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 consisting of ibuprofen and tranexamic acid, (1 ) An aqueous solution containing ethanol at a concentration of 65 w / w% or more and less than 100 w / w%, containing ibuprofen and Add a mixed powder of ibuprofen and tranexamic acid, or add the aqueous solution to the mixed powder, The ratio of the content of the aqueous solution to the total mass of fen and tranexamic acid is 0.09 mL. (1) To obtain a mixture that is 1 / g or more, and (2) To produce the crystals from the obtained mixture. A manufacturing method that includes [the ingredient].

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 antiplasmin 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 be suppressed from expanding 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, the present invention The present invention provides a novel method for producing crystals composed of ibuprofen and tranexamic acid. This is the purpose. [Means for solving the problem]

[0007] The inventors have found a method by which ibuprofen and tranexamic acid are formed We discovered that crystals can be efficiently produced, which led to the completion of this invention.

[0008] In other words, this application encompasses the following inventions. [1] A method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Add ibuprofen to an aqueous solution containing ethanol at a concentration of 65 w / w% or more and less than 100 w / w% Add a mixture of benzoyl peroxide and tranexamic acid, or add the aqueous solution to the mixture, and The ratio of the content of the aqueous solution to the total mass of profen and tranexamic acid is 0.09 To obtain a mixture of mL / g or more, (2) To produce the crystals from the obtained mixture, A manufacturing method that includes this. [2] The aforementioned ratio is 0.09 mL / g or more and 0.20 mL / g or less. The manufacturing method described in [1]. [3] The above (2) crystal formation is achieved by kneading 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 above mixture, the molar ratio of ibuprofen to tranexamic acid (ibuprofen The ratio of ibuprofen (ibuprofen) to tranexamic acid is 1:0.5 to 1:5, [1] to [5] any one of the production methods described in. [7] The content (molar amount) of ibuprofen and tranexamic acid contained in the mixture is small Based on one of them, 80 mol% or more of the one contained in the mixture is the crystal Forming, [1] to [6] any one of the production methods described in.

Effect 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] The results of differential scanning calorimetry (DSC) in Example 1 and Comparative Example 1 are shown.

Modes for Carrying Out the Invention

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

[0012] (Method for producing crystals) In the first aspect, A method for producing crystals composed of ibuprofen and tranexamic acid, (1) In an aqueous solution containing 65 w / w% or more and less than 100 w / w% ethanol, ibuprofen Add a mixture of benzoyl peroxide and tranexamic acid, or add the aqueous solution to the mixture, and The ratio of the content of the above aqueous solution to the total mass of profen and tranexamic acid is 0.09 To obtain a mixture of mL / g or more, (2) A manufacturing method comprising generating crystals from the obtained mixture. It will be provided.

[0013] 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.

[0014] As used herein, "tranexamic acid" refers to CAS Registry Number 1197-18- 8, C8H 15 It is a compound represented by the chemical formula NO2 (molecular weight: 157.21 g / (moles). Tranexamic acid is used as an active ingredient in anti-inflammatory drugs, etc. Tranexamic acid The salt is not particularly limited as long as it is pharmacologically acceptable.

[0015] ibuprofen and tranexamic acid produced by the manufacturing method according to this embodiment In the crystal, ibuprofen and tranexamic acid exist in a 1:1 molar ratio. Good. Also, in the crystal, ibuprofen and tranexamic acid are present in 4 molecules each. It may form a positional lattice.

[0016] 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.

[0017] 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.

[0018] 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 (18.5, 19.1, 21.1, 25.6 ± 0.5°). The crystal is It may have one or more characteristics of the crystal disclosed in Japanese Patent Publication No. 2022-70674, The crystal may be one of those disclosed in Public Publication No. 2022-70674.

[0019] A conventional method for producing crystals consisting of ibuprofen and tranexamic acid is, for example, [Japanese Patent Publication No. 1] One example is the method described in Publication No. 2022-70674. This publication includes the following method A ~C is specified.

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

[0021] Method B: (i) obtain tranexamic acid in a fluid form, (ii) the obtained fluid form Fluidity obtained by adding or heating tranexamic acid, ibuprofen, or a solvent. (iii) Mixing ibuprofen with a certain fluid, and producing crystals from the resulting mixture. A method that includes causing something to happen.

[0022] Method C: (i) Add ibuprofen and tranexamic acid to the solvent to obtain a solution or dispersion. (ii) spraying and drying the obtained solution or dispersion, or (i) obtaining The prepared solution is allowed to stand, and the product obtained after standing is filtered and the product is dried. Methods that include...

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

[0024] The manufacturing method according to this embodiment involves adding a mixture of ibuprofen and tranexamic acid powder to a solvent. In contrast to adding a solvent to a mixture of ibuprofen and tranexamic acid, In methods A and B described in Publication No. 2022-70674, ibuprofen is used as the solvent. After adding ibuprofen or tranexamic acid to obtain a fluid of ibuprofen or tranexamic acid, Ibuprofen or tranexamic acid is added to this fluid.

[0025] Furthermore, the manufacturing method according to this embodiment uses a solvent at a predetermined concentration, for example, 65 w / w% or more. In contrast to using an aqueous solution containing less than 00 w / w% ethanol, JP 2022-706 Method C described in Publication No. 74 uses a 50 w / w% ethanol aqueous solution. The manufacturing method relating to the application form uses an aqueous solution containing a small amount of ethanol, whereas Japanese Patent Application Publication No. 20 Method C described in Publication No. 22-70674 involves a large amount of aqueous ethanol solution (e.g., Eve (4-20g of ethanol aqueous solution per 1g of the total amount of profen and tranexamic acid) Use this.

[0026] Surprisingly, according to this embodiment, as described in Japanese Patent Publication No. 2022-70674 Compared to various other methods, this method efficiently produces crystals composed of ibuprofen and tranexamic acid. Specifically, according to this embodiment, it is possible to obtain a product with a high crystal formation rate in a short time. Yes, it is possible. Also, according to this embodiment, the solvent used (specifically, for example, ethanol) The amount can be significantly reduced.

[0027] The crystal formation rate is the ratio of the total amount of ibuprofen or tranexamic acid used as a raw material to the total amount of ibuprofen or tranexamic acid used. This refers to the ratio of ibuprofen and tranexamic acid that formed crystals. More specifically, When ibuprofen and tranexamic acid are used in equal amounts (molar ratio) as raw materials, the raw materials and Of the ibuprofen used, ibuprofen that formed crystals with tranexamic acid. This refers to the ratio. The raw materials are ibuprofen and tranexamic acid in different amounts (molar ratios). When used, the lower molar ratio of ibuprofen and tranexamic acid is considered. The percentage of ibuprofen and tranexamic acid crystals formed from the total amount used as raw materials. It means...

[0028] Therefore, the crystal formation rate is such that (1) the mixture is obtained in the manufacturing method according to this embodiment. ibuprofen and the mixture in (hereinafter also referred to as "step (1)") are included in the mixture. Using the lower of the two tranexamic acid content (molar amount) as the baseline, the amount contained in the mixture is... It is defined as the proportion of one of the two that formed crystals. In the mixed powder, tranexamic acid When added in an amount equal to or greater than that of ibuprofen, the crystal formation rate is in step (1). The ibuprofen contained in the resulting crystals relative to the total ibuprofen contained in the mixture It can be defined as a percentage.

[0029] The crystal formation rate in the manufacturing method according to this embodiment is 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, The crystallization rate may be 99 mol% or more, or 100 mol%. The method for measuring the crystallization rate is described in the examples. You can refer to the methods described and implement them as appropriate.

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

[0031] In step (1), an aqueous solution containing ethanol at a concentration of 65 w / w% or more and less than 100 w / w% is used. By using this method, a product with a high crystal formation rate can be obtained in a short time. The ol concentration is preferably 65 w / w% to 99 w / w%, and 70 w / w% to 98 w / w%. w / w% or less, 75w / w% or more and 95w / w% or less, 80w / w% or more and 93w / w% or less or 85 w / w% or more and 90 w / w% or less. Note that "w / w%" can be rephrased as mass%. It is also possible to take ethanol concentration as an example, the mass of ethanol relative to the total mass of the aqueous solution. It represents the proportion.

[0032] An aqueous solution containing ethanol is a solution containing at least ethanol and water. The aqueous solution containing ethanol may be an aqueous solution consisting of ethanol and water, or ethanol and water It may be a substantially aqueous solution. "Substantially" means a substantially aqueous solution containing impurities other than those present in the solution. This means that the solution consists of ethanol and water. Therefore, in an aqueous solution containing ethanol... The total amount of ethanol and water is 95 w / w% or more, 98 w / w% or more, and 99 w / w% or more. Above, 99.9 w / w% or higher, 99.99 w / w% or higher, 99.999 w / w% or higher, or It can be 100 w / w%.

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

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

[0035] In step (1), ibuprofen and tranexamic acid are mixed in the ethanol aqueous solution. Add the combined powder, or add the above ethanol aqueous solution to the mixed powder of ibuprofen and tranexamic acid. The mixture is prepared by adding ibuprofen and to By bringing a mixed powder of ranexamic acid and an aqueous ethanol solution into contact at the same time, the crystalline form can be formed in a short time. A product with a high success rate can be obtained. In this step (1), ibuprofen and It is sufficient for tranexamic acid to come into contact with an aqueous ethanol solution at the same time, either as a mixed powder or an aqueous ethanol solution. The liquid does not need to be added all at once. For example, the mixed powder or ethanol aqueous solution can be added in multiple steps. They may be added separately.

[0036] In the manufacturing method according to this embodiment, in step (1), ibuprofen and tranexamic acid are used. The ratio of the amount of the above aqueous solution to the total mass of the acid is 0.09 mL / g or more. The mixing ratio is adjusted during the preparation of the mixture. By setting the above ratio to 0.09 mL / g or higher, Therefore, a product with a high crystal formation rate can be obtained in a short time. From this viewpoint, the above ratio is 0. It is preferable to have a concentration of 10 mL / g or more, 0.11 mL / g or more, or 0.12 mL / g or more. It's nice.

[0037] In addition, in step (1), a small amount of ibuprofen is added to the mixed powder of ibuprofen and tranexamic acid. It is preferable to use the above ethanol aqueous solution. Specifically, the above ratio is preferably, 0.80mL / g or less, 0.50mL / g or less, 0.40mL / g or less, 0.30mL / It is less than or equal to g, less than or equal to 0.25 mL / g, or less than or equal to 0.20 mL / g. By doing so, ibuprofen and tranexamic acid, which have excellent ibuprofen dissolution properties, It tends to produce crystals of a certain type. From the above perspective, the above ratio should be 0.09 mL / g or higher. It is particularly preferable to keep it below 20 mL / g, but the upper and lower limits within this range are as follows: You may also replace it with the values ​​mentioned above.

[0038] In the manufacturing method according to this embodiment, a compound containing ibuprofen and tranexamic acid in a 1:1 ratio is used. Crystals may form. Therefore, in step (1), ibuprof added as a raw material The molar ratio of ethanol to tranexamic acid may be 1:1, but in order to increase the crystal formation rate, Alternatively, considering the amount to be added to the solid composition described later, ibuprofen and tranexamic acid The molar ratio with acid may be adjusted as appropriate.

[0039] In step (1), for example, the molar ratio of ibuprofen to tranexamic acid (ibuprofen The proportions of fen (tranexamic acid) used in the mixture preparation should be such that they are in a ratio of 1:0.5 to 1:5. It may be adjusted. Ibuprofen and tranexamic acid in the mixture obtained in step (1) The molar ratio of ibuprofen to tranexamic acid in the mixed powder used (i.e., the molar ratio of ibuprofen to tranexamic acid in the mixed powder used) The ratio may be 1:0.7 to 1:3, or 1:0.9 to 1:3. This refers to the mass ratio of ibuprofen to tranexamic acid (ibuprofen:tranexamic acid). This is expressed as the ratio of ibuprofen to tranexamic acid content in the solid composition described later. This may be considered the scope of what is included.

[0040] Furthermore, the molar ratio of ibuprofen to tranexamic acid in the mixture was changed from 1:1. For example, when increasing tranexamic acid relative to ibuprofen, the manufacturing according to this embodiment In addition to crystals composed of ibuprofen and tranexamic acid, the products obtained by the manufacturing method include, It contains ibuprofen and tranexamic acid that does not form crystals. The ibuprofen or tranexamic acid that did not work may be removed, but ibuprofen It may be incorporated into the solid composition described later, together with crystals consisting of and tranexamic acid.

[0041] In step (1), the above mixture contains components other than ibuprofen and tranexamic acid. Other components may be added, but it is preferable that no other components are added. Examples of components that may be added 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 preferably It is carried out at room temperature.

[0043] In the manufacturing method according to this embodiment, (2) generating crystals (hereinafter referred to as "step (2)") Also known as ), crystals are produced from the mixture obtained in step (1). In step (2) For example, if at least a portion of the ethanol and water are removed from the mixture obtained in step (1) By removing the substances, crystals composed of ibuprofen and tranexamic acid are formed.

[0044] A small amount of the above ethanol aqueous solution is used with the mixed powder of ibuprofen and tranexamic acid. Since it is preferable that the mixture obtained in step (1) is kneaded, step (2) is to knead the mixture obtained in step (1). It is preferable to include it. Mixing is done using a mortar and pestle, a Henschel mixer, or a mixer torque rheometer. - Stirring and mixing granulator, Shinagawa type universal mixing and stirring machine, high-speed kneading granulator, extrusion granulator, extor This may be done using a commander or similar device.

[0045] If the process (2) includes a mixing process, the mixing time is not particularly limited. The crystal formation rate tends to improve as the process is repeated. The manufacturing method according to this embodiment allows for quick formation. Since a product with a high crystal formation rate can be obtained, the mixing time is preferably 1 to 20 minutes, 2 The durations are approximately 18 minutes, 3-15 minutes, 3-12 minutes, or 4-8 minutes.

[0046] The above steps (1) and (2) may be carried out in succession. That is, in step (1) In this process, a mixture of ibuprofen and tranexamic acid powder is mixed with an aqueous ethanol solution. The mixture may be kneaded together, and then the kneading may be continued to carry out step (2). The manufacturing method according to the embodiment involves adding ibuprofen and tranexamic acid to the above-mentioned aqueous ethanol solution. Add the mixed powder of muic acid, or add the aqueous solution to the mixed powder, and knead these mixtures together. This was a manufacturing method that produced crystals consisting of ibuprofen and tranexamic acid. That's fine.

[0047] In this configuration, the mixing time is 1-20 minutes, 2-18 minutes, 3-15 minutes, 3-12 minutes, 4 When the time is set to ~8 minutes or 5 minutes, the crystal formation rate is 80 mol% or more, 80-100 mol%, 8 Preferably, the concentration is 3-100 mol%, 85-100 mol%, or 90-100 mol%. The crystal formation rate may be measured after crystals are formed in step (2), but the following drying step ( For example, it is preferable to measure after drying at 60°C for 1 hour.

[0048] Step (2) involves kneading the mixture and then drying the granules obtained from the kneading. It may also be included. Including such a drying process can further increase the crystal formation rate. This is the tendency. The drying temperature is preferably 30-80°C, and more preferably 40-70°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, and may be performed at room temperature. It may be done. For example, if step (2) includes the above-mentioned mixing step and drying step, the mixing step may be The process may be carried out at room temperature, or the drying process may be carried out under conditions where the temperature is heated to the above-mentioned drying temperature.

[0050] The manufacturing method according to this embodiment includes steps other than steps (1) and (2) described above. It is acceptable to do so. One such method involves using the mixed powder in step (1) to contain ibuprofen and to This process includes steps such as mixing ranexamic acid to obtain the resulting crystals, and isolating the produced crystals.

[0051] The crystals produced by the manufacturing method according to this embodiment can be used in solid compositions, particularly solid pharmaceutical compositions. It is suitably used in combination. The following contains crystals produced by the manufacturing method according to this embodiment. This document describes a solid composition and a method for producing the same.

[0052] (solid composition) The solid composition contains ibuprofen and tranexamic acid produced by the manufacturing method according to this embodiment. It contains crystals composed of ibuprofen and tranexamic acid. The solid composition consists of ibuprofen and tranexamic acid. In addition to crystals, non-crystallized ibuprofen and / or non-crystallized tranexamic acid It may contain muic acid.

[0053] 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 may be crystallized.

[0054] Each component contained in the solid composition may be present in a pharmaceutically acceptable salt form, and other It may be included as a complex with the components of the following: "Pharmacologically acceptable salt" means, for example, a medical It contains salts with bases and acids that are acceptable as medicines. 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. ru.

[0055] Unless otherwise specified, the following descriptions regarding the amount of ibuprofen refer to the crystallization with tranexamic acid. This concerns the amount in which crystallized ibuprofen and crystallized It may also be the total amount of ibuprofen that has not been used. Similarly, unless otherwise specified, the amount of tranexamic acid described herein does not apply. The amount listed is for ibuprofen in crystal form, but the amount is for when it is crystallized. The total amount of tranexamic acid and uncrystallized tranexamic acid may also be used.

[0056] The amount of ibuprofen or its salt included in the composition is determined by the use of ibuprofen or its salt in the composition. The dosage may be adjusted as appropriate depending on the symptoms, age, weight, sex, etc. of the recipient. For example, ibuprofen When profen or its salts are formulated as a nonsteroidal anti-inflammatory drug, they are administered to adults. The daily dose of ibuprofen or its salt is 30 mg to 2000 mg, preferably 1 It can be adjusted within the range of 00 mg to 1000 mg, more preferably 200 mg to 600 mg. In this invention, "adult" means males and females aged 15 years or older. However, the solid composition is for adults. This is not limited to medications taken orally, but also applies to medications taken by children under 15 years of age. It is also acceptable. When administered to children, the dosage may be half the amount that adults take daily, depending on the age group. It can be used in reduced quantities, such as 2 / 3 of the original amount.

[0057] The above dosage is an example, and the amount of ibuprofen or its composition administered per day The salt content is, for example, about 1% by mass to about 70% by mass, preferably about 5% by mass to about 50% by mass. More preferably, it is about 10% by mass to about 30% by mass.

[0058] In one embodiment, ibuprofen or a salt thereof contained in a composition administered daily The content is 1% to 70% by mass, preferably 5 to 50% by mass, more preferably 10 to 30% by mass It is expressed as mass percent.

[0059] The weight and dosage of the above composition are the daily dose (daily amount), but the same amount is 1 The drug may be administered to the subject multiple times a day, for example, two or three times, preferably in three divided doses. The same applies to ingredients other than rophene or its salts. Also, each dose is the total amount. Therefore, 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 a tablet, and the above dosage is 3 tablets, 6 tablets, or 9 tablets. This refers to the amount of the ingredient contained within, preferably the amount of the ingredient in 9 tablets. In this embodiment, For adults (15 years and older), the single dose is three times a day, with each dose consisting of 2, 3, or 4 tablets. Preferably, the single dose is 3 tablets.

[0061] The amount of tranexamic acid or its salts used in the composition is determined by the use of tranexamic acid or its salts in the composition. The amount of tranexamic acid or its salt is adjusted as needed. Depending on the amount of ibuprofen, etc. The amount may vary, but for example, the daily amount is 10 mg to 3000 mg, preferably. The range is 100 mg to 2000 mg, more preferably 200 mg to 1000 mg.

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

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

[0064] (Other ingredients) The solid composition may contain components other than those listed above, depending on its intended use. This is a symptom of the common cold, such as runny nose, nasal congestion, sneezing, sore throat, cough, phlegm, chills, etc. When used to relieve fever, headache, joint pain, muscle pain, etc., bromhexyl In addition to meloxicam and acetaminophen, antipyretic analgesics, especially those other than ibuprofen. The active ingredients of nonsteroidal anti-inflammatory drugs (NSAIDs) and other pharmacologically acceptable substances Ingredients may be included.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] Cough suppressants and expectorants include noscapine, noscapine hydrochloride hydrate, and tipepidine hibenzate. Dextromethorphan hydrobromide hydrate, bromhexine hydrochloride, dihydrocodiol methyl ephedrine phosphate, dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt Examples include pseudoephedrine hydrochloride, ambroxol hydrochloride, and L-carbocysteine. It can be done.

[0070] 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.

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

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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, silicon dioxide, lactose monohydrate, lactose granules, sucrose, potato Sweet potato starch, hydroxypropyl starch, partially pregelatinized starch, powdered sugar, powdered candy, powdered syrup Original maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polio Xyethylene hydrogenated castor oil 60, maltitol, D-mannitol, aluminum metasilicate Examples include magnesium sulfate, calcium sulfate, erythritol, glucose, and fructose.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

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

[0081] 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, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid, stearic acid, poly Vinyl acetal diethylaminoacetate / hydroxypropyl methylcellulose 29 10 mixtures, polyvinyl acetal diethylaminoacetate, aluminometasilicate Examples include magnesium.

[0082] 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.

[0083] 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, hydrated silicon dioxide, dried sodium carbonate Glycine, Glycerin, Glycerin fatty acid ester, Calcium gluconate hydrate Substances, sodium gluconate, magnesium gluconate, potassium L-glutamate, L- Sodium glutamate, L-lysine glutamate, light anhydrous silicic acid, crystalline phosphate diphosphate Sodium hydrogen, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine Ingredients: 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) Glyco Polyoxyethylene (160) polyoxypropylene (30) glycol, polio Xyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene Coconut oil fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, Resorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, ma Logol 400, Macrogol 4000, Anhydrous Citric Acid, Anhydrous Sodium Citrate, Anhydrous Sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, magnesium aluminometasilicate Umum, methylcellulose, l-menthol, glyceryl monostearate, medicinal charcoal, sulfuric acid Magnesium hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate Um, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol, acrylic Examples include acid-methyl methacrylate copolymers.

[0084] 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.

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

[0086] 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.

[0087] 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.

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

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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 sucrose, gelatin, shellac, precipitated calcium carbonate Cium, white shellac, sucrose, hydroxypropylcellulose, hypromellose, pullulose Povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macro Gol 4000, Macrogol 6000, Macrogol 6000NF, Calcium Hydrogen Phosphate Umium hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol, acrylic acid, meta Examples include methyl acrylate copolymers.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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, magnesium aluminometasilicate Examples include nesium and calcium hydrogen phosphate granules.

[0099] 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.

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

[0101] (Dosage form) Solid compositions include, for example, orally administered preparations (tablets (orally disintegrating tablets, chewable tablets, etc.)). (Including foam tablets, dispersible tablets, dissolvable tablets, etc.), capsules, granules, and powders, etc.), for oral use. Preparations that include oral tablets, lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums, etc. ) and other dosage forms as described in the General Provisions for Preparations of the 18th Revised Japanese Pharmacopoeia, etc. Solid composition The substance 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 can be coated with sugar or film by known methods as needed. It may be coated with a coating or the like. 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 is packaged in bottles, PTP blister packs, pouches, stick packs, and SP packs. They can be individually packaged and stored airtight. They can also be pillow-wrapped and then placed in a box or similar container. It may be stored. The material used for pillow packaging is not particularly limited, for example, poly Propylene film, polyethylene terephthalate film, polyethylene film, etc. Resin films or resin films with aluminum foil attached can be used. It can be done. If moisture absorption is a concern, a desiccant or similar should be kept inside the bottle packaging or pillow packaging at the same time. It may be kept.

[0104] The solid composition may be contained in a packaging container to form a package. The solid composition may be, for example, air It may be contained in tight packaging. By using packaging, for example, when using the solid composition... This can improve convenience. The packaging, specifically, is for pharmaceuticals.

[0105] As for the packaging form of the solid composition, the solid composition can be packaged in a bottle or in PTP (Press Through Packaging). Packages are initially packaged using methods such as pouch packaging, stick packaging, and SP packaging (Strip Package). They may be stored in an airtight container. Furthermore, they may be pillow-wrapped and stored in a box or similar container. It is also possible to use a desiccant inside the bottle packaging or pillow packaging from the viewpoint of reducing moisture absorption of the solid composition. They may be stored together in the same packaging container.

[0106] 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.

[0107] 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 [mention specific packaging].

[0108] 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.

[0109] 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.

[0110] 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.

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

[0112] The crystals produced by the manufacturing method according to this embodiment are further subjected to a granulation process to produce granules ( It is also possible to manufacture granules. In this case, they may be granulated together with other components or separately. Granules (granulated products) containing each component may be prepared separately. The granulation may be wet or dry. .

[0113] The obtained granules (granulated products) may be directly used, or additives may be blended into the granules and then tabletted and molded to produce tablets, or further film-coated. .

[0114] For example, when the solid composition is a tablet, tablets can be produced in accordance with the section "Tablets" in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia. When the solid composition contains components outside the granules, post-milled components are added to the granulated granules so as to form the outside of the granulated granules, and tablets can be produced by tabletting these mixtures. Also, components outside the granules may be in granular form.

[0115] To explain the present invention in more detail, examples are described below, but the present invention is not limited thereto. .

Examples

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

Table 1

[0117] 2. Production of crystals composed of ibuprofen and tranexamic acid (Reference Example 1) Using a mixer torque rheometer 3 (manufactured by Caleva), 11.1 g of ibuprofen and 13.9 g of tranexamic acid were placed in a stirring container and mixed, and then the additive solution described in Table 2 was added at the additive solution ratio described in Table 2 and kneaded for the kneading time described in Table 2. The obtained 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) Aside from the fact that the mixture was kneaded using the additive solution, additive solution ratio, and kneading time described in Tables 2 and 3, Dried granules were obtained according to Reference Example 1.

[0119] Place the dried granules of Example 1 or Comparative Example 1 into an aluminum pan and use a differential scanning calorimeter (DSC3). Using a Mettler-Toledo instrument, the temperature range of 25-250°C was measured at a rate of 10°C per minute. The measurement results are shown in Figure 1. From Figure 1, it can be seen that the crystals composed of ibuprofen and tranexamic acid are The efficiently formed Example 1, compared to Comparative Example 1, was due to ibuprofen at around 75°C. The resulting peak becomes very small, and around 180°C, ibuprofen and tranexamic acid... It was confirmed that the peak originated from the crystal. Thus, in the example, We confirmed that crystals with a molar ratio of ibuprofen to tranexamic acid of 1:1 were obtained. Ta.

[0120] 3. Calculation of crystal formation rate For the samples produced in each example, a differential scanning calorimeter DSC3+ (Mettler-Toledo) was used. The amount of heat absorbed is measured, and the dried granules are processed according to the method described in Japanese Patent Publication No. 2022-70674. The crystal formation rate was calculated for this. The results are shown in Tables 2 and 3. Note that in the crystal, Buprofen and tranexamic acid exist in a 1:1 molar ratio. Specifically, the crystal formation rate The following was used for measurement.

[0121] (1) The amount of endothermic heat at melting (around 75°C) obtained from the measurement results of ibuprofen alone (approximately 1 19.47 J / g) is involved in the formation of crystals composed of ibuprofen and tranexamic acid. The standard endothermic value was set for ibuprofen without any added substances (free ibuprofen). (2) The amount of endothermic heat around 75°C obtained from the measurement results of the sample is the free ibuprofen in the sample. This was defined as the heat absorbed by the fan. (3) The standard endothermic amount of free ibuprofen in (1) is used to determine the amount of ibuprofen added to the sample. Multiply by the weight ratio of ibuprofen (weight of ibuprofen / weight of sample) to determine if all ibuprofen in the sample is fluorescein. The endothermic amount was calculated assuming it was Lie's ibuprofen. (4) The amount of ibuprofen in the sample (moles) is greater than the amount of tranexamic acid (moles) If the amounts are small or the same, the amount of ibuprofen (moles) is used as the reference amount, and (2) (3) The percentage of free ibuprofen in the sample was calculated (free ibuprofen in the sample The endothermic amount of ibuprofen / all ibuprofen in the sample is free ibuprofen. The amount of heat absorbed in this case (free ibuprofen rate). (5) The amount of ibuprofen in the sample (moles) is greater than the amount of tranexamic acid (moles) If the amount is large, the amount of substance (moles) of tranexamic acid is used as the base amount, and the endothermic amount calculated in (3) The amount minus the reference amount gives the percentage of ibuprofen ((amount of ibuprofen in the sample - reference amount)). The value obtained by multiplying (amount) / (amount of ibuprofen in the sample) is subtracted from the endothermic amount measured in (2). Next, the endothermic effect of a standard amount of free ibuprofen was calculated. (6) The amount of ibuprofen in the sample (moles) is greater than the amount of tranexamic acid (moles) If the amount is large, the amount of substance (moles) of tranexamic acid is used as the base amount, and the endothermic amount calculated in (3) Multiply the quantity by the ratio of the standard amount (standard amount / amount of ibuprofen in the sample) and calculate the standard amount of ibuprofen. The amount of endothermic heat was calculated assuming that all the profen was free ibuprofen. (7) The amount of ibuprofen in the sample (moles) is greater than the amount of tranexamic acid (moles) When it is large, from (5) and (6), the ratio of free ibuprofen among the reference amount of ibuprofen is calculated (the heat absorption amount of free ibuprofen among the reference amount of ibuprofen in the sample / the heat absorption amount when all the reference amount of ibuprofen is free ibuprofen = free ibuprofen rate). From the ratio of free ibuprofen calculated in (8), (4) or (7), the ratio of ibuprofen involved in crystal formation among the reference amount of ibuprofen is calculated, and the crystal formation rate is calculated ((1 - free ibuprofen rate) × 100 = crystal formation rate (%)). When it is assumed that all of the reference amount of ibuprofen is free ibuprofen Heat absorption amount = free ibuprofen rate). (8) From the ratio of free ibuprofen calculated in (4) or (7), the ratio of ibuprofen involved in crystal formation among the reference amount of ibuprofen is calculated, and the crystal formation rate is calculated ((1 - free ibuprofen rate) × 100 = crystal formation rate (%)). Among the reference amount of ibuprofen, the ratio of ibuprofen involved in crystal formation is calculated, and the crystal formation rate is calculated ((1 - free ibuprofen rate) × 100 = crystal formation rate (%)).

[0122]

Table 2

[0123]

Table 3

[0124] As shown in Table 2, in Reference Examples 1 and 2 with a long mixing time, the crystal formation rate was high, but in Comparative Examples 1 to 4 with a shortened mixing time, the crystal formation rate was low. On the other hand, 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 even in a short mixing time in Examples 1 to 4. Moreover, as shown in Table 3, by setting the ratio of the blending amount of the ethanol aqueous solution to 0.09 mL / g or more with respect to the total mass of ibuprofen and tranexamic acid, high crystal formation rates were achieved even in a short mixing time. 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 even in a short mixing time in Examples 1 to 4. High crystal formation rates were achieved even in a short mixing time.

[0125] Also, as shown in Table 3, by setting the ratio of the blending amount of the ethanol aqueous solution to 0.09 mL / g or more with respect to the total mass of ibuprofen and tranexamic acid, high crystal formation rates were achieved even in a short mixing time. By setting the ratio of the blending amount of the ethanol aqueous solution to 0.09 mL / g or more with respect to the total mass of ibuprofen and tranexamic acid, high crystal formation rates were achieved even in a short mixing time. High crystal formation rates were achieved even in a short mixing time.

[0126] 4. Evaluation of ibuprofen elution property The elution properties of ibuprofen in the dried granules obtained in Examples 4-8 were as follows: The evaluation was conducted using the "dissolution test method (paddle method)" described in the 18th edition of the Japanese Pharmacopoeia. Therefore, the dissolution test was performed using a dissolution tester (NTR-6400AC, Toyama Sangyo Co., Ltd.). Dried granules and Mix croscarmellose sodium (manufactured by Dupont) with the mixture in a mass ratio of 3:1. 150 mg of the compound was filled into a No. 1 capsule. The prepared capsule was placed in a sinker and then used by Nippon Pharmaceutical Co., Ltd. Dissolve the substance in 600 mL of the first solution of the pharmacopoeia-compliant dissolution test (Fujifilm Wako Pure Chemical Corporation), and then... The test was conducted at 50 revolutions per minute using the 50-revolution method, and the dissolution rate of ibuprofen was evaluated 30 minutes after the start of the test. The results are shown in Table 4.

[0127] [Table 4]

[0128] As shown in Table 4, the ethanol aqueous solution ratio of ibuprofen and tranexamic acid to the total mass In Examples 4 and 6, where the ratio of liquid amounts was 0.20 mL / g or less, ibuprofen dissolves We were able to obtain dried granules with particularly excellent exudation properties.

[0129] 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 method for producing crystals consisting of ibuprofen and tranexamic acid, (1) Add ibuprofen to an aqueous solution containing ethanol at a concentration of 65 w / w% or more and less than 100 w / w% Add a mixture of tranexamic acid and iodine, or add the aqueous solution to the mixture, and The ratio of the content of the aqueous solution to the total mass of profen and tranexamic acid is 0.09 To obtain a mixture that is 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 The ratio of fen (to tranexamic acid) is 1:0.5 to 1:

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

7. The amount (molar amount) of ibuprofen and tranexamic acid contained in the aforementioned mixture is small. Using one as a reference, 80 mol% or more of the one contained in the mixture is the crystal to form The manufacturing method according to claim 1 or 2.

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