Solid preparations and pharmaceutical products

Abstract

The solid preparation of the present application contains: (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeine, the above solid preparation is in the form of a tablet or a pill, and satisfies: in a dissolution test, at a time point of 15 minutes, the dissolution rate of the (A) component is 60% or more.

Description

Technical Field

[0001] This invention relates to solid dosage forms and pharmaceuticals. Background Technology

[0002] Currently, compound cold medicines and antipyretic analgesics widely use formulations that combine multiple active ingredients. For example, compound cold medicines are known to contain multiple ingredients such as antipyretics, analgesics, antitussives, expectorants, and rhinitis medications. These medications are widely sold as over-the-counter drugs, and from the perspective of efficacy and safety, they need to have excellent stability as formulations.

[0003] Loxoprofen sodium or its hydrate is widely used clinically as a nonsteroidal antipyretic analgesic. In addition, tranexamic acid, as an anti-inflammatory agent, is often used as an active ingredient in compound cold medicines.

[0004] There are reports on pharmaceutical compositions involving the combined use of loxoprofen sodium or its hydrate with tranexamic acid, and combinations thereof (see Patent Document 1). This document describes how, by further containing magnesium oxide, a solid formulation possessing the contradictory properties of high hardness and good disintegration can be obtained.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent Application Publication No. 2014-162743 Summary of the Invention

[0008] However, the inventors' research found that tablets manufactured under the compression conditions described in Patent Document 1 still have room for improvement in terms of loxoprofen dissolution.

[0009] Further research by the inventors revealed that in a solid dosage form containing: component (A) selected from at least one of loxoprofen, its salts and their hydrates, component (B) selected from at least one of tranexamic acid and its salts, and component (C) selected from at least one of magnesium oxide, glycine, erythritol and caffeine, the solubility of loxoprofen in the shaped solid dosage form can be improved by moderately reducing the pressure during the formulation process, thereby completing the present invention.

[0010] According to one aspect of the present invention, the following solid dosage forms and pharmaceutical products are provided.

[0011] 1. A solid dosage form comprising the following components (A), (B) and (C):

[0012] (A) Selected from at least one of loxoprofen, its salts and their hydrates.

[0013] (B) Selected from at least one of tranexamic acid and its salts.

[0014] (C) Selected from at least one of magnesium oxide, glycine, erythritol and caffeine;

[0015] This solid dosage form is in tablet or pill form.

[0016] The solid dosage form meets the following requirement: at the 15-minute time point in the dissolution test, the dissolution rate of component (A) above is 60% or more.

[0017] 2. The solid dosage form according to claim 1, wherein,

[0018] The above solid dosage form satisfies the following condition: at the 15-minute time point in the above dissolution test, the standard deviation of the dissolution rate of component (A) is less than 11.0%.

[0019] 3. The solid dosage form according to 1 or 2, wherein,

[0020] The above solid dosage form meets the following requirement: at the 30-minute time point in the dissolution test, the dissolution rate of component (A) is above 90%.

[0021] 4. The solid dosage form according to any one of 1 to 3, wherein the hardness is 40 N or more.

[0022] 5. The solid dosage form according to any one of 1 to 4, wherein,

[0023] Let the content of the above-mentioned component (A) in the solid dosage form be C. A The content of the above-mentioned component (B) is set as C. B The content of the above-mentioned component (C) is set as C. C hour,

[0024] C C / (C A +C B +C C The value ranges from 0.02 to 0.95.

[0025] 6. A pharmaceutical product comprising any one of the solid dosage forms described in 1 to 5.

[0026] According to the present invention, a solid dosage form of loxoprofen with excellent dissolution properties and a pharmaceutical product using the solid dosage form can be provided. Detailed Implementation

[0027] The following describes the solid dosage form of this embodiment.

[0028] (Solid dosage form)

[0029] The solid dosage form of this embodiment contains the following components (A), (B) and (C):

[0030] (A) Selected from at least one of loxoprofen, its salts and their hydrates.

[0031] (B) Selected from at least one of tranexamic acid and its salts.

[0032] (C) Selected from at least one of magnesium oxide, glycine, erythritol, and caffeine.

[0033] This solid dosage form is in tablet or pill form.

[0034] The solid dosage form meets the following requirement: the dissolution rate of component (A) is greater than 60% at time point 15 minutes in the dissolution test.

[0035] According to the inventors' understanding, it has been found that if the external pressure applied during solid dosage form preparation is set high, a delay in the dissolution of loxoprofen in the solid dosage form is observed.

[0036] The detailed mechanism has not yet been determined, but it is speculated that if the external pressure applied during the solid dosage form is too large, the components contained in the dosage form will agglomerate and be difficult to dissolve to the outside.

[0037] Based on the above understanding, the inventors' in-depth research revealed that suppressing the pressure during the tableting process, such as the compression pressure, which imparts shape to the formulation, to a moderately low level can improve the dissolution of loxoprofen in solid dosage forms.

[0038] It was clarified that by using the initial dissolution rate of component (A), i.e., the dissolution rate of component (A) at the 15-minute time point in the dissolution test, as an indicator, the pressure level during the excipient formation process can be stably evaluated. Therefore, by setting the initial dissolution rate of component (A) above the aforementioned lower limit, a solid dosage form is produced under moderately low pressure conditions, thus improving the dissolution properties of loxoprofen.

[0039] In this embodiment, for example, by appropriately selecting the types and amounts of each component contained in the solid dosage form, and the preparation method of the solid dosage form, the dissolution rate of component (A) at the 15-minute time point in the dissolution test can be controlled. Among these factors, examples of setting the dissolution rate of component (A) at the 15-minute time point in the dissolution test to a desired range include, for example, setting the external pressure applied during solid dosage form preparation to be moderately low.

[0040] Here, the dissolution rate of component (A) at time points of 15 minutes and 30 minutes in the dissolution test is referred to as the dissolution rate at 15 minutes and the dissolution rate at 30 minutes, respectively.

[0041] The lower limit of the dissolution rate at 15 minutes is 60% or more, preferably 62% or more, and more preferably 65% ​​or more.

[0042] On the other hand, there is no specific limit to the upper limit of the dissolution rate at 15 minutes, which can be below 95%.

[0043] Furthermore, the upper limit of the standard deviation of the dissolution rate at 15 minutes is, for example, 11.0% or less, preferably 7.0% or less, and more preferably 6.0% or less. This ensures that the active ingredient in the formulation can exert its therapeutic effect stably.

[0044] On the other hand, there is no specific limit to the lower limit of the standard deviation of the dissolution rate at 15 minutes; it can be above 0%.

[0045] Furthermore, in the determination of the standard deviation of dissolution rate mentioned above, any number of solid dosage forms contained in the same packaging can be used as samples. There is no particular limitation on the number of samples measured; for example, more than three samples can be used.

[0046] The lower limit of the dissolution rate at 30 minutes is 90% or more, preferably 95% or more, and more preferably 96% or more. This can further improve the dissolution properties of loxoprofen.

[0047] On the other hand, there is no specific upper limit to the dissolution rate at 30 minutes; it can be below 100%.

[0048] The lower limit of the hardness of solid dosage forms is, for example, 40 N or more, preferably 45 N or more, and more preferably 50 N or more. This can suppress cracks and defects that may occur during manufacturing and transportation, thus preventing damage to the appearance of the dosage form.

[0049] On the other hand, there is no specific upper limit to the hardness of solid dosage forms, which can be below 200N.

[0050] As a solid dosage form, specific examples include tablets or pills as described in the 18th revised edition of the Japanese Pharmacopoeia. Tablets are preferably an example of the "solid dosage form" of this invention.

[0051] The tablets described above are preferably coated with water-soluble polymers or sugars. Specifically, preferred tablet forms include film-coated tablets and sugar-coated tablets.

[0052] In addition, among the tablets mentioned above, multi-layer tablets are also preferred, which are formed by stacking and compressing powders or granules of different compositions in two or three or more layers.

[0053] Furthermore, the solid dosage form of this embodiment has excellent antipyretic effects, making it suitable for use as a cold medicine, such as a compound cold medicine, or as an antipyretic analgesic. For example, by adding various ingredients, it can be administered to patients with various cold symptoms, especially fever, chills, headache, sore throat, runny nose, nasal congestion, cough, phlegm, joint pain, muscle pain, sneezing, etc., to relieve these symptoms.

[0054] Solid dosage forms are considered from the point of view of easy intake, for example, they can be used as oral solid dosage forms.

[0055] (Manufacturing method of solid dosage form)

[0056] An example of the solid dosage form manufacturing method of this embodiment includes: a wet granulation step in which water is added to and mixed with a raw material containing component (A), component (B) and component (C) for granulation, and a drying step in which the granules after the wet granulation step are dried.

[0057] In the wet granulation process, it is preferred to implement a granulation treatment selected from fluidized bed granulation, extrusion granulation, and stirred granulation. However, it is not limited to these granulation treatments, and known methods may also be used.

[0058] The drying process is not particularly limited; for example, the heating temperature can be 30–100°C, preferably 60–90°C. Furthermore, the heating time can be, for example, 0.01–24 h, preferably 0.1–6 h.

[0059] In addition, the environmental conditions in the drying process can be, for example, at atmospheric pressure.

[0060] Furthermore, without affecting the scope of this invention, other pharmaceutically active ingredients may be added to the raw material components in the wet granulation process according to conventional methods, and additives may also be added as needed.

[0061] For example, when the solid dosage form is a tablet, the mixture of component (A), component (B), component (C) and appropriate other components is wet-granulated, the granules are dried, and a post-component is added to the resulting granules in a manner that forms the exterior of the granules. The tablets are then compressed to manufacture tablets.

[0062] That is, tablets can be manufactured, for example, by the following steps: manufacturing granulated particles (at least one type of granulated particle) containing ingredient (A), ingredient (B), ingredient (C) and suitable other ingredients; and mixing the granulated particles with a desired additive (added ingredient) and then compressing them into tablets. Furthermore, ingredients disposed on the outside of the particles may also optionally be granulated.

[0063] The upper limit of the pressure during tablet compression can be set to, for example, 9 kN or less, preferably 8 kN or less, and more preferably 7 kN or less.

[0064] On the other hand, there is no particular limit to the lower limit of the pressure during tablet compression; it can be set to 3 kN or higher.

[0065] The added component (exterior of the granulated particles) is the portion that forms the exterior of the granulated particles in the tablet. For example, it can be a portion formed to cover one granulated particle in the tablet, or it can be a portion formed to cover multiple granulated particles. Alternatively, it can be a portion that covers at least one granulated particle in the tablet and forms the outer surface of the tablet.

[0066] In addition, in one embodiment of the present invention, the solid dosage form can be used as a material (intermediate material) composed of component (A), component (B) and component (C), or it can be manufactured as a solid dosage form (material / intermediate material) composed of component (A), component (B) and component (C), thereby including components other than component (A), (B) and (C).

[0067] That is, the solid dosage form in this invention may contain a solid dosage form consisting of component (A), component (B) and component (C) as an intermediate material, and may be used in the form of pills or tablets.

[0068] In other words, the pharmaceutical product in one embodiment of the present invention comprises the solid dosage form of the present invention, and may be in the form of pills or tablets.

[0069] The preferred method for preserving solid dosage forms is to seal them in glass bottles, PTP containers, or other suitable containers. For stringent preservation conditions, an external ambient temperature of 30°C or higher and / or an external ambient humidity of 60%RH or higher may be used.

[0070] The following details the components contained in solid dosage forms.

[0071] <Ingredients (A)>

[0072] Component (A) contains at least one selected from loxoprofen, its salts and their hydrates.

[0073] At least one of loxoprofen, its salts and their hydrates, including one or more of loxoprofen, loxoprofen sodium, loxoprofen sodium monohydrate and loxoprofen sodium dihydrate.

[0074] Loxoprofen sodium dihydrate is listed as loxoprofen sodium hydrate in the 18th revised edition of the Japanese Pharmacopoeia.

[0075] The amount of component (A) contained in the solid dosage form is not particularly limited, but is 1 to 80 parts by weight per 100 parts by weight of the solid dosage form, preferably 2 to 50 parts by weight, more preferably 5 to 30 parts by weight, and may also be 7 to 20 parts by weight.

[0076] <Ingredient (B)>

[0077] Component (B) contains at least one selected from tranexamic acid and its salts.

[0078] Ingredient (B) is a known compound that can be manufactured by known methods or is available commercially available. Tranexamic acid is described in the 18th revised edition of the Japanese Pharmacopoeia.

[0079] Furthermore, the content of component (B) is not particularly limited, but from the viewpoint of improving the antipyretic effect, it is preferably 10% or more by mass in 100% by mass of the solid dosage form, and more preferably 12.5% ​​or more by mass.

[0080] Furthermore, without particular limitation, from the viewpoint of making the formulation more favorable, the content of component (B) in 100% by mass of solid dosage form is preferably 50% by mass or less, more preferably 40% by mass or less.

[0081] The drying loss (mass%) of the solid dosage form measured at 80°C at a time point where the mass loss is less than 1 mg per 50 seconds is taken as the moisture content.

[0082] The moisture content of the solid dosage form is, for example, 2.5% by mass or less, preferably 1.5% by mass or less, and more preferably 1.0% by mass or less. Therefore, even after storage under stringent conditions, the decrease in the proportion of component (A) in the solid dosage form can be suppressed.

[0083] <Ingredient (C)>

[0084] Ingredient (C) contains at least one selected from magnesium oxide, glycine, erythritol and caffeine.

[0085] Let the content of component (A) in the solid dosage form be C. A The content of component (B) is set as C. B The content of component (C) is set as C. C .

[0086] At this time, C C / (C A +C B +C C For example, the value can be 0.02–0.95, 0.2–0.9, or 0.25–0.8, preferably 0.26–0.7, and more preferably 0.27–0.65. Setting it to a value above or above the lower limit improves dissolution. Setting it to a value below or above the upper limit improves storage stability.

[0087] Magnesium oxide can be readily obtained using the magnesium oxide listed in the 18th revised edition of the Japanese Pharmacopoeia.

[0088] As commercially available magnesium oxide, there are no particular restrictions, and products such as light-grade magnesium oxide manufactured by Tomita Pharmaceutical Co., Ltd. and heavy-grade magnesium oxide manufactured by Kyowa Chemical Co., Ltd. can be used.

[0089] The proportion of magnesium oxide in solid dosage forms is based on the total mass of the solid dosage form and can be 0-80% by mass, or 0.1-70% by mass, preferably 1-30% by mass.

[0090] Glycine is listed in the 18th revised edition of the Japanese Pharmacopoeia and is readily available commercially. Commercially available glycine can be used by appropriate pulverization. Examples include glycine (Organic Synthetic Pharmaceuticals Co., Ltd.), glycine "Manufacturing Specific" (Fujifilm and Wako Pure Chemical Industries Co., Ltd.), glycine (Ajinomoto Health Supply Co., Ltd.), glycine (crystals) (Merck Corporation), and glycine (granules) (Merck Corporation). The amount of glycine contained in solid dosage forms is not particularly limited, but can be 0.01 to 90 parts by weight per 100 parts by weight of the solid dosage form, preferably 0.05 to 80 parts by weight, and more preferably 0.1 to 70 parts by weight.

[0091] Erythritol is readily available from the market. Examples of erythritol include erythritol (Busan Food Science Co., Ltd.). There are no particular limitations on the amount of erythritol contained in solid dosage forms; the amount may be 0.1 to 95 parts by weight, 0.5 to 90 parts by weight, or 1 to 80 parts by weight per 100 parts by weight of the solid dosage form, more preferably 10 to 75 parts by weight, and even more preferably 20 to 70 parts by weight.

[0092] Caffeine derivatives are selected from one or more of anhydrous caffeine, caffeine hydrate, and sodium caffeine benzoate. These are included in the 18th revised edition of the Japanese Pharmacopoeia.

[0093] There is no particular limitation on the amount of caffeine contained in the solid dosage form, but it is 1 to 80 parts by weight per 100 parts by weight, preferably 2 to 50 parts by weight, and more preferably 5 to 30 parts by weight.

[0094] In this embodiment, the solid dosage form may further include components other than (A), (B) and (C).

[0095] Furthermore, the solid dosage form of the present invention can be used as a material (intermediate material) composed of components (A), (B) and (C), and can also be in the form of containing components other than components (A), (B) and (C).

[0096] Examples of these ingredients are listed below.

[0097] <Acid neutralizer>

[0098] In this embodiment, from the viewpoint of inhibiting gastric mucosal damage, the solid dosage form preferably also includes an antacid.

[0099] As an antacid, for example, as an alkaline earth metal and / or alkaline earth metal-based basic inorganic compound, examples include magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, magnesium hydroxide-potassium aluminum sulfate coprecipitate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminum metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, dicalcium phosphate, anhydrous dicalcium phosphate, and other metal inorganic salts selected from magnesium, aluminum, and calcium; in addition, as an alkali metal-based basic inorganic compound, examples include dried sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and other metal inorganic salts selected from sodium and potassium, and others include oyster shells, etc., which can be combined with one or more components selected from these compositions. Preferably, it is selected from one or more of magnesium aluminum metasilicate, synthetic aluminum silicate, and precipitated calcium carbonate.

[0100] When using magnesium aluminum silicate, the magnesium aluminum silicate listed in the 18th revised edition of the Japanese Pharmacopoeia can also be used, which is readily available.

[0101] As commercially available aluminum magnesium metasilicate, there are no particular limitations; for example, there is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.

[0102] The proportion of magnesium aluminum metasilicate in solid dosage forms can be appropriately selected considering the disintegration properties of the solid dosage form, drug solubility, and its function as an antacid. There are no particular limitations. Based on the total mass of the solid dosage form, it can be 0-80% by mass or more than 0-80% by mass, or 0.1-70% by mass, preferably 1-50% by mass.

[0103] <Crude Drugs (Crude Drug Components)>

[0104] The solid dosage forms of this invention may also include medicinal herbs.

[0105] The types of raw medicinal materials used in this invention are not particularly limited. For example, they can be selected from ephedra, nandina, cherry bark, polygala, licorice, platycodon, plantain seed, plantain herb, lycoris, polygala tenuifolia, fritillaria, fennel, phellodendron bark, coptis, turmeric, chamomile, cinnamon, gentian, bezoar, animal bile (including bear bile), glehnia, ginger, atractylodes, clove, tangerine peel, atractylodes macrocephala, earthworm, bamboo rhizome, ginseng, wild parasol tree, asarum, epimedium, corydalis, scutellaria, polygonatum, etc. Valerian, Trichosanthes fruit, apricot kernel, wolfberry, wolfberry leaf, schizonepeta, cassia seed, geranium, cyperus rhizome, schisandra fruit, asarum, Sichuan pepper, aster root, lycium bark, peony root, musk, magnolia flower, chuanxiong rhizome, angelica root, mulberry bark, perilla, garlic, angelica root, ipecac root, ophiopogon root, pinellia tuber, saffron, rhinoceros horn, angelica dahurica, poria cocos, peony bark, oyster shell, deer antler, fangji, and other crude medicinal herbs and their extracts (extracts, tinctures, dried extracts, etc.).

[0106] The solid preparation of the present invention preferably contains at least one of licorice extract, peony extract, and valerian extract.

[0107] The proportion of crude medicinal materials in the solid dosage form of the present invention is not particularly limited. For example, when each crude medicinal material is an extract, the proportion is 1 to 80% by mass based on the total mass of the solid dosage form, or it can be 1 to 50% by mass, or it can be 1 to 40% by mass, or it can be 1 to 30% by mass.

[0108] The raw medicinal herbs used in this invention, such as licorice, peony, and valerian, have been used medicinally since ancient times as single-ingredient formulas or in traditional Chinese medicine prescriptions. The raw herb powder or extracts obtained according to their respective conventional methods can be used directly. The form of the raw herb powder or extracts can also be commercially available products or their processed forms. For example, the raw herb powder can be used as a powder (micro-powder) obtained by further micronizing dried and finely chopped products. Furthermore, there are no particular limitations on the form of the extracts from the raw herbs; for example, they can be used in any form, such as dried extracts, extract powders, soft extracts, fluid extracts, tinctures containing ethanol or ethanol and water. Preferably, the raw herbs contain extracts with high formulation flexibility, such as soft extracts or dried extract powders.

[0109] The extracted components are obtained from the aforementioned crude drugs using conventional methods, such as extraction with an extraction solvent, to extract the active ingredients with antibacterial effects. As extraction solvents, water, hydrophilic solvents, or mixtures thereof are commonly used. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, and tert-butanol; cellolytic agents such as methyl cellolytic agents and ethyl cellolytic agents; ketones such as acetone; and diethyl cellolytic agents. Hydrophilic solvents include ethers such as alkanes and tetrahydrofurans; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents can be used alone or as a mixture of two or more solvents.

[0110] As before, licorice can be used as an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive and expectorant, gastrointestinal medicine, anthelmintic, oral medicine for rhinitis, throat cooler, stomachic cooler, vitamin supplement, sweetener, flavoring agent, coloring agent, flavoring agent, spice or excipient.

[0111] When using "licorice" in this invention, it is preferable to use the licorice described in the 18th revised edition of the Japanese Pharmacopoeia.

[0112] Other types of licorice besides those mentioned above are also commercially available and readily accessible.

[0113] Commercially available licorice extracts, such as those using water or a 30% ethanol aqueous solution as extraction solvents, are sold in various forms, including licorice extract, dried licorice extract, soft licorice extract, and fluid licorice extract, with different conversion rates based on the raw herb. In addition to these licorice extracts, licorice extracts and licorice extract solutions may also be used appropriately, without particular limitation.

[0114] When commercially available licorice is used in oral pharmaceutical compositions, licorice can be used in a manner appropriate to the amount of licorice in a tablet, for example, taking into account the conversion ratio of raw drug.

[0115] There is no particular limitation on the content of licorice (licorice or licorice extract) in the solid dosage form of the present invention. The amount of the ingredient contained in the tablets as a daily dosage is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, or 500 mg to 1500 mg, and is administered 1 to 3 times a day.

[0116] In the solid dosage form of the present invention, for example, when using dried licorice extract, the content of dried licorice extract is not particularly limited, and can be 0.1 to 80% by mass or 1 to 50% by mass based on the total mass of the tablet, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0117] When “valerian” is used in this invention, the “valerian” referred to in the 18th revised edition of the Japanese Pharmacopoeia may be used.

[0118] Valerian other than those mentioned above is also commercially available and readily accessible.

[0119] As commercially available valerian, valerian powder, valerian extract (such as soft extract, dry extract, etc.) can be used, without particular limitation.

[0120] When using commercially available valerian in oral pharmaceutical compositions, the conversion ratio of the raw drug should be taken into account, and valerian should be used in a manner that is appropriate for the content of valerian in the tablet.

[0121] When using "valerian (valerian or valerian extract)" in this invention, there is no particular limitation on the content. For example, the amount of the ingredient contained in a tablet for a daily dosage is 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, and even more preferably 60 mg to 1000 mg, or 60 to 450 mg, and the dosage is 1 to 3 times a day.

[0122] In the solid dosage form of the present invention, for example when valerian extract is used, the content of valerian extract is not particularly limited, but is 1 to 50% by mass based on the total mass of the dosage form, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0123] When using "peony" in this invention, the preferred "peony" is the one described in the 18th revised edition of the Japanese Pharmacopoeia.

[0124] Peonies other than those mentioned above are also commercially available and readily accessible.

[0125] As commercially available peony, peony powder or peony extract (such as dried extract or soft extract) can be used, without any particular limitation.

[0126] When using commercially available peony in oral drug compositions, the conversion ratio of the original drug should be considered, and peony should be used in a manner that is appropriate in the amount of peony in the formulation.

[0127] When using "peony (peony or its extract)" in this invention, there is no particular limitation on the content. The preferred dosage, converted from raw peony, is 100-5000 mg per day, more preferably 150-2000 mg, and particularly preferably 200-900 mg, and the dosage is 1-3 times per day.

[0128] In the solid dosage form of the present invention, for example, when using dried peony extract, the content of dried peony extract is not particularly limited, but is 1 to 50% by mass based on the total mass of the dosage form, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0129] During formulation, known methods and additives may be used appropriately. Additives may be added appropriately without impairing the effects of the present invention.

[0130] Additives, such as pharmaceutically permissible carriers, include excipients, binders, disintegrants, disintegrant aids, lubricants, flow aids, gloss agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, flavorings, aromatics, colorants, bases, coating agents, sugar coatings, plasticizers, dispersants, and defoamers. Pharmaceutical additives previously known to be used in solid dosage forms can be used for the purposes described above. These can be used alone or in combination of two or more.

[0131] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, anhydrous dicalcium phosphate, anhydrous dicalcium phosphate granules, monodicalcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate granules, dicalcium phosphate hydrate, didicalcium phosphate hydrate, crystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate·hydroxypropyl starch· Crystalline cellulose, wheat starch, rice flour, rice starch, heavy silicic anhydride, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, powdered sugar, powdered maltose syrup, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene cured castor oil, polyoxyethylene cured castor oil 60, maltitol, D-mannitol, magnesium aluminum metasilicate, calcium sulfate, glucose, fructose, etc. These can be used alone or in combination of two or more.

[0132] As an adhesive, it can be combined with one or more components selected from gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0133] Examples of disintegrants include carboxymethyl ethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. These can be used alone or in combination of two or more.

[0134] Examples of disintegrating agents include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol (macrogol) 1500, and polyethylene glycol 4000.

[0135] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerol fatty acid esters, polyethylene glycol, hardened oil, and sodium fumarate stearate.

[0136] As a flow aid, it can be combined with one or more components selected from synthetic aluminum silicate, heavy anhydrous silicate, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and dicalcium phosphate granules.

[0137] As a glossing agent, it can be combined with one or more ingredients selected from carnauba wax, white beeswax, refined shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc.

[0138] As a foaming agent, it can be combined with one or more components selected from dried sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium bicarbonate, anhydrous citric acid, etc.

[0139] As a desiccant, it can be combined with one or more of the following components: ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, and polyvinyl acetal diethylaminoacetate.

[0140] As a surfactant, it may be combined with one or more components selected from sucrose fatty acid esters, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) diol, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene (120) polyoxypropylene (40) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, monooleic sorbitan, glyceryl monostearate, monostearate sorbitan, monolaurate sorbitan, sodium lauryl sulfate, etc.

[0141] As stabilizers, they can be combined with, for example, diacid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridine chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine L-hydrochloride, cocoa butter, carboxyvinyl polymers, etc. Carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydrated silica, dried sodium carbonate, glycerol, glycerol fatty acid esters, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamic acid, L-lysine, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, refined gelatin, refined soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, carbonate Sodium hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerol, povidone, polyoxyethylene hardened castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hardened castor oil, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54)polyoxypropylene (39) glycol, polyoxyethylene (160)polyoxypropylene (30) glycol, polyoxyethylene (196)polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty acid glyceride (7E.O.) The following are one or more of the following components: polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0142] Examples of emulsifiers include glycerol fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerol fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean lecithin.

[0143] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, palmitic acid ascorbate, and sodium metabisulfite.

[0144] Examples of fillers include RSS No.1 raw rubber, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0145] Examples of preservatives include benzoic acid, sodium benzoate, ethylparaben, propylparaben, methylparaben, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0146] As a sweetener, it can be combined with one or more ingredients selected from aspartame, acesulfame potassium, sweet tea, sweet tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, refined stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, etc.

[0147] As a flavoring agent, it can be combined with one or more ingredients selected from sodium chloride, citrus, citrus oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citrate hydrate, sodium citrate hydrate, L-glutamic acid, monosodium glutamate, grapefruit extract, brown sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sucralose, stevia extract, stevia extract, saccharin, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharides, sugar powder, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0148] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0149] As a flavoring, it can be combined with one or more ingredients selected from citrus flavoring, guarana extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach extract, fruit extract, peppermint, melon powder flavoring, L-menthol, peppermint oil, etc.

[0150] Examples of aromatic agents include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder flavoring 51357, pineapple powder flavoring 59492, peppermint water, peppermint oil, vanilla powder flavoring 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, and rose oil.

[0151] As a coloring agent, it can be combined with one or more of the following ingredients: yellow iron oxide, yellow ferric oxide, citrus extract, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium dioxide, ferric oxide, diazo yellow, edible blue 1, edible yellow 4, edible yellow 5, edible blue 2 aluminum lake, edible yellow 4 aluminum lake, edible red 2, edible red 3, edible red 102, ferric oxide-glycerol suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc.

[0152] As a base agent, it can be formulated with, for example, gum arabic powder, α-starch, partially α-starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, glycerol fatty acid esters, light anhydrous silicate, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic magnesium silicate sodium, titanium dioxide, tartaric acid, sucrose fatty acid esters, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerol, potato starch, hydroxypropyl... The product contains one or more of the following components: cellulose, hydroxypropyl methylcellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, shark liver oil monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0153] Examples of coating agents include: ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers E and RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersions, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, glycerol fatty acid esters, cured oil, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, refined shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methylcellulose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2 Mixture 910, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0154] As a sugar coating agent, it can be combined with one or more components selected from gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyoxyethylene stearate 40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, dicalcium phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0155] As a plasticizer, it can be combined with one or more components selected from triethyl citrate, glycerol, glyceryl fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetic acid glycerides, concentrated glycerol, castor oil, polyoxyethylene hardened castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc.

[0156] As a dispersant, it can be formulated with, for example, aminoalkyl methacrylate polymers RS, gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, glycerol fatty acid esters, magnesium silicate, light alumina, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, and polymethyl methacrylate. The following are one or more of the following components: ethylene oxide-cured castor oil, polyoxyethylene-cured castor oil 40, polyoxyethylene-cured castor oil 50, polyoxyethylene-cured castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0157] As an antifoaming agent, it can be combined with one or more ingredients selected from ethanol, glycerol fatty acid esters, dimethyl polysiloxane (for internal use), a mixture of dimethyl polysiloxane and silica, sucrose fatty acid esters, silicone defoamers, silicone oil, sorbitan fatty acid esters, polysorbate 80, etc.

[0158] These additives are not limited to those listed above; in addition, one of them may be used, or two or more may be used in combination.

[0159] Furthermore, in solid dosage forms, as needed, pharmacologically active ingredients other than components (A), (B), and (C) may be appropriately added within the scope that does not impair the effects of the present invention, such as antipyretics, analgesics, antitussives and expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives; if there are contraindications to these, appropriate formulations such as particle separation can be carried out.

[0160] As an antipyretic and analgesic, it can be combined with one or more of the following ingredients: aspirin, aluminum aspirin, acetaminophen, ethylsalicylate, disalicylate, salicylamide, lactylfenatidine, ibuprofen, isopropyl antipyrine, pranoprofen, diclofenac sodium, mefenamic acid, indomethacin, farnesyl ester, acemetacin, etodoxacin, naproxen, meloxicam, celecoxib, sodium salicylate, and thiamide hydrochloride.

[0161] Examples of antitussive and expectorant agents include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium bis(2-naphthyl)sulfonate, dimethionine phosphate, tepperidine citrate, tepperidine hypothalamic acid salt, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein, alopramide hydrochloride, clopidogrel hydrochloride, clopidogrel fendizole salt, pentoxyverine citrate, noscapine, noscapine hydrochloride, tratoquinol hydrochloride, norephedrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, L-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaiacol glyceryl ether, guaiacol potassium sulfonate, cresol potassium sulfonate, L-carboxycysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine ​​hydrochloride.

[0162] Examples of antihistamines include azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emesamtine fumarate, oxamide, olopatadine hydrochloride, carbixamine, chlormastine fumarate, diphenyl disulfonate, carbixamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpiraline hydrochloride, and diphenylpiraline tea. Chloride, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannic acid, triprolidine hydrochloride, tripenamin hydrochloride, sinepromine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, methaqualone hydrochloride, methaqualone hydrochloride, loratadine, isoamyl ester hydrochloride, dibenzyl terbutaline hydrochloride, methaqualone hydrochloride, methaqualone disulfonic acid, promethazine methylene disalicylic acid, dibenzyl terbutaline phosphate, etc.

[0163] Examples of anti-inflammatory agents include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.).

[0164] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-scopolamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropylamide iodide, diphenylpiperidinylmethyldioxane iodide, scopolamine extract, scopolamine root, and total scopolamine root alkaloids citrate.

[0165] Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, niacin, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium magnesium aspartate mixture, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, glucuronide lactone, glucuronide, chondroitin sulfate sodium, ginseng, coix seed, and iodic acid.

[0166] Examples of sedatives include allyl isopropyl acetylurea and bromoisovalerate.

[0167] These additives are not limited to those listed above; in addition, one of them may be used, or two or more may be used in combination.

[0168] Solid dosage forms are preferably intended for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient is selected from at least one of loxoprofen, its salts, and their hydrates, which has antipyretic, analgesic, and anti-inflammatory effects, it is suitable as an antipyretic analgesic. Specifically, it is suitable for relieving pain in headaches, dysmenorrhea (menstrual pain), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, stiff neck and shoulder pain, earaches, sprains, fractures, strains, and external injuries, as well as for reducing fever in cases of chills and fever. Furthermore, it is suitable as a cold treatment to relieve various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0169] (Dosage form)

[0170] Solid dosage forms can be defined as dosage forms such as oral administration preparations (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and oral preparations (including oral tablets, lozenges, sublingual tablets, buccal tablets, attached tablets, gels, etc.), as described in the 18th revised edition of the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia.

[0171] In addition, examples of solid dosage forms include pills and tablets. These solid dosage forms may also be coated with sugar coating, film coating, etc., by known methods as needed. Solid dosage forms are preferably plain tablets, film-coated tablets, or sugar-coated tablets, and more preferably plain tablets, film-coated tablets, or sugar-coated tablets.

[0172] (Packaging)

[0173] The packaging refers to the container in which the solid dosage form described in this embodiment is housed. By creating a packaging, for example, the convenience of using the solid dosage form can be improved.

[0174] (Packaging format)

[0175] Regarding the packaging form of solid dosage forms, they can be preserved airtightly through single-use packaging such as strip packages, press-through packages, strip packages, bottle packages, and bag packages. That is, solid dosage forms can also be stored in airtight packaging. Furthermore, they can also be packaged in pillow-type containers and stored in boxes, etc.

[0176] In other words, a pharmaceutical product according to one embodiment of the present invention may also include the solid dosage form and packaging material for packaging the solid dosage form as described above.

[0177] There are no restrictions on the materials used for SP packaging, PTP packaging, strip packaging, and pillow packaging. For example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as multilayer films composed of these resin films, and aluminum foil attached to these resin films can be used.

[0178] The packaging material for solid dosage forms is preferably a material that is not easily affected by moisture (a package formed from at least one of moisture-proof material and gas barrier material).

[0179] For example, packaging made of materials with low moisture impact (moisture-proof materials) can also be designed as PTP (polypropylene) + polyethylene aluminum pillow packaging (a combination of PTP and polyethylene aluminum pillow packaging). Furthermore, considering factors such as inhibition of moisture level rise in tablets, tablet storage stability, and tablet stability after opening, packaging made of materials less susceptible to moisture impact (moisture-proof materials) can use PTP packaging with aluminum on both sides (Al-Al packaging).

[0180] In addition, if hygroscopicity is a concern, desiccants can be stored in bottle packaging, pillow packaging, or other similar containers.

[0181] The gas barrier material can be any known material, without particular limitation. For example, it can be a laminate with a functional barrier layer, which can have the functions of the aforementioned moisture-proof material or be used in combination with the aforementioned moisture-proof material.

[0182] In addition, packaging containers can be designed with environmental considerations in mind. For example, some or all of the packaging materials can be made from environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics.

[0183] The embodiments of the present invention have been described above, but these are merely examples, and various configurations other than those described can be employed. Furthermore, the present invention is not limited to the above embodiments, and modifications and alterations that can be made without departing from the spirit and scope of the present invention are also included in the present invention.

[0184] Example

[0185] The present invention will be described in detail below with reference to the embodiments, but the present invention is not limited in any way by these embodiments.

[0186] <Manufacturing of Solid Dosage Forms>

[0187] (Example 1)

[0188] Weigh loxoprofen sodium hydrate (manufactured by KOLON), tranexamic acid (manufactured by Kyowa Pharma Chemical), magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), and calcium carboxymethyl cellulose (manufactured by Gotoku Pharmaceutical Co., Ltd.), add an appropriate amount of purified water, knead in a mortar and pestle, and dry at 80°C for 1 hour to obtain granules.

[0189] After sieving the obtained granules through an 18-mesh sieve, weigh them and add magnesium stearate (manufactured by Taiping Chemical Company) as an additive. Mix the mixture 100 times in a 10K bottle to obtain a mixture of granules and additive.

[0190] The resulting mixture was compressed using a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) with a die ring of 9.0 mm in diameter and a punch with an R-surface of 10.8 mm radius of curvature at a tableting pressure of 5 kN, thereby obtaining tablets (solid dosage forms) with a weight of 341.9 mg per tablet.

[0191] The ingredients and content (mg) of each tablet obtained are shown in Table 1.

[0192] (Examples 2-4)

[0193] Tablets were obtained by operating in the same manner as in Example 1, except that glycine (manufactured by Fujifilm and Koichi Pure Chemical Industries Co., Ltd.), erythritol (manufactured by Busan Food Science Co., Ltd.), or crystalline cellulose (manufactured by Asahi Kasei Corporation) and anhydrous caffeine (manufactured by Shizuoka Caffeine Industrial Co., Ltd.) were used instead of magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.).

[0194] (Comparative Example 1)

[0195] Except for using crystalline cellulose (manufactured by Asahi Kasei Corporation) instead of magnesium oxide (manufactured by Kyowa Chemical Industry Co., Ltd.) and changing the tableting pressure to 10 kN, the same procedure as in Example 1 was followed to obtain tablets.

[0196] (Comparative Example 2)

[0197] Except for changing the tableting pressure to 10kN, the same procedure as in Example 1 was followed to obtain tablets.

[0198]

[0199] The following evaluations were performed on the resulting tablets.

[0200] <Hardness>

[0201] The tablet hardness (N) was determined using a tablet tester (Tablet Tester 8M, manufactured by Dr. Schleuniger Pharmatron). The hardness was the average of two samples (n=2). The results are shown in Table 1.

[0202] In addition, the hardness of Example 1 was less than that of any of Examples 2 to 4, and less than that of any of Comparative Examples 1 and 2.

[0203] <Disintegration Time>

[0204] The disintegration time (min) of Comparative Example 1 and 2 tablets was determined using a disintegration tester (NT-2HSF, manufactured by Toyama Sangyo Co., Ltd.) according to the 18th revised edition of the Japanese Pharmacopoeia's "Disintegration Test Method". The disintegration time is the average of the two sample sizes. The results are shown in Table 1.

[0205] Dissolution Test

[0206] The dissolution rate of loxoprofen sodium hydrate in the tablets was determined according to the 18th revised edition of the Japanese Pharmacopoeia's Dissolution Test Method, specifically Method 2 (paddle method). 900 mL of purified water was used as the test solution, and the dissolution test was conducted at 50 rpm. The dissolution rate (%) was measured at 15 minutes and 30 minutes. Using the measured values ​​from a sample size of 3, the mean and standard deviation of each dissolution rate were calculated. The results are shown in Table 1.

[0207] Furthermore, the time (min) for the dissolution rate to reach 90% was obtained as a theoretical value calculated from the approximation formula.

[0208] The solid dosage forms of Examples 1-4 showed excellent dissolution properties of loxoprofen (component (A)) compared to Comparative Examples 1 and 2.

[0209] The preferred embodiments and examples of the present invention have been described above, but the present invention is not limited thereto. Additions, omissions, substitutions, and other changes to the configuration may be made without departing from the spirit of the present invention.

[0210] Industrial availability

[0211] In this invention, solid dosage forms are extremely useful in terms of quality due to their excellent storage stability.

[0212] Solid dosage forms are suitable for use as antipyretic analgesics. Specifically, they are suitable for relieving pain in headaches, dysmenorrhea (menstrual pain), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, stiff neck and shoulder pain, earaches, sprains, fractures, strains, and traumatic pain, as well as for reducing fever in cases of chills and fever. In addition, they are suitable for use as cold medicines to relieve various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0213] This application claims priority based on Japanese Patent Application No. 2024-045259, filed on March 21, 2024, the entire disclosure of which is incorporated herein by reference.

Claims

1. A solid dosage form comprising the following components (A), (B) and (C): (A) Selected from at least one of loxoprofen, its salts and their hydrates. (B) Selected from at least one of tranexamic acid and its salts. (C) Selected from at least one of magnesium oxide, glycine, erythritol and caffeine; The solid dosage form is in the form of tablets or pills. The solid dosage form satisfies the following condition: at the 15-minute time point in the dissolution test, the dissolution rate of component (A) is 60% or more.

2. The solid dosage form according to claim 1, wherein, The solid dosage form satisfies the following condition: at the 15-minute time point in the dissolution test, the standard deviation of the dissolution rate of component (A) is less than 11.0%.

3. The solid dosage form according to claim 1 or 2, wherein, The solid dosage form satisfies the following condition: at the 30-minute time point in the dissolution test, the dissolution rate of component (A) is above 90%.

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

5. The solid dosage form according to any one of claims 1 to 4, wherein, Let the content of component (A) contained in the solid dosage form be C. A The content of the component (B) is set as C. B The content of the component (C) is set as C. C hour, C C / (C A +C B +C C The value ranges from 0.02 to 0.

95.

6. A pharmaceutical product comprising the solid dosage form according to any one of claims 1 to 5.

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