Crystal manufacturing method

Abstract

This invention provides a novel method for producing crystals composed of ibuprofen and tranexamic acid. [Solution] A method for producing crystals comprising ibuprofen and tranexamic acid, comprising: (1) adding a mixed powder of ibuprofen and tranexamic acid to an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, or adding the aqueous solution to the mixed powder to obtain a mixture in which the ratio of the content of the aqueous solution to the total mass of ibuprofen and tranexamic acid is 0.09 mL / g or more; and (2) generating the crystals from the obtained mixture.

Description

Technical Field

[0001] The present invention broadly relates to a method for producing crystals composed of ibuprofen and tranexamic acid.

Background Art

[0002] Ibuprofen is widely used as a non-steroidal antipyretic and analgesic drug. Tranexamic acid has an anti-plasmin effect and is used for symptoms of colds such as throat pain.

[0003] Ibuprofen and tranexamic acid may be simultaneously formulated as active ingredients in pharmaceutical compositions such as anti-inflammatory, antipyretic and analgesic drugs and cold remedies.

[0004] For example, Patent Document 1 discloses crystals composed of ibuprofen and tranexamic acid. Patent Document 1 discloses that crystals composed of ibuprofen and tranexamic acid can suppress expansion even when stored at high temperatures.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] Patent Document 1 discloses crystals composed of ibuprofen and tranexamic acid and a method for producing the same. However, in the production method described in Patent Document 1, it is difficult to efficiently produce crystals composed of ibuprofen and tranexamic acid. Therefore, an object of the present invention is to provide a novel method for producing crystals composed of ibuprofen and tranexamic acid.

Means for Solving the Problems

[0007] The inventors of the present invention have discovered that crystals composed of ibuprofen and tranexamic acid can be efficiently produced by using a predetermined method, and have completed the present invention.

[0008] In other words, this application encompasses the following inventions. [1] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) To obtain a mixture in which a mixed powder of ibuprofen and tranexamic acid is added to an aqueous solution containing ethanol of 65 w / w% or more and less than 100 w / w%, or the aqueous solution is added to the mixed powder, and the ratio of the content of the aqueous solution to the total mass of ibuprofen and tranexamic acid is 0.09 mL / g or more. (2) To produce the crystals from the obtained mixture, A manufacturing method that includes this. [2] The ratio is 0.09 mL / g or more and 0.20 mL / g or less. The manufacturing method described in [1]. [3] (2) The process of generating crystals is to knead the mixture. The manufacturing method described in [1] or [2]. [4] The mixing time is 10 minutes or less. [3] The manufacturing method described below. [5] The process further includes drying the granules obtained by the aforementioned kneading. The manufacturing method described in [3] or [4]. [6] In the aforementioned mixture, the molar ratio of ibuprofen to tranexamic acid (ibuprofen:tranexamic acid) is 1:0.5 to 1:5. A manufacturing method described in any one of [1] to [5]. [7] Based on the lower content (molar amount) of ibuprofen and tranexamic acid in the mixture, 80 mol% or more of the one of the two in the mixture forms the crystals. The production method according to any one of [1] to [6].

Advantages of the Invention

[0009] According to the present invention, a novel production method of crystals composed of ibuprofen and tranexamic acid can be provided.

Brief Description of the Drawings

[0010] [Figure 1] Shows the results of differential scanning calorimetry (DSC) in Example 1 and Comparative Example 1.

Embodiments for Carrying Out the Invention

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

[0012] (Production Method of Crystals) In the first aspect, A method for producing crystals composed of ibuprofen and tranexamic acid, (1) Adding a mixed powder of ibuprofen and tranexamic acid to an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, or adding the above aqueous solution to the above mixed powder, to obtain a mixture in which the ratio of the content of the above aqueous solution to the total mass of ibuprofen and tranexamic acid is 0.09 mL / g or more; (2) Generating crystals from the obtained mixture, A production method is provided.

[0013] As used herein, "ibuprofen" has a CAS registration number of 15687-27-1 and C

[0013] , 18 , , , 13 H 18It is a compound represented by the chemical formula of O2 (molecular weight: 206.29 g / mol). Ibuprofen is used as an active ingredient in anti-inflammatory, analgesic, antipyretic agents, etc. The salt of ibuprofen is not particularly limited as long as it is pharmacologically acceptable.

[0014] As used in this specification, "tranexamic acid" has a CAS registration number of 1197-18-8 and is a compound represented by the chemical formula of C8H 15 NO2 (molecular weight: 157.21 g / mol). Tranexamic acid is used as an active ingredient in anti-inflammatory agents, etc. The salt of tranexamic acid is not particularly limited as long as it is pharmacologically acceptable.

[0015] In the crystal composed of ibuprofen and tranexamic acid produced by the production method according to this embodiment, ibuprofen and tranexamic acid may be present in a molar ratio of 1:1. Also, in the crystal, ibuprofen and tranexamic acid may form a crystal unit cell of four molecules each.

[0016] In the crystal, hydrogen bonds may be formed between the carboxylic acid group of ibuprofen and the carboxylic acid group of tranexamic acid, and between the carboxylic acid group of ibuprofen and the amino group of tranexamic acid.

[0017] The crystal may have an endothermic peak around 180°C in differential scanning calorimetry (DSC). Around 180°C may be, for example, in the range of 180°C ± 20°C, or in the range of 180°C ± 10°C. In the DSC of the crystal, the melting heat peak around 75°C characteristic of ibuprofen may disappear. <00)0107> The crystal may have, for example, the crystal structure shown in Figure 1 of Japanese Patent Publication No. 2022-70674, and may have the X-ray diffraction pattern shown in Figure 2 of the same publication. The crystal may have seven main peaks (2θ = 6.3, 8.4, 16.2, 18.5, 19.1, 21.1, 25.6 ± 0.5°) in its X-ray diffraction pattern. The crystal may have one or more features of the crystal disclosed in Japanese Patent Publication No. 2022-70674, and may be the crystal disclosed in Japanese Patent Publication No. 2022-70674.

[0019] A conventional method for producing crystals composed of ibuprofen and tranexamic acid is, for example, the method described in Japanese Patent Publication No. 2022-70674. This publication describes the following methods A to C.

[0020] Method A: A method comprising (i) producing ibuprofen in a fluid state by adding a solvent or heating, (ii) mixing the obtained fluid ibuprofen with tranexamic acid, and (iii) producing crystals from the obtained mixture.

[0021] Method B: A method comprising (i) obtaining tranexamic acid in a fluid form, (ii) mixing the obtained fluid tranexamic acid with ibuprofen, or ibuprofen in a fluid form obtained by adding a solvent or heating, and (iii) generating crystals from the obtained mixture.

[0022] Method C: A method comprising (i) adding ibuprofen and tranexamic acid to a solvent to obtain a solution or dispersion, and (ii) spraying and drying the obtained solution or dispersion, or allowing the solution obtained in step (i) to stand, filtering the product obtained after standing, and drying the product.

[0023] In contrast, the manufacturing method according to this embodiment includes (1) adding a mixed powder of ibuprofen and tranexamic acid to an aqueous solution containing ethanol of a predetermined concentration, or adding the aqueous solution to the mixed powder to obtain a mixture containing a predetermined amount of the mixed powder and the aqueous solution, and (2) generating crystals from the obtained mixture.

[0024] In the manufacturing method according to this embodiment, a mixed powder of ibuprofen and tranexamic acid is added to a solvent, or a solvent is added to a mixed powder of ibuprofen and tranexamic acid. In contrast, methods A and B described in Japanese Patent Application Publication No. 2022-70674 involve adding ibuprofen or tranexamic acid to a solvent to obtain a fluid of ibuprofen or tranexamic acid, and then adding ibuprofen or tranexamic acid to this fluid.

[0025] Furthermore, the manufacturing method according to this embodiment uses an aqueous solution containing ethanol at a predetermined concentration, for example, 65 w / w% or more and less than 100 w / w%, as a solvent, whereas method C described in Japanese Patent Publication No. 2022-70674 uses a 50 w / w% ethanol aqueous solution. Also, the manufacturing method according to this embodiment uses an aqueous solution containing a small amount of ethanol, whereas method C described in Japanese Patent Publication No. 2022-70674 uses a large amount of ethanol aqueous solution (for example, 4 to 20 g of ethanol aqueous solution per 1 g of the total amount of ibuprofen and tranexamic acid).

[0026] Surprisingly, this embodiment allows for the efficient production of crystals composed of ibuprofen and tranexamic acid compared to the various methods described in Japanese Patent Application Publication No. 2022-70674. Specifically, this embodiment allows for the production of a product with a high crystal formation rate in a short time. Furthermore, this embodiment allows for a significant reduction in the amount of solvent used (specifically, for example, ethanol).

[0027] The crystallization rate refers to the proportion of ibuprofen and tranexamic acid that formed crystals relative to the total amount of ibuprofen or tranexamic acid used as raw materials. More specifically, when equal amounts (molar ratio) of ibuprofen and tranexamic acid are used as raw materials, it refers to the proportion of ibuprofen that formed crystals with tranexamic acid out of the total amount of ibuprofen used as raw materials. When different amounts (molar ratios) of ibuprofen and tranexamic acid are used as raw materials, it refers to the proportion of ibuprofen and tranexamic acid that formed crystals out of the total amount of ibuprofen and tranexamic acid used, with the lower molar ratio being the proportion of ibuprofen and tranexamic acid used as raw materials.

[0028] Therefore, the crystal formation rate is defined as the proportion of the ibuprofen and tranexamic acid contained in the mixture in step (1) to obtain the mixture (hereinafter also referred to as "step (1)") in the manufacturing method according to this embodiment, with the smaller of the two amounts (moles) of ibuprofen and tranexamic acid contained in the mixture as the standard, and the proportion of the one that formed crystals in the mixture. If the amount of tranexamic acid in the mixed powder is equal to or greater than the amount of ibuprofen, the crystal formation rate may be defined as the ratio of ibuprofen contained in the generated crystals to the total amount of ibuprofen contained in the mixture in step (1).

[0029] The crystal formation rate in the manufacturing method according to this embodiment may be 80 mol% or more, 82 mol% or more, 85 mol% or more, 90 mol% or more, 91 mol% or more, 92 mol% or more, 93 mol% or more, 94 mol% or more, 95 mol% or more, 96 mol% or more, 97 mol% or more, 98 mol% or more, 99 mol% or more, or 100 mol%. The method for measuring the crystal formation rate can be appropriately carried out by referring to the method described in the examples.

[0030] In the manufacturing method according to this embodiment, as step (1), a mixture of ibuprofen and tranexamic acid is added to an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, or the aqueous solution is added to the above mixture to obtain a mixture.

[0031] In step (1), by using an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, a product with a high crystal formation rate can be obtained in a short time. The ethanol concentration of the aqueous solution is preferably 65 w / w% or more and 99 w / w% or less, 70 w / w% or more and 98 w / w% or less, 75 w / w% or more and 95 w / w% or less, 80 w / w% or more and 93 w / w% or less, or 85 w / w% or more and 90 w / w% or less. Note that "w / w%" can also be replaced with mass%, and in the case of ethanol concentration, it means the ratio of the mass of ethanol to the total mass of the aqueous solution.

[0032] An aqueous solution containing ethanol is a solution containing at least ethanol and water. An aqueous solution containing ethanol may be an aqueous solution consisting of ethanol and water, or it may be substantially an aqueous solution consisting of ethanol and water. "Substantially" means that the components of the aqueous solution other than impurities consist of ethanol and water. Therefore, the total amount of ethanol and water in an aqueous solution containing ethanol may be 95 w / w% or more, 98 w / w% or more, 99 w / w% or more, 99.9 w / w% or more, 99.99 w / w% or more, 99.999 w / w% or more, or 100 w / w%.

[0033] The concentration of water in the aqueous solution is greater than 0 w / w% and less than or equal to 35 w / w%, preferably between 1 w / w% and 35 w / w%, between 2 w / w% and 30 w / w%, between 5 w / w% and 25 w / w%, between 7 w / w% and 20 w / w%, or between 10 w / w% and 15 w / w%.

[0034] An aqueous solution containing ethanol may contain components other than ethanol and water. Such components include acetone and other solvents such as dimethyl sulfoxide.

[0035] In step (1), a mixture is prepared by adding a mixed powder of ibuprofen and tranexamic acid to the ethanol aqueous solution, or by adding the ethanol aqueous solution to a mixed powder of ibuprofen and tranexamic acid. Surprisingly, by bringing the mixed powder of ibuprofen and tranexamic acid into contact with the ethanol aqueous solution at the same time, a product with a high crystal formation rate can be obtained in a short time. Note that in step (1), it is sufficient for ibuprofen and tranexamic acid to come into contact with the ethanol aqueous solution at the same time; the mixed powder or ethanol aqueous solution does not need to be added all at once. For example, the mixed powder or ethanol aqueous solution may be added in multiple stages.

[0036] In the manufacturing method according to this embodiment, in step (1), the amount of the mixture is adjusted during preparation so that the ratio of the content of the aqueous solution to the total mass of ibuprofen and tranexamic acid is 0.09 mL / g or more. By setting the above ratio to 0.09 mL / g or more, a product with a high crystal formation rate can be obtained in a short time. From this viewpoint, it is preferable that the above ratio be 0.10 mL / g or more, 0.11 mL / g or more, or 0.12 mL / g or more.

[0037] Furthermore, in step (1), it is preferable to use a small amount of the above ethanol aqueous solution with respect to the mixed powder of ibuprofen and tranexamic acid. Specifically, the above ratio is preferably 0.80 mL / g or less, 0.50 mL / g or less, 0.40 mL / g or less, 0.30 mL / g or less, 0.25 mL / g or less, or 0.20 mL / g or less. By setting the ratio within this range, it is possible to produce crystals consisting of ibuprofen and tranexamic acid that have excellent ibuprofen dissolution properties. From the above viewpoint, it is particularly preferable to set the above ratio to 0.09 mL / g or more and 0.20 mL / g or less, but the upper and lower limits of this range may be replaced with the above values, respectively.

[0038] In the manufacturing method according to this embodiment, crystals containing ibuprofen and tranexamic acid in a 1:1 ratio can be formed. Therefore, in step (1), the molar ratio of ibuprofen to tranexamic acid added as raw materials may be 1:1, but the molar ratio of ibuprofen to tranexamic acid may be appropriately adjusted to increase the crystal formation rate or to take into consideration the amount to be added to the solid composition described later.

[0039] In step (1), for example, the amount of each ingredient used in the mixture preparation may be adjusted so that the molar ratio of ibuprofen to tranexamic acid (ibuprofen:tranexamic acid) is 1:0.5 to 1:5. The molar ratio of ibuprofen to tranexamic acid in the mixture obtained in step (1) (i.e., the molar ratio of ibuprofen to tranexamic acid in the mixed powder used) may be 1:0.7 to 1:3, or 1:0.9 to 1:3. Alternatively, the mass ratio of ibuprofen to tranexamic acid (ibuprofen:tranexamic acid) may be described as the ratio of ibuprofen to tranexamic acid content in the solid composition described later.

[0040] If the molar ratio of ibuprofen to tranexamic acid in the mixture is changed from 1:1, for example, by increasing the amount of tranexamic acid relative to ibuprofen, the product obtained by the manufacturing method according to this embodiment will contain not only crystals composed of ibuprofen and tranexamic acid, but also tranexamic acid that has not formed crystals with ibuprofen. Such ibuprofen or tranexamic acid that has not formed crystals may be removed, but may also be incorporated into the solid composition described later together with the crystals composed of ibuprofen and tranexamic acid.

[0041] In step (1), other components besides ibuprofen and tranexamic acid may be added to the mixture, but it is preferable that no other components are added. Examples of components that may be added to the mixture include those that may be included in the solid composition described later.

[0042] Step (1) may be carried out while heating or cooling the raw materials or mixture, but is preferably carried out at room temperature.

[0043] In the manufacturing method according to this embodiment, (2) crystal formation (hereinafter also referred to as "step (2)") is performed by forming crystals from the mixture obtained in step (1). In step (2), for example, by removing at least a portion of ethanol and water from the mixture obtained in step (1), crystals consisting of ibuprofen and tranexamic acid are formed.

[0044] Since it is preferable to use a small amount of the above ethanol aqueous solution with the mixed powder of ibuprofen and tranexamic acid, step (2) preferably includes kneading the mixture obtained in step (1). Kneading may be carried out using a mortar and pestle, a Henschel mixer, a mixer torque rheometer, a stirring and mixing granulator, a Shinagawa type universal mixing and stirring machine, a high-speed kneading granulator, an extruder, or the like.

[0045] If step (2) includes a mixing step, the mixing time is not particularly limited. The longer the mixing time, the higher the crystal formation rate tends to be. In this embodiment, since the manufacturing method can obtain a product with a high crystal formation rate in a short time, the mixing time is preferably 1 to 20 minutes, 2 to 18 minutes, 3 to 15 minutes, 3 to 12 minutes, or 4 to 8 minutes.

[0046] Steps (1) and (2) described above may be carried out in succession. That is, in step (1), the mixed powder of ibuprofen and tranexamic acid may be kneaded with an aqueous ethanol solution, and then step (2) may be carried out by continuing the kneading. Therefore, the manufacturing method according to this embodiment may be a method for producing crystals consisting of ibuprofen and tranexamic acid by adding the mixed powder of ibuprofen and tranexamic acid to the aqueous ethanol solution, or by adding the aqueous solution to the mixed powder and kneading the mixture.

[0047] In this embodiment, when the mixing time is 1 to 20 minutes, 2 to 18 minutes, 3 to 15 minutes, 3 to 12 minutes, 4 to 8 minutes, or 5 minutes, it is preferable that the crystal formation rate is 80 mol% or more, 80 to 100 mol%, 83 to 100 mol%, 85 to 100 mol%, or 90 to 100 mol%. The crystal formation rate may be measured after crystal formation in step (2), but it is preferable that it be measured after the following drying step (for example, drying at 60°C for 1 hour).

[0048] Step (2) may further include drying the granules obtained by kneading the mixture after kneading. Including such a drying step tends to further increase the crystal formation rate. The drying temperature is preferably 30 to 80°C, and more preferably 40 to 70°C. The drying time is preferably 15 minutes to 3 hours, and more preferably 30 minutes to 2 hours.

[0049] Step (2) may be carried out while heating or cooling the mixture or product, or it may be carried out at room temperature. For example, if step (2) includes the mixing step and the drying step described above, the mixing step may be carried out at room temperature, and the drying step may be carried out under conditions where the mixture is heated to the drying temperature described above.

[0050] The manufacturing method according to this embodiment may include steps other than steps (1) and (2) described above. Such methods include a step of obtaining the mixed powder used in step (1) by mixing ibuprofen and tranexamic acid, and a step of isolating the generated crystals.

[0051] The crystals produced by the manufacturing method according to this embodiment are suitably used when incorporated into solid compositions, particularly solid pharmaceutical compositions. A solid composition containing the crystals produced by the manufacturing method according to this embodiment, and a method for producing the same, will be described below.

[0052] (solid composition) The solid composition contains crystals made of ibuprofen and tranexamic acid produced by the manufacturing method according to this embodiment. In addition to the crystals made of ibuprofen and tranexamic acid, the solid composition may also contain uncrystallized ibuprofen and / or uncrystallized tranexamic acid.

[0053] In one embodiment, ibuprofen contained in the solid composition may be crystalline at a rate of 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, 96% by mass, 97% by mass, 98% by mass, 99% by mass, or 100% by mass.

[0054] Each component in the solid composition may be present in the form of a pharmacokinetically acceptable salt, or as a complex with other components. "Pharmacokinetically acceptable salt" includes, for example, salts with pharmacokinetically acceptable bases or acids. Non-specific examples of pharmacologically acceptable salts include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts of inorganic bases (ammonium hydroxide or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids.

[0055] Unless otherwise specified, the amounts of ibuprofen mentioned below refer to the amounts in crystalline form with tranexamic acid, but these amounts may also refer to the total amount of crystalline and non-crystalline ibuprofen. Similarly, unless otherwise specified, any amounts of tranexamic acid described herein refer to the amount in crystal form with ibuprofen, but such amounts may be the total amount of crystalline and non-crystalline tranexamic acid.

[0056] The amount of ibuprofen or its salt included in the composition is appropriately adjusted according to the intended use of ibuprofen or its salt in the composition, the symptoms of the recipient, age, weight, sex, etc. For example, when ibuprofen or its salt is included as a nonsteroidal anti-inflammatory drug, the daily amount of ibuprofen or its salt administered to adults can be adjusted to a range of 30 mg to 2000 mg, preferably 100 mg to 1000 mg, and more preferably 200 mg to 600 mg. In this invention, "adult" means men and women aged 15 years or older. However, the solid composition is not limited to those taken by adults, and may also be taken by children under 15 years of age. When taken by children, the amount can be reduced to 1 / 2 or 2 / 3 of the amount taken by adults per day, depending on the age group.

[0057] The above dosages are examples, and the ibuprofen or salt content per composition administered daily is, for example, about 1% to about 70% by mass, preferably about 5% to about 50% by mass, and more preferably about 10% to about 30% by mass.

[0058] In one embodiment, the content of ibuprofen or a salt thereof in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0059] The weight and dosage of the above composition are for a single day, but the same amount may be administered to the subject multiple times a day, for example, two or three times, preferably three times. The same applies to components other than ibuprofen or its salts. Also, since each dosage is a total amount, the content of each component in the composition may vary depending on the single dose and the dosage form of the composition.

[0060] In certain embodiments, the composition is in tablet form, and the above dosage is the amount of the ingredient contained in 3, 6, or 9 tablets, preferably the amount of the ingredient in 9 tablets. In this embodiment, the single dose for adults (15 years of age or older) is 3 times, with each dose being 2, 3, or 4 tablets, preferably 3 tablets.

[0061] The amount of tranexamic acid or its salt is adjusted as appropriate depending on the intended use of tranexamic acid or its salt in the composition. The amount of tranexamic acid or its salt varies depending on the amount of ibuprofen, etc., but for example, the daily amount is in the range of 10 mg to 3000 mg, preferably 100 mg to 2000 mg, and more preferably 200 mg to 1000 mg.

[0062] The content of tranexamic acid or its salt contained in the composition administered daily is 1% to 70% by mass, preferably 5% to 50% by mass, and more preferably 10% to 30% by mass.

[0063] The amount of tranexamic acid or a salt thereof contained in the composition administered daily is, for example, 0.5 to 3.5 parts by mass, preferably 0.6 to 3.0 parts by mass, and more preferably 0.7 to 2.8 parts by mass, per 1 part by mass of ibuprofen.

[0064] (Other ingredients) The solid composition may contain components other than those listed above, depending on its intended use. When the solid composition is used to alleviate various cold symptoms, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, fever, headache, joint pain, and muscle pain, in addition to bromhexine, meloxicam, and acetaminophen, it may contain antipyretic analgesics, particularly nonsteroidal anti-inflammatory drugs (NSAIDs) other than ibuprofen, and other pharmacologically acceptable components.

[0065] Nonsteroidal anti-inflammatory drugs (NSAIDs) are broadly classified into COX-2 nonselective inhibitors such as diclofenac, loxoprofen, zaltoprofen, pranoprofen, oxaprozin, tiaprofenic acid, naproxen, lornoxicam, ampiroxicam, piroxicam, nabumetone, indomethacin, sulindac, mofezolac, and mefenamic acid, and COX-2 selective inhibitors such as meloxicam, etodolac, and celecoxib. Meloxicam may be included in the composition as a NSAID. It is preferable that the NSAID is a COX-2 nonselective inhibitor. The NSAID may also be in salt form.

[0066] Other pharmacologically acceptable ingredients that may be added include antihistamines, antipyretic analgesics, cough and expectorant agents, anti-inflammatory drugs, central nervous system stimulants, vitamins, anticholinergics, and antiplasmins, which are commonly found in combination cold medicines, antipyretic analgesics, and rhinitis medicines.

[0067] For example, antihistamines include isopendyl hydrochloride, difeterol hydrochloride, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, diphenhydramine hydrochloride, diphenhydramine salicylate, alimazine tartrate, diphenhydramine tannate, triprolidine hydrochloride hydrate, mebhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, difeterol phosphate, clemastine fumarate, and mequitazine.

[0068] Examples of antipyretic analgesics other than nonsteroidal anti-inflammatory drugs include aspirin, acetaminophen, ethenzamide, sazapyrine, salicylamide, lactylphenetidine, and isopropylantipyrine. Acetaminophen may be included in the composition as an antipyretic analgesic.

[0069] Examples of cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, tipepidine hibenzate, dextromethorphan hydrobromide hydrate, bromhexine hydrochloride, dihydrocodeine phosphate, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine.

[0070] Examples of anti-inflammatory drugs include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

[0071] Examples of central nervous system stimulants include caffeine and anhydrous caffeine.

[0072] Examples of vitamin supplements include vitamin B1 and its derivatives and their salts (e.g., benfotiamine), vitamin B2 and its derivatives and their salts (e.g., riboflavin), vitamin C and its derivatives and their salts (e.g., ascorbic acid), hesperidin and its derivatives and their salts, and so on.

[0073] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, belladonna extract, belladonna root, and total belladonna root alkaloid citrate.

[0074] Pharmaceutical additives may be added to the solid composition according to this embodiment as needed. Examples of pharmaceutical additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, antioxidants, fillers, sweeteners, flavoring agents, cooling agents, fragrances, aromatics, colorants, bases, coating agents, sugar coating agents, plasticizers, dispersants, defoaming agents, fluidizing agents, and flavoring agents / fragrances. Pharmaceutical additives that are conventionally known and can be used in solid formulations can be used for the above purposes.

[0075] Excipients include, for example, sugar powder, gum arabic, gum arabic powder, 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 (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, 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 hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc.

[0076] Examples of binders include gum arabic, gum arabic powder, kanbai flour, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate / methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0077] Examples of disintegrants include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and partially pregelatinized starch.

[0078] Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose monohydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, and the like.

[0079] Examples of glossing agents include carnauba wax, bleached beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, and beeswax.

[0080] Examples of foaming agents include anhydrous sodium carbonate, tartaric acid, potassium bitartrate, sodium bicarbonate, and anhydrous citric acid.

[0081] Examples of moisture-proofing agents include ethylcellulose, olive oil, 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 sucrose, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylaminoacetate, and magnesium aluminometasilicate.

[0082] Examples of surfactants include sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, and sodium lauryl sulfate.

[0083] Examples of stabilizers include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, disodium calcium edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, and sodium chloride. Iron, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose sodium, hydrated silicon dioxide, anhydrous sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-glutamate, light anhydrous silicic acid, crystalline sodium dihydrogen phosphate, ko Sodium lentil sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, refined gelatin, refined soy lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene Stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene coconut oil fat glyceryl (7E.O.)Examples include polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0084] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, and sodium pyrosulfite. In the case of a solid composition containing acetaminophen, it is preferable not to include tocopherols as antioxidants or stabilizers.

[0085] Examples of fillers include RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium dioxide, silicon dioxide, and calcium monohydrogen phosphate.

[0086] Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, and erythritol.

[0087] Examples of flavoring agents include sodium chloride, Phellodendron bark powder, Parmesan extract, Coptis japonica, Coptis japonica powder, orange, orange oil, cocoa powder, fructose, caramel, licorice, licorice extract, licorice powder, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, grapefruit extract, brown sugar, cinnamon powder, cinnamon oil, saccharin, sodium saccharin hydrate, Japanese pepper powder, tartaric acid, D-tartaric acid, potassium bitartrate, DL-tartaric acid Examples include sodium glycyrrhizate, ginger powder, sucralose, stevia extract, stevia extract, swertia japonica, D-sorbitol, tannic acid, clove oil, citrus peel tincture, chili pepper, chili pepper powder, spruce powder, trehalose hydrate, porcini powder, plum extract, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, bonito flakes, bonito flakes powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0088] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0089] Examples of flavorings include orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, and peppermint oil.

[0090] Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, cinnamon powder, cinnamon oil, ginger oil, agarwood powder, spearmint oil, clove oil, turpentine oil, chili pepper powder, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0091] Examples of coloring agents include yellow iron oxide, yellow ferric oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, licorice extract, gold leaf, black iron oxide, titanium dioxide, ferric oxide, dizazo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide / glycerin suspension, copper chlorophyllin sodium, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc.

[0092] The base ingredients include: acacia powder, pregelatinized starch, ethylcellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic magnesium sodium silicate, titanium dioxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid / glycolic acid copolymer, concentrated glycerin, potato starch. Examples include hydroxypropylcellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0093] Examples of coating agents include: ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium dioxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910 / titanium dioxide / macrogol 400 mixture, hypromellose, fumaric acid / stearic acid / polyvinyl acetal diethylaminoacetate / Hypermethylcellulose Examples include droxypropyl methylcellulose 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate / methacrylic acid / methyl methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0094] Examples of sugar coating agents include gum arabic, gum arabic powder, ethylcellulose, carnauba wax, carboxymethylcellulose sodium, titanium dioxide, stearic acid, polyoxyl 40 stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, precipitated calcium carbonate, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc.

[0095] Examples of plasticizers include triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, and liquid paraffin.

[0096] The dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic 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, titanium dioxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soy lecithin, and low-substituted hydroxypropyl cellulose. Examples include dextrin, corn starch, lactose monohydrate, concentrated glycerin, potato starch, hydroxyethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, hypromellose, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0097] Examples of defoaming agents include ethanol, glycerin fatty acid esters, dimethylpolysiloxane (for oral use), dimethylpolysiloxane / silicon dioxide mixture, sucrose fatty acid esters, silicone defoaming agents, silicone oil, sorbitan fatty acid esters, and polysorbate 80.

[0098] Examples of fluidizing agents include hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, magnesium aluminometasilicate, and calcium hydrogen phosphate granules.

[0099] Examples of fragrances and scentings include fennel powder, fennel oil, ethyl vanillin, orange, orange extract, orange essence, orange oil, chamomile oil, caramel, licorice 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, cedarwood oil, fruit flavor, Flavor G1, hesperidin peppermint essence, bergamot oil, vermouth flavor, d-borneol, dl-borneol, matcha, mixed flavor, mint flavor, dl-menthol, l-menthol, eucalyptus oil, lavender oil, bonito flakes, bonito flakes powder, lemon powder, lemon oil, rose water, rose oil, peppermint oil, etc.

[0100] These components may be present individually or in combination of two or more types.

[0101] (Dosage form) The solid composition may be in dosage forms described in the General Provisions for Preparations of the 18th Edition of the Japanese Pharmacopoeia, such as oral preparations (tablets (including orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders), or preparations applied orally (including oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.). The solid composition is preferably an oral solid composition.

[0102] Examples of dosage forms for solid compositions include tablets, capsules, pills, granules, and fine granules. These solid compositions may be coated by known methods, such as sugar coating or film coating, as needed. The dosage form of the solid composition is preferably a tablet. Specific examples of tablets include uncoated tablets, film-coated tablets, and sugar-coated tablets.

[0103] The solid composition may be initially packaged in bottles, PTP packaging, pouches, stick packaging, or SP packaging and stored airtight. Furthermore, these may be pillow-packaged, or stored in boxes or similar containers. The material used for pillow packaging is not particularly limited; for example, resin films such as polypropylene film, polyethylene terephthalate film, or polyethylene film, or these resin films with aluminum foil attached, can be used. If hygroscopicity is a concern, a desiccant may be stored simultaneously in the bottle or pillow packaging.

[0104] The solid composition may be contained in a packaging container to form a package. The solid composition may, for example, be contained in an airtight package. Using a package can improve, for example, the convenience of using the solid composition. Specifically, the package is a pharmaceutical product.

[0105] As for the packaging form of the solid composition, the solid composition may be initially packaged in a bottle, PTP (Press Through Package), pouch, stick, or SP (Strip Package) and stored airtight. Furthermore, these may be pillow-packed, or stored in a box or similar container. In addition, from the viewpoint of reducing moisture absorption of the solid composition, a desiccant may be stored simultaneously in the packaging container, such as the bottle or pillow packaging.

[0106] Materials used in SP packaging, PTP packaging, stick packaging, pillow packaging, etc., include, for example, resin films such as polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as resin films to which aluminum foil is attached. Either single-layer films or multi-layer films (e.g., laminate films) may be used.

[0107] Furthermore, it is preferable that the materials constituting the packaging container include materials that are less susceptible to the effects of moisture. Examples of such packaging include packaging formed from at least one of a moisture-proof material and a gas barrier material.

[0108] Examples of moisture-proof materials include a combination of PTP (polypropylene) and polyethylene aluminum pillow packaging. Furthermore, when the solid composition is a tablet, PTP packaging with aluminum on both sides (Al-Al packaging) may be used as a moisture-proof material, considering factors such as suppressing the rise in moisture content of the tablet, the storage stability of the tablet, and the stability of the tablet after opening.

[0109] Known materials may be used as the gas barrier material, for example, a laminate film having a functional barrier layer, and may be used to serve the same purpose as the moisture barrier material, or in combination with the moisture barrier material.

[0110] Furthermore, the packaging containers may be made environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used in part or all of the packaging materials.

[0111] (Method for producing solid compositions) The crystals produced by the manufacturing method according to this embodiment are incorporated into a solid composition by being blended with other components as described above. The production of the solid composition can be carried out using known techniques. Each component is added at any step and finally comes into contact with each other. A solvent and a binder may be added to the mixture after contact and kneaded, and the resulting mixture may be used as the solid composition.

[0112] The crystals produced by the manufacturing method according to this embodiment can also be subjected to a granulation process to produce granules (granulated material). In this case, they may be granulated together with other components or separately. Granules (granulated material) containing each component may also be prepared separately. Granulation may be carried out wet or dry.

[0113] The resulting granules (granulated material) can be used as is, or additives can be added to the granules, and then compressed into tablets to produce uncoated tablets. Alternatively, these can be film-coated.

[0114] For example, when the solid composition is a tablet, the tablet can be manufactured in accordance with the section on "tablets" in the General Provisions of the Japanese Pharmacopoeia. When the solid composition contains non-granular components, the tablet may be manufactured by adding the final component to the granulated granules so as to form an outer layer of granulated granules, and then compressing the mixture into a tablet. The non-granular components may also be in granular form.

[0115] Examples are described below to illustrate the present invention in more detail, but the present invention is not limited to these examples. [Examples]

[0116] 1.Raw materials In this example, the following raw materials were used. [Table 1]

[0117] 2. Preparation of crystals consisting of ibuprofen and tranexamic acid (Reference example 1) Using a mixer torque rheometer 3 (Caleva), 11.1 g of ibuprofen and 13.9 g of tranexamic acid were placed in a stirring vessel and mixed. Then, the additive solutions listed in Table 2 were added in the proportions listed in Table 2, and the mixture was kneaded for the kneading time listed in Table 2. The resulting wet granules were dried at 60°C for 1 hour to obtain dry granules.

[0118] (Reference Example 2, Comparative Examples 1-7, Examples 1-8) Except for the additive solution, additive solution ratio, and mixing time described in Tables 2 and 3, dried granules were obtained in accordance with Reference Example 1.

[0119] The dried granules of Example 1 or Comparative Example 1 were placed in an aluminum pan, and the temperature range of 25 to 250°C was measured at a rate of 10°C per minute using a differential scanning calorimeter DSC3+ (Mettler Toledo). The measurement results are shown in Figure 1. From Figure 1, it was confirmed that in Example 1, where crystals consisting of ibuprofen and tranexamic acid were efficiently formed, the peak originating from ibuprofen around 75°C was very small compared to Comparative Example 1, and there was a peak originating from the crystals consisting of ibuprofen and tranexamic acid around 180°C. Thus, it was confirmed that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained in the examples.

[0120] 3. Calculation of crystal formation rate For each sample prepared in the example, the endothermic amount was measured using a differential scanning calorimeter DSC3+ (Mettler-Toledo), and the crystal formation rate of the dried granules was calculated using the method described in Japanese Patent Publication No. 2022-70674. The results are shown in Tables 2 and 3. In the crystals, ibuprofen and tranexamic acid are present in a 1:1 molar ratio. Specifically, the crystal formation rate was measured as follows.

[0121] (1) The endothermic value (approximately 119.47 J / g) obtained from the measurement results of ibuprofen alone at the time of melting (around 75°C) was used as the reference endothermic value for ibuprofen that is not involved in the formation of crystals consisting of ibuprofen and tranexamic acid (free ibuprofen). (2) The endothermic amount at around 75°C obtained from the measurement results of the sample was taken as the endothermic amount of free ibuprofen in the sample. (3) The standard endothermic amount of free ibuprofen in (1) was multiplied by the weight ratio of ibuprofen blended in the sample (weight of ibuprofen / weight of sample) to calculate the endothermic amount assuming that all ibuprofen in the sample was free ibuprofen. (4) If the amount of ibuprofen (moles) in the sample is less than or equal to the amount of tranexamic acid (moles), the amount of ibuprofen (moles) is used as the reference amount, and the proportion of free ibuprofen in the sample is calculated from (2) and (3) (endothermic amount of free ibuprofen in the sample / endothermic amount if all ibuprofen in the sample were free ibuprofen = free ibuprofen rate). (5) If the amount of ibuprofen in the sample is greater than the amount of tranexamic acid, the amount of tranexamic acid is used as the reference amount, and the endothermic amount calculated in (3) is multiplied by the ratio of ibuprofen after subtracting the reference amount ((amount of ibuprofen in the sample - reference amount) / amount of ibuprofen in the sample), and this value is subtracted from the endothermic amount measured in (2) to calculate the endothermic amount of free ibuprofen in the reference amount. (6) If the amount of ibuprofen in the sample is greater than the amount of tranexamic acid, the amount of tranexamic acid is used as the reference amount, and the endothermic amount calculated in (3) is multiplied by the ratio of the reference amount (reference amount / amount of ibuprofen in the sample) to calculate the endothermic amount assuming that the reference amount of ibuprofen is all free ibuprofen. (7) If the amount of ibuprofen in the sample is greater than the amount of tranexamic acid, the proportion of free ibuprofen in the standard amount of ibuprofen was calculated from (5) and (6) (endothermic charge of free ibuprofen in the standard amount of ibuprofen in the sample / endothermic charge if the standard amount of ibuprofen were all free ibuprofen = free ibuprofen rate). (8) From the percentage of free ibuprofen calculated in (4) or (7), the percentage of ibuprofen in the standard amount of ibuprofen that is involved in crystal formation was calculated, and the crystal formation rate was calculated ((1 - percentage of free ibuprofen) × 100 = crystal formation rate (%)).

[0122] [Table 2]

[0123] [Table 3]

[0124] As shown in Table 2, Reference Examples 1 and 2, which involved longer mixing times, showed high crystal formation rates, while Comparative Examples 1 to 4, which involved shorter mixing times, showed low crystal formation rates. In contrast, by adjusting the ethanol concentration of the additive solution to 65 w / w% or more and less than 100 w / w%, high crystal formation rates were achieved in Examples 1 to 4 even with short mixing times.

[0125] Furthermore, as shown in Table 3, a high crystal formation rate was achieved even with short mixing times by setting the ratio of the amount of ethanol aqueous solution to the total mass of ibuprofen and tranexamic acid to 0.09 mL / g or higher.

[0126] 4. Evaluation of ibuprofen elution properties The dissolution properties of ibuprofen in the dried granules obtained in Examples 4-8 were evaluated as follows. Specifically, the dissolution test was performed using a dissolution tester (NTR-6400AC, Toyama Sangyo Co., Ltd.) in accordance with the "Dissolution Test Method (Paddle Method)" described in the 18th edition of the Japanese Pharmacopoeia. Dried granules and croscarmellose sodium (Dupont) were mixed in a mass ratio of 3:1, and 150 mg of the mixture was filled into a No. 1 capsule. The prepared capsule was placed in a sinker and immersed in 600 mL of the Japanese Pharmacopoeia-compliant dissolution test solution No. 1 (Fujifilm Wako Pure Chemical Industries, Ltd.). The test was performed using the paddle method at 50 rotations per minute, and the dissolution rate of ibuprofen 30 minutes after the start of the test was evaluated. The results are shown in Table 4.

[0127] [Table 4]

[0128] As shown in Table 4, in Examples 4 and 6, where the ratio of the amount of ethanol aqueous solution to the total mass of ibuprofen and tranexamic acid was 0.20 mL / g or less, dried granules with particularly excellent ibuprofen dissolution properties were obtained.

[0129] Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

Claims

1. A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Adding a mixed powder of ibuprofen and tranexamic acid to an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, or adding the aqueous solution to the mixed powder, to obtain a mixture in which the ratio of the content of the aqueous solution to the total mass of ibuprofen and tranexamic acid is 0.09 mL / g or more. (2) To produce the crystals from the obtained mixture, A manufacturing method that includes this.

2. The ratio is 0.09 mL / g or more and 0.20 mL / g or less. The manufacturing method according to claim 1.

3. (2) The process of generating crystals is to knead the mixture. The manufacturing method according to claim 1 or 2.

4. The mixing time is 10 minutes or less. The manufacturing method according to claim 3.

5. The process further includes drying the granules obtained by the aforementioned kneading. The manufacturing method according to claim 3.

6. In the above mixture, the molar ratio of ibuprofen to tranexamic acid (ibuprofen:tranexamic acid) is 1:0.5 to 1:

5. The manufacturing method according to claim 1 or 2.

7. Based on the lower content (molar amount) of ibuprofen and tranexamic acid in the mixture, 80 mol% or more of the one of the two in the mixture forms the crystals. The manufacturing method according to claim 1 or 2.

Images