura extract, and methylscopolamine. Bromides, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine Bromides, belladonna alkaloids, belladonna extract, total belladonna alkaloids, iodine Isopropamide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, ro Examples include belladonna root, belladonna root total alkaloid citrate, etc.

[0062] The solid composition according to this embodiment may be further modified by adding a formulation additive as needed. Possible alternatives include pharmaceutically acceptable carriers, such as excipients, binders, and disintegrants. Disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, Sweeteners, flavoring agents, cooling agents, fragrances, air fresheners, coloring agents, bases, coating agents, sugar coating agents, etc. Examples include plasticizers, dispersants, defoamers, fluidizers, and flavoring agents / fragrances, etc., as well as conventionally known solid formulations. Pharmaceutical additives that can be used for the above purposes may be used for the above purposes.

[0063] Excipients include, for example, sugar powder, gum arabic, powdered gum arabic, cocoa butter, caramel. Sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon dioxide, Xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate Light anhydrous silicic acid, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose Lurose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate Synthetic aluminum silicate, hydroxypropyl starch, crystalline cellulose, wheat cellulose Pun, rice flour, rice starch, heavy anhydrous silicic acid, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low degree of substitution Hydroxypropylcellulose, dextrin, corn starch, corn Starch granules, trehalose, lactose monohydrate, lactose granules, sucrose, potato starch, Hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered reduced maltose syrup Powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene Castor oil 60%, maltitol, D-mannitol, magnesium aluminometasilicate Examples include calcium sulfate, erythritol, glucose, and fructose.

[0064] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, and ceramic. Hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, Lulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified) (Diluted methacrylate), methacrylate copolymer L, methacrylate copolymer LD, methacrylate Copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose Examples include polyvinyl alcohol-acrylic acid-methyl methacrylate copolymers.

[0065] Examples of disintegrants include sodium carboxymethyl starch, carmellose, and caramel. Mellose calcium, croscarmellose sodium, croscarmellose sodium, Crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch Examples include partially pregelatinized starch.

[0066] Examples of disintegration aids include carboxymethyl starch sodium, carmellose, Carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose Sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch -ch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1 Examples include 500 and macrogol 4000.

[0067] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, and macromolecules. Goal 400, Macro Goal 1500, Macro Goal 4000, Macro Goal 6000, Examples include macrogol 6000NF and beeswax.

[0068] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, and carbonated water. Examples include sodium chloride and anhydrous citric acid.

[0069] Examples of moisture-proofing agents include ethylcellulose, olive oil, and dried aluminum hydroxide gel. Glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, Refined sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid, stearin Acid, polyvinyl acetal diethylaminoacetate, hydroxypropyl methylcellulose -2910 mixture, polyvinyl acetal diethylaminoacetate, aluminum metasilicate Examples include magnesium methyl phosphate.

[0070] Examples of surfactants include sucrose fatty acid esters and polyoxyethylene hydrogenated castor oil. Oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether , polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, Polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, Polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene Poly(105)polyoxypropylene(5)glycol, polyoxyethylene(120) Polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene Polypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) Cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macro Logol 400, sorbitan monooleate, glyceryl monostearate, monostearate Examples include sorbitan phosphate, sorbitan monolaurate, and sodium lauryl sulfate. ru.

[0071] Examples of stabilizers include adipic acid, L-aspartic acid, and L-aspartic acid sodium. Thorium, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, A Sodium benzoate, propylene glycol alginate, benzoic acid, sodium benzoate Thorium, ethylenediamine, calcium disodium edetate, sodium edetate, Tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, salt Calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride Nesium, cysteine ​​hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer , carmellose calcium, carmellose sodium, anhydrous sodium carbonate, glycine, Glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate L-Glutamate, Magnesium Gluconate, Potassium L-Glutamate, Sodium L-Glutamate Um, L-glutamic acid L-lysine, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, ko Sodium rhoidin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sodium phosphate Sugar fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin Hydrolyzed cellulose, sorbitan fatty acid ester, taurine, talc, calcium carbonate, carbonated water Potassium phosphate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin Min E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone Polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, poly Oxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxy Hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) Recall, polyoxyethylene (54) polyoxypropylene (39) glycol, poly Oxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) Polyoxypropylene (67) Glycol, Polyoxyethylene Coconut Oil Fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate T80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 4 00, Macrogol 4000, Anhydrous Citric Acid, Anhydrous Sodium Citrate, Anhydrous Phosphate Monohydrate Sodium phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methyl Cellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate Malic acid hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, phosphorus Calcium dihydrogen hydrate, L-leucine, polyvinyl alcohol, acrylic acid, metha Examples include methyl lylate copolymers.

[0072] Examples of antioxidants include ascorbic acid, L-ascorbic acid, and steate. Ingredients: Citric acid hydrate, soy lecithin, natural vitamin E, tocopherol tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, etc. Examples include: In the case of a solid composition containing acetaminophen, an antioxidant or stabilizer. It is preferable not to include tocopherols.

[0073] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, and Examples include silicon dioxide water, titanium dioxide, and calcium monohydrogen phosphate.

[0074] Examples of sweeteners include aspartame, acesulfame potassium, amacha, and ama. Tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, Dipotassium lycyrrhizinate, disodium glycyrrhizinate, saccharin, saccharin Thorium hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose Examples include sucrose, maltitol, D-mannitol, and erythritol.

[0075] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, and others. Uren powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract Ingredients: licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate L-hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract Brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper Powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-sodium tartrate, ginger Powder, sucralose, stevia extract, stevia extract refined product, Swertia japonica, D-sorbitol Tannic acid, clove oil, dried tangerine peel tincture, chili pepper, chili pepper powder, spruce powder, trefoil Halos hydrate, senna powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder - D-mannitol, dl-menthol, l-menthol, menthol powder, ryu Uno, Ophiopogon powder, green tea powder, DL-malic acid, DL-malate sodium, lemon oil Examples include rose oil.

[0076] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, and cinnamon oil. Examples include peppermint water, peppermint oil, and l-menthol.

[0077] Flavorings include, for example, orange flavor, guarana extract, sweet orange, and Strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder Dark flavor, peach essence, fruit essence, peppermint, melon powder Examples include flavorings, l-menthol, and peppermint oil.

[0078] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, and d-camphor. dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint Oil, clove oil, turpentine oil, chili pepper powder, pineapple powder, flavoring 51357, pineapple Apple powder flavoring 59492, peppermint water, peppermint oil, vanilla powder flavoring 54286, vanillin Bergamot oil, d-borneol, dl-borneol, dl-menthol, l- Examples include ethanol, eucalyptus oil, rose water, and rose oil.

[0079] Examples of coloring agents include yellow iron oxide, yellow iron(III) oxide, orange essence, and brown iron oxide. Iron, carbon black, caramel, beta-carotene, licorice extract, gold leaf, black iron oxide, acid Titanium oxide, iron(III) oxide, dizuazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5 Food-grade Blue No. 2 aluminum lake, Food-grade Yellow No. 4 aluminum lake, Food-grade Red No. 2, Food Red No. 3, Food Red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin Thorium, copper chlorophyll, phenol red, malachite green, methylene blue, Medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate Examples include um, green tea powder, and rose oil.

[0080] The base ingredients are acacia powder, pregelatinized starch, ethylcellulose, and cocoa butter. Carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium Reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, can Ten powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous Silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium silicate Thorium, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, sucrose Magnesium thearate, gelatin, D-sorbitol, talc, calcium carbonate, tofu Sorghum starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer Combined ingredients, concentrated glycerin, potato starch, hydroxypropylcellulose, hypromello Polysorbate 60, Polysorbate 80, Poly Vinyl alcohol (partially saponified), microcrystalline wax, macrogol 20 0, Macrogol 300, Macrogol 400, Macrogol 1000, Macrogol 1 500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macro Gol 6000NF, Macrogol 20000, D-mannitol, Monostearate Lycerin, sorbitan monostearate, batyl monostearate, pryl monostearate Polyethylene glycol, polyethylene glycol monostearate, sodium lauryl sulfate Examples include polyvinyl alcohol, acrylic acid, and methyl methacrylate copolymers.

[0081] Examples of coating agents include ethyl acrylate / methyl methacrylate copolymer. Dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate Polymer RS, gum arabic, gum arabic powder, ethylcellulose, ethylcellulose water Dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate Glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester , stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, Shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate Gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose Rose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl Pyrmethylcellulose 2910, titanium dioxide, macrogol 400 mixture, hypromellol S, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydro Xypropylmethylcellulose 2910 mixture, pullulan, polysorbate 80, polypropylmethylcellulose Nylacetal diethylaminoacetate, povidone, polyvinyl alcohol (partially hydrated) (Monster), Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Mac Logol 6000NF, Macrogol 20000, Macrogol 35000, Methacrylic Acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, metasilicic acid Magnesium aluminate, methyl acrylate, methacrylic acid, methyl methacrylate Tocopolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate • Methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate N, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl sulfate Examples include a copolymer of methyl methacrylate, acrylic acid, and methyl alcohol.

[0082] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, and carnauba. Uva wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxy stearate Sil-40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitate Calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose Pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500 Macrogol 4000, Macrogol 6000, Macrogol 6000NF, Hydrophosphate Calcium hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol, acrylic Examples include acid-methyl methacrylate copolymers.

[0083] Examples of plasticizers include triethyl citrate, glycerin, and glycerin fatty acid ester. Lu, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil Castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polysorbate 80, Macroglucose Lu 400, Macrogol 600, Macrogol 1500, Macrogol 4000, Macro Gol 6000, Macrogol 6000NF, Glyceryl Monostearate, Linoleic Acid Examples include isopropyl alcohol and liquid paraffin.

[0084] Dispersants include aminoalkyl methacrylate polymer RS, acacia gum, and arabic Agumon powder, 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, acid Titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sol Bitol, soy lecithin, low-substituted hydroxypropyl cellulose, dextrin, Corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethyl Cellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromene Rose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, Polyoxyethylene hydrogenated castor oil 50, Polyoxyethylene hydrogenated castor oil 60, Resorbate 20, Polysorbate 60, Polysorbate 80, Microcrystalline Macrogol, Macrogol 300, Macrogol 4000, Macrogol 6000, Macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methyl Cellulose, glyceryl monooleate, sorbitan monooleate, monostearin Aluminum phosphate, glyceryl monostearate, sorbitan monostearate, monopal Examples include sorbitan mitinate, sorbitan monolaurate, and sodium lauryl sulfate. ru.

[0085] Antifoaming agents include ethanol, glycerin fatty acid ester, and dimethylpolysiloxane. (For oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid ester, sil Examples include antifoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80. ru.

[0086] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, and synthetic aluminum silicate. Um, heavy anhydrous silicic acid, aluminum magnesium hydroxide, stearic acid, calcium stearate Cium, magnesium stearate, tricalcium phosphate, talc, aluminum metasilicate Examples include magnesium phosphate and calcium hydrogen phosphate granules.

[0087] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, and oleo. Orange, orange extract, orange essence, orange oil, chamomile oil, caramel, can Elephant powder, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, citronella oil, sugar - Flavor, spearmint oil, cherry flavor, clove oil, chili flavor, Spruce tincture, spruce oil, pine oil, peppermint oil, vanilla flavor, vanillin, bitter Essence, Vitabase, Himalayan cedar oil, fruit flavor, Flavor G1, Hess Peridine peppermint essence, bergamot oil, vermouth flavor, d-borneol All, dl-borneol, matcha, mixed flavor, mint flavor, dl -Menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flake powder Examples include lemon powder, lemon oil, rose water, rose oil, and peppermint oil.

[0088] These components may be present individually or in combination of two or more types.

[0089] (Dosage form) The solid composition of this embodiment is, for example, an orally administered preparation (tablet (orally disintegrating tablet, tubular disintegrating tablet, tubular disintegrating tablet)). (Including Abul tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders, etc.) Preparations for oral application (oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums) This includes, etc. ) and other dosage forms as described in the General Provisions for Preparations of the 18th Revised Japanese Pharmacopoeia, etc. The solid composition of this embodiment is preferably an oral solid composition.

[0090] The dosage forms of the solid composition in this embodiment include, for example, tablets, capsules, pills, granules, and Examples include fine granules. These solid compositions may be sugar-coated or by known methods as needed. It may be coated with a film coating or the like. The dosage form of the solid composition is preferably It is a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets. It can be done.

[0091] The solid composition of this embodiment is packaged in bottles, PTP packaging, pouches, sticks, and SPs. They can be packaged and stored airtight. They can also be pillow-wrapped. These may be stored in boxes or the like. The materials used for pillow packaging are not particularly limited. For example, polypropylene film, polyethylene terephthalate film, polyethylene The materials used include resin films such as film, and resin films to which aluminum foil has been attached. It can be placed inside the bottle packaging or pillow packaging if moisture absorption is a concern. It may also be saved internally at the same time.

[0092] The solid composition of this embodiment may be contained in a packaging container to form a package. The solid composition may be contained, for example, in an airtight package. By using a package, For example, it can improve the convenience of using solid compositions. Packaging in this embodiment Specifically, these are pharmaceuticals.

[0093] As for the packaging form of solid dosage forms, the solid composition can be packaged in bottles, PTP packaging (Press Through Packaging). Once packaged, it is packaged in a pouch, stick, or strip package (SP). They may be stored in an airtight container. Furthermore, they may be pillow-wrapped and stored in a box or similar container. Alternatively, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be placed inside the bottle packaging, pillow packaging, etc. They may be stored together in the same packaging container.

[0094] Examples of materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc. include: For example, polypropylene film, polyethylene terephthalate film, polyethylene film Examples include resin films such as acrylic, and those made by attaching aluminum foil to these resin films. It can be made from either a single-layer film or a multi-layer film (e.g., laminate film). You may use it.

[0095] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Such packaging is formed of at least one of a moisture-proof material and a gas barrier material. Examples of packaging include:

[0096] For example, PTP (polypropylene) and polyethylene aluminum pillow - A combination of packaging is an example. Also, when the solid composition is a tablet, Considering the suppression of moisture content increase, the storage stability of tablets, and the stability of tablets after opening, as a moisture-proof material Alternatively, PTP packaging (Al-Al packaging) using aluminum on both sides may be used.

[0097] As the gas barrier material, known materials may be used, for example, materials having a functional barrier layer It may also be a laminate film, which serves the same function as the above moisture-proof material, or in combination with the above moisture-proof material. They may be used together.

[0098] Furthermore, packaging containers may be made with environmentally friendly materials. For example, recycled plastics or bio-based materials. Environmentally friendly materials such as mass plastics and biodegradable plastics are used as part of the packaging material or It can be used for all of them.

[0099] (Manufacturing method) In a second embodiment, the material comprises (A) ibuprofen and (B) tipepidine and its salts. (C) Select at least one from the group and from the group consisting of tranexamic acid and its salts A method for producing a solid composition is provided, comprising the step of contacting at least one selected element. It will be done.

[0100] The production of the solid composition can be carried out using known techniques. Each component can be produced in any step. They are added and finally come into contact with each other. After contact, a solvent and binder are added to the mixture and kneaded together. The resulting mixture may be used as a solid composition. The crystal can be produced by the method described in Japanese Patent Publication No. 2022-70674 (listed above). After forming crystals consisting of buprofen and tranexamic acid, the crystals and (B) tipepid At least one selected from the group consisting of and its salts is brought into contact with or kneaded. That's fine.

[0101] The resulting mixture is further subjected to drying and granulation processes to produce granules (granulated material). This is also possible. In this case, granules (granulated materials) containing each component may be prepared separately. Granulation is It can be either wet or dry.

[0102] The resulting granules (granulated material) can be used as is, or the granules can be mixed with additives and then compressed into tablets. The tablets can be molded and manufactured without a protective film, or they can be further coated with a film. .

[0103] (Property change inhibitor) In a third embodiment, at least selected from the group consisting of tranexamic acid and its salts Select from the group consisting of (I) ibuprofen and (II) tipepidine and its salts, including one of the following: A property change inhibitor for solid compositions is provided, comprising at least one selected type.

[0104] For at least one selected from the group consisting of tranexamic acid and its salts, the actual As explained in component (C) of the solid composition relating to the application form, the above component (I) and Regarding (II), see components (A) and (B) of the solid composition according to this embodiment. As I have explained.

[0105] The property change inhibitor is derived from tranexamic acid and its salts relative to component (I) or (II). The amount of at least one component selected from the group is the component of the solid composition according to this embodiment ( It is preferable that C) be used in an amount that falls within the range described as the preferred content. Furthermore, tranexamic acid crystallizes with ibuprofen (in its crystallized state) and then forms a solid composition. It is preferable that it be added to a substance.

[0106] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. It is not something that should be done. [Examples]

[0107] 1.Raw materials In this example, the following raw materials were used. [Table 1]

[0108] 2. Preparation of the solid composition (Comparative Example 1) Measure out 50g of tipepidine hibenzate and 50g of ibuprofen (manufactured by SI Group). The mixture was then taken and mixed in bags 100 times. After sieving with a 42-mesh sieve, it was mixed in bags again. The process was repeated 100 times to obtain a physical mixture powder. 2g of the obtained physical mixture powder was weighed into a 1K standard bottle and sealed tightly. Afterward, the sample was adjusted to have a uniform thickness and used as the sample for Comparative Example 1.

[0109] (Example 1, Comparative Examples 2-4) To 5g of the physical mixture powder obtained in Comparative Example 1, tranexamic acid (manufactured by Kyowa Pharma Chemical), Add 2.5g of either tartaric acid, sodium bicarbonate, or noscapine, and mix in a bag. The process was repeated 00 times. 2g of the resulting mixture was weighed into a 1K standard bottle, sealed tightly, and the thickness was uniform. The samples were adjusted to achieve the desired result and used as the samples for Example 1 and Comparative Examples 2-4.

[0110] (Example 2) Tipepidine hibenzate 10g, ibuprofen (manufactured by SI Group) 10g, and Weigh out 7.6g of tranexamic acid (manufactured by Kyowa Pharma Chemical) and mix it in a bag 100 times. After sieving with a 42-mesh sieve, the mixture was further mixed in bags 100 times to obtain a physically mixed powder. Obtained. Weigh 2g of the obtained physical mixture powder into a 1K standard bottle and seal it tightly, ensuring the thickness is uniform. The sample was adjusted to become the sample for Example 2.

[0111] (Example 3) Ibuprofen (manufactured by Yonezawa Hamari) 240.0g, and tranexamic acid (manufactured by AMI) 182g 0.9g was placed into a stirring and mixing granulator (Vertical Granulator VG-5 (Powrec)) The ingredients were mixed together to form a powder. Ethanol (99.5% purity) (manufactured by Kanto Chemical Co., Ltd.) was added to this powder. A mixture of [the substance] and purified water (mass ratio 8:2) was poured in 69g and kneaded and granulated to obtain a paste. Paste It was wet-crushed with a power mill (manufactured by Dalton) under the conditions of low speed and 32 mesh. Then, It was stored in a thermostat at 70 °C for 89 hours, and crystals composed of ibuprofen and tranexamic acid were obtained.

[0112] 6 mg of the obtained crystals were placed in an aluminum pan, and using a differential scanning calorimeter DSC3+ (manufactured by Mettler · Toledo), the range from 25 to 350 °C was measured at a rate of 60 °C per minute. The results are shown in Figure 1 As shown in Figure 1, the peak derived from ibuprofen around 75 °C disappeared, and there was a peak derived from the crystal composed of ibuprofen and tranexamic acid around 180 °C. From this, it was confirmed that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained.

[0113] Next, 17.6 g of the obtained crystals and 10 g of tipepidine hibenzate were weighed and mixed in a bag 100 times. After sieving through a 42-mesh sieve, the bag mixing was further performed 100 times to obtain a physically mixed powder. 2 g of the obtained physically mixed powder was weighed into a 1 K standard bottle and sealed, and then the thickness was adjusted to be uniform to obtain the sample of Example 3.

[0114] The blending ratios (mass ratios) of each sample are shown in the following table. In the following table, "IB-TXA crystal" means a crystal composed of ibuprofen and tranexamic acid.

Table 2

[0115] 3. Evaluation of the change in properties of the solid composition Each sample of Example 1 and Comparative Examples 1 to 4 was stored under the conditions of 80 °C for 24 hours, and the change in properties was evaluated. The changes in properties included state changes such as aggregation, solidification, moisture absorption, separation, and liquefaction. ​​​​​​​​Observed. The state changes were visually inspected before and after storage to confirm whether powder aggregation, solidification, moisture absorption, separation, and liquefaction had occurred. occurred.

[0116] Next, the state changes were evaluated according to the following criteria. State change A: No change, B: Slight change, C: Change, D: Marked change

[0117] The results of the state changes compared with the start of high-temperature storage are shown in the following table. Marked state changes were observed in Comparative Examples 1 to 4. Specifically, in Comparative Examples 1, 2, and 4, part of the sample was liquefied and separated into two layers. In Comparative Example 3, aggregation and solidification occurred. On the other hand, in Example 1, the state change was suppressed. Specifically, although aggregation and solidification occurred, the change was suppressed compared with Comparative Example 3. From the above results, it was shown that tranexamic acid added in Example 1 could suppress the property changes of ibuprofen and tipepidine hibenzate under high-temperature conditions.

[0118]

Table 3

[0119] Next, each sample of Example 2, Example 3, and Comparative Example 1 was stored under the conditions of 80°C for 2 weeks to evaluate more long-term property changes. As the property changes, color tone changes and state changes such as aggregation, solidification, moisture absorption, separation , and liquefaction were observed. The color tone change was visually inspected before and after storage to confirm whether a change in color tone was confirmed. The state change was visually inspected before and after storage to confirm whether powder aggregation, solidification , moisture absorption, separation, and liquefaction had occurred.

[0120] Next, the color tone change and the state change were evaluated according to the following criteria. Color tone change A: No discoloration, B: Slight discoloration, C: Discoloration, D: Marked discoloration​​ State change A: No change, B: Slight change, C: Change present, D: Significant change

[0121] The following table shows the results of color and condition changes compared to the start of high-temperature storage. In Comparative Example 1... Significant changes were observed in both color tone and condition. Specifically, when it turned dark brown... In both cases, a portion liquefied and separated into two layers. In contrast, in Example 2, the change in state was It was suppressed. Specifically, although it turned brown and coagulation and solidification occurred, the coagulation and solidification were only partial. Yes, it was. Furthermore, in Example 3, both color change and state change were suppressed. Specifically, Even after two weeks, it remained in the state of a white powder. From the above, tranexamic acid is It is possible to suppress the changes in properties of profen and tipepidine hibenzate under high-temperature conditions. In particular, its effect is evident when crystals composed of ibuprofen and tranexamic acid are formed. It was indicated that it would become an author.

[0122] [Table 4]

[0123] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. This does not mean adding, omitting, substituting, or otherwise modifying the configuration without departing from the spirit of the present invention. It is possible to change this.

Claims

1. A property change inhibitor for a solid composition comprising (I) ibuprofen and (II) at least one selected from the group consisting of tipepidine and its salts, A property change inhibitor comprising at least one selected from the group consisting of tranexamic acid and its salts.

2. The property change inhibitor according to claim 1, wherein the mass ratio of the total amount of component (I) to the total amount of component (II) in the solid composition is 1:1 to 16:1 ((I):(II)).

3. The property change inhibitor according to claim 1 or 2, wherein the solid composition comprises crystals composed of ibuprofen and tranexamic acid.

4. The property change inhibitor according to claim 3, wherein the molar ratio of ibuprofen to tranexamic acid in the crystal is 1:

1.

5. A method for suppressing changes in the properties of a solid composition comprising (I) ibuprofen and (II) at least one selected from the group consisting of tipepidine and its salts, A method comprising adding at least one selected from the group consisting of tranexamic acid and its salts to the solid composition.

Images